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01_08 Cover_Sept2012_v3.indd 1 8/10/12 11:42 AM Save the Date for ENDO 2013

Join us for ENDO 2013, The Endocrine Society’s 95th Annual Meeting & Expo, in the beautiful city by the bay. Mealtime insulin therapy But it ﬁ rst needs to ﬁ t matters inside the body. your patient’s life.

Choose Humalog and the MiniMed Paradigm® REAL-Time Revel™ Insulin Pump For adult patients with type 1 diabetes ready to have a conversation about using an insulin pump

• Humalog® (100 units /mL) can be used in a Paradigm Revel Insulin Pump1

Indication for Humalog • Humalog is an insulin analog indicated to improve glycemic control in adults and children with diabetes mellitus. Select Safety Information for Humalog Select Safety Information for Humalog, continued • Humalog is contraindicated during episodes of hypoglycemia • Humalog should not be diluted or mixed when used in an external and in patients who are hypersensitive to Humalog or any of insulin pump. Change Humalog in the reservoir at least every 7 days. its excipients. Change the infusion set and insertion site at least every 3 days. • Closely monitor blood glucose in all patients treated with insulin. • Catheter occlusions and infusion-site reactions have been Change insulin regimens cautiously. reported in patients receiving Humalog as a continuous subcutaneous infusion. • Hypoglycemia is the most common adverse effect of Humalog therapy. The risk of hypoglycemia increases with tighter glycemic Reference ® control. Severe hypoglycemia may be life threatening and can cause 1. Paradigm REAL-Time Revel™ User Guide. Starting on Insulin.©2009 Medtronic MiniMed, Inc. 47. seizures or death. Please see Important Safety Information on next page and • Humalog should be given within 15 minutes before or immediately Brief Summary of Full Prescribing Information for Humalog after a meal. on following pages. For more information about Humalog, please call The Lilly Answers Center at 1-800-LillyRx (1-800-545-5979), or visit Registration opens in the fall of 2012. www.Humalog.com. For more information about Paradigm® REAL-Time Revel™, please call Medtronic at 1-888-350-3199, For more information, visit www.endo-society.org/endo2013 or visit www.medtronicdiabetes.com.

ENDO2013_STD_AD.indd01_08 Cover_Sept2012_v3.indd 1 2 4/16/128/10/12 4:57:0511:42 AM PM

54300_elhmlp_HI76205_ap_ja_updt_fa.indd 1 6/25/12 4:14 PM Save the Date for ENDO 2013

Choose Humalog and the MiniMed Paradigm® REAL-Time Revel™ Insulin Pump For adult patients with type 1 diabetes ready to have a conversation about using an insulin pump

• Humalog® (100 units /mL) can be used in a Paradigm Revel Insulin Pump1

ENDO2013_STD_AD.indd 1 4/16/12 4:57:05 PM 01_08 Cover_Sept2012_v3.indd 3 8/10/12 11:42 AM

54300_elhmlp_HI76205_ap_ja_updt_fa.indd 1 6/25/12 4:14 PM Important Safety Information for Humalog ImportantImportant Safety Information Safety Information for Humalog, for Humalog, continued continued MiniMedMiniMed Paradigm Paradigm® REAL-Time® REAL-Time Revel™ Revel™Insulin Pump Insulin Pump Contraindications WarningsWarnings and Precautions, and Precautions, continued continued IndicationsIndications for Use for Use • Humalog® is contraindicated during episodes of hypoglycemia • Renal or• Hepatic Renal or Impairment: Hepatic Impairment: Frequent Frequentglucose monitoring glucose monitoring Pump Pump and in patients who are hypersensitive to Humalog or any of and insulinand dose insulin reduction dose reduction may be required may be inrequired patients in withpatients with • The Paradigm• The Paradigm Revel insulin Revel pump insulin is indicated pump is indicated for the for the its excipients. renal or hepaticrenal or impairment. hepatic impairment. continuouscontinuous delivery of delivery insulin, of at insulin, set and at variable set and rates, variable for rates,the for the Warnings and Precautions • Mixing •of Mixing Insulins: of HumalogInsulins: Humalogfor subcutaneous for subcutaneous injection injection managementmanagement of diabetes of mellitusdiabetes in mellitus persons in requiring persons requiring insulin. insulin. • Dose Adjustment and Monitoring: Closely monitor blood should notshould be mixed not bewith mixed insulins with other insulins than other NPH than insulin. NPH insulin. MiniMedMiniMed Paradigm Paradigm REAL-Time REAL-Time Revel Insulin Revel Pump Insulin Pump glucose in all patients treated with insulin. Change insulin If HumalogIf Humalogis mixed withis mixed NPH with insulin, NPH Humalog insulin, Humalogshould be should be ImportantImportant Safety Information Safety Information regimens cautiously. Concomitant oral antidiabetic treatment drawn intodrawn the syringe into the fi syringerst. Injection first. Injectionshould occur should occur may need to be adjusted. immediatelyimmediately after mixing. after mixing. ContraindicationsContraindications • Pump therapy• Pump is therapy not recommended is not recommended for people for who people are who are The time course of action for Humalog may vary in different • Subcutaneous • Subcutaneous Insulin Infusion Insulin Pump:Infusion Humalog Pump: Humalogshould not should not unwilling unwillingor unable or to unable perform to aperform minimum a minimum of four blood of four blood individuals or at different times in the same individual and is be dilutedbe or diluted mixed orwhen mixed used when in an used external in an insulinexternal pump. insulin pump. glucose testsglucose per testsday and per to day maintain and to maintaincontact with contact their with their dependent on many conditions, including delivery site, local Change HumalogChange Humalogin the reservoir in the reservoirat least every at least 7 days. every 7 days. healthcarehealthcare professional. professional. Successful Successful insulin pump insulin therapy pump therapy blood supply, or local temperature. Patients who change their Change theChange infusion the set infusion and insertion set and insertionsite at least site every at least every requires suffirequires cient sufficient vision or hearingvision or to hearing allow recognition to allow recognition of of level of physical activity or meal plan may require insulin 3 days. 3 days. the pumpthe signals pump and signals alarms. and alarms. dose adjustment. MalfunctionMalfunction of the insulin of the pump insulin or infusionpump or set infusion or insulin set or insulin WarningsWarnings • Hypoglycemia: Hypoglycemia is the most common adverse degradationdegradation can rapidly can lead rapidly to hyperglycemia lead to hyperglycemia and ketosis. and ketosis. • The pump• The is not pump suitable is not for suitable use in for the use presence in the presence of of effect of Humalog. The risk of hypoglycemia increases with Prompt correctionPrompt correction of the cause of the of hyperglycemiacause of hyperglycemia or ketosis or ketosis a fl ammablea flammable anesthetic anesthetic mixture with mixture air, oxygen, with air, or oxygen, or tighter glycemic control. Educate patients to recognize and is necessary.is necessary. Interim subcutaneous Interim subcutaneous injections injections with Humalog with Humalog nitrous oxide.nitrous oxide. manage hypoglycemia. Hypoglycemia can happen suddenly may be required.may be required.Train patients Train usingpatients an insulinusing an pump insulin to pump to and symptoms may vary for each person and may change administeradminister insulin by insulin injection by injectionand to have and alternate to have alternateinsulin insulin • Standard • Standard Luer sets Luerare not sets compatible are not compatible with the Medtronicwith the Medtronic over time. Early warning symptoms of hypoglycemia may therapy availabletherapy availablein case of in pump case failure.of pump failure. MiniMed MiniMedParadigm Paradigm pump. Medtronic pump. Medtronic Paradigm Paradigm reservoirs reservoirs be different or less pronounced under conditions such as and Paradigm-compatibleand Paradigm-compatible infusion sets infusion are specifi sets are cally specifically • Drug Interactions:• Drug Interactions: Some medications Some medications may alter may glucose alter glucose long-standing diabetes, diabetic nerve disease, use of designeddesigned for use with for theuse pump.with the pump. metabolism,metabolism, insulin requirements, insulin requirements, and the risk and for the risk for medications such as beta-blockers, or intensifi ed diabetes hypoglycemiahypoglycemia or hyperglycemia. or hyperglycemia. Signs of hypoglycemia Signs of hypoglycemia • D o not modify• D o not your modify Paradigm your Paradigm reservoir reservoiror Paradigm- or Paradigm- control. These situations may result in severe hypoglycemia may be reducedmay be orreduced absent or in absentpatients in takingpatients anti-adrenergic taking anti-adrenergic compatiblecompatible infusion set. infusion set. and possibly loss of consciousness prior to the patient’s drugs. Particularlydrugs. Particularly close monitoring close monitoring may be required. may be required. • D o not put• D any o not other put any drugs/medications other drugs/medications inside your inside reservoir your reservoir awareness of hypoglycemia. Severe hypoglycemia may be to use withto thisuse pump.with this Only pump. insulin Only that insulin has been that hasprescribed been prescribed life threatening and can cause seizures or death. Adverse ReactionsAdverse Reactions • Adverse • reactionsAdverse reactions associated associated with Humalog with Humaloginclude include by your physicianby your physician can be used can in be this used pump. in this pump. U s e caution in patients with hypoglycemia unawareness hypoglycemia,hypoglycemia, hypokalemia, hypokalemia, allergic reactions, allergic reactions, injection-site injection-site • D o not use• D pump o not use cases pump that cases have that a magnetic have a magnetic clasp. clasp. and who may be predisposed to hypoglycemia. The patient’s reactions,reactions, lipodystrophy, lipodystrophy, pruritus, rash,pruritus, weight rash, gain, weight and gain, and ability to concentrate and react may be impaired as a result • D o not expose• D o not your expose insulin your pump insulin to MRIpump equipment to MRI equipment or other or other peripheralperipheral edema. edema. of hypoglycemia. Rapid changes in serum glucose levels may devices thatdevices generate that generate very strong very magnetic strong magnetic fi elds. The fields. The induce symptoms similar to hypoglycemia in persons with Use in SpecifiUse cin Populations Specific Populations magneticmagnetic fi elds in the fields immediate in the immediate vicinity of vicinity these devicesof these devices diabetes, regardless of the glucose value. • Pediatrics: • Pediatrics: Humalog Humaloghas not been has notstudied been in studied children in with children with can damagecan thedamage part of the the part pump’s of the motor pump’s that motor regulates that regulates type 1 diabetestype 1 lessdiabetes than less3 years than of 3 age years or ofin childrenage or in children insulin delivery,insulin delivery,possibly resultingpossibly resultingin over-delivery in over-delivery and and T i m i n g of hypoglycemia usually refl ects the time-action with typewith 2 diabetes. type 2 diabetes. severe hypoglycemia.severe hypoglycemia. Your pump Your must pump be removedmust be removedand and profi le of administered insulins. Other factors such as kept outsidekept the outside room the during room magnetic during magnetic resonance resonance imaging imaging changes in food intake, injection site, exercise, and Dosage andDosage Administration and Administration (MRI) procedures.(MRI) procedures. concomitant medications may alter the risk of hypoglycemia. • Humalog • Humalog should be should given withinbe given 15 within minutes 15 beforeminutes or before or immediatelyimmediately after a meal. after a meal. • I f your pump• I f your is inadvertently pump is inadvertently exposed toexposed a strong to magnetic a strong magnetic • Allergic Reactions: Severe, life-threatening, generalized fi eld, discontinuefield, discontinue use and contact use and our contact 24-Hour our HelpLine24-Hour HelpLinefor for allergy, including anaphylaxis, can occur with Humalog. Please seePlease following see following pages for pages Brief forSummary Brief Summary of of Full PrescribingFull Prescribing Information Information for Humalog. for Humalog. further assistance.further assistance. • Hypokalemia: Humalog can cause hypokalemia, which, Please visitPlease http://www.medtronicdiabetes.com/about/ visit http://www.medtronicdiabetes.com/about/ if untreated, may result in respiratory paralysis, ventricular HI HCP ISI HI08JUN2011 HCP ISI 08JUN2011 safety.htmlsafety.html for complete for complete safety information. safety information. arrhythmia, and death. Use caution in patients who may be at risk for hypokalemia (eg, patients using potassium- Humalog® isHumalog a registered® is a registeredtrademark trademarkof Eli Lilly and of Eli Company Lilly and Company and is availableand is by available prescription by prescription only. only. lowering medications or medications sensitive to serum ® ® potassium concentrations). MiniMed isMiniMed a registered is a registeredtrademark trademarkof Medtronic of MedtronicMiniMed, Inc. MiniMed, Inc. Paradigm® Paradigmis a registered® is a registeredtrademark trademarkof Medtronic of MedtronicMiniMed, Inc. MiniMed, Inc. Revel™ is aRevel™ trademark is a trademarkof Medtronic of MedtronicMiniMed, Inc. MiniMed, Inc. CareLink® isCareLink a registered® is a registeredtrademark trademarkof Medtronic of MedtronicMiniMed, Inc. MiniMed, Inc. The MiniMedThe Paradigm MiniMed Revel Paradigm Insulin Revel Pump Insulin is Continuous Pump is Continuous Glucose Glucose MonitoringMonitoring (CGM) ready. (CGM) Optional ready. glucose Optional sensor glucose and sensor MiniLink and® MiniLink® REAL-TimeREAL-Time transmitter transmitter are available are separately available separatelyfrom Medtronic. from Medtronic. For informationFor information on the MiniMed on the Paradigm MiniMed Revel Paradigm Insulin Revel Pump Insulin integrated Pump integrated with CGM, pleasewith CGM, contact please your contact Medtronic your Medtronicrepresentative. representative. Please seePlease Important see Important Safety Information Safety Information for Humalog for Humalog on on

01_08 Cover_Sept2012_v3.indd 4 8/10/12 11:42 AM

54300_elhmlp_HI76205_ap_ja_updt_fa.indd 2 6/25/12 4:14 PM 54300_elhmlp_HI76205_ap_ja_updt_fa.indd 3 6/25/12 4:14 PM Important Safety Information for Humalog ImportantImportant Safety Information Safety Information for Humalog, for Humalog, continued continued MiniMedMiniMed Paradigm Paradigm® REAL-Time® REAL-Time Revel™ Revel™Insulin Pump Insulin Pump Contraindications WarningsWarnings and Precautions, and Precautions, continued continued IndicationsIndications for Use for Use • Humalog® is contraindicated during episodes of hypoglycemia • Renal or• Hepatic Renal or Impairment: Hepatic Impairment: Frequent Frequentglucose monitoring glucose monitoring Pump Pump and in patients who are hypersensitive to Humalog or any of and insulinand dose insulin reduction dose reduction may be required may be inrequired patients in withpatients with • The Paradigm• The Paradigm Revel insulin Revel pump insulin is indicated pump is indicated for the for the its excipients. renal or hepaticrenal or impairment. hepatic impairment. continuouscontinuous delivery of delivery insulin, of at insulin, set and at variable set and rates, variable for rates,the for the Warnings and Precautions • Mixing •of Mixing Insulins: of HumalogInsulins: Humalogfor subcutaneous for subcutaneous injection injection managementmanagement of diabetes of mellitusdiabetes in mellitus persons in requiring persons requiring insulin. insulin. • Dose Adjustment and Monitoring: Closely monitor blood should notshould be mixed not bewith mixed insulins with other insulins than other NPH than insulin. NPH insulin. MiniMedMiniMed Paradigm Paradigm REAL-Time REAL-Time Revel Insulin Revel Pump Insulin Pump glucose in all patients treated with insulin. Change insulin If HumalogIf Humalogis mixed withis mixed NPH with insulin, NPH Humalog insulin, Humalogshould be should be ImportantImportant Safety Information Safety Information regimens cautiously. Concomitant oral antidiabetic treatment drawn intodrawn the syringe into the fi syringerst. Injection first. Injectionshould occur should occur may need to be adjusted. immediatelyimmediately after mixing. after mixing. ContraindicationsContraindications • Pump therapy• Pump is therapy not recommended is not recommended for people for who people are who are The time course of action for Humalog may vary in different • Subcutaneous • Subcutaneous Insulin Infusion Insulin Pump:Infusion Humalog Pump: Humalogshould not should not unwilling unwillingor unable or to unable perform to aperform minimum a minimum of four blood of four blood individuals or at different times in the same individual and is be dilutedbe or diluted mixed orwhen mixed used when in an used external in an insulinexternal pump. insulin pump. glucose testsglucose per testsday and per to day maintain and to maintaincontact with contact their with their dependent on many conditions, including delivery site, local Change HumalogChange Humalogin the reservoir in the reservoirat least every at least 7 days. every 7 days. healthcarehealthcare professional. professional. Successful Successful insulin pump insulin therapy pump therapy blood supply, or local temperature. Patients who change their Change theChange infusion the set infusion and insertion set and insertionsite at least site every at least every requires suffirequires cient sufficient vision or hearingvision or to hearing allow recognition to allow recognition of of level of physical activity or meal plan may require insulin 3 days. 3 days. the pumpthe signals pump and signals alarms. and alarms. dose adjustment. MalfunctionMalfunction of the insulin of the pump insulin or infusionpump or set infusion or insulin set or insulin WarningsWarnings • Hypoglycemia: Hypoglycemia is the most common adverse degradationdegradation can rapidly can lead rapidly to hyperglycemia lead to hyperglycemia and ketosis. and ketosis. • The pump• The is not pump suitable is not for suitable use in for the use presence in the presence of of effect of Humalog. The risk of hypoglycemia increases with Prompt correctionPrompt correction of the cause of the of hyperglycemiacause of hyperglycemia or ketosis or ketosis a fl ammablea flammable anesthetic anesthetic mixture with mixture air, oxygen, with air, or oxygen, or tighter glycemic control. Educate patients to recognize and is necessary.is necessary. Interim subcutaneous Interim subcutaneous injections injections with Humalog with Humalog nitrous oxide.nitrous oxide. manage hypoglycemia. Hypoglycemia can happen suddenly may be required.may be required.Train patients Train usingpatients an insulinusing an pump insulin to pump to and symptoms may vary for each person and may change administeradminister insulin by insulin injection by injectionand to have and alternate to have alternateinsulin insulin • Standard • Standard Luer sets Luerare not sets compatible are not compatible with the Medtronicwith the Medtronic over time. Early warning symptoms of hypoglycemia may therapy availabletherapy availablein case of in pump case failure.of pump failure. MiniMed MiniMedParadigm Paradigm pump. Medtronic pump. Medtronic Paradigm Paradigm reservoirs reservoirs be different or less pronounced under conditions such as and Paradigm-compatibleand Paradigm-compatible infusion sets infusion are specifi sets are cally specifically • Drug Interactions:• Drug Interactions: Some medications Some medications may alter may glucose alter glucose long-standing diabetes, diabetic nerve disease, use of designeddesigned for use with for theuse pump.with the pump. metabolism,metabolism, insulin requirements, insulin requirements, and the risk and for the risk for medications such as beta-blockers, or intensifi ed diabetes hypoglycemiahypoglycemia or hyperglycemia. or hyperglycemia. Signs of hypoglycemia Signs of hypoglycemia • D o not modify• D o not your modify Paradigm your Paradigm reservoir reservoiror Paradigm- or Paradigm- control. These situations may result in severe hypoglycemia may be reducedmay be orreduced absent or in absentpatients in takingpatients anti-adrenergic taking anti-adrenergic compatiblecompatible infusion set. infusion set. and possibly loss of consciousness prior to the patient’s drugs. Particularlydrugs. Particularly close monitoring close monitoring may be required. may be required. • D o not put• D any o not other put any drugs/medications other drugs/medications inside your inside reservoir your reservoir awareness of hypoglycemia. Severe hypoglycemia may be to use withto thisuse pump.with this Only pump. insulin Only that insulin has been that hasprescribed been prescribed life threatening and can cause seizures or death. Adverse ReactionsAdverse Reactions • Adverse • reactionsAdverse reactions associated associated with Humalog with Humaloginclude include by your physicianby your physician can be used can in be this used pump. in this pump. U s e caution in patients with hypoglycemia unawareness hypoglycemia,hypoglycemia, hypokalemia, hypokalemia, allergic reactions, allergic reactions, injection-site injection-site • D o not use• D pump o not use cases pump that cases have that a magnetic have a magnetic clasp. clasp. and who may be predisposed to hypoglycemia. The patient’s reactions,reactions, lipodystrophy, lipodystrophy, pruritus, rash,pruritus, weight rash, gain, weight and gain, and ability to concentrate and react may be impaired as a result • D o not expose• D o not your expose insulin your pump insulin to MRIpump equipment to MRI equipment or other or other peripheralperipheral edema. edema. of hypoglycemia. Rapid changes in serum glucose levels may devices thatdevices generate that generate very strong very magnetic strong magnetic fi elds. The fields. The induce symptoms similar to hypoglycemia in persons with Use in SpecifiUse cin Populations Specific Populations magneticmagnetic fi elds in the fields immediate in the immediate vicinity of vicinity these devicesof these devices diabetes, regardless of the glucose value. • Pediatrics: • Pediatrics: Humalog Humaloghas not been has notstudied been in studied children in with children with can damagecan thedamage part of the the part pump’s of the motor pump’s that motor regulates that regulates type 1 diabetestype 1 lessdiabetes than less3 years than of 3 age years or ofin childrenage or in children insulin delivery,insulin delivery,possibly resultingpossibly resultingin over-delivery in over-delivery and and T i m i n g of hypoglycemia usually refl ects the time-action with typewith 2 diabetes. type 2 diabetes. severe hypoglycemia.severe hypoglycemia. Your pump Your must pump be removedmust be removedand and profi le of administered insulins. Other factors such as kept outsidekept the outside room the during room magnetic during magnetic resonance resonance imaging imaging changes in food intake, injection site, exercise, and Dosage andDosage Administration and Administration (MRI) procedures.(MRI) procedures. concomitant medications may alter the risk of hypoglycemia. • Humalog • Humalog should be should given withinbe given 15 within minutes 15 beforeminutes or before or immediatelyimmediately after a meal. after a meal. • I f your pump• I f your is inadvertently pump is inadvertently exposed toexposed a strong to magnetic a strong magnetic • Allergic Reactions: Severe, life-threatening, generalized fi eld, discontinuefield, discontinue use and contact use and our contact 24-Hour our HelpLine24-Hour HelpLinefor for allergy, including anaphylaxis, can occur with Humalog. Please seePlease following see following pages for pages Brief forSummary Brief Summary of of Full PrescribingFull Prescribing Information Information for Humalog. for Humalog. further assistance.further assistance. • Hypokalemia: Humalog can cause hypokalemia, which, Please visitPlease http://www.medtronicdiabetes.com/about/ visit http://www.medtronicdiabetes.com/about/ if untreated, may result in respiratory paralysis, ventricular HI HCP ISI HI08JUN2011 HCP ISI 08JUN2011 safety.htmlsafety.html for complete for complete safety information. safety information. arrhythmia, and death. Use caution in patients who may be at risk for hypokalemia (eg, patients using potassium- Humalog® isHumalog a registered® is a registeredtrademark trademarkof Eli Lilly and of Eli Company Lilly and Company and is availableand is by available prescription by prescription only. only. lowering medications or medications sensitive to serum ® ® potassium concentrations). MiniMed isMiniMed a registered is a registeredtrademark trademarkof Medtronic of MedtronicMiniMed, Inc. MiniMed, Inc. Paradigm® Paradigmis a registered® is a registeredtrademark trademarkof Medtronic of MedtronicMiniMed, Inc. MiniMed, Inc. Revel™ is aRevel™ trademark is a trademarkof Medtronic of MedtronicMiniMed, Inc. MiniMed, Inc. CareLink® isCareLink a registered® is a registeredtrademark trademarkof Medtronic of MedtronicMiniMed, Inc. MiniMed, Inc. The MiniMedThe Paradigm MiniMed Revel Paradigm Insulin Revel Pump Insulin is Continuous Pump is Continuous Glucose Glucose MonitoringMonitoring (CGM) ready. (CGM) Optional ready. glucose Optional sensor glucose and sensor MiniLink and® MiniLink® REAL-TimeREAL-Time transmitter transmitter are available are separately available separatelyfrom Medtronic. from Medtronic. For informationFor information on the MiniMed on the Paradigm MiniMed Revel Paradigm Insulin Revel Pump Insulin integrated Pump integrated with CGM, pleasewith CGM, contact please your contact Medtronic your Medtronicrepresentative. representative. Please seePlease Important see Important Safety Information Safety Information for Humalog for Humalog on on

01_08 Cover_Sept2012_v3.indd 5 8/10/12 11:42 AM

54300_elhmlp_HI76205_ap_ja_updt_fa.indd 2 6/25/12 4:14 PM 54300_elhmlp_HI76205_ap_ja_updt_fa.indd 3 6/25/12 4:14 PM ® HumalogHumalog® ADVERSE REACTIONSADVERSE REACTIONS Table 3: CatheterTable 3: Occlusions Catheter Occlusions and Infusion and Site Infusion Reactions Site Reactions 2 weeks prior2 weeks to cohabitation prior to cohabitation through Gestation through Day Gestation 19. There Day were19. There no adverse were no effects adverse effects The following adverse reactions are discussed elsewhere: (insulin lispro(insulin injection, lispro injection,USP [rDNA USP origin]) [rDNA origin]) The following adverse reactions are discussed elsewhere: HUMALOG HUMALOG Regular humanRegular insulin human insulinon female fertility,on female implantation, fertility, implantation, or fetal viability or fetal and viability morphology. and morphology. However, fetal However, growth fetal growth t Brief Summary:Brief Summary: Consult theConsult package the package insert for insert complete for complete prescribing prescribing tHypoglycemiaHypoglycemia [see Warnings [see and Warnings Precautions] and Precautions]. . (n=38) (n=38) (n=39) (n=39) retardation retardationwas produced was atproduced the 20 units/kg/day-doseat the 20 units/kg/day-dose as indicated as by indicated decreased by decreasedfetal fetal t weight and an increased incidence of fetal runts/litter. information.information. tHypokalemiaHypokalemia [see Warnings [see and Warnings Precautions] and Precautions]. . Catheter occlusions/monthCatheter occlusions/month 0.09 0.09 0.10 0.10 weight and an increased incidence of fetal runts/litter. In an embryo-fetalIn an embryo-fetal development development study in pregnant study in rabbits, pregnant insulin rabbits, lispro insulin doses lispro of 0.1, doses of 0.1, INDICATIONS AND USAGE Infusion siteInfusion reactions site reactions 2.6% (1/38)2.6% (1/38) 2.6% (1/39)2.6% (1/39) INDICATIONS AND USAGE Clinical TrialClinical Experience— Trial Experience—Because clinicalBecause trials clinical are conducted trials are conductedunder widely under varying widely varying 0.25, and 0.750.25, unit/kg/day and 0.75 unit/kg/day (0.03, 0.08, (0.03, and 0.24 0.08, times and 0.24the human times thesubcutaneous human subcutaneous dose of 1 dose of 1 HUMALOG is an insulin analog indicated to improve glycemic control in adults and HUMALOG is an insulin analog indicated to improve glycemic control in adults and designs, thedesigns, adverse the reaction adverse rates reaction reported rates in reported one clinical in one trial clinical may not trial be may easily not be easily In a randomized,In a randomized, 16-week, open-label, 16-week, open-label, parallel design parallel study design of children study andof children adolescents and adolescents unit/kg/day, unit/kg/day, based on units/body based on surfaceunits/body area, surface respectively) area, respectively) were injected were subcutaneously injected subcutaneously children with diabetes mellitus. children with diabetes mellitus. compared withcompared those rateswith those reported rates in reportedanother clinicalin another trial, clinical and may trial, not and reect may thenot ratesreect the rates with type 1with diabetes, type 1adverse diabetes, event adverse reports event related reports to infusion-site related to infusion-site reactions were reactions similar were similaron Gestation on days Gestation 7 through days 19.7 through There were 19. There no adverse were noeffects adverse on fetaleffects viability, on fetal weight, viability, weight, CONTRAINDICATIONSCONTRAINDICATIONS actually observedactually in observed clinical practice. in clinical practice. for insulin forlispro insulin and insulinlispro and aspart insulin (21% aspart of 100 (21% patients of 100 versus patients 17% versus of 198 patients, 17% of 198 patients, and morphology and morphology at any dose. at any dose. HUMALOG is contraindicated: respectively).respectively). In both groups, In both the groups, most frequently the most reportedfrequently infusion reported site infusion adverse site events adverse events HUMALOG is contraindicated: The frequenciesThe frequencies of Treatment-Emergent of Treatment-Emergent Adverse Events Adverse during Events HUMALOG during clinicalHUMALOG trials clinical trials Nursing Mothers—Nursing Mothers—It is unknownIt is whether unknown insulin whether lispro insulin is excreted lispro is in excreted human inmilk. human milk. t tduring episodes of hypoglycemia were infusionwere site infusion erythema site and erythema infusion and site infusion reaction. site reaction. during episodes of hypoglycemia in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the Because manyBecause drugs many are excreteddrugs are in excreted human milk,in human caution milk, should caution be shouldexercised be when exercised when t tin patients who are hypersensitive to HUMALOG or to any of its excipients. in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the Allergic ReactionsAllergic Reactions in patients who are hypersensitive to HUMALOG or to any of its excipients. HUMALOG HUMALOG is administered is administered to a nursing to woman. a nursing Use woman. of HUMALOG Use of HUMALOGis compatible is compatible with with tables below.tables below. Local AllergyLocal — As Allergy with any— As insulin with anytherapy, insulin patients therapy, taking patients HUMALOG taking mayHUMALOG experience may experience WARNINGSWARNINGS AND PRECAUTIONS AND PRECAUTIONS breastfeeding,breastfeeding, but women but with women diabetes with who diabetes are lactating who are may lactating require may adjustments require adjustments of of Table 1: Treatment-EmergentTable 1: Treatment-Emergent Adverse Events Adverse in Patients Events in with Patients with redness, swelling,redness, or swelling, itching ator theitching site atof thethe siteinjection. of the These injection. minor These reactions minor usuallyreactions usually Dose AdjustmentDose Adjustment and Monitoring— and Monitoring—Glucose monitoringGlucose monitoring is essential is for essential patients for patients resolve in a few days to a few weeks, but in some occasions, may require discontinuationtheir insulin their doses. insulin doses. receiving insulin therapy. Changes to an insulin regimen should be made cautiously Type 1 DiabetesType 1 Mellitus Diabetes Mellitus resolve in a few days to a few weeks, but in some occasions, may require discontinuation receiving insulin therapy. Changes to an insulin regimen should be made cautiously of HUMALOG.of HUMALOG.In some instances, In some theseinstances, reactions these may reactions be related may beto factorsrelated otherto factors than otherPediatric than Use—PediatricHUMALOG Use— HUMALOG is approved is for approved use in for children use in for children subcutaneous for subcutaneous daily daily and only underand onlymedical under supervision. medical supervision. Changes in Changes insulin strength, in insulin manufacturer, strength, manufacturer, type, or type, or (adverse events with frequency ≥5%) (adverse events with frequency ≥5%) insulin, suchinsulin, as irritants such asin airritants skin cleansing in a skin agent cleansing or poor agent injection or poor technique. injection technique. injections andinjections for subcutaneous and for subcutaneous continuous continuousinfusion by infusionexternal byinsulin external pump. insulin HUMALOG pump. HUMALOG method of administrationmethod of administration may result inmay the result need infor the a changeneed for in a insulin change dose. in insulin Concomitant dose. Concomitant Events, n (%) Lispro Regular human Total Systemic AllergySystemic — Allergy Severe, — life-threatening,Severe, life-threatening, generalized generalized allergy, including allergy, includinghas not beenhas studied not been in pediatric studied in patients pediatric younger patients than younger 3 years than of age.3 years HUMALOG of age. hasHUMALOG not has not oral antidiabeticoral antidiabetic treatment may treatment need tomay be needadjusted. to be adjusted. Events, n (%) Lispro Regular human Total (n=81) (n=81)insulin (n=86)insulin (n=86)(n=167) (n=167) anaphylaxis,anaphylaxis, may occur may with occur any insulin, with any including insulin, HUMALOG. including HUMALOG. Generalized Generalized allergy to allergybeen tostudied been in pediatric studied in patients pediatric with patients type 2 with diabetes. type 2 diabetes. As with all insulin preparations, the time course of action for HUMALOG may vary As with all insulin preparations, the time course of action for HUMALOG may vary Flu syndromeFlu syndrome 28 (34.6)28 (34.6) 28 (32.6) 28 (32.6) 56 (33.5) 56 (33.5) insulin mayinsulin cause maywhole cause body whole rash (includingbody rash pruritus), (including dyspnea, pruritus), wheezing, dyspnea, hypotension,wheezing, hypotension, As in adults,As the in adults, dosage the of dosageHUMALOG of HUMALOGmust be individualized must be individualized in pediatric in patients pediatric patients in different inindividuals different individualsor at different or at times different in the times same in individualthe same andindividual is dependent and is dependenton on tachycardia, or diaphoresis. based on metabolic needs and results of frequent monitoring of blood glucose. PharyngitisPharyngitis 27 (33.3)27 (33.3) 29 (33.7) 29 (33.7) 56 (33.5) 56 (33.5) tachycardia, or diaphoresis. based on metabolic needs and results of frequent monitoring of blood glucose. many conditions,many conditions,including the including site of injection,the site of local injection, blood localsupply, blood or localsupply, temperature. or local temperature. In controlledIn clinical controlled trials, clinical pruritus trials, (with pruritus or without (with or rash) without was rash)seen in was 17 seen patients in 17 patients Rhinitis Rhinitis 20 (24.7)20 (24.7) 25 (29.1) 25 (29.1) 45 (26.9) 45 (26.9) Geriatric Use—GeriatricOf the Use— totalOf number the total of number subjects of (n=2834) subjects in (n=2834) eight clinical in eight studies clinical studies Patients whoPatients change who their change level oftheir physical level ofactivity physical or mealactivity plan or maymeal require plan may adjustment require adjustment receiving regularreceiving human regular insulin human (n=2969) insulin and (n=2969) 30 patients and 30 receiving patients HUMALOG receiving (n=2944).HUMALOG (n=2944). Headache 24 (29.6) 19 (22.1) 43 (25.7) of HUMALOG,of HUMALOG, twelve percent twelve (n=338) percent were (n=338) 65 years were of 65 age years or over.of age The or majority over. The of majority of of insulin dosages.of insulin dosages. Headache 24 (29.6) 19 (22.1) 43 (25.7) Localized reactionsLocalized and reactions generalized and generalized myalgias have myalgias been have reported been with reported injected with injected these had typethese 2 haddiabetes. type 2 HbA1c diabetes. values HbA1c and valueshypoglycemia and hypoglycemia rates did not rates differ did by not age. differ by age. Pain Pain 16 (19.8)16 (19.8) 14 (16.3) 14 (16.3) 30 (18.0) 30 (18.0) metacresol,metacresol, which is an which excipient is an in excipient HUMALOG in [seeHUMALOG Contraindications]. [see Contraindications]. Hypoglycemia—Hypoglycemia—HypoglycemiaHypoglycemia is the most is common the most adverse common effect adverse associated effect associated with with Pharmacokinetic/pharmacodynamicPharmacokinetic/pharmacodynamic studies to assessstudies theto assesseffect ofthe age effect on theof ageonset on ofthe onset of insulins, includinginsulins, HUMALOG. including HUMALOG.The risk of Thehypoglycemia risk of hypoglycemia increases withincreases tighter with glycemic tighter glycemicCough increasedCough increased 14 (17.3) 14 (17.3) 15 (17.4) 15 (17.4) 29 (17.4) 29 (17.4) Antibody ProductionAntibody Production HUMALOG action HUMALOG have action not been have performed. not been performed. control. Patientscontrol. must Patients be educated must be to educated recognize to and recognize manage and hypoglycemia. manage hypoglycemia. Hypoglycemia Hypoglycemia Infection Infection 11 (13.6)11 (13.6) 18 (20.9) 18 (20.9) 29 (17.4) 29 (17.4) In large clinicalIn large trials clinical with patientstrials with with patients type 1 with (n=509) type and1 (n=509) type 2 and(n=262) type diabetes2 (n=262) diabetes can happencan suddenly happen and suddenly symptoms and symptomsmay be different may be for different each person for each and person may change and may changeNausea Nausea 5 (6.2) 5 (6.2) 13 (15.1)13 (15.1) 18 (10.8) 18 (10.8) mellitus, anti-insulinmellitus, anti-insulin antibody (insulinantibody lispro-specic (insulin lispro-specic antibodies, antibodies, insulin-specic insulin-specic OVERDOSAGE OVERDOSAGE antibodies, cross-reactive antibodies) formation was evaluated in patients receiving both from time tofrom time. time Severe to time. hypoglycemia Severe hypoglycemia can cause seizurescan cause and seizures may be and life-threatening may be life-threatening Accidental injuryAccidental injury 7 (8.6) 7 (8.6) 10 (11.6)10 (11.6) 17 (10.2) 17 (10.2) antibodies, cross-reactive antibodies) formation was evaluated in patients receiving both Excess insulinExcess administration insulin administration may cause hypoglycemiamay cause hypoglycemia and hypokalemia. and hypokalemia. Mild episodes Mild episodes regular humanregular insulin human and insulinHUMALOG and HUMALOG(including patients(including previously patients treatedpreviously with treated human with human of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, or cause death.or cause death. Surgical procedureSurgical procedure 5 (6.2) 5 (6.2) 12 (14.0)12 (14.0) 17 (10.2) 17 (10.2) of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, insulin andinsulin naive and patients). naive As patients). expected, As the expected, largest the increase largest in increase the antibody in the levels antibody meal levels patterns, meal or patterns, exercise or may exercise be needed. may be More needed. severe More episodes severe with episodes coma, with seizure, coma, seizure, The timing Theof hypoglycemia timing of hypoglycemia usually reects usually the reects time-action the time-action pro le of the pro le administered of the administered Fever Fever 5 (6.2) 5 (6.2) 10 (11.6) 10 (11.6) 15 (9.0) 15 (9.0) occurred inoccurred patients newin patients to insulin new therapy. to insulin The therapy. antibody The levels antibody peaked levels by 12peaked months by 12and months or neurologicand or neurologicimpairment impairment may be treated may bewith treated intramuscular/subcutaneous with intramuscular/subcutaneous glucagon or glucagon or insulin formulations.insulin formulations. Other factors Other such factors as changes such as in changesfood intake in food(e.g., intake amount (e.g., of foodamount or of foodAbdominal or Abdominalpain pain 6 (7.4) 6 (7.4) 7 (8.1) 7 (8.1) 13 (7.8) 13 (7.8) declined over the remaining years of the study. These antibodies do not appear to cause timing of meals), injection site, exercise, and concomitant medications may also alter the declined over the remaining years of the study. These antibodies do not appear to cause concentratedconcentrated intravenous intravenous glucose. Sustained glucose. carbohydrate Sustained carbohydrate intake and observationintake and observation may be may be timing of meals), injection site, exercise, and concomitant medications may also alter the Asthenia Asthenia 6 (7.4) 6 (7.4) 7 (8.1) 7 (8.1) 13 (7.8) 13 (7.8) deteriorationdeterioration in glycemic in control glycemic or necessitate control or necessitate an increase an in increaseinsulin dose. in insulin There dose. was Thereno was no necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia risk of hypoglycemiarisk of hypoglycemia [see Drug Interactions] [see Drug Interactions]. . necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia Bronchitis Bronchitis 6 (7.4) 6 (7.4) 6 (7.0) 6 (7.0) 12 (7.2) 12 (7.2) statisticallystatistically signicant relationshipsignicant relationship between the between change the in thechange total indaily the insulin total daily dose insulin and dose and must be corrected appropriately. must be corrected appropriately. As with all Asinsulins, with all use insulins, caution use in patientscaution inwith patients hypoglycemia with hypoglycemia unawareness unawareness and in andDiarrhea in Diarrhea 7 (8.6) 7 (8.6) 5 (5.8) 5 (5.8) 12 (7.2) 12 (7.2) the changethe in percent change antibodyin percent binding antibody for bindingany of the for antibodyany of the types. antibody types. patients who may be predisposed to hypoglycemia (e.g., the pediatric population and DOSAGE ANDDOSAGE ADMINISTRATION AND ADMINISTRATION patients who may be predisposed to hypoglycemia (e.g., the pediatric population and DysmenorrheaDysmenorrhea 5 (6.2) 5 (6.2) 6 (7.0) 6 (7.0) 11 (6.6) 11 (6.6) Postmarketing Experience—The following additional adverse reactions have been patients who fast or have erratic food intake). The patient’s ability to concentrate and react Postmarketing Experience—The following additional adverse reactions have been Dosage Considerations—When given subcutaneously, HUMALOG has a more rapid patients who fast or have erratic food intake). The patient’s ability to concentrate and react Myalgia 6 (7.4) 5 (5.8) 11 (6.6) identied duringidentied post-approval during post-approval use of HUMALOG. use of HUMALOG.Because these Because reactions these are reactions reported are reportedDosage Considerations—When given subcutaneously, HUMALOG has a more rapid may be impaired as a result of hypoglycemia. This may present a risk in situations whereMyalgia 6 (7.4) 5 (5.8) 11 (6.6) onset of action and a shorter duration of action than regular human insulin. may be impaired as a result of hypoglycemia. This may present a risk in situations where voluntarily fromvoluntarily a population from a ofpopulation uncertain of size, uncertain it is not size, always it is notpossible always to possiblereliably estimate to reliably estimateonset of action and a shorter duration of action than regular human insulin. these abilities are especially important, such as driving or operating other machinery.Urinary tractUrinary tract 5 (6.2) 5 (6.2) 4 (4.7) 4 (4.7) 9 (5.4) 9 (5.4) The dosage of HUMALOG must be individualized. Blood glucose monitoring is essential these abilities are especially important, such as driving or operating other machinery. their frequencytheir orfrequency establish or a establishcausal relationship a causal relationship to drug exposure. to drug exposure. The dosage of HUMALOG must be individualized. Blood glucose monitoring is essential infection infection in all patients receiving insulin therapy. Rapid changesRapid in changesserum glucose in serum levels glucose may levelsinduce may symptoms induce similarsymptoms to hypoglycemia similar to hypoglycemia Medication Medication errors in which errors other in which insulins other have insulins been have accidentally been accidentally substituted substituted for in all for patients receiving insulin therapy. The total dailyThe insulin total daily requirement insulin requirement may vary and may is varyusually and between is usually 0.5 between to 1 unit/kg/day. 0.5 to 1 unit/kg/day. in persons inwith persons diabetes, with regardless diabetes, regardlessof the glucose of the value. glucose Early value. warning Early symptoms warning symptomsof of Table 2: Treatment-EmergentTable 2: Treatment-Emergent Adverse Events Adverse in Patients Events in with Patients with HUMALOG have HUMALOG been identiedhave been during identied postapproval during postapproval use. use. hypoglycemia may be different or less pronounced under certain conditions, such Insulin requirementsInsulin requirements may be altered may during be altered stress, during major stress, illness, major or with illness, changes or with in exercise,changes in exercise, hypoglycemia may be different or less pronounced under certain conditions, such Type 2 DiabetesType 2 Mellitus Diabetes Mellitus DRUG INTERACTIONS as longstandingas longstanding diabetes, diabetic diabetes, nerve diabetic disease, nerve use disease, of medications use of medications such as beta- such as beta- DRUG INTERACTIONS meal patterns,meal or patterns, coadministered or coadministered drugs. drugs. (adverse events (adverse with events frequency with frequency≥5%) ≥5%) A number ofA drugsnumber affect of drugs glucose affect metabolism glucose metabolism and may require and may insulin require dose insulin adjustment dose adjustment blockers [seeblockers Drug [see Interactions] Drug Interactions], or intensi ed, or intensi ed diabetes control. diabetes These control. situations These may situations may SubcutaneousSubcutaneous Administration— Administration—HUMALOG shouldHUMALOG be givenshould within be given 15 minutes within 15 before minutes a before a result in severe hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s Events, n (%) Lispro Regular human Total and particularlyand particularly close monitoring. close monitoring. result in severe hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s Events, n (%) Lispro Regular human Total Following are some of the examples: meal or immediatelymeal or immediately after a meal. after a meal. awareness awarenessof hypoglycemia. of hypoglycemia. (n=714) (n=714)insulin (n=709)insulin (n=709)(n=1423) (n=1423) Following are some of the examples: tDrugs ThattDrugs May Increase That May the Increase Blood-Glucose-Lowering the Blood-Glucose-Lowering Effect of HUMALOG Effect of HUMALOGand andHUMALOG givenHUMALOG by subcutaneous given by subcutaneous injection should injection generally should be generally used in regimensbe used in with regimens with Headache Headache 63 (11.6) 63 (11.6) 66 (9.3)66 (9.3) 149 (10.5) 149 (10.5) HypersensitivityHypersensitivity and Allergic and Reactions— Allergic Reactions—Severe, life-threatening,Severe, life-threatening, generalized generalized allergy, allergy, SusceptibilitySusceptibility to Hypoglycemia: to Hypoglycemia: Oral antidiabetic Oral antidiabetic agents, salicylates, agents, salicylates,sulfonamide sulfonamide an intermediate- an intermediate- or long-acting or long-acting insulin. insulin. Pain 77 (10.8) 71 (10.0) 148 (10.4) including anaphylaxis,including anaphylaxis, can occur withcan occurinsulin with products, insulin including products, HUMALOG including [seeHUMALOG Adverse [see AdversePain 77 (10.8) 71 (10.0) 148 (10.4) antibiotics, antibiotics, monoamine monoamine oxidase inhibitors, oxidase uoxetine,inhibitors, uoxetine, pramlintide, pramlintide, disopyramide, disopyramide, HUMALOG administeredHUMALOG administered by subcutaneous by subcutaneous injection should injection be givenshould in be the given abdominal in the abdominal Reactions]. Reactions]. Infection Infection 72 (10.1) 72 (10.1) 54 (7.6) 54 (7.6) 126 (8.9) 126 (8.9) brates, propoxyphene,brates, propoxyphene, pentoxifylline, pentoxifylline, ACE inhibitors, ACE inhibitors, angiotensin angiotensin II receptor II receptorwall, thigh, wall,upper thigh, arm, upperor buttocks. arm, or Injection buttocks. sites Injection should sites be rotated should withinbe rotated the same within region the same region Hypokalemia—Hypokalemia—All insulin All products, insulin including products, HUMALOG, including HUMALOG, cause a shift cause in potassiuma shift in potassiumPharyngitis Pharyngitis 47 (6.6) 47 (6.6) 58 (8.2) 58 (8.2) 105 (7.4) 105 (7.4) blocking agents,blocking and agents, somatostatin and somatostatin analogs (e.g., analogs octreotide). (e.g., octreotide). (abdomen, (abdomen,thigh, upper thigh, arm, upperor buttocks) arm, or from buttocks) one injection from one to injectionthe next toto thereduce next the to reducerisk the risk from the extracellularfrom the extracellular to intracellular to intracellular space, possibly space, leading possibly to hypokalemia.leading to hypokalemia. Untreated UntreatedRhinitis Rhinitis 58 (8.1) 58 (8.1) 47 (6.6) 47 (6.6) 105 (7.4) 105 (7.4) tDrugs ThattDrugs May That Reduce May the Reduce Blood-Glucose-Lowering the Blood-Glucose-Lowering Effect of HUMALOG:Effect of HUMALOG:of lipodystrophy of lipodystrophy [see Adverse [see Reactions] Adverse . Reactions]. hypokalemiahypokalemia may cause may respiratory cause respiratory paralysis, ventricular paralysis, ventricular arrhythmia, arrhythmia, and death. and Use death.Flu Use syndrome Flu syndrome 44 (6.2) 44 (6.2) 58 (8.2) 58 (8.2) 102 (7.2) 102 (7.2) corticosteroids,corticosteroids, isoniazid, niacin, isoniazid, estrogens, niacin, estrogens, oral contraceptives, oral contraceptives, phenothiazines, phenothiazines, Continuous Continuous Subcutaneous Subcutaneous Infusion (Insulin Infusion Pump)— (InsulinHUMALOG Pump)— mayHUMALOG be administered may be administered danazol, diuretics, sympathomimetic agents (e.g., epinephrine, albuterol, caution in patientscaution inwho patients may be who at riskmay forbe hypokalemiaat risk for hypokalemia (e.g., patients (e.g., using patients potassium- using potassium-Surgical procedureSurgical procedure 53 (7.4) 53 (7.4) 48 (6.8) 48 (6.8) 101 (7.1) 101 (7.1) danazol, diuretics, sympathomimetic agents (e.g., epinephrine, albuterol, by continuousby continuous subcutaneous subcutaneous infusion by infusion an external by an insulin external pump. insulin Do notpump. use Do diluted not use diluted lowering medications,lowering medications, patients taking patients medications taking medications sensitive to sensitive serum to potassium serum potassium terbutaline),terbutaline), somatropin, somatropin, atypical antipsychotics, atypical antipsychotics, glucagon, proteaseglucagon, inhibitors, protease andinhibitors, or andmixed insulinsor mixed in insulinsexternal ininsulin external pumps. insulin Infusion pumps. sites Infusion should sites be rotatedshould bewithin rotated the within the concentrations).concentrations). Insulin initiationInsulin and initiation intensi cation and intensi cation of glucose controlof glucose control thyroid hormones.thyroid hormones. same region to reduce the risk of lipodystrophy [see Adverse Reactions]. Change the t same region to reduce the risk of lipodystrophy [see Adverse Reactions]. Change the Renal or Hepatic Impairment—Frequent glucose monitoring and insulin dose reductionIntensi cation Intensi cation or rapid improvement or rapid improvement in glucose incontrol glucose has control been associatedhas been associatedwith a with a tDrugs ThatDrugs May That Increase May or Increase Reduce or the Reduce Blood-Glucose-Lowering the Blood-Glucose-Lowering Effect of EffectHUMALOG of inHUMALOG the reservoir in the at reservoir least every at least7 days, every change 7 days, the changeinfusion the sets infusion and the sets infusion and the infusion Renal or Hepatic Impairment—Frequent glucose monitoring and insulin dose reduction HUMALOG: beta-blockers, clonidine, lithium salts, and alcohol. Pentamidine may may be requiredmay be in requiredpatients inwith patients renal orwith hepatic renal impairment.or hepatic impairment. transitory, reversibletransitory, ophthalmologic reversible ophthalmologic refraction disorder, refraction worsening disorder, ofworsening diabetic retinopathy,of diabetic retinopathy, HUMALOG: beta-blockers, clonidine, lithium salts, and alcohol. Pentamidine may set insertionset site insertion at least site every at least3 days. every 3 days. cause hypoglycemia,cause hypoglycemia, which may whichsometimes may sometimesbe followed be by followed hyperglycemia. by hyperglycemia. The initial programming of the external insulin infusion pump should be based on the Mixing of Insulins—HUMALOG for subcutaneous injection should not be mixedand with acute painfuland acute peripheral painful neuropathy.peripheral neuropathy. However, long-term However, glycemiclong-term control glycemic decreases control decreases t The initial programming of the external insulin infusion pump should be based on the Mixing of Insulins—HUMALOG for subcutaneous injection should not be mixed with tDrugs ThatDrugs May ThatReduce May the Reduce Signs theof Hypoglycemia: Signs of Hypoglycemia: beta-blockers, beta-blockers, clonidine, clonidine, total daily insulin dose of the previous regimen. Although there is signicant variability insulin preparations other than NPH insulin. If HUMALOG is mixed with NPH insulin,the risk of diabeticthe risk retinopathyof diabetic retinopathy and neuropathy. and neuropathy. total daily insulin dose of the previous regimen. Although there is signicant variability insulin preparations other than NPH insulin. If HUMALOG is mixed with NPH insulin, guanethidine, guanethidine, and reserpine. and reserpine. among patients, approximately 50% of the total dose is usually given as meal-related HUMALOG shouldHUMALOG be drawn should into be drawnthe syringe into the rst. syringe Injection rst. should Injection occur should immediately occur immediately after after Lipodystrophy among patients, approximately 50% of the total dose is usually given as meal-related Lipodystrophy USE IN SPECIFIC POPULATIONS boluses of HUMALOG and the remainder is given as a basal infusion. HUMALOG is mixing. mixing. USE IN SPECIFIC POPULATIONS boluses of HUMALOG and the remainder is given as a basal infusion. HUMALOG is Long-term Long-termuse of insulin, use includingof insulin, HUMALOG, including HUMALOG,can cause lipodystrophycan cause lipodystrophy at the site ofat the site of recommended for use in pump systems suitable for insulin infusion such as MiniMed, Do not mixDo HUMALOG not mix HUMALOG with other with insulins other for insulins use in for an use external in an subcutaneous external subcutaneous Pregnancy—Pregnancy—Pregnancy Pregnancy Category B. Category All pregnancies B. All pregnancies have a background have a background risk of birth risk ofrecommended birth for use in pump systems suitable for insulin infusion such as MiniMed, repeated insulinrepeated injections insulin or injections infusion. orLipodystrophy infusion. Lipodystrophy includes lipohypertrophy includes lipohypertrophy (thickening (thickening Disetronic, and other equivalent pumps. infusion pump.infusion pump. defects, loss,defects, or other loss, adverse or other outcome adverse regardless outcome ofregardless drug exposure. of drug This exposure. background This background risk Disetronic, risk and other equivalent pumps. of adipose of tissue) adipose and tissue) lipoatrophy and lipoatrophy (thinning of (thinning adipose of tissue), adipose and tissue), may affect and may insulin affect insulin is increased in pregnancies complicated by hyperglycemia and may be decreased with SubcutaneousSubcutaneous Insulin Infusion Insulin Pumps— InfusionWhen Pumps— usedWhen in an used external in an insulin external pump insulin for pump for is increased in pregnancies complicated by hyperglycemia and may be decreased with HOW SUPPLIED/STORAGEHOW SUPPLIED/STORAGE AND HANDLING AND HANDLING absorption. absorption.Rotate insulin Rotate injection insulin or injection infusion orsites infusion within sites the samewithin region the same to reduce region the to reduce the good metabolicgood control.metabolic It is control. essential It is for essential patients for with patients diabetes with or diabetes history ofor gestational history of gestational subcutaneoussubcutaneous infusion, HUMALOG infusion, shouldHUMALOG not shouldbe diluted not orbe mixeddiluted with or mixed any other with insulin. any other insulin. How Supplied risk of lipodystrophyrisk of lipodystrophy [see Dosage [see and Dosage Administration]. and Administration]. diabetes to diabetesmaintain to good maintain metabolic good control metabolic before control conception before conceptionand throughout and throughoutpregnancy. pregnancy.How Supplied Change theChange HUMALOG the inHUMALOG the reservoir in the at reservoir least every at least7 days, every change 7 days, the change infusion the sets infusion and sets and HUMALOG 100HUMALOG units per 100 mL units (U-100) per mL is available(U-100) is as: available as: the infusion set insertion site at least every 3 days. HUMALOG should not be exposedWeight to gainWeight gain In patients In with patients diabetes with or diabetes gestational or gestational diabetes insulin diabetes requirements insulin requirements may decrease may decrease the infusion set insertion site at least every 3 days. HUMALOG should not be exposed to during the rst trimester, generally increase during the second and third trimesters, and 10 mL vials NDC 0002-7510-01 (VL-7510) temperaturestemperatures greater than greater 98.6°F than (37°C). 98.6°F (37°C). Weight gainWeight can occur gain can with occur insulin with therapy, insulin including therapy, HUMALOG, including HUMALOG, and has been and has been during the rst trimester, generally increase during the second and third trimesters, and 10 mL vials NDC 0002-7510-01 (VL-7510) Malfunction of the insulin pump or infusion set or insulin degradation can rapidly rapidly declinerapidly after decline delivery. after Careful delivery. monitoring Careful monitoringof glucose ofcontrol glucose is essentialcontrol is in essential these in3 these mL vials 3 mL vials NDC 0002-7510-17NDC 0002-7510-17 (VL-7533) (VL-7533) Malfunction of the insulin pump or infusion set or insulin degradation can rapidly attributed toattributed the anabolic to the effects anabolic of insulin effects and of insulinthe decrease and the in decrease glucosuria. in glucosuria. 1 lead to hyperglycemia and ketosis. Prompt identi cation and correction of the cause of patients. Therefore,patients. femaleTherefore, patients female should patients be advised should beto telladvised their tophysicians tell their ifphysicians they intend if they 5intend x 3 mL cartridges5 x 3 mL1 cartridges NDC 0002-7516-59NDC 0002-7516-59 (VL-7516) (VL-7516) lead to hyperglycemia and ketosis. Prompt identi cation and correction of the cause of Peripheral EdemaPeripheral Edema to become, or if they become pregnant while taking HUMALOG. hyperglycemiahyperglycemia or ketosis isor necessary.ketosis is necessary.Interim subcutaneous Interim subcutaneous injections withinjections HUMALOG with HUMALOG to become, or if they become pregnant while taking HUMALOG. 5 x 3 mL prelled5 x 3 mL pen prelled pen NDC 0002-8725-59NDC 0002-8725-59 (HP-8725) (HP-8725) Insulin, includingInsulin, HUMALOG, including HUMALOG,may cause maysodium cause retention sodium and retention edema, and particularly edema, particularly if if Although there are limited clinical studies of the use of HUMALOG in pregnancy, may be required.may be Patients required. using Patients continuous using continuoussubcutaneous subcutaneous insulin infusion insulin pump infusion therapy pump therapy Although there are limited clinical studies of the use of HUMALOG in pregnancy, 5 x 3 mL Humalog5 x 3 mL KwikPen Humalog (prelled) KwikPen (prelled) NDC 0002-8799-59 NDC 0002-8799-59 (HP-8799) (HP-8799) previously poor metabolic control is improved by intensi ed insulin therapy. published studies with human insulins suggest that optimizing overall glycemic control, must be trainedmust be to trainedadminister to administer insulin by insulininjection by and injection have alternateand have insulin alternate therapy insulin therapypreviously poor metabolic control is improved by intensi ed insulin therapy. published studies with human insulins suggest that optimizing overall glycemic control, including postprandial control, before conception and during pregnancy improvesStorage fetal Storage available inavailable case of in pump case failure of pump [see failure Dosage [see and Dosage Administration and Administration and How Supplied/ and How Supplied/Adverse ReactionsAdverse with Reactions Continuous with Continuous Subcutaneous Subcutaneous Insulin Infusion Insulin (CSII) Infusion (CSII) including postprandial control, before conception and during pregnancy improves fetal outcome. Do not use Doafter not the use expiration after the date.expiration date. Storage andStorage Handling] and. Handling]. In a 12-week,In a randomized, 12-week, randomized, crossover study crossover in adult study patients in adult with patients type 1 with diabetes type 1 diabetes outcome. In a combined fertility and embryo-fetal development study, female rats were givenUnopened HUMALOGUnopened shouldHUMALOG be storedshould in be a storedrefrigerator in a refrigerator (36° to 46°F (36° [2° to to 46°F 8°C]), [2° but to 8°C]), but (n=39), the rates of catheter occlusions and infusion site reactions were similar for In a combined fertility and embryo-fetal development study, female rats were given Drug Interactions—Drug Interactions—Some medicationsSome medications may alter insulinmay alter requirements insulin requirements and the risk and for the risk(n=39), for the rates of catheter occlusions and infusion site reactions were similar for subcutaneoussubcutaneous insulin lispro insulin injections lispro of injections 5 and 20 ofunits/kg/day 5 and 20 units/kg/day (0.8 and 3 times (0.8 and the 3human times the humannot in the freezer.not in the Do freezer.not use Do HUMALOG not use HUMALOGif it has been if it frozen.has been In-use frozen. HUMALOG In-use HUMALOGvials, vials, hypoglycemiahypoglycemia or hyperglycemia or hyperglycemia [see Drug Interactions] [see Drug Interactions]. . HUMALOG andHUMALOG regular and human regular insulin human treated insulin patients treated (see patients Table 3).(see Table 3). subcutaneoussubcutaneous dose of 1 unit/kg/day, dose of 1 unit/kg/day, based on units/body based on surfaceunits/body area, surface respectively) area, respectively) from cartridges, from cartridges, pens, and pens, HUMALOG and HUMALOG KwikPen® KwikPen should be® should stored be at roomstored temperature, at room temperature,

01_08 Cover_Sept2012_v3.indd 6 8/10/12 11:42 AM 54300_elhmlp_HI76205_ap_ja_updt_fa.indd 4 6/25/12 4:14 PM 54300_elhmlp_HI76205_ap_ja_updt_fa.indd 5 6/25/12 4:14 PM ® HumalogHumalog® ADVERSE REACTIONSADVERSE REACTIONS Table 3: CatheterTable 3: Occlusions Catheter Occlusions and Infusion and Site Infusion Reactions Site Reactions 2 weeks prior2 weeks to cohabitation prior to cohabitation through Gestation through Day Gestation 19. There Day were19. There no adverse were no effects adverse effects The following adverse reactions are discussed elsewhere: (insulin lispro(insulin injection, lispro injection,USP [rDNA USP origin]) [rDNA origin]) The following adverse reactions are discussed elsewhere: HUMALOG HUMALOG Regular humanRegular insulin human insulinon female fertility,on female implantation, fertility, implantation, or fetal viability or fetal and viability morphology. and morphology. However, fetal However, growth fetal growth t Brief Summary:Brief Summary: Consult theConsult package the package insert for insert complete for complete prescribing prescribing tHypoglycemiaHypoglycemia [see Warnings [see and Warnings Precautions] and Precautions]. . (n=38) (n=38) (n=39) (n=39) retardation retardationwas produced was atproduced the 20 units/kg/day-doseat the 20 units/kg/day-dose as indicated as by indicated decreased by decreasedfetal fetal t weight and an increased incidence of fetal runts/litter. information.information. tHypokalemiaHypokalemia [see Warnings [see and Warnings Precautions] and Precautions]. . Catheter occlusions/monthCatheter occlusions/month 0.09 0.09 0.10 0.10 weight and an increased incidence of fetal runts/litter. In an embryo-fetalIn an embryo-fetal development development study in pregnant study in rabbits, pregnant insulin rabbits, lispro insulin doses lispro of 0.1, doses of 0.1, INDICATIONS AND USAGE Infusion siteInfusion reactions site reactions 2.6% (1/38)2.6% (1/38) 2.6% (1/39)2.6% (1/39) INDICATIONS AND USAGE Clinical TrialClinical Experience— Trial Experience—Because clinicalBecause trials clinical are conducted trials are conductedunder widely under varying widely varying 0.25, and 0.750.25, unit/kg/day and 0.75 unit/kg/day (0.03, 0.08, (0.03, and 0.24 0.08, times and 0.24the human times thesubcutaneous human subcutaneous dose of 1 dose of 1 HUMALOG is an insulin analog indicated to improve glycemic control in adults and HUMALOG is an insulin analog indicated to improve glycemic control in adults and designs, thedesigns, adverse the reaction adverse rates reaction reported rates in reported one clinical in one trial clinical may not trial be may easily not be easily In a randomized,In a randomized, 16-week, open-label, 16-week, open-label, parallel design parallel study design of children study andof children adolescents and adolescents unit/kg/day, unit/kg/day, based on units/body based on surfaceunits/body area, surface respectively) area, respectively) were injected were subcutaneously injected subcutaneously children with diabetes mellitus. children with diabetes mellitus. compared withcompared those rateswith those reported rates in reportedanother clinicalin another trial, clinical and may trial, not and reect may thenot ratesreect the rates with type 1with diabetes, type 1adverse diabetes, event adverse reports event related reports to infusion-site related to infusion-site reactions were reactions similar were similaron Gestation on days Gestation 7 through days 19.7 through There were 19. There no adverse were noeffects adverse on fetaleffects viability, on fetal weight, viability, weight, CONTRAINDICATIONSCONTRAINDICATIONS actually observedactually in observed clinical practice. in clinical practice. for insulin forlispro insulin and insulinlispro and aspart insulin (21% aspart of 100 (21% patients of 100 versus patients 17% versus of 198 patients, 17% of 198 patients, and morphology and morphology at any dose. at any dose. HUMALOG is contraindicated: respectively).respectively). In both groups, In both the groups, most frequently the most reportedfrequently infusion reported site infusion adverse site events adverse events HUMALOG is contraindicated: The frequenciesThe frequencies of Treatment-Emergent of Treatment-Emergent Adverse Events Adverse during Events HUMALOG during clinicalHUMALOG trials clinical trials Nursing Mothers—Nursing Mothers—It is unknownIt is whether unknown insulin whether lispro insulin is excreted lispro is in excreted human inmilk. human milk. t tduring episodes of hypoglycemia were infusionwere site infusion erythema site and erythema infusion and site infusion reaction. site reaction. during episodes of hypoglycemia in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the Because manyBecause drugs many are excreteddrugs are in excreted human milk,in human caution milk, should caution be shouldexercised be when exercised when t tin patients who are hypersensitive to HUMALOG or to any of its excipients. in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the Allergic ReactionsAllergic Reactions in patients who are hypersensitive to HUMALOG or to any of its excipients. HUMALOG HUMALOG is administered is administered to a nursing to woman. a nursing Use woman. of HUMALOG Use of HUMALOGis compatible is compatible with with tables below.tables below. Local AllergyLocal — As Allergy with any— As insulin with anytherapy, insulin patients therapy, taking patients HUMALOG taking mayHUMALOG experience may experience WARNINGSWARNINGS AND PRECAUTIONS AND PRECAUTIONS breastfeeding,breastfeeding, but women but with women diabetes with who diabetes are lactating who are may lactating require may adjustments require adjustments of of Table 1: Treatment-EmergentTable 1: Treatment-Emergent Adverse Events Adverse in Patients Events in with Patients with redness, swelling,redness, or swelling, itching ator theitching site atof thethe siteinjection. of the These injection. minor These reactions minor usuallyreactions usually Dose AdjustmentDose Adjustment and Monitoring— and Monitoring—Glucose monitoringGlucose monitoring is essential is for essential patients for patients resolve in a few days to a few weeks, but in some occasions, may require discontinuationtheir insulin their doses. insulin doses. receiving insulin therapy. Changes to an insulin regimen should be made cautiously Type 1 DiabetesType 1 Mellitus Diabetes Mellitus resolve in a few days to a few weeks, but in some occasions, may require discontinuation receiving insulin therapy. Changes to an insulin regimen should be made cautiously of HUMALOG.of HUMALOG.In some instances, In some theseinstances, reactions these may reactions be related may beto factorsrelated otherto factors than otherPediatric than Use—PediatricHUMALOG Use— HUMALOG is approved is for approved use in for children use in for children subcutaneous for subcutaneous daily daily and only underand onlymedical under supervision. medical supervision. Changes in Changes insulin strength, in insulin manufacturer, strength, manufacturer, type, or type, or (adverse events with frequency ≥5%) (adverse events with frequency ≥5%) insulin, suchinsulin, as irritants such asin airritants skin cleansing in a skin agent cleansing or poor agent injection or poor technique. injection technique. injections andinjections for subcutaneous and for subcutaneous continuous continuousinfusion by infusionexternal byinsulin external pump. insulin HUMALOG pump. HUMALOG method of administrationmethod of administration may result inmay the result need infor the a changeneed for in a insulin change dose. in insulin Concomitant dose. Concomitant Events, n (%) Lispro Regular human Total Systemic AllergySystemic — Allergy Severe, — life-threatening,Severe, life-threatening, generalized generalized allergy, including allergy, includinghas not beenhas studied not been in pediatric studied in patients pediatric younger patients than younger 3 years than of age.3 years HUMALOG of age. hasHUMALOG not has not oral antidiabeticoral antidiabetic treatment may treatment need tomay be needadjusted. to be adjusted. Events, n (%) Lispro Regular human Total (n=81) (n=81)insulin (n=86)insulin (n=86)(n=167) (n=167) anaphylaxis,anaphylaxis, may occur may with occur any insulin, with any including insulin, HUMALOG. including HUMALOG. Generalized Generalized allergy to allergybeen tostudied been in pediatric studied in patients pediatric with patients type 2 with diabetes. type 2 diabetes. As with all insulin preparations, the time course of action for HUMALOG may vary As with all insulin preparations, the time course of action for HUMALOG may vary Flu syndromeFlu syndrome 28 (34.6)28 (34.6) 28 (32.6) 28 (32.6) 56 (33.5) 56 (33.5) insulin mayinsulin cause maywhole cause body whole rash (includingbody rash pruritus), (including dyspnea, pruritus), wheezing, dyspnea, hypotension,wheezing, hypotension, As in adults,As the in adults, dosage the of dosageHUMALOG of HUMALOGmust be individualized must be individualized in pediatric in patients pediatric patients in different inindividuals different individualsor at different or at times different in the times same in individualthe same andindividual is dependent and is dependenton on tachycardia, or diaphoresis. based on metabolic needs and results of frequent monitoring of blood glucose. PharyngitisPharyngitis 27 (33.3)27 (33.3) 29 (33.7) 29 (33.7) 56 (33.5) 56 (33.5) tachycardia, or diaphoresis. based on metabolic needs and results of frequent monitoring of blood glucose. many conditions,many conditions,including the including site of injection,the site of local injection, blood localsupply, blood or localsupply, temperature. or local temperature. In controlledIn clinical controlled trials, clinical pruritus trials, (with pruritus or without (with or rash) without was rash)seen in was 17 seen patients in 17 patients Rhinitis Rhinitis 20 (24.7)20 (24.7) 25 (29.1) 25 (29.1) 45 (26.9) 45 (26.9) Geriatric Use—GeriatricOf the Use— totalOf number the total of number subjects of (n=2834) subjects in (n=2834) eight clinical in eight studies clinical studies Patients whoPatients change who their change level oftheir physical level ofactivity physical or mealactivity plan or maymeal require plan may adjustment require adjustment receiving regularreceiving human regular insulin human (n=2969) insulin and (n=2969) 30 patients and 30 receiving patients HUMALOG receiving (n=2944).HUMALOG (n=2944). Headache 24 (29.6) 19 (22.1) 43 (25.7) of HUMALOG,of HUMALOG, twelve percent twelve (n=338) percent were (n=338) 65 years were of 65 age years or over.of age The or majority over. The of majority of of insulin dosages.of insulin dosages. Headache 24 (29.6) 19 (22.1) 43 (25.7) Localized reactionsLocalized and reactions generalized and generalized myalgias have myalgias been have reported been with reported injected with injected these had typethese 2 haddiabetes. type 2 HbA1c diabetes. values HbA1c and valueshypoglycemia and hypoglycemia rates did not rates differ did by not age. differ by age. Pain Pain 16 (19.8)16 (19.8) 14 (16.3) 14 (16.3) 30 (18.0) 30 (18.0) metacresol,metacresol, which is an which excipient is an in excipient HUMALOG in [seeHUMALOG Contraindications]. [see Contraindications]. Hypoglycemia—Hypoglycemia—HypoglycemiaHypoglycemia is the most is common the most adverse common effect adverse associated effect associated with with Pharmacokinetic/pharmacodynamicPharmacokinetic/pharmacodynamic studies to assessstudies theto assesseffect ofthe age effect on theof ageonset on ofthe onset of insulins, includinginsulins, HUMALOG. including HUMALOG.The risk of Thehypoglycemia risk of hypoglycemia increases withincreases tighter with glycemic tighter glycemicCough increasedCough increased 14 (17.3) 14 (17.3) 15 (17.4) 15 (17.4) 29 (17.4) 29 (17.4) Antibody ProductionAntibody Production HUMALOG action HUMALOG have action not been have performed. not been performed. control. Patientscontrol. must Patients be educated must be to educated recognize to and recognize manage and hypoglycemia. manage hypoglycemia. Hypoglycemia Hypoglycemia Infection Infection 11 (13.6)11 (13.6) 18 (20.9) 18 (20.9) 29 (17.4) 29 (17.4) In large clinicalIn large trials clinical with patientstrials with with patients type 1 with (n=509) type and1 (n=509) type 2 and(n=262) type diabetes2 (n=262) diabetes can happencan suddenly happen and suddenly symptoms and symptomsmay be different may be for different each person for each and person may change and may changeNausea Nausea 5 (6.2) 5 (6.2) 13 (15.1)13 (15.1) 18 (10.8) 18 (10.8) mellitus, anti-insulinmellitus, anti-insulin antibody (insulinantibody lispro-specic (insulin lispro-specic antibodies, antibodies, insulin-specic insulin-specic OVERDOSAGE OVERDOSAGE antibodies, cross-reactive antibodies) formation was evaluated in patients receiving both from time tofrom time. time Severe to time. hypoglycemia Severe hypoglycemia can cause seizurescan cause and seizures may be and life-threatening may be life-threatening Accidental injuryAccidental injury 7 (8.6) 7 (8.6) 10 (11.6)10 (11.6) 17 (10.2) 17 (10.2) antibodies, cross-reactive antibodies) formation was evaluated in patients receiving both Excess insulinExcess administration insulin administration may cause hypoglycemiamay cause hypoglycemia and hypokalemia. and hypokalemia. Mild episodes Mild episodes regular humanregular insulin human and insulinHUMALOG and HUMALOG(including patients(including previously patients treatedpreviously with treated human with human of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, or cause death.or cause death. Surgical procedureSurgical procedure 5 (6.2) 5 (6.2) 12 (14.0)12 (14.0) 17 (10.2) 17 (10.2) of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, insulin andinsulin naive and patients). naive As patients). expected, As the expected, largest the increase largest in increase the antibody in the levels antibody meal levels patterns, meal or patterns, exercise or may exercise be needed. may be More needed. severe More episodes severe with episodes coma, with seizure, coma, seizure, The timing Theof hypoglycemia timing of hypoglycemia usually reects usually the reects time-action the time-action pro le of the pro le administered of the administered Fever Fever 5 (6.2) 5 (6.2) 10 (11.6) 10 (11.6) 15 (9.0) 15 (9.0) occurred inoccurred patients newin patients to insulin new therapy. to insulin The therapy. antibody The levels antibody peaked levels by 12peaked months by 12and months or neurologicand or neurologicimpairment impairment may be treated may bewith treated intramuscular/subcutaneous with intramuscular/subcutaneous glucagon or glucagon or insulin formulations.insulin formulations. Other factors Other such factors as changes such as in changesfood intake in food(e.g., intake amount (e.g., of foodamount or of foodAbdominal or Abdominalpain pain 6 (7.4) 6 (7.4) 7 (8.1) 7 (8.1) 13 (7.8) 13 (7.8) declined over the remaining years of the study. These antibodies do not appear to cause timing of meals), injection site, exercise, and concomitant medications may also alter the declined over the remaining years of the study. These antibodies do not appear to cause concentratedconcentrated intravenous intravenous glucose. Sustained glucose. carbohydrate Sustained carbohydrate intake and observationintake and observation may be may be timing of meals), injection site, exercise, and concomitant medications may also alter the Asthenia Asthenia 6 (7.4) 6 (7.4) 7 (8.1) 7 (8.1) 13 (7.8) 13 (7.8) deteriorationdeterioration in glycemic in control glycemic or necessitate control or necessitate an increase an in increaseinsulin dose. in insulin There dose. was Thereno was no necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia risk of hypoglycemiarisk of hypoglycemia [see Drug Interactions] [see Drug Interactions]. . necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia Bronchitis Bronchitis 6 (7.4) 6 (7.4) 6 (7.0) 6 (7.0) 12 (7.2) 12 (7.2) statisticallystatistically signicant relationshipsignicant relationship between the between change the in thechange total indaily the insulin total daily dose insulin and dose and must be corrected appropriately. must be corrected appropriately. As with all Asinsulins, with all use insulins, caution use in patientscaution inwith patients hypoglycemia with hypoglycemia unawareness unawareness and in andDiarrhea in Diarrhea 7 (8.6) 7 (8.6) 5 (5.8) 5 (5.8) 12 (7.2) 12 (7.2) the changethe in percent change antibodyin percent binding antibody for bindingany of the for antibodyany of the types. antibody types. patients who may be predisposed to hypoglycemia (e.g., the pediatric population and DOSAGE ANDDOSAGE ADMINISTRATION AND ADMINISTRATION patients who may be predisposed to hypoglycemia (e.g., the pediatric population and DysmenorrheaDysmenorrhea 5 (6.2) 5 (6.2) 6 (7.0) 6 (7.0) 11 (6.6) 11 (6.6) Postmarketing Experience—The following additional adverse reactions have been patients who fast or have erratic food intake). The patient’s ability to concentrate and react Postmarketing Experience—The following additional adverse reactions have been Dosage Considerations—When given subcutaneously, HUMALOG has a more rapid patients who fast or have erratic food intake). The patient’s ability to concentrate and react Myalgia 6 (7.4) 5 (5.8) 11 (6.6) identied duringidentied post-approval during post-approval use of HUMALOG. use of HUMALOG.Because these Because reactions these are reactions reported are reportedDosage Considerations—When given subcutaneously, HUMALOG has a more rapid may be impaired as a result of hypoglycemia. This may present a risk in situations whereMyalgia 6 (7.4) 5 (5.8) 11 (6.6) onset of action and a shorter duration of action than regular human insulin. may be impaired as a result of hypoglycemia. This may present a risk in situations where voluntarily fromvoluntarily a population from a ofpopulation uncertain of size, uncertain it is not size, always it is notpossible always to possiblereliably estimate to reliably estimateonset of action and a shorter duration of action than regular human insulin. these abilities are especially important, such as driving or operating other machinery.Urinary tractUrinary tract 5 (6.2) 5 (6.2) 4 (4.7) 4 (4.7) 9 (5.4) 9 (5.4) The dosage of HUMALOG must be individualized. Blood glucose monitoring is essential these abilities are especially important, such as driving or operating other machinery. their frequencytheir orfrequency establish or a establishcausal relationship a causal relationship to drug exposure. to drug exposure. The dosage of HUMALOG must be individualized. Blood glucose monitoring is essential infection infection in all patients receiving insulin therapy. Rapid changesRapid in changesserum glucose in serum levels glucose may levelsinduce may symptoms induce similarsymptoms to hypoglycemia similar to hypoglycemia Medication Medication errors in which errors other in which insulins other have insulins been have accidentally been accidentally substituted substituted for in all for patients receiving insulin therapy. The total dailyThe insulin total daily requirement insulin requirement may vary and may is varyusually and between is usually 0.5 between to 1 unit/kg/day. 0.5 to 1 unit/kg/day. in persons inwith persons diabetes, with regardless diabetes, regardlessof the glucose of the value. glucose Early value. warning Early symptoms warning symptomsof of Table 2: Treatment-EmergentTable 2: Treatment-Emergent Adverse Events Adverse in Patients Events in with Patients with HUMALOG have HUMALOG been identiedhave been during identied postapproval during postapproval use. use. hypoglycemia may be different or less pronounced under certain conditions, such Insulin requirementsInsulin requirements may be altered may during be altered stress, during major stress, illness, major or with illness, changes or with in exercise,changes in exercise, hypoglycemia may be different or less pronounced under certain conditions, such Type 2 DiabetesType 2 Mellitus Diabetes Mellitus DRUG INTERACTIONS as longstandingas longstanding diabetes, diabetic diabetes, nerve diabetic disease, nerve use disease, of medications use of medications such as beta- such as beta- DRUG INTERACTIONS meal patterns,meal or patterns, coadministered or coadministered drugs. drugs. (adverse events (adverse with events frequency with frequency≥5%) ≥5%) A number ofA drugsnumber affect of drugs glucose affect metabolism glucose metabolism and may require and may insulin require dose insulin adjustment dose adjustment blockers [seeblockers Drug [see Interactions] Drug Interactions], or intensi ed, or intensi ed diabetes control. diabetes These control. situations These may situations may SubcutaneousSubcutaneous Administration— Administration—HUMALOG shouldHUMALOG be givenshould within be given 15 minutes within 15 before minutes a before a result in severe hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s Events, n (%) Lispro Regular human Total and particularlyand particularly close monitoring. close monitoring. result in severe hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s Events, n (%) Lispro Regular human Total Following are some of the examples: meal or immediatelymeal or immediately after a meal. after a meal. awareness awarenessof hypoglycemia. of hypoglycemia. (n=714) (n=714)insulin (n=709)insulin (n=709)(n=1423) (n=1423) Following are some of the examples: tDrugs ThattDrugs May Increase That May the Increase Blood-Glucose-Lowering the Blood-Glucose-Lowering Effect of HUMALOG Effect of HUMALOGand andHUMALOG givenHUMALOG by subcutaneous given by subcutaneous injection should injection generally should be generally used in regimensbe used in with regimens with Headache Headache 63 (11.6) 63 (11.6) 66 (9.3)66 (9.3) 149 (10.5) 149 (10.5) HypersensitivityHypersensitivity and Allergic and Reactions— Allergic Reactions—Severe, life-threatening,Severe, life-threatening, generalized generalized allergy, allergy, SusceptibilitySusceptibility to Hypoglycemia: to Hypoglycemia: Oral antidiabetic Oral antidiabetic agents, salicylates, agents, salicylates,sulfonamide sulfonamide an intermediate- an intermediate- or long-acting or long-acting insulin. insulin. Pain 77 (10.8) 71 (10.0) 148 (10.4) including anaphylaxis,including anaphylaxis, can occur withcan occurinsulin with products, insulin including products, HUMALOG including [seeHUMALOG Adverse [see AdversePain 77 (10.8) 71 (10.0) 148 (10.4) antibiotics, antibiotics, monoamine monoamine oxidase inhibitors, oxidase uoxetine,inhibitors, uoxetine, pramlintide, pramlintide, disopyramide, disopyramide, HUMALOG administeredHUMALOG administered by subcutaneous by subcutaneous injection should injection be givenshould in be the given abdominal in the abdominal Reactions]. Reactions]. Infection Infection 72 (10.1) 72 (10.1) 54 (7.6) 54 (7.6) 126 (8.9) 126 (8.9) brates, propoxyphene,brates, propoxyphene, pentoxifylline, pentoxifylline, ACE inhibitors, ACE inhibitors, angiotensin angiotensin II receptor II receptorwall, thigh, wall,upper thigh, arm, upperor buttocks. arm, or Injection buttocks. sites Injection should sites be rotated should withinbe rotated the same within region the same region Hypokalemia—Hypokalemia—All insulin All products, insulin including products, HUMALOG, including HUMALOG, cause a shift cause in potassiuma shift in potassiumPharyngitis Pharyngitis 47 (6.6) 47 (6.6) 58 (8.2) 58 (8.2) 105 (7.4) 105 (7.4) blocking agents,blocking and agents, somatostatin and somatostatin analogs (e.g., analogs octreotide). (e.g., octreotide). (abdomen, (abdomen,thigh, upper thigh, arm, upperor buttocks) arm, or from buttocks) one injection from one to injectionthe next toto thereduce next the to reducerisk the risk from the extracellularfrom the extracellular to intracellular to intracellular space, possibly space, leading possibly to hypokalemia.leading to hypokalemia. Untreated UntreatedRhinitis Rhinitis 58 (8.1) 58 (8.1) 47 (6.6) 47 (6.6) 105 (7.4) 105 (7.4) tDrugs ThattDrugs May That Reduce May the Reduce Blood-Glucose-Lowering the Blood-Glucose-Lowering Effect of HUMALOG:Effect of HUMALOG:of lipodystrophy of lipodystrophy [see Adverse [see Reactions] Adverse . Reactions]. hypokalemiahypokalemia may cause may respiratory cause respiratory paralysis, ventricular paralysis, ventricular arrhythmia, arrhythmia, and death. and Use death.Flu Use syndrome Flu syndrome 44 (6.2) 44 (6.2) 58 (8.2) 58 (8.2) 102 (7.2) 102 (7.2) corticosteroids,corticosteroids, isoniazid, niacin, isoniazid, estrogens, niacin, estrogens, oral contraceptives, oral contraceptives, phenothiazines, phenothiazines, Continuous Continuous Subcutaneous Subcutaneous Infusion (Insulin Infusion Pump)— (InsulinHUMALOG Pump)— mayHUMALOG be administered may be administered danazol, diuretics, sympathomimetic agents (e.g., epinephrine, albuterol, caution in patientscaution inwho patients may be who at riskmay forbe hypokalemiaat risk for hypokalemia (e.g., patients (e.g., using patients potassium- using potassium-Surgical procedureSurgical procedure 53 (7.4) 53 (7.4) 48 (6.8) 48 (6.8) 101 (7.1) 101 (7.1) danazol, diuretics, sympathomimetic agents (e.g., epinephrine, albuterol, by continuousby continuous subcutaneous subcutaneous infusion by infusion an external by an insulin external pump. insulin Do notpump. use Do diluted not use diluted lowering medications,lowering medications, patients taking patients medications taking medications sensitive to sensitive serum to potassium serum potassium terbutaline),terbutaline), somatropin, somatropin, atypical antipsychotics, atypical antipsychotics, glucagon, proteaseglucagon, inhibitors, protease andinhibitors, or andmixed insulinsor mixed in insulinsexternal ininsulin external pumps. insulin Infusion pumps. sites Infusion should sites be rotatedshould bewithin rotated the within the concentrations).concentrations). Insulin initiationInsulin and initiation intensi cation and intensi cation of glucose controlof glucose control thyroid hormones.thyroid hormones. same region to reduce the risk of lipodystrophy [see Adverse Reactions]. Change the t same region to reduce the risk of lipodystrophy [see Adverse Reactions]. Change the Renal or Hepatic Impairment—Frequent glucose monitoring and insulin dose reductionIntensi cation Intensi cation or rapid improvement or rapid improvement in glucose incontrol glucose has control been associatedhas been associatedwith a with a tDrugs ThatDrugs May That Increase May or Increase Reduce or the Reduce Blood-Glucose-Lowering the Blood-Glucose-Lowering Effect of EffectHUMALOG of inHUMALOG the reservoir in the at reservoir least every at least7 days, every change 7 days, the changeinfusion the sets infusion and the sets infusion and the infusion Renal or Hepatic Impairment—Frequent glucose monitoring and insulin dose reduction HUMALOG: beta-blockers, clonidine, lithium salts, and alcohol. Pentamidine may may be requiredmay be in requiredpatients within patients renal orwith hepatic renal impairment.or hepatic impairment. transitory, reversibletransitory, ophthalmologic reversible ophthalmologic refraction disorder, refraction worsening disorder, ofworsening diabetic retinopathy,of diabetic retinopathy, HUMALOG: beta-blockers, clonidine, lithium salts, and alcohol. Pentamidine may set insertionset site insertion at least site every at least3 days. every 3 days. cause hypoglycemia,cause hypoglycemia, which may whichsometimes may sometimesbe followed be by followed hyperglycemia. by hyperglycemia. The initial programming of the external insulin infusion pump should be based on the Mixing of Insulins—HUMALOG for subcutaneous injection should not be mixedand with acute painfuland acute peripheral painful neuropathy.peripheral neuropathy. However, long-term However, glycemiclong-term control glycemic decreases control decreases t The initial programming of the external insulin infusion pump should be based on the Mixing of Insulins—HUMALOG for subcutaneous injection should not be mixed with tDrugs ThatDrugs May ThatReduce May the Reduce Signs theof Hypoglycemia: Signs of Hypoglycemia: beta-blockers, beta-blockers, clonidine, clonidine, total daily insulin dose of the previous regimen. Although there is signicant variability insulin preparations other than NPH insulin. If HUMALOG is mixed with NPH insulin,the risk of diabeticthe risk retinopathyof diabetic retinopathy and neuropathy. and neuropathy. total daily insulin dose of the previous regimen. Although there is signicant variability insulin preparations other than NPH insulin. If HUMALOG is mixed with NPH insulin, guanethidine, guanethidine, and reserpine. and reserpine. among patients, approximately 50% of the total dose is usually given as meal-related HUMALOG shouldHUMALOG be drawn should into be drawnthe syringe into the rst. syringe Injection rst. should Injection occur should immediately occur immediately after after Lipodystrophy among patients, approximately 50% of the total dose is usually given as meal-related Lipodystrophy USE IN SPECIFIC POPULATIONS boluses of HUMALOG and the remainder is given as a basal infusion. HUMALOG is mixing. mixing. USE IN SPECIFIC POPULATIONS boluses of HUMALOG and the remainder is given as a basal infusion. HUMALOG is Long-term Long-termuse of insulin, use includingof insulin, HUMALOG, including HUMALOG,can cause lipodystrophycan cause lipodystrophy at the site ofat the site of recommended for use in pump systems suitable for insulin infusion such as MiniMed, Do not mixDo HUMALOG not mix HUMALOG with other with insulins other for insulins use in for an use external in an subcutaneous external subcutaneous Pregnancy—Pregnancy—Pregnancy Pregnancy Category B. Category All pregnancies B. All pregnancies have a background have a background risk of birth risk ofrecommended birth for use in pump systems suitable for insulin infusion such as MiniMed, repeated insulinrepeated injections insulin or injections infusion. orLipodystrophy infusion. Lipodystrophy includes lipohypertrophy includes lipohypertrophy (thickening (thickening Disetronic, and other equivalent pumps. infusion pump.infusion pump. defects, loss,defects, or other loss, adverse or other outcome adverse regardless outcome ofregardless drug exposure. of drug This exposure. background This background risk Disetronic, risk and other equivalent pumps. of adipose of tissue) adipose and tissue) lipoatrophy and lipoatrophy (thinning of (thinning adipose of tissue), adipose and tissue), may affect and may insulin affect insulin is increased in pregnancies complicated by hyperglycemia and may be decreased with SubcutaneousSubcutaneous Insulin Infusion Insulin Pumps— InfusionWhen Pumps— usedWhen in an used external in an insulin external pump insulin for pump for is increased in pregnancies complicated by hyperglycemia and may be decreased with HOW SUPPLIED/STORAGEHOW SUPPLIED/STORAGE AND HANDLING AND HANDLING absorption. absorption.Rotate insulin Rotate injection insulin or injection infusion orsites infusion within sites the samewithin region the same to reduce region the to reduce the good metabolicgood control.metabolic It is control. essential It is for essential patients for with patients diabetes with or diabetes history ofor gestational history of gestational subcutaneoussubcutaneous infusion, HUMALOG infusion, shouldHUMALOG not shouldbe diluted not orbe mixeddiluted with or mixed any other with insulin. any other insulin. How Supplied risk of lipodystrophyrisk of lipodystrophy [see Dosage [see and Dosage Administration]. and Administration]. diabetes to diabetesmaintain to good maintain metabolic good control metabolic before control conception before conceptionand throughout and throughoutpregnancy. pregnancy.How Supplied Change theChange HUMALOG the inHUMALOG the reservoir in the at reservoir least every at least7 days, every change 7 days, the change infusion the sets infusion and sets and HUMALOG 100HUMALOG units per 100 mL units (U-100) per mL is available(U-100) is as: available as: the infusion set insertion site at least every 3 days. HUMALOG should not be exposedWeight to gainWeight gain In patients In with patients diabetes with or diabetes gestational or gestational diabetes insulin diabetes requirements insulin requirements may decrease may decrease the infusion set insertion site at least every 3 days. HUMALOG should not be exposed to during the rst trimester, generally increase during the second and third trimesters, and 10 mL vials NDC 0002-7510-01 (VL-7510) temperaturestemperatures greater than greater 98.6°F than (37°C). 98.6°F (37°C). Weight gainWeight can occur gain can with occur insulin with therapy, insulin including therapy, HUMALOG, including HUMALOG, and has been and has been during the rst trimester, generally increase during the second and third trimesters, and 10 mL vials NDC 0002-7510-01 (VL-7510) Malfunction of the insulin pump or infusion set or insulin degradation can rapidly rapidly declinerapidly after decline delivery. after Careful delivery. monitoring Careful monitoringof glucose ofcontrol glucose is essentialcontrol is in essential these in3 these mL vials 3 mL vials NDC 0002-7510-17NDC 0002-7510-17 (VL-7533) (VL-7533) Malfunction of the insulin pump or infusion set or insulin degradation can rapidly attributed toattributed the anabolic to the effects anabolic of insulin effects and of insulinthe decrease and the in decrease glucosuria. in glucosuria. 1 lead to hyperglycemia and ketosis. Prompt identi cation and correction of the cause of patients. Therefore,patients. femaleTherefore, patients female should patients be advised should beto telladvised their tophysicians tell their ifphysicians they intend if they 5intend x 3 mL cartridges5 x 3 mL1 cartridges NDC 0002-7516-59NDC 0002-7516-59 (VL-7516) (VL-7516) lead to hyperglycemia and ketosis. Prompt identi cation and correction of the cause of Peripheral EdemaPeripheral Edema to become, or if they become pregnant while taking HUMALOG. hyperglycemiahyperglycemia or ketosis isor necessary.ketosis is necessary.Interim subcutaneous Interim subcutaneous injections withinjections HUMALOG with HUMALOG to become, or if they become pregnant while taking HUMALOG. 5 x 3 mL prelled5 x 3 mL pen prelled pen NDC 0002-8725-59NDC 0002-8725-59 (HP-8725) (HP-8725) Insulin, includingInsulin, HUMALOG, including HUMALOG,may cause maysodium cause retention sodium and retention edema, and particularly edema, particularly if if Although there are limited clinical studies of the use of HUMALOG in pregnancy, may be required.may be Patients required. using Patients continuous using continuoussubcutaneous subcutaneous insulin infusion insulin pump infusion therapy pump therapy Although there are limited clinical studies of the use of HUMALOG in pregnancy, 5 x 3 mL Humalog5 x 3 mL KwikPen Humalog (prelled) KwikPen (prelled) NDC 0002-8799-59 NDC 0002-8799-59 (HP-8799) (HP-8799) previously poor metabolic control is improved by intensi ed insulin therapy. published studies with human insulins suggest that optimizing overall glycemic control, must be trainedmust be to trainedadminister to administer insulin by insulininjection by and injection have alternateand have insulin alternate therapy insulin therapypreviously poor metabolic control is improved by intensi ed insulin therapy. published studies with human insulins suggest that optimizing overall glycemic control, including postprandial control, before conception and during pregnancy improvesStorage fetal Storage available inavailable case of in pump case failure of pump [see failure Dosage [see and Dosage Administration and Administration and How Supplied/ and How Supplied/Adverse ReactionsAdverse with Reactions Continuous with Continuous Subcutaneous Subcutaneous Insulin Infusion Insulin (CSII) Infusion (CSII) including postprandial control, before conception and during pregnancy improves fetal outcome. Do not use Doafter not the use expiration after the date.expiration date. Storage andStorage Handling] and. Handling]. In a 12-week,In a randomized, 12-week, randomized, crossover study crossover in adult study patients in adult with patients type 1 with diabetes type 1 diabetes outcome. In a combined fertility and embryo-fetal development study, female rats were givenUnopened HUMALOGUnopened shouldHUMALOG be storedshould in be a storedrefrigerator in a refrigerator (36° to 46°F (36° [2° to to 46°F 8°C]), [2° but to 8°C]), but (n=39), the rates of catheter occlusions and infusion site reactions were similar for In a combined fertility and embryo-fetal development study, female rats were given Drug Interactions—Drug Interactions—Some medicationsSome medications may alter insulinmay alter requirements insulin requirements and the risk and for the risk(n=39), for the rates of catheter occlusions and infusion site reactions were similar for subcutaneoussubcutaneous insulin lispro insulin injections lispro of injections 5 and 20 ofunits/kg/day 5 and 20 units/kg/day (0.8 and 3 times (0.8 and the 3human times the humannot in the freezer.not in the Do freezer.not use Do HUMALOG not use HUMALOGif it has been if it frozen.has been In-use frozen. HUMALOG In-use HUMALOGvials, vials, hypoglycemiahypoglycemia or hyperglycemia or hyperglycemia [see Drug Interactions] [see Drug Interactions]. . HUMALOG andHUMALOG regular and human regular insulin human treated insulin patients treated (see patients Table 3).(see Table 3). subcutaneoussubcutaneous dose of 1 unit/kg/day, dose of 1 unit/kg/day, based on units/body based on surfaceunits/body area, surface respectively) area, respectively) from cartridges, from cartridges, pens, and pens, HUMALOG and HUMALOG KwikPen® KwikPen should be® should stored be at roomstored temperature, at room temperature,

01_08 Cover_Sept2012_v3.indd 7 8/10/12 11:42 AM 54300_elhmlp_HI76205_ap_ja_updt_fa.indd 4 6/25/12 4:14 PM 54300_elhmlp_HI76205_ap_ja_updt_fa.indd 5 6/25/12 4:14 PM 01_08 Cover_Sept2012_v3.indd 8 8/13/12 1:58 PM SEPTEMBER 2012 Vol. 37 No. 9 contents NEWS & INSIGHTS FOR THE ENDOCRINE COMMUNITY WWW.ENDO-SOCIETY. O RG

Features Departments COVER STORY pg. 22 Sex Ed for Seniors 10 ...... Viewpoint 22By Melissa Mapes It is becoming less and less surpris- 11 ...... Editor’s Page ing that 60-somethings and beyond are sexually active, but boomers can still learn a few things about safe 12 ...... Trends & Insights sex. 36 ...... Practice Resources Diabetes and Kids 40 ...... Spotlight on Policy 32 By Eric Seaborg As the rate of type 2 diabetes among American youth increases, doctors 44 ...... Trainee Corner weigh the effectiveness of various treatments. 49 ...... Research Briefs

Downsizing Supersizes 50 ...... Society Update 36 By Kelly Horvath Food portions have doubled (even 51 ...... Classiﬁeds quintupled) in the last 40 years. Experts, including one famous mayor, 54 ...... Back Story are on a mission to trim them to healthy amounts.

Military Medicine 54 By Marian Smith Holmes An historic museum dedicated to the pg. 32 study of medical care for Civil War soldiers still has relevance today—if you can get past the “ick” factor. Need Tips on How to Lose Weight? Read the Hormone Health Network’s fact sheet on Proven Weight Loss Methods (pages 37,38)

Scan this QR code with your smartphone/mobile pg. 36 device for Endocrine News Online. ENDOCRINE NEWS • SEPTEMBER 2012 9

09 TOC Sept2012.indd 9 8/10/12 11:43 AM VIEWPOINT

to create a successful career in endocrine research for as many as 50 young basic research and clinical trainees. The workshop will offer joint sessions that cover general Support For Young Professionals and translational topics and breakout sessions on topics of specific interest to each track. Session topics will Dear Colleagues: include practical guidance for pursuing NIH funding, how to establish an effective mentor relationship, balancing The Endocrine Society continues career and family life, and more. In addition, fellows will its strong commitment to preparing receive guidance from Society experts who are on hand future endocrine leaders by creating to provide constructive feedback on the fellows’ research career development programming projects. More details of this workshop are presented in that has substantial impact on the Trainees and Students section of the Society’s Web young professionals pursuing ca- site (www.endo-society.org/awards/eiw). William F. Young, Jr. reers in endocrinology. The Society M.D., M.Sc. has a trainee membership of nearly Career Advancement 3,000 and provides a strong portfolio of programs aimed The Society continues to offer the Mentor Exchange, at supporting trainees’ work at the cutting edge of re- an online portal for endocrinologists of all experience search and practice. The portfolio of career development levels to mentor students, fellows in training, and other programming has been enhanced by including curricula members. Society mentors offer a variety of perspectives to address critical issues for junior faculty and mid-career on the diverse opportunities an endocrinology career professionals. affords. More than 110 members have volunteered to be mentors and are available to connect with early-career Programming for Early- and Mid-Career professionals. Details on becoming a mentor or finding a Professionals at ENDO 2012 mentor are on the Mentor Exchange section of the Soci- ENDO 2012, held in Houston, was highlighted by dy- ety’s Web site at www.endo-society.org/mentor. You may namic programming for young professionals in our field. also find great tips and career advice on the revamped The 6th Annual Endocrine Trainee Day Workshop, co-spon- EndoCareers® Web site at www.endocareers.org. Finally, sored by Women in Endocrinology, hosted more than 230 the new EndoGrants CentralTM is a database of funding trainees who attended interactive sessions in clinical and opportunities of particular interest to the endocrine com- basic science tracks. These sessions were hosted by pre- munity. Members may search for grants or post opportu- eminent leaders in the field and began a series of activi- nities at www.endo-society.org/awards/EndoGrants/. ties specifically designed to meet the needs of trainees. In the coming months, the Society will begin the The very popular Career Development Workshops 2013 awards season with calls for applications for the featured new sessions this year, including the half-day numerous Society awards and travel grants for trainees workshop, “How to Secure Promotion and Tenure for Ju- and early-career professionals. I encourage all those who nior Faculty and Mid-Career Professionals,” and the “Writ- are eligible to apply. ing a Successful R01 and Other Independent Research As you can see, many exciting opportunities exist Grant Applications: Tips for the Mid-Career Professional” within The Endocrine Society to promote the develop- evening session. ment of early-career professionals while building a com- Trainee posters were identified for special consideration munity where young endocrinologists will thrive. in the Presidential Poster Competition. Many trainees met Most importantly, your opinions and ideas are essential in with old friends and made new connections at the Trainee helping us create quality programming, and I invite you to Reception and used the Trainee Career Center to continue submit any comments or suggestions to me c/o president@ networking with leaders and one another. A new network- endo-society.org. ■ ing event added this year included the Mentor Connection Breakfast, where volunteer mentors who participate in the Sincerely, Society’s Mentor Exchange were available to meet one-on- one with early career professionals seeking advice and mentorship. 2012 Early Investigators Workshop The Early Investigators Workshop will be held on William F. Young, Jr., M.D. September 28–29, 2012, in San Francisco. This event President, The Endocrine Society

ENDOCRINE NEWS • SEPTEMBER 2012 will provide an intensive introduction on what it takes 10

10 Viewpoint Sept2012.indd 10 8/10/12 11:44 AM FROM THE EDITOR

Endocrine News® is a registered trademark owned by The Endocrine Society. William F. Young, Jr., M.D. Dear Readers, sity and type 2 diabetes are linked, President prevention through exercise and diet is [email protected] The people who brought us the sex- a highly favored strategy. Healthy eat- Teresa K. Woodruff, Ph.D. President-Elect ual revolution of the 1960s are now ing, however, is a daunting challenge, [email protected] senior citizens. Many are still going as our story on portion sizes attests. Janet E. Hall, M.D. strong—enjoying careers, traveling, Writer Kelly Horvath reports that some Past President playing sports, and, yes, having sex. servings are ﬁve times larger than they [email protected] Although no longer concerned about were in 1970. Health advocates offer John C. Marshall, M.D., Ph.D. Secretary-Treasurer unwanted pregnancies, this population tips for portion control (page 36). [email protected] often needs a refresher course in sex War brings casualties. The National Scott Hunt education to deal with today’s sexual is- Museum of Health and Medicine, a re- Executive Director & CEO sues, Melissa Mapes writes in our cover pository of military medical history [email protected] story. Like the sex and aging seminars near Washington, D.C., is a reminder Eleanore Tapscott Senior Director of Publications cropping up across the country, her of the extraordinary efforts medical [email protected] story offers a frank discussion of sex personnel make to save lives and care Doug Byrnes among seniors (page 22). for the wounded. The museum’s history Director of Publications We used to call type 2 diabetes and ongoing service, the focus of our [email protected] “adult onset,” but the increasing in- Back Story this month, are well worth Marian Smith Holmes Managing Editor cidence among American youth has exploring (page 54). ■ [email protected] widened the scope of the chronic condi- Jacqueline Ruttimann, Ph.D. tion and raised awareness of an evolv- Sincerely, Associate Editor ing health problem. How best to treat [email protected] children with the diseases is a matter Marian Smith Holmes Cynthia Richardson Product/Production Manager of debate and research, free-lancer Eric Managing Editor [email protected] Seaborg writes (page 32). Because obe- Endocrine News touch three Magazine Design & Production www.touch3.com Cenveo Publisher Services Printing & Prepress ENDOCRINE NEWS ONLINE EXCLUSIVES www.cenveo.com The following articles are housed online only. See Endocrine News Online to read them and ﬁnd related links (www.endo-society.org/endo_news).

news ® Social Network for Diabetes ® A new trial shows that young teens with Type 1 diabetes may Endocrine News is published 12 times a year by The Endocrine Society, 8401 Connecticut Ave., beneﬁt from Internet programs. Suite 900, Chevy Chase, MD 20815 Phone 301-941-0200 • Fax 301-941-0259 www.endo-society.org. Print ISSN 2157-2089 Online ISSN 2157-2097 Copyright © 2011 by The Endocrine Society. All rights reserved. • For reprints, please contact Caffeine and Pregnancy [email protected]. The commonly consumed stimulant in coffee, chocolate, and • Please send letters to the editor, comments, and suggestions for Endocrine News® to other foods may inhibit a successful pregnancy, research suggests. [email protected]. Advertising • For product print and product online display advertising, by Pharmaceutical Media, Inc., please contact Joe Schuldner, [email protected], or Joann Mitchell, [email protected]. No Weigh! • For classified advertising, print and online, contact Christine Whorton at A new study ﬁnds that Americans typically underestimate the [email protected] or 800-361-3906.

number of pounds they’ve gained. The statements and opinions expressed in Endocrine News® are those of individual authors and do not necessarily reﬂect the views of The Endocrine Society. Advertising appearing in this publication does not ® constitute endorsement of its content by Endocrine News ENDOCRINE NEWS • SEPTEMBER 2012 or The Endocrine Society. 11

11 Editor Sept2012.indd 11 8/10/12 11:45 AM News, Notes, & Insights www.endo-society.org

Boxers or Briefs and 12 months were recruited men with previous testicu- Other Male Fertility through United King- lar surgery, possibly due Factors dom fertility clinics and to similar factors found assessed for job histories, in undescended testicles ➤ Boxers or briefs? A lifestyle, and health fac- that reduce fertility. Men light-hearted question tors. Those with medical doing manual work also often asked of celebrities conditions or treatments had low MSC, and this can and politicians may known to cause infertil- be explained, in part, by be a critical deci- ity were excluded. Those exposure to toxicants. Stu- sion in regards to chosen to participate were dents and the unemployed a man’s fertility. interviewed about cloth- are at a similarly high risk Research from ing choices, recreational with little explanation as the Universities drug use, and fertility to why. of Manchester and history. MSC was not lowered, Sheffield in England, re- Wearing boxers was however, by smoking, al- cently published in Human associated with higher cohol, or recreational drug Reproduction [humrep. motile sperm concentra- use, the study concluded. oxfordjournals.org], shows tion (MSC). Previous stud- Although direct changes to boxers are better for fertil- ies have suggested that sperm were either insignif- ity, but surprisingly, sev- tight underwear such as icant or undetected in this eral other lifestyle choices briefs may elevate the study, these habits may af- seem to have little effect temperature of the tes- fect fertility through other on sperm motility. ticles and slow down pro- means. ■ Men unsuccessfully duction of sperm. Dan Kelly attempting conception for Low (MSC) occurred in

Quality of Life of Pediatric Cancer Patients Better than Expected in adult patients has been linked to improved QOL. In this study, no dif- ➤ It’s hard to hear of a child with a since diagnosis or therapeutic factors ference was found between the QOL rare disease but surely harder to live altered anxiety levels and QOL be- scores of adolescents who received as one. Quality of life (QOL) can suf- yond norms in the control group or rhTSH and those managed with use fer from even the stress of diagnosis healthy population. of withdrawal L-T4. and treatment. Pediatric differenti- Assessed through 3 question- Following up through an endocri- ated thyroid cancer (DTC) spreads to naires, 16 DTC patients aged 10–18 nology clinic instead of an oncology the cervical lymph nodes in 40–90 years measured QOL scores and anxi- clinic might inﬂuence these scores, percent of patients and metasta- ety levels similar to 16 adolescents as might discussions of “excellent sizes distantly in 20–30 percent. with autoimmune hypothyroidism prognosis.” However, QOL in other Despite the aggressiveness of this receiving L-thyroxine (L-T4) therapy. long-term pediatric cancer survivors rare disease, QOL has gone mostly L-T4 has been found to increase anx- improves from diagnosis to levels unstudied. iety during administration with only similar to those in the healthy popu- Researchers at the Hospital for a slight decrease during withdrawal. lation. Compared to healthy siblings, Sick Children in Toronto predicted None of the 16 DTC patients were long-term pediatric cancer survivors pediatric DTC patients to have low experiencing withdrawal at the time have scored lower only on assessment QOL and high anxiety. Their study, of the study, and their free T4 levels of physical well-being. It may well lead by Asaf Oren and to be pub- did not correlate to their scores. be the ability of children to adapt lished in The Journal of Clinical Recombinant human thyroid easily and accentuate the positive Endocrinology & Metabolism [jcem. stimulating hormone (rhTSH) and that gives adolescent cancer patients endojournals.org], found the op- L-T4 withdrawal are typically used a better self-perceived QOL. ■

ENDOCRINE NEWS • SEPTEMBER 2012 posite. Neither age, length of time in follow-up of DTC and use of rhTSH Dan Kelly 12

12_21 Trends Sept2012.indd 12 8/10/12 11:46 AM Number of β-Cells Set by Age 5 terward, the rate of β-cell prolifera- tion dropped to about 0.5 percent. ➤ Type-2 diabetes is sometimes munoﬂuorescence examinations on In the article, the researchers linked to a patient’s low level of pancreatic tissue samples from 40 conclude that baseline β-cell popu- pancreatic β-cells, which control human cadavers between the ages lation and its link with other islet insulin. A new study investigates of 23 weeks premature and 72 years. cell types are established in humans why some patients have lower None of the subjects had a personal before 5 years of age. They write pancreatic β-cells than others and or family history of diabetes and that genetic factors and the mater- whether the differences are ge- none were obese. Cell counts and nal intrauterine environment could netic or environmental. A team of islet size were done on at least 25 inﬂuence the degree of human pan- scientists led by Brigid Gregg, M.D., sample images from each subject’s creatic islet formation and the size of Kovler Diabetes Center, University pancreatic section. of baseline β-cell mass. If this is of Chicago, explored whether there The study, published in The small, they report, then a likelihood is a baseline number of β-cells in Journal of Clinical Endocrinology of developing diabetes can be set humans. They also analyzed if this & Metabolism [jcem.endojournals. very early on in life. ■ number is established by birth or if org], found that the highest rate Glenda Fauntleroy it can change later in life. of β-cell creation occurred preterm The researchers performed im- and up to about 2 years of age. Af-

Exercise Increases how exercise would affect sRAGE, Benefits the levels of sRAGE and its Diabetes Patients impact on cardiometabolic risk factors. ➤ Scientists have In their study soon to known for some time be published in The Jour- that advanced glycation nal of Clinical Endocrinol- end products (AGEs) and ogy & Metabolism [jcem. their receptor (RAGE) play endojournals.org], 75 Asian an important role in the women with T2DM were development of atheroscle- randomized either into a rosis in patients with type control or aerobic exer- 2 diabetes. New research cise groups. The patients’ now reveals that low levels average age was 54.4 of the soluble form of years, average body mass RAGE (sRAGE)—a critical index 26.8, and all had a risk factor for cardiovas- sedentary lifestyle. While cular disease—may be the control group contin- improved with exercise. ued their normal routines, Exercise helps protect the exercise group was against atherosclerosis by instructed to walk at a reducing or preventing oxi- moderate pace for an hour in aerobic capacity and factor. These decreases dative stress and systemic five days per week for 12 decreased body weight, were not found in the inflammation, symptoms weeks. Exercise sessions waist size, blood pressure, control group. exacerbated by AGEs. A were monitored every two cholesterol levels, glucose The researchers show team of Korean research- weeks by a multi-record levels, and visceral fat that sRAGE is a potential ers, led by Kyung Mook accelerometer. area. The exercise group mechanism underlying the Choi, M.D., Ph.D., from the After 12 weeks, the ex- also had increases in benefits of exercise in type Division of Endocrinology ercisers showed significant sRAGE levels and decreases 2 diabetes patients. ■ and Metabolism in the Col- improvements in many in high sensitive C-reac- Glenda Fauntleroy lege of Medicine at Korea cardiometabolic risk fac- tive protein levels, another

University, Seoul, explored tors, including an increase cardiovascular disease risk Continued on page 18 ENDOCRINE NEWS • SEPTEMBER 2012 13

12_21 Trends Sept2012.indd 13 8/10/12 11:46 AM BYETTA added to titrated insulin glargine achieved a signiﬁ cantly greater A1C reduction vs titrated insulin glargine alone

Patients with type 2 diabetes on insulin glargine alone or in combination with oral Mean change in A1C at 30 weeks agents (metformin, thiazolidinedione, or both) were enrolled in a 30-week, randomized, double-blind, placebo-controlled clinical study to receive either BYETTA (5 mcg BID for 0 (BL = 8.3) (BL = 8.5) 4 weeks then 10 mcg BID) or placebo in addition to titrated insulin glargine. In both (n = 137) (n = 122) arms, under investigator guidance, insulin was titrated to achieve a targeted fasting -0.4 glucose level of <100 mg/dL using the Treat-to-Target algorithm. -1.0% -0.8 H BYETTA did not increase the risk of hypoglycemia over that Start a smart seen with insulin glargine alone and provided the potential -1. 2 benefit of weight loss (on average, 4.0 lb over 30 weeks).* -1.7% Consider reducing the dose of insulin glargine in patients at partnership -1.6 increased risk for hypoglycemia. LS mean change in A1C (%) -2.0 * BYETTA is not indicated for the management of obesity, and weight change was a secondary endpoint. For patients not at goal BYETTA plus titrated insulin glargine (n = 137) P < .01 vs titrated insulin glargine alone. on insulin glargine, adding Titrated insulin glargine alone (n = 122) ITT population. BYETTA® can deliver a Abbreviations: LS, least squares; BL, baseline; ITT, intent to treat. complementary approach Warnings and precautions (cont‘d) Drug interactions H No clinical studies establishing conclusive evidence of macrovascular H BYETTA slows gastric emptying and can reduce the extent and to glycemic control risk reduction with BYETTA or any other antidiabetic drug. rate of absorption of orally administered drugs. Use with caution with medications that have a narrow therapeutic index or Adverse reactions require rapid gastrointestinal absorption. Medications dependent on threshold concentrations for efficacy should be taken at least H Most common adverse reactions in registration trials associated with BYETTA vs placebo (PBO): nausea (44% vs 18%), 1 hour before BYETTA. vomiting (13% vs 4%), and diarrhea (13% vs 6%). Other H Postmarketing reports of increased international normalized ratio adverse reactions ≥5% and more than PBO: feeling jittery, (INR) sometimes associated with bleeding with concomitant use dizziness, headache, and dyspepsia. With a thiazolidinedione of warfarin. Monitor INR frequently until stable upon initiation or (TZD), adverse reactions were similar; as monotherapy, most alteration of BYETTA. common was nausea (8% vs 0%). With insulin glargine: nausea Indication and usage discontinued promptly. BYETTA should not be restarted (41% vs 8%), vomiting (18% vs 4%), diarrhea (18% vs 8%), Use in specific populations if pancreatitis is confirmed. headache (14% vs 4%), constipation (10% vs 2%), dyspepsia H Based on animal data, BYETTA may cause fetal harm and should BYETTA is indicated as an adjunct to diet and exercise to H Increased risk of hypoglycemia when used in combination with (7% vs 2%), asthenia (5% vs 1%). be used during pregnancy only if the potential benefit justifies the improve glycemic control in adults with type 2 diabetes mellitus. glucose-independent insulin secretagogues (eg, sulfonylureas); H Hypoglycemia incidence, BYETTA vs PBO, with metformin potential risk to the fetus. H Not a substitute for insulin and should not be used in reduction of the sulfonylurea dose may be needed. When used (MET): 5.3% (10 mcg) and 4.5% (5 mcg) vs 5.3%; with SFU, H Caution should be exercised when administered to a nursing woman. patients with type 1 diabetes or diabetic ketoacidosis. with insulin, evaluate and consider reducing the insulin dose in 35.7% (10 mcg) and 14.4% (5 mcg) vs 3.3%; with MET + SFU, H Safety and effectiveness have not been established in pediatric patients. H Concurrent use with prandial insulin cannot be patients at increased risk of hypoglycemia. 27.8% (10 mcg) and 19.2% (5 mcg) vs 12.6%; with TZD, 10.7% recommended. H (10 mcg) vs 7.1%; as monotherapy, 3.8% (10 mcg) and 5.2% Postmarketing reports of altered renal function, including To learn more, visit www.ByettaHCP.com. H Has not been studied in patients with a history of pancreatitis. increased serum creatinine, renal impairment, worsened (5 mcg) vs 1.3%; with insulin glargine, 24.8% (10 mcg) vs 29.5%. It is unknown whether patients with a history of pancreatitis H Withdrawals: as monotherapy, 2 of 155 BYETTA patients chronic renal failure, and acute renal failure, sometimes For additional safety profile and other important are at increased risk for pancreatitis while using BYETTA; requiring hemodialysis and kidney transplantation. BYETTA withdrew due to headache and nausea vs 0 PBO; with MET and/ consider other antidiabetic therapies for these patients. should not be used in patients with severe renal impairment or SFU vs PBO, nausea (3% vs <1%) and vomiting (1% vs 0); prescribing considerations, please see the adjacent pages or end-stage renal disease. Use with caution in patients with with TZD ± MET, nausea (9%) and vomiting (5%), with <1% of for Brief Summary of Prescribing Information. Important Safety Information renal transplantation or when initiating or escalating the PBO patients withdrawing due to nausea; with insulin glargine vs PBO, nausea (5.1% vs 0), vomiting (2.9% vs 0). Contraindications dose in patients with moderate renal failure. H Not recommended in patients with severe gastrointestinal H BYETTA is contraindicated in patients with prior severe disease (eg, gastroparesis). hypersensitivity reactions to exenatide or to any of the H Patients may develop antibodies to exenatide. In 3 TA® H product components. ET AS registration trials, antibody levels were measured in 90% BY A Warnings and precautions of patients, with up to 4% of patients having high-titer antibodies and attenuated glycemic response. If worsening Over 6 years on the market H Based on postmarketing data BYETTA has been † of or failure to achieve adequate glycemic control occurs, Over 1 million patients associated with acute pancreatitis, including fatal and Over 8.5 years of clinical experience non-fatal hemorrhagic or necrotizing pancreatitis. After consider alternative antidiabetic therapy. P H initiation and dose increases of BYETTA, observe patients Postmarketing reports of serious hypersensitivity reactions RO RY carefully for pancreatitis (persistent severe abdominal (eg, anaphylaxis and angioedema). If this occurs, patients should VEN HISTO pain, sometimes radiating to the back, with or without discontinue BYETTA and other suspect medications and 02-11-12444-B ©2012 AMYLIN PHARMACEUTICALS, INC. PRINTED IN USA. ALL RIGHTS RESERVED. † vomiting). If pancreatitis is suspected, BYETTA should be promptly seek medical advice. The BYETTA mark and BYETTA design mark are registered trademarks of Amylin Pharmaceuticals, Inc. SDI data, December 2009.

PALIO Date: 4.3.12 • Client: Amylin • Product: Byetta • File Name: 20658_pambyg_launch_jrnl_Endocrine_News.indd PALIO Date: 4.3.12 • Client: Amylin • Product: Byetta • File Name: 20658_pambyg_launch_jrnl_Endocrine_News.indd Ad Page 1 Trim: 8.125” x 10.875” • Bleed: 8.375” x 11.125” • Live: 7.875” x 10.625” Endocrine News Ad12_21 Page Trends Sept2012.indd 2 Trim: 8.125” 15 x 10.875” • Bleed: 8.375” x 11.125” • Live: 7.875” x 10.625” Endocrine8/10/12 News 11:46 AM BYETTA® (exenatide) injection Macrovascular Outcomes In the 24-week trial of BYETTA used as monotherapy, 40 patients (28%) had low titer USE IN SPECIFIC POPULATIONS There have been no clinical studies establishing conclusive evidence of macrovascular antibodies to exenatide at 24 weeks. The level of glycemic control in these patients was Brief Summary: For complete details, please see full Prescribing Information. Pregnancy risk reduction with BYETTA or any other antidiabetic drug. generally comparable to that observed in the 101 patients (70%) without antibody titers. Pregnancy Category C An additional 3 patients (2%) had higher titer antibodies at 24 weeks. Of these patients, 1 INDICATIONS AND USAGE ADVERSE REACTIONS There are no adequate and well-controlled studies of BYETTA use in pregnant women. In (1% overall) had an attenuated glycemic response to BYETTA; the remaining 2 (1% overall) had animal studies, exenatide caused cleft palate, irregular skeletal ossification and an increased Type 2 Diabetes Mellitus Clinical Trial Experience a glycemic response comparable to that of patients without antibodies. number of neonatal deaths. BYETTA should be used during pregnancy only if the potential BYETTA is indicated as an adjunct to diet and exercise to improve glycemic control in Because clinical trials are conducted under widely varying conditions, adverse reaction Antibodies to exenatide were not assessed in the 30-week trial of BYETTA used in benefit justifies the potential risk to the fetus. adults with type 2 diabetes mellitus. rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical combination with insulin glargine. Female mice given SC doses of 6, 68, or 760 mcg/kg/day beginning 2 weeks prior to Important Limitations of Use trials of another drug and may not reflect the rates observed in practice. Two hundred and ten patients with antibodies to exenatide in the BYETTA clinical trials and throughout mating until gestation day 7 had no adverse fetal effects. At the maximal dose, were tested for the presence of cross-reactive antibodies to GLP-1 and/or glucagon. No BYETTA is not a substitute for insulin. BYETTA should not be used for the treatment of Hypoglycemia 760 mcg/kg/day, systemic exposures were up to 390 times the human exposure resulting from type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings. treatment-emergent cross reactive antibodies were observed across the range of titers. the maximum recommended dose of 20 mcg/day, based on AUC. Table 1: Incidence (%) and Rate of Hypoglycemia When BYETTA was Used as Monotherapy Other Adverse Reactions The concurrent use of BYETTA with prandial insulin has not been studied and cannot be or With Concomitant Antidiabetic Therapy in Six Placebo-Controlled Clinical Trials* In developmental toxicity studies, pregnant animals received exenatide subcutaneously recommended. Monotherapy during organogenesis. Specifically, fetuses from pregnant rabbits given SC doses of 0.2, 2, 22, 156, or Based on postmarketing data BYETTA has been associated with acute pancreatitis, BYETTA Adverse reactions (excluding hypoglycemia) for the 24-week placebo-controlled study of 260 mcg/kg/day from gestation day 6 through 18 experienced irregular skeletal ossifications including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. BYETTA has not been BYETTA BID (N = 155) when used as a monotherapy, with an incidence ≥2% and occurring more from exposures 12 times the human exposure resulting from the maximum recommended Placebo 5 mcg 10 mcg frequently in BYETTA-treated patients versus placebo BID-treated patients (N = 77): nausea studied in patients with a history of pancreatitis. It is unknown whether patients with a history twice daily twice daily twice daily dose of 20 mcg/day, based on AUC. Moreover, fetuses from pregnant mice given SC doses of of pancreatitis are at increased risk for pancreatitis while using BYETTA. Other antidiabetic (8% vs 0%), vomiting (4% vs 0%), and dyspepsia (3% vs 0%). 6, 68, 460, or 760 mcg/kg/day from gestation day 6 through 15 demonstrated reduced fetal Monotherapy (24 Weeks) therapies should be considered in patients with a history of pancreatitis. Adverse reactions reported in ≥1.0 to <2.0% of patients receiving BYETTA and reported and neonatal growth, cleft palate and skeletal effects at systemic exposure 3 times the human N 77 77 78 more frequently than with placebo included decreased appetite, diarrhea, and dizziness. The exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. most frequently reported adverse reaction associated with BYETTA, nausea, occurred in a DOSAGE AND ADMINISTRATION % Overall 1.3% 5.2% 3.8% Lactating mice given SC doses of 6, 68, or 760 mcg/kg/day from gestation day 6 through dose-dependent fashion. lactation day 20 (weaning), experienced an increased number of neonatal deaths. Deaths were Recommended Dosing Rate 0.03 0.21 0.52 Two of the 155 patients treated with BYETTA withdrew due to adverse reactions of observed on postpartum days 2-4 in dams given 6 mcg/kg/day, a systemic exposure 3 times Inject subcutaneously within 60 minutes prior to morning and evening meals (or before (episodes/patient-year) headache and nausea. No placebo-treated patients withdrew due to adverse reactions. the two main meals of the day, approximately 6 hours or more apart). Initiate at 5 mcg per dose the human exposure resulting from the maximum recommended dose of 20 mcg/day, based % Severe 0.0% 0.0% 0.0% Combination Therapy on AUC. twice daily; increase to 10 mcg twice daily after 1 month based on clinical response. Do not Add-on to metformin and/or sulfonylurea mix with insulin. Do not transfer BYETTA from the pen to a syringe or vial. With Metformin (30 Weeks) Adverse reactions (excluding hypoglycemia) in the three 30-week controlled trials Pregnancy Registry N 113 110 113 of BYETTA BID (N = 963) add-on to metformin and/or sulfonylurea, with an incidence ≥2% Amylin Pharmaceuticals, Inc. maintains a Pregnancy Registry to monitor pregnancy CONTRAINDICATIONS outcomes of women exposed to exenatide during pregnancy. Physicians are encouraged to % Overall 5.3% 4.5% 5.3% and occurring more frequently in BYETTA-treated patients versus placebo-treated patients Hypersensitivity (N = 483): nausea (44% vs 18%), vomiting (13% vs 4%), diarrhea (13% vs 6%), feeling jittery register patients by calling 1-800-633-9081. BYETTA is contraindicated in patients with prior severe hypersensitivity reactions to Rate 0.12 0.13 0.12 (9% vs 4%), dizziness (9% vs 6%), headache (9% vs 6%), dyspepsia (6% vs 3%), asthenia (episodes/patient-year) Nursing Mothers exenatide or to any of the product components. (4% vs 2%), gastroesophageal reflux disease (3% vs 1%), and hyperhydrosis (3% vs 1%). It is not known whether exenatide is excreted in human milk. However, exenatide is % Severe 0.0% 0.0% 0.0% Adverse reactions reported in ≥1.0 to <2.0% of patients receiving BYETTA and WARNINGS AND PRECAUTIONS present at low concentrations (less than or equal to 2.5% of the concentration in maternal With a Sulfonylurea (30 Weeks) reported more frequently than with placebo included decreased appetite. Nausea was the plasma following subcutaneous dosing) in the milk of lactating mice. Many drugs are excreted Acute Pancreatitis most frequently reported adverse reaction and occurred in a dose-dependent fashion. With N 123 125 129 in human milk and because of the potential for clinically significant adverse reactions in Based on postmarketing data BYETTA has been associated with acute pancreatitis, continued therapy, the frequency and severity decreased over time in most of the patients nursing infants from exenatide, a decision should be made whether to discontinue nursing or including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. After initiation of % Overall 3.3% 14.4% 35.7% who initially experienced nausea. Patients in the long-term uncontrolled open-label extension discontinue the drug, taking into account these potential risks against the glycemic benefits to BYETTA, and after dose increases, observe patients carefully for signs and symptoms Rate 0.07 0.64 1.61 studies at 52 weeks reported no new types of adverse reactions than those observed in the the lactating woman. Caution should be exercised when BYETTA is administered to a nursing of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the (episodes/patient-year) 30-week controlled trials. woman. back, which may or may not be accompanied by vomiting). If pancreatitis is suspected, The most common adverse reactions leading to withdrawal for BYETTA-treated patients BYETTA should promptly be discontinued and appropriate management should be % Severe 0.0% 0.0% 0.0% were nausea (3% of patients) and vomiting (1%). For placebo-treated patients, <1% withdrew Pediatric Use initiated. If pancreatitis is confirmed, BYETTA should not be restarted. Consider With Metformin and a Sulfonylurea (30 Weeks) due to nausea and none due to vomiting. Safety and effectiveness of BYETTA have not been established in pediatric patients. antidiabetic therapies other than BYETTA in patients with a history of pancreatitis. N 247 245 241 Add-on to thiazolidinedione with or without metformin Geriatric Use Adverse reactions (excluding hypoglycemia) for the 16-week placebo-controlled Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age Use with Medications Known to Cause Hypoglycemia % Overall 12.6% 19.2% 27.8% The risk of hypoglycemia is increased when BYETTA is used in combination with a study of BYETTA BID (N = 121) add-on to a thiazolidinedione, with or without metformin, suggests that age does not influence the pharmacokinetic properties of exenatide. BYETTA sulfonylurea. Therefore, patients receiving BYETTA and a sulfonylurea may require a lower Rate 0.58 0.78 1.71 with an incidence ≥2% and occurring more frequently in BYETTA-treated patients versus was studied in 282 patients 65 years of age or older and in 16 patients 75 years of age or older. dose of the sulfonylurea to reduce the risk of hypoglycemia. (episodes/patient-year) placebo-treated patients (N = 112): nausea (40% vs 15%), vomiting (13% vs 1%), dyspepsia No differences in safety or effectiveness were observed between these patients and younger When BYETTA is used in combination with insulin, the dose of insulin should be % Severe 0.0% 0.4% 0.0% (7% vs 1%), diarrhea (6% vs 3%), and gastroesophageal refiux disease (3% vs 0%). patients. Because elderly patients are more likely to have decreased renal function, care should Adverse reactions reported in ≥1.0 to <2.0% of patients receiving BYETTA and reported more be taken in dose selection in the elderly based on renal function. evaluated. In patients at increased risk of hypoglycemia consider reducing the dose of With a Thiazolidinedione (16 Weeks) insulin. The concurrent use of BYETTA with prandial insulin has not been studied and cannot frequently than with placebo included decreased appetite. Chills (n = 4) and injection-site reactions N 112 not evaluated 121 (n = 2) occurred only in BYETTA-treated patients. The two patients who reported an injection-site OVERDOSAGE be recommended. It is also possible that the use of BYETTA with other glucose-independent In a clinical study of BYETTA, three patients with type 2 diabetes each experienced a single insulin secretagogues (e.g. meglitinides) could increase the risk of hypoglycemia. % Overall 7.1% not evaluated 10.7% reaction had high titers of antibodies to exenatide. Two serious adverse events (chest pain and chronic hypersensitivity pneumonitis) were reported in the BYETTA arm. No serious adverse overdose of 100 mcg SC (10 times the maximum recommended dose). Effects of the overdoses Rate 0.56 not evaluated 0.98 Renal Impairment events were reported in the placebo arm. included severe nausea, severe vomiting, and rapidly declining blood glucose concentrations. (episodes/patient-years) BYETTA should not be used in patients with severe renal impairment (creatinine clearance The most common adverse reactions leading to withdrawal for BYETTA-treated patients One of the three patients experienced severe hypoglycemia requiring parenteral glucose < 30 mL/min) or end-stage renal disease and should be used with caution in patients with % Severe 0.0% not evaluated 0.0% were nausea (9%) and vomiting (5%). For placebo-treated patients, <1% withdrew due to administration. The three patients recovered without complication. In the event of overdose, renal transplantation. In patients with end-stage renal disease receiving dialysis, single doses appropriate supportive treatment should be initiated according to the patient’s clinical signs With Insulin Glargine (30 Weeks) † nausea. of BYETTA 5 mcg were not well-tolerated due to gastrointestinal side effects. Because BYETTA Add-on to insulin glargine with or without metformin and/or thiazolidinedione and symptoms. may induce nausea and vomiting with transient hypovolemia, treatment may worsen renal N 122 not evaluated 137 Adverse reactions (excluding hypoglycemia) for the 30-week placebo-controlled study Manufactured for Amylin Pharmaceuticals, Inc., San Diego, CA 92121 function. Caution should be applied when initiating or escalating doses of BYETTA from 5 mcg % Overall 29.5% not evaluated 24.8% of BYETTA BID (N = 137) as add-on to insulin glargine with or without oral antihyperglycemic to 10 mcg in patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min). Rate 1.58 not evaluated 1.61 medications with an incidence ≥2% and occurring more frequently in BYETTA-treated This product and its use are covered by US Patent Nos. 5,424,286, 6,858,576, 6,872,700, There have been postmarketing reports of altered renal function, including increased (episodes/patient-years) patients versus placebo-treated patients (N = 122): nausea (41% vs 8%), vomiting (18% vs 6,902,744, 6,956,026, 7,297,761, 7,521,423, 7,741,269, and other patents pending. serum creatinine, renal impairment, worsened chronic renal failure and acute renal failure, 4%), diarrhea (18% vs 8%), headache (14% vs 4%), constipation (10% vs 2%), dyspepsia % Severe 0.8% not evaluated 0.0% 1-800-868-1190 sometimes requiring hemodialysis or kidney transplantation. Some of these events occurred in (7% vs 2%), asthenia (5% vs 1%), abdominal distension (4% vs 1%), decreased appetite patients receiving one or more pharmacologic agents known to affect renal function or hydration * A hypoglycemic episode was recorded if a patient reported symptoms of hypoglycemia with (3% vs 0%), flatulence (2% vs 1%), gastroesophageal reflux disease (2% vs 1%). http://www.BYETTA.com status, such as angiotensin converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, or without a blood glucose value consistent with hypoglycemia. Severe hypoglycemia was The most frequently reported adverse reactions leading to withdrawal for BYETTA-treated Literature Revised December 2011 or diuretics. Some events occurred in patients who had been experiencing nausea, vomiting, or defined as an event with symptoms consistent with hypoglycemia requiring the assistance of patients were nausea (5.1%) and vomiting (2.9%). No placebo-treated patients withdrew due diarrhea, with or without dehydration. Reversibility of altered renal function has been observed another person and associated with either a blood glucose value consistent with hypoglycemia to nausea or vomiting. in many cases with supportive treatment and discontinuation of potentially causative agents, or prompt recovery after treatment for hypoglycemia. Post-Marketing Experience including BYETTA. Exenatide has not been found to be directly nephrotoxic in preclinical or † When BYETTA was initiated in combination with insulin glargine, the dose of insulin glargine The following additional adverse reactions have been reported during post-approval use clinical studies. was decreased by 20% in patients with an HbA ≤ 8.0 % to minimize the risk of hypoglycemia. 1c of BYETTA. Because these events are reported voluntarily from a population of uncertain size, See Table 9 for insulin dose titration algorithm. Gastrointestinal Disease it is generally not possible to reliably estimate their frequency or establish a causal relationship N = The number of Intent-to-Treat subjects in each treatment group. BYETTA has not been studied in patients with severe gastrointestinal disease, including to drug exposure. gastroparesis. Because BYETTA is commonly associated with gastrointestinal adverse Immunogenicity Allergy/Hypersensitivity: injection-site reactions, generalized pruritus and/or urticaria, reactions, including nausea, vomiting, and diarrhea, the use of BYETTA is not recommended in Antibodies were assessed in 90% of subjects in the 30-week, 24-week and 16-week macular or papular rash, angioedema, anaphylactic reaction. patients with severe gastrointestinal disease. studies of BYETTA. In the 30-week controlled trials of BYETTA add-on to metformin and/or Drug Interactions: International normalized ratio (INR) increased with concomitant Immunogenicity sulfonylurea, antibodies were assessed at 2- to 6-week intervals. The mean antibody titer warfarin use sometimes associated with bleeding. Patients may develop antibodies to exenatide following treatment with BYETTA. Antibody peaked at week 6 and was reduced by 55% by week 30. Three hundred and sixty patients Gastrointestinal: nausea, vomiting, and/or diarrhea resulting in dehydration; abdominal levels were measured in 90% of subjects in the 30-week, 24-week and 16-week studies of (38%) had low titer antibodies (<625) to exenatide at 30 weeks. The level of glycemic control distension, abdominal pain, eructation, constipation, flatulence, acute pancreatitis, hemorrhagic BYETTA. In 3%, 4% and 1% of these patients, respectively, antibody formation was associated (HbA1c) in these patients was generally comparable to that observed in the 534 patients (56%) and necrotizing pancreatitis sometimes resulting in death. with an attenuated glycemic response. If there is worsening glycemic control or failure to without antibody titers. An additional 59 patients (6%) had higher titer antibodies (≥625) at Neurologic: dysgeusia; somnolence achieve targeted glycemic control, alternative antidiabetic therapy should be considered. 30 weeks. Of these patients, 32 (3% overall) had an attenuated glycemic response to BYETTA; Renal and Urinary Disorders: altered renal function, including increased serum creatinine, the remaining 27 (3% overall) had a glycemic response comparable to that of patients without renal impairment, worsened chronic renal failure or acute renal failure (sometimes requiring Hypersensitivity antibodies. hemodialysis), kidney transplant and kidney transplant dysfunction. There have been postmarketing reports of serious hypersensitivity reactions In the 16-week trial of BYETTA add-on to thiazolidinediones, with or without metformin, Skin and Subcutaneous Tissue Disorders: alopecia (e.g. anaphylaxis and angioedema) in patients treated with BYETTA. If a hypersensitivity 36 patients (31%) had low titer antibodies to exenatide at 16 weeks. The level of glycemic reaction occurs, the patient should discontinue BYETTA and other suspect medications and control in these patients was generally comparable to that observed in the 69 patients (60%) promptly seek medical advice. without antibody titer. An additional 10 patients (9%) had higher titer antibodies at 16 weeks. BYETTA is a registered trademark of Amylin Pharmaceuticals, Inc. Of these patients, 4 (4% overall) had an attenuated glycemic response to BYETTA; the remaining © 2005, 2011 Amylin Pharmaceuticals, Inc. All rights reserved. 822017-AA 6 (5% overall) had a glycemic response comparable to that of patients without antibodies. 02-09-9300-E

12_21 Trends Sept2012.inddPALIO 16 Date: 4.3.12 • Client: Amylin • Product: Byetta • File Name: 20658_pambyg_launch_jrnl_Endocrine_News.indd 8/10/12 11:46 AM PALIO Date: 4.3.12 • Client: Amylin • Product: Byetta • File Name: 20658_pambyg_launch_jrnl_Endocrine_News.indd BS Page 1 Trim: 8.125” x 10.875” • Bleed: 8.375” x 11.125” • Live: 7.875” x 10.625” Endocrine News BS Page 2 Trim: 8.125” x 10.875” • Bleed: 8.375” x 11.125” • Live: 7.875” x 10.625” Endocrine News BYETTA® (exenatide) injection Macrovascular Outcomes In the 24-week trial of BYETTA used as monotherapy, 40 patients (28%) had low titer USE IN SPECIFIC POPULATIONS There have been no clinical studies establishing conclusive evidence of macrovascular antibodies to exenatide at 24 weeks. The level of glycemic control in these patients was Brief Summary: For complete details, please see full Prescribing Information. Pregnancy risk reduction with BYETTA or any other antidiabetic drug. generally comparable to that observed in the 101 patients (70%) without antibody titers. Pregnancy Category C An additional 3 patients (2%) had higher titer antibodies at 24 weeks. Of these patients, 1 INDICATIONS AND USAGE ADVERSE REACTIONS There are no adequate and well-controlled studies of BYETTA use in pregnant women. In (1% overall) had an attenuated glycemic response to BYETTA; the remaining 2 (1% overall) had animal studies, exenatide caused cleft palate, irregular skeletal ossification and an increased Type 2 Diabetes Mellitus Clinical Trial Experience a glycemic response comparable to that of patients without antibodies. number of neonatal deaths. BYETTA should be used during pregnancy only if the potential BYETTA is indicated as an adjunct to diet and exercise to improve glycemic control in Because clinical trials are conducted under widely varying conditions, adverse reaction Antibodies to exenatide were not assessed in the 30-week trial of BYETTA used in benefit justifies the potential risk to the fetus. adults with type 2 diabetes mellitus. rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical combination with insulin glargine. Female mice given SC doses of 6, 68, or 760 mcg/kg/day beginning 2 weeks prior to Important Limitations of Use trials of another drug and may not reflect the rates observed in practice. Two hundred and ten patients with antibodies to exenatide in the BYETTA clinical trials and throughout mating until gestation day 7 had no adverse fetal effects. At the maximal dose, were tested for the presence of cross-reactive antibodies to GLP-1 and/or glucagon. No BYETTA is not a substitute for insulin. BYETTA should not be used for the treatment of Hypoglycemia 760 mcg/kg/day, systemic exposures were up to 390 times the human exposure resulting from type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings. treatment-emergent cross reactive antibodies were observed across the range of titers. the maximum recommended dose of 20 mcg/day, based on AUC. Table 1: Incidence (%) and Rate of Hypoglycemia When BYETTA was Used as Monotherapy Other Adverse Reactions The concurrent use of BYETTA with prandial insulin has not been studied and cannot be or With Concomitant Antidiabetic Therapy in Six Placebo-Controlled Clinical Trials* In developmental toxicity studies, pregnant animals received exenatide subcutaneously recommended. Monotherapy during organogenesis. Specifically, fetuses from pregnant rabbits given SC doses of 0.2, 2, 22, 156, or Based on postmarketing data BYETTA has been associated with acute pancreatitis, BYETTA Adverse reactions (excluding hypoglycemia) for the 24-week placebo-controlled study of 260 mcg/kg/day from gestation day 6 through 18 experienced irregular skeletal ossifications including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. BYETTA has not been BYETTA BID (N = 155) when used as a monotherapy, with an incidence ≥2% and occurring more from exposures 12 times the human exposure resulting from the maximum recommended Placebo 5 mcg 10 mcg frequently in BYETTA-treated patients versus placebo BID-treated patients (N = 77): nausea studied in patients with a history of pancreatitis. It is unknown whether patients with a history twice daily twice daily twice daily dose of 20 mcg/day, based on AUC. Moreover, fetuses from pregnant mice given SC doses of of pancreatitis are at increased risk for pancreatitis while using BYETTA. Other antidiabetic (8% vs 0%), vomiting (4% vs 0%), and dyspepsia (3% vs 0%). 6, 68, 460, or 760 mcg/kg/day from gestation day 6 through 15 demonstrated reduced fetal Monotherapy (24 Weeks) therapies should be considered in patients with a history of pancreatitis. Adverse reactions reported in ≥1.0 to <2.0% of patients receiving BYETTA and reported and neonatal growth, cleft palate and skeletal effects at systemic exposure 3 times the human N 77 77 78 more frequently than with placebo included decreased appetite, diarrhea, and dizziness. The exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. most frequently reported adverse reaction associated with BYETTA, nausea, occurred in a DOSAGE AND ADMINISTRATION % Overall 1.3% 5.2% 3.8% Lactating mice given SC doses of 6, 68, or 760 mcg/kg/day from gestation day 6 through dose-dependent fashion. lactation day 20 (weaning), experienced an increased number of neonatal deaths. Deaths were Recommended Dosing Rate 0.03 0.21 0.52 Two of the 155 patients treated with BYETTA withdrew due to adverse reactions of observed on postpartum days 2-4 in dams given 6 mcg/kg/day, a systemic exposure 3 times Inject subcutaneously within 60 minutes prior to morning and evening meals (or before (episodes/patient-year) headache and nausea. No placebo-treated patients withdrew due to adverse reactions. the two main meals of the day, approximately 6 hours or more apart). Initiate at 5 mcg per dose the human exposure resulting from the maximum recommended dose of 20 mcg/day, based % Severe 0.0% 0.0% 0.0% Combination Therapy on AUC. twice daily; increase to 10 mcg twice daily after 1 month based on clinical response. Do not Add-on to metformin and/or sulfonylurea mix with insulin. Do not transfer BYETTA from the pen to a syringe or vial. With Metformin (30 Weeks) Adverse reactions (excluding hypoglycemia) in the three 30-week controlled trials Pregnancy Registry N 113 110 113 of BYETTA BID (N = 963) add-on to metformin and/or sulfonylurea, with an incidence ≥2% Amylin Pharmaceuticals, Inc. maintains a Pregnancy Registry to monitor pregnancy CONTRAINDICATIONS outcomes of women exposed to exenatide during pregnancy. Physicians are encouraged to % Overall 5.3% 4.5% 5.3% and occurring more frequently in BYETTA-treated patients versus placebo-treated patients Hypersensitivity (N = 483): nausea (44% vs 18%), vomiting (13% vs 4%), diarrhea (13% vs 6%), feeling jittery register patients by calling 1-800-633-9081. BYETTA is contraindicated in patients with prior severe hypersensitivity reactions to Rate 0.12 0.13 0.12 (9% vs 4%), dizziness (9% vs 6%), headache (9% vs 6%), dyspepsia (6% vs 3%), asthenia (episodes/patient-year) Nursing Mothers exenatide or to any of the product components. (4% vs 2%), gastroesophageal reflux disease (3% vs 1%), and hyperhydrosis (3% vs 1%). It is not known whether exenatide is excreted in human milk. However, exenatide is % Severe 0.0% 0.0% 0.0% Adverse reactions reported in ≥1.0 to <2.0% of patients receiving BYETTA and WARNINGS AND PRECAUTIONS present at low concentrations (less than or equal to 2.5% of the concentration in maternal With a Sulfonylurea (30 Weeks) reported more frequently than with placebo included decreased appetite. Nausea was the plasma following subcutaneous dosing) in the milk of lactating mice. Many drugs are excreted Acute Pancreatitis most frequently reported adverse reaction and occurred in a dose-dependent fashion. With N 123 125 129 in human milk and because of the potential for clinically significant adverse reactions in Based on postmarketing data BYETTA has been associated with acute pancreatitis, continued therapy, the frequency and severity decreased over time in most of the patients nursing infants from exenatide, a decision should be made whether to discontinue nursing or including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. After initiation of % Overall 3.3% 14.4% 35.7% who initially experienced nausea. Patients in the long-term uncontrolled open-label extension discontinue the drug, taking into account these potential risks against the glycemic benefits to BYETTA, and after dose increases, observe patients carefully for signs and symptoms Rate 0.07 0.64 1.61 studies at 52 weeks reported no new types of adverse reactions than those observed in the the lactating woman. Caution should be exercised when BYETTA is administered to a nursing of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the (episodes/patient-year) 30-week controlled trials. woman. back, which may or may not be accompanied by vomiting). If pancreatitis is suspected, The most common adverse reactions leading to withdrawal for BYETTA-treated patients BYETTA should promptly be discontinued and appropriate management should be % Severe 0.0% 0.0% 0.0% were nausea (3% of patients) and vomiting (1%). For placebo-treated patients, <1% withdrew Pediatric Use initiated. If pancreatitis is confirmed, BYETTA should not be restarted. Consider With Metformin and a Sulfonylurea (30 Weeks) due to nausea and none due to vomiting. Safety and effectiveness of BYETTA have not been established in pediatric patients. antidiabetic therapies other than BYETTA in patients with a history of pancreatitis. N 247 245 241 Add-on to thiazolidinedione with or without metformin Geriatric Use Adverse reactions (excluding hypoglycemia) for the 16-week placebo-controlled Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age Use with Medications Known to Cause Hypoglycemia % Overall 12.6% 19.2% 27.8% The risk of hypoglycemia is increased when BYETTA is used in combination with a study of BYETTA BID (N = 121) add-on to a thiazolidinedione, with or without metformin, suggests that age does not influence the pharmacokinetic properties of exenatide. BYETTA sulfonylurea. Therefore, patients receiving BYETTA and a sulfonylurea may require a lower Rate 0.58 0.78 1.71 with an incidence ≥2% and occurring more frequently in BYETTA-treated patients versus was studied in 282 patients 65 years of age or older and in 16 patients 75 years of age or older. dose of the sulfonylurea to reduce the risk of hypoglycemia. (episodes/patient-year) placebo-treated patients (N = 112): nausea (40% vs 15%), vomiting (13% vs 1%), dyspepsia No differences in safety or effectiveness were observed between these patients and younger When BYETTA is used in combination with insulin, the dose of insulin should be % Severe 0.0% 0.4% 0.0% (7% vs 1%), diarrhea (6% vs 3%), and gastroesophageal refiux disease (3% vs 0%). patients. Because elderly patients are more likely to have decreased renal function, care should Adverse reactions reported in ≥1.0 to <2.0% of patients receiving BYETTA and reported more be taken in dose selection in the elderly based on renal function. evaluated. In patients at increased risk of hypoglycemia consider reducing the dose of With a Thiazolidinedione (16 Weeks) insulin. The concurrent use of BYETTA with prandial insulin has not been studied and cannot frequently than with placebo included decreased appetite. Chills (n = 4) and injection-site reactions N 112 not evaluated 121 (n = 2) occurred only in BYETTA-treated patients. The two patients who reported an injection-site OVERDOSAGE be recommended. It is also possible that the use of BYETTA with other glucose-independent In a clinical study of BYETTA, three patients with type 2 diabetes each experienced a single insulin secretagogues (e.g. meglitinides) could increase the risk of hypoglycemia. % Overall 7.1% not evaluated 10.7% reaction had high titers of antibodies to exenatide. Two serious adverse events (chest pain and chronic hypersensitivity pneumonitis) were reported in the BYETTA arm. No serious adverse overdose of 100 mcg SC (10 times the maximum recommended dose). Effects of the overdoses Rate 0.56 not evaluated 0.98 Renal Impairment events were reported in the placebo arm. included severe nausea, severe vomiting, and rapidly declining blood glucose concentrations. (episodes/patient-years) BYETTA should not be used in patients with severe renal impairment (creatinine clearance The most common adverse reactions leading to withdrawal for BYETTA-treated patients One of the three patients experienced severe hypoglycemia requiring parenteral glucose < 30 mL/min) or end-stage renal disease and should be used with caution in patients with % Severe 0.0% not evaluated 0.0% were nausea (9%) and vomiting (5%). For placebo-treated patients, <1% withdrew due to administration. The three patients recovered without complication. In the event of overdose, renal transplantation. In patients with end-stage renal disease receiving dialysis, single doses appropriate supportive treatment should be initiated according to the patient’s clinical signs With Insulin Glargine (30 Weeks) † nausea. of BYETTA 5 mcg were not well-tolerated due to gastrointestinal side effects. Because BYETTA Add-on to insulin glargine with or without metformin and/or thiazolidinedione and symptoms. may induce nausea and vomiting with transient hypovolemia, treatment may worsen renal N 122 not evaluated 137 Adverse reactions (excluding hypoglycemia) for the 30-week placebo-controlled study Manufactured for Amylin Pharmaceuticals, Inc., San Diego, CA 92121 function. Caution should be applied when initiating or escalating doses of BYETTA from 5 mcg % Overall 29.5% not evaluated 24.8% of BYETTA BID (N = 137) as add-on to insulin glargine with or without oral antihyperglycemic to 10 mcg in patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min). Rate 1.58 not evaluated 1.61 medications with an incidence ≥2% and occurring more frequently in BYETTA-treated This product and its use are covered by US Patent Nos. 5,424,286, 6,858,576, 6,872,700, There have been postmarketing reports of altered renal function, including increased (episodes/patient-years) patients versus placebo-treated patients (N = 122): nausea (41% vs 8%), vomiting (18% vs 6,902,744, 6,956,026, 7,297,761, 7,521,423, 7,741,269, and other patents pending. serum creatinine, renal impairment, worsened chronic renal failure and acute renal failure, 4%), diarrhea (18% vs 8%), headache (14% vs 4%), constipation (10% vs 2%), dyspepsia % Severe 0.8% not evaluated 0.0% 1-800-868-1190 sometimes requiring hemodialysis or kidney transplantation. Some of these events occurred in (7% vs 2%), asthenia (5% vs 1%), abdominal distension (4% vs 1%), decreased appetite patients receiving one or more pharmacologic agents known to affect renal function or hydration * A hypoglycemic episode was recorded if a patient reported symptoms of hypoglycemia with (3% vs 0%), flatulence (2% vs 1%), gastroesophageal reflux disease (2% vs 1%). http://www.BYETTA.com status, such as angiotensin converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, or without a blood glucose value consistent with hypoglycemia. Severe hypoglycemia was The most frequently reported adverse reactions leading to withdrawal for BYETTA-treated Literature Revised December 2011 or diuretics. Some events occurred in patients who had been experiencing nausea, vomiting, or defined as an event with symptoms consistent with hypoglycemia requiring the assistance of patients were nausea (5.1%) and vomiting (2.9%). No placebo-treated patients withdrew due diarrhea, with or without dehydration. Reversibility of altered renal function has been observed another person and associated with either a blood glucose value consistent with hypoglycemia to nausea or vomiting. in many cases with supportive treatment and discontinuation of potentially causative agents, or prompt recovery after treatment for hypoglycemia. Post-Marketing Experience including BYETTA. Exenatide has not been found to be directly nephrotoxic in preclinical or † When BYETTA was initiated in combination with insulin glargine, the dose of insulin glargine The following additional adverse reactions have been reported during post-approval use clinical studies. was decreased by 20% in patients with an HbA ≤ 8.0 % to minimize the risk of hypoglycemia. 1c of BYETTA. Because these events are reported voluntarily from a population of uncertain size, See Table 9 for insulin dose titration algorithm. Gastrointestinal Disease it is generally not possible to reliably estimate their frequency or establish a causal relationship N = The number of Intent-to-Treat subjects in each treatment group. BYETTA has not been studied in patients with severe gastrointestinal disease, including to drug exposure. gastroparesis. Because BYETTA is commonly associated with gastrointestinal adverse Immunogenicity Allergy/Hypersensitivity: injection-site reactions, generalized pruritus and/or urticaria, reactions, including nausea, vomiting, and diarrhea, the use of BYETTA is not recommended in Antibodies were assessed in 90% of subjects in the 30-week, 24-week and 16-week macular or papular rash, angioedema, anaphylactic reaction. patients with severe gastrointestinal disease. studies of BYETTA. In the 30-week controlled trials of BYETTA add-on to metformin and/or Drug Interactions: International normalized ratio (INR) increased with concomitant Immunogenicity sulfonylurea, antibodies were assessed at 2- to 6-week intervals. The mean antibody titer warfarin use sometimes associated with bleeding. Patients may develop antibodies to exenatide following treatment with BYETTA. Antibody peaked at week 6 and was reduced by 55% by week 30. Three hundred and sixty patients Gastrointestinal: nausea, vomiting, and/or diarrhea resulting in dehydration; abdominal levels were measured in 90% of subjects in the 30-week, 24-week and 16-week studies of (38%) had low titer antibodies (<625) to exenatide at 30 weeks. The level of glycemic control distension, abdominal pain, eructation, constipation, flatulence, acute pancreatitis, hemorrhagic BYETTA. In 3%, 4% and 1% of these patients, respectively, antibody formation was associated (HbA1c) in these patients was generally comparable to that observed in the 534 patients (56%) and necrotizing pancreatitis sometimes resulting in death. with an attenuated glycemic response. If there is worsening glycemic control or failure to without antibody titers. An additional 59 patients (6%) had higher titer antibodies (≥625) at Neurologic: dysgeusia; somnolence achieve targeted glycemic control, alternative antidiabetic therapy should be considered. 30 weeks. Of these patients, 32 (3% overall) had an attenuated glycemic response to BYETTA; Renal and Urinary Disorders: altered renal function, including increased serum creatinine, the remaining 27 (3% overall) had a glycemic response comparable to that of patients without renal impairment, worsened chronic renal failure or acute renal failure (sometimes requiring Hypersensitivity antibodies. hemodialysis), kidney transplant and kidney transplant dysfunction. There have been postmarketing reports of serious hypersensitivity reactions In the 16-week trial of BYETTA add-on to thiazolidinediones, with or without metformin, Skin and Subcutaneous Tissue Disorders: alopecia (e.g. anaphylaxis and angioedema) in patients treated with BYETTA. If a hypersensitivity 36 patients (31%) had low titer antibodies to exenatide at 16 weeks. The level of glycemic reaction occurs, the patient should discontinue BYETTA and other suspect medications and control in these patients was generally comparable to that observed in the 69 patients (60%) promptly seek medical advice. without antibody titer. An additional 10 patients (9%) had higher titer antibodies at 16 weeks. BYETTA is a registered trademark of Amylin Pharmaceuticals, Inc. Of these patients, 4 (4% overall) had an attenuated glycemic response to BYETTA; the remaining © 2005, 2011 Amylin Pharmaceuticals, Inc. All rights reserved. 822017-AA 6 (5% overall) had a glycemic response comparable to that of patients without antibodies. 02-09-9300-E

PALIO Date: 4.3.12 • Client: Amylin • Product: Byetta • File Name: 20658_pambyg_launch_jrnl_Endocrine_News.indd 12_21 Trends Sept2012.inddPALIO 17 Date: 4.3.12 • Client: Amylin • Product: Byetta • File Name: 20658_pambyg_launch_jrnl_Endocrine_News.indd 8/10/12 11:46 AM BS Page 1 Trim: 8.125” x 10.875” • Bleed: 8.375” x 11.125” • Live: 7.875” x 10.625” Endocrine News BS Page 2 Trim: 8.125” x 10.875” • Bleed: 8.375” x 11.125” • Live: 7.875” x 10.625” Endocrine News Continued from page 13

Slug’s Potential for Prostate Cancer Treatment microarrays that examined gene expression in prostate cancer tissues. ➤ Like its namesake, Slug, the Dallas, and Dalin He, M.D., at First In their paper, to be published soon most recently identified member of Afﬁliated Hospital, Medical School of in Molecular Endocrinology [mend. the zinc finger transcription factor Xi’an Jiaotong University, in China, endojournals.org], the researchers family Snail, is sticky—it binds to scientists stained and analyzed report that the Slug–AR reciprocal the androgen receptor (AR) regard- 400 human prostate cancer tissue relationship hyperactivates tran- less of the presence of androgen. specimens, categorized by hormone scriptional activity of AR, which This finding could be useful in pa- therapy status, Gleason score, and contributes to the progression of tients with castration-resistant pros- primary or end-stage status, to show CRPC—that is, the androgen-inde- tate cancer (CRPC), a deadly cancer the concurrent elevation of Slug and pendent form. that contains cells with altered and AR. The study also shows both Slug The researchers conclude that increased AR levels. and AR interacting with each other, due to its key role in CRPC, Slug has Led by Jer-Tsong Hsieh, Ph.D. at thereby forming a complex. Signiﬁ- potential in both prostate cancer UT Southwestern Medical Center at cantly, in the presence of Slug, AR prognosis as a marker and in therapy does not need androgen to become as a drug target. ■

STAT active. Researchers backed up these Kelly Horvath observations with at least two CDNA Limiting daily sitting to < 3 hours increases U.S. life expectancy by 2 years. experiences before in JAMA and after Roux-en- [jama.jama- Source: Katzmarzyk PT, Lee I-M. Sedentary Y gastric bypass network.com], behavior and life expectancy in the USA: A cause- (RYGB) and lapa- the researchers deleted life table analysis. BMJ Open, 2012, roscopic adjustable noted evidence 2:e000828. doi:10.1136/bmjopen-2012-000828. gastric banding that some bariatric (LAGB) surgery. procedures, includ- Participants ing RYGB and sleeve completed pre- gastrectomy, alter the and postoperative pharmacokinetics of assessments on their alcohol. These patients experience with alcohol feel the effects of alcohol use disorders, such as more quickly and reach a Bariatric Surgery alcohol abuse and depen- higher peak alcohol level. Raises Risks of dence. The prevalence of The researchers identi- Alcoholism symptoms did not differ fied several risk factors from the year before sur- that increase the like- ➤ Patients who have gery to the first year af- lihood of alcohol gastric bypass surgery are ter, but was significantly problems: male 30 percent more likely to higher in the second year, sex, younger have problems with alco- going from 7.6 percent age, regular hol, according to a new before surgery, to 7.3 alcohol consump- prospective study. percent the year after, to tion, recreational Spurred by anecdotal 9.6 percent in the second drug use, and less reports linking bariatric year. The increase was interpersonal support. surgery to an increased risk almost entirely among They recommend that al- of alcohol abuse disorders, the RYGB patients, who cohol screening and refer- researchers led by Wendy C. made up 70 percent of the ral be offered to patients King, Ph.D., of the Univer- study group, with virtu- both before and after the sity of Pittsburgh, designed ally no increase in the surgery. ■ a multicenter study to LAGB patients. Eric Seaborg

ENDOCRINE NEWS • SEPTEMBER 2012 compare 1,945 patients’ In an article published 18

12_21 Trends Sept2012.indd 18 8/10/12 11:46 AM Growth Hormone increased adiposity reduces on regular chow. Linked to Healthy GH secretion. These find- In their paper, to Aging ings have led researchers be published soon in to believe that impaired Endocrinology [endo- ➤ If a baby continued GH may contribute to the journals.org], the re- growing at the rate she development of metabolic searchers report increased does the first year of maladies such as obesity. adiposity in high-fat diet life (about 10 inches in Seeking to find out mice, with adipose tissue length), by the time she what happens to GH also found in the liver, turned 60, she would be secretion in young adults and decreased levels of 600 inches or 50 feet tall! with dietary-induced insulin-like growth factor Luckily by 2 years of age, weight gain, Lili Huang, I (IGF-I), which works in a baby’s height growth M.D., Frederick J. Steyn, concert with GH to main- stabilizes at a steady rate Ph.D., and a team of tain healthy aging and of 2.5 inches per year scientists led by Chen phenotype. IGF-I attrition until adolescence. Chen, M.D., Ph.D., at is also characteristic of Growth hormone (GH) the School of Biomedical obesity. parallels this downward Sciences, University of The researchers con- spiral, in that its secre- Queensland in Brisbane, clude that weight gain tion naturally declines Australia, fed wild-type speeds up GH secretion after adolescence at a mice either a standard decline, which may yield rate of 14 percent each or high-fat diet until the gigantic health problems decade. Elderly people and mice reached early adult- throughout the lifespan, patients with adult onset hood (~11 weeks). Blood including increased risk GH deficiency have similar sample analysis revealed for hyperinsulinemia, body compositions with lower serum GH levels obesity, and impaired liver reduced muscle and bone between ages 12 and 16 function. ■ and increased fat. The weeks in the high fat-fed Kelly Horvath converse is also true— mice compared to those

Irregular Menstrual Cycles as Markers for Health Risks centrations of FSH and estradiol with low luteal phase progesterone ➤ Much of a woman’s health cen- hormone (LH) also peaking later. LH are a classic pattern of reproductive ters on her menstrual cycle. Exposure concentrations remained high across aging. to endogenous hormones factors into the cycle, which may actually delay Both short and long cycles were both reproductive development and FSH and rising estradiol production associated with an increased risk of risk of various cancers and diseases. and follicular development. anovulation as compared to regular Menstrual cycles are typically used to Women with short cycles show cycles. These ﬁndings, to be pub- measure these risks rather than the concentrations of FSH higher in early lished in The Journal of Clinical hormones directly, but how hormone follicular and late luteal phases. Endocrinology & Metabolism [jcem. concentrations and cycle length Follicular phase estradiol was also endojournals.org], add strength to interact is largely unknown. higher. Short cycles themselves and using cycle length in measuring Assessing 259 regularly men- short follicular phases speciﬁcally anovulation risk and hormone expo- struating women age 18–44 years, are conjectured to be due to early sure in normally cycling women. researchers at the National Insti- rises in FSH and faster follicular “[It’s] a potentially valuable tool,” tutes of Health and the University development. writes article author Sunni Mumford, at Buffalo found marked differences An early rise of estradiol may Ph.D., “for measuring a woman’s between hormone levels of long mean per-cycle exposure is low, but lifetime exposure to hormones and and short cycles. Follicular phase a greater number of cycles experi- in understanding associations with estradiol had a late rise during enced over a lifetime may increase health outcomes.” ■ longer cycles, with follicle stimulat- exposure to levels above even regular Dan Kelly

ing hormone (FSH) and luteinizing cycles. Early follicular phase con- ENDOCRINE NEWS • SEPTEMBER 2012 19

12_21 Trends Sept2012.indd 19 8/10/12 11:46 AM Vitamin D Dietary advised dietary supple- more effective for increas- In their paper, to be Supplements No Help ments of calcium plus ing calcium absorption. published soon in The in Normal Calcium vitamin D in this popu- Scientists led by Chris Journal of Clinical Endo- Absorption lation. A recent cross- Gallagher, M.D., at the crinology & Metabolism sectional study postulated Creighton University [jcem.endojournals.org], ➤ Calcitriol, the vitamin that there was a threshold Medical Center in Omaha, the researchers report D active metabolite, is of serum 25OHD of 30 ng/ Nebraska, tested where that in this longitudinal known to mediate calcium mL (75 nmol/L) at which this threshold lies by study, the threshold for absorption in the gut. It is point increasing supple- analyzing data from the normal calcium absorp- dependent on an adequate mentary vitamin D became ViDOS (Vitamin D supple- tion occurred at a very substrate of mentation in low level of serum 25OHD, serum 25OHD. Older Subjects) less than 5–10 ng/mL Also well trial, in which (12.5–25 nmol/L) —this documented is 143 postmeno- being the 25OHD level at the age-related pausal women which serum 1,25(OH)2D decline in the were given di- fell—much lower than efficiency of etary supplements previously reported. this mechanism of 200 mg calcium The researchers and a concomi- plus one of seven conclude that vitamin D tant decrease in levels of vitamin supplementation may not endogenous cal- D supplement be useful in older women citriol produc- ranging from unless they have severe vi- tion. Due to the 400–4,800 IU tamin D deﬁciency (< 5–10 high incidence or placebo daily ng/mL). This population of calcium defi- for one year to can achieve the desired ciency–related measure calcium level of calcium absorption disorders such absorption across by drinking an extra 100 as osteoporosis a range of result- ml of milk or with a 100- among older ing serum 25OHD mg calcium supplement, adult women, levels, from 10 they add. ■ health care pro- to 66 ng/mL Kelly Horvath viders have long (25–165 nmol/L).

Building a Better Diabetes Drug obese rhesus monkeys showed similar results in these measures, with ➤ Fibroblast growth factor 21 by Jing Xu, Ph.D. and Murielle M. the Fc-FGF21(RG) having greater (FGF21), a novel hormone involved Véniant, Ph.D., of Amgen, Inc., in effects than the hrFGF21. An in glucose and energy homeostasis, Thousand Oaks, California, fused the important difference: Both species shows promise in treating obesity hormone containing two engineered were treated with the Fc-FGF21(RG) and diabetes. In rodents and pri- mutations with an Fc fragment to only once every five to seven days, mates, it has been shown to normal- generate a molecule they called Fc- compared with daily administration ize blood sugar and lipid levels and FGF21(RG). They then compared the of hrFGF21. decrease weight. The only catch is efficacy of their new creation with In an article awaiting publication its short life. FGF21 stays in the that of hrFGF21 in diet-induced obese in Endocrinology [endo.endojour- body for only one to two hours. To mice and obese rhesus monkeys. nals.org], the researchers note that get the desired effects, researchers The diet-induced obese mice finding in two species that weekly would have to give multiple injec- treated with either compound Fc-FGF21(RG) showed efficacy simi- tions, thus failing to avoid the same showed several metabolic improve- lar to or greater than daily hrFGF21 complication that most insulin users ments: decreased body weight; offers a promising avenue to explore already face. decreased glucose, insulin, choles- for new therapeutic options. ■ In hopes of developing a longer- terol, and triglyceride levels; and Eric Seaborg

ENDOCRINE NEWS • SEPTEMBER 2012 acting alternative, researchers, led improved glucose tolerance. The 20

12_21 Trends Sept2012.indd 20 8/10/12 11:46 AM Fructose Transporter Becomes Latest Obesity Drug Target Preadipocytes that were incubat- ➤ One factor in the increased ergy intake as fructose, they develop ed in fructose had a greater pro- obesity epidemic is the overindul- features of metabolic syndrome such pensity toward differentiation into gence in dietary sugars such as as abdominal obesity, dyslipidemia, full-fledged fat cells than those on high-fructose corn syrup (HFCS). and inflammation. regular cell culture medium. When Researchers are honing in on how To gain greater insight into how these cells were hit with a specific fructose is involved in fat cell forma- fructose promotes fat, Anthony GluT5 inhibitor, differentiation de- tion. Data from the U.S. National Heaney, M.D., and his research group creased. Similarly, GluT5 -/- mice had Health and Nutrition Examination from the University of California, less white adipose tissue compared Survey (NHANES) suggest that about Los Angeles, examined a mouse with wild-type mice and were resis- 15 percent of Americans consume pre-adipocyte cell line, 3T3-L1 and tant to diet-induced obesity. greater than 25 percent of their mice that lacked a glucose/fructose These findings suggest a new tar- energy from added sugars such as transporter, GluT5. Their results are get for weight loss drugs, suggested HFCS. Research in rhesus monkeys discussed in an upcoming issue of the authors. ■ has shown that when these animals Molecular Endocrinology [mend. Jacqueline Ruttimann are fed about 30 percent of their en- endojournals.org].

Gonadotropins Not rates in embryos produced stimulated cycle—tak- mosomal abnormalities. Linked to Higher IVF from natural fertiliza- ing about 10 days of a The researchers con- Failures tion, could be traced to combination dose of 150 clude in their upcoming the use of gonadotropins IU follicle-stimulating article in The Journal ➤ Although it has be- to stimulate the ovaries hormone and 75 IU of of Clinical Endocrinol- come a popular option for during IVF. highly purified human ogy & Metabolism [jcem. women seeking treatment The study took place menopausal gonadotropin. endojournals.org] that the for infertility, the rates in a private infertility The same sperm donor use of moderate doses of of in vitro fertilization clinic over a four-year was used for both cycles. gonadotropins for ovarian (IVF) resulting in a viable period. Researchers In the women who stimulation during an IVF pregnancy still remain low, recruited healthy, fertile completed both cycles, cycle does not significant- mostly due to the high oocyte and sperm donors 34.8 percent of the ly increase the abnormal- numbers of embryos pro- between the ages of 18 embryos showed chro- ity rate in young women duced with chromosomal and 34. An unstimu- mosomal abnormalities with normal ovulation. ■ abnormalities. lated IVF cycle was first in the unstimulated Glenda Fauntleroy Researchers from the conducted on 51 oocyte cycle compared with 40.6 University of Valencia donors, which resulted percent in the stimulated in Spain, led by Elena in 35.3 percent of the cycle. The study found no Labarta, M.D., explored embryos having chro- differences between the whether the high chromo- mosomal abnormalities. unstimulated and stimu- somal abnormality rates, Of those 51 women, 46 lated cycles in embryo as compared with the later completed a second quality and type of chro- ENDOCRINE NEWS • SEPTEMBER 2012 21

12_21 Trends Sept2012.indd 21 8/10/12 11:46 AM COVER STORY ENDOCRINE NEWS • SEPTEMBER 2012 22

22_31 F1_Cover_Sept2012.indd 22 8/10/12 11:49 AM COVER STORY COVER 23 1CvrSp21.nd23 22_31 F1_Cover_Sept2012.indd Sex Seniors S of protection. safely. Unfortunately, seniors are active. Sex 26 percent of 57–64 years, in the participants upto sexual activity in one Centers for much The refresher course: grandparents. indicate thatanimportant demographic isdue for percent of reported skyrocketing rates of faster thaninteens. Younger groups are transmitted diseases(STDs)inseniors is growing adolescents, but important stepfor not elderly maynot begin to after acertainage, of than syphilis and single and A People often assume thatsexual activity ceases they are not are mean they 2009AARPsurvey found years of age of 50years greater overall UnitedStatesfound diminish.The Although sex sation almost asmuch dread ex people 50years canbegood for for reigns king over DiseaseControl and 53percent of those ages men and dating men the chlamydia alone talkmuch years of age. of 90years infamous birds and when sex riskof during the education remains an awkward truthisquitethe Britishstudy, whichincluded engaging init.More years to 75–85years those ages and general health ifpracticed aboutsex, butthatdoes 73percent of alltabootopics. Parents infection,butthe hormones and older thatonly12percent 32percent of Prevention (CDC)has STDsinpeople more astheir children do. have nearly tripled. A decade. past less likelyuse to comparable study years, and 65–74years, reported regular riskof recent studies beesconver- opposite. The

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of bringing inpets for nursing gray area not thathas be allowed into ordenied falls innursing homes concerns for patients basedonthe care workers relationships during the Medical Ethics A from a to to homes living inseniorcommunities ornursing mental and lack opportunitiesfor who being. Elders a is released during and orgasm inmen of The years and older, and patients 50years AIDS diagnoses inthe of their age to sex. One role recent Australian study published inthe petting and us, allnew their peers for sex and discuss sex The Studies show Bene tsofOxytocin seniors included. hormone The insocialbonding and degenerative mental condition like dementia. study also discusses claims thatsome health homes theory isthatolder nancy, doubled in STD rates among Sexually Transmitted Infections indicates that a consistently used protection during sex. As and group. The result, research from the HIVdiagnoses and physical health. It patients. The dating women ininstitutions among prohibited sex cuddling withanimals have beenshown showed work to somecondoms seniors forgo thathuman contact is good for physical contact, even live relatively isolatedlives often assume thatSTDsrarely occurin one decade. one patients. The staff’s personal beliefs staff’s orsafety that patients still pursue sexual hard truthisthat17percent received much UnitedStatesin2009were intimacy, whichcanpromote earlier stages earlier of the touch combatthe those inthisage questionof years of age and older and age of 45years ouroverall populations are according t to By MelissaMapes isnot 23percent of Without of fear therapeutic effects unusual for when sex oxytocin, which attention. Some Britishjournal women, plays such illnesses. sense of ifsuffering group have

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23 /01 11:49 AM 8/10/12 ENDOCRINENEWS • SEPTEMBER 2012 ated with an increased risk of STDs.” Research has not definitely explained why STD rates are increasing among older women, however, even though a higher pH has always been the norm among them, nor can it explain why the rates are increasing in older men. Erectile dysfunction (ED) drugs like Viagra provide one of the connections. A study published in the Annals of Medicine tested the hypothesis that older men using ED drugs were more likely to contract STDs than those who did not request these drugs from their physician. By reviewing thousands of insurance claims, Anupam B. Jena, M.D., Ph.D., an assistant professor of health care policy at Harvard Medical School and a physician at Massachusetts General Hospital, found that men more than 40 years of age using ED drugs were to increase oxytocin levels among older people who may be 2–3 times more likely to contract an STD than other men in deficient in the hormone. the same age group. Although taking ED medications can- Although the benefits of touch and sexual activity are not be said to directly increase a patients’ risk of infection, clearly documented, providing comprehensive information Jena said, “the introduction of these medications allowed to sexually active seniors has its challenges. Society’s youth- them to either have sex or to have sex more frequently, oriented culture often results in a negative portrayal of and by definition having sex more often one would expect physical intimacy among old people, which can make some that STD rates would go up.” of them less forthcoming about sexual problems. Diagnos- ing sexually transmitted diseases and infections in seniors Safe Sex Campaigns can be difficult due to the confusing of aging and disease Longer lives and higher divorce rates have also been pin- symptoms. Patients may chalk up frequent urination and pointed as factors in the spread of STDs among older adults. other mild aches and pains as a natural progression into the With good health lasting longer into life, people are more golden years. By the time an STD is caught and treated, it likely to remain sexually active after retirement. This factor, might have already spread to other sexual partners. combined with an uptick in divorces, many later in life, in- Physical effects of aging also catalyze the spread of creases the likelihood of having a greater number of sexual diseases during sex. Vaginal atrophy, a thinning of vagi- partners over a lifetime. Von Simson explained that the STD nal membranes after menopause and a decline in estro- trend has led to the inclusion of elders in the National Survey gen, puts women at risk for tearing during sex and for of Sexual Health and Behavior, started by Dr. Alfred Kinsey transmission of sexual diseases. “There is an argument in the 1940s. A similar report, “NATSAL [National Survey of that changes to the vaginal Sexual Attitudes and Lifestyles], is mucosa postmenopause may expanding to include older adults, make the tissues more friable but this will only give us a snap- and create microabrasions, shot of now, not of how behaviors which enhance transmis- Society's negative may have changed,” Von Simson sion of sexually transmitted portrayal of physi- said. The lack of historical evi- infections,” said Rachel Von cal intimacy among dence on the sexual behavior of Simson, a final year medical seniors presents a challenge for student at the King’s College old people can researchers seeking the source in London and co-author of a make some of of increasing STD infections. She recent editorial called “Sexual believes that many opportunities Health and the Older Adult” them less forth- remain for research in this field. in the Student BMJ. “Vaginal coming about Because contracting STDs is pH is higher postmenopause, sexual problems. still far more common among and in younger adults a higher young adults, the primary focus

ENDOCRINE NEWS • SEPTEMBER 2012 vaginal pH has been associ- of the medical community has 24 } }

22_31 F1_Cover_Sept2012.indd 24 8/10/12 11:49 AM been on the adolescent cohort. But the changing tides 80 years, especially in those who are married. Healthy levels of sex-related issues in elders has inspired a new wave of of this hormone promote important bodily functions and safe sex campaigns and seminars in several cities, from help keep muscle-to-fat ratios in check. Physical intimacy New York to San Jose. In May 2012, SaferSex4Seniors.org and touch set off a complex chain of hormonal responses released a risqué public service announcement in the form that have been shown to enhance quality of life at any of a YouTube video. The 30-second video shows fully-clothed age. When it comes to sex, a number of studies show that seniors demonstrating various sexual positions in rapid overall health is much more critical that one’s calendar succession. The clip ends with the statistic that STD rates age. From a scientiﬁc point of view it is perfectly ﬁne for among seniors in Florida have risen 71 percent. The tagline seniors to “do it.” encourages seniors to “Do it. Safely.” The conclusive cause of increasing STD rates in older populations many continue to elude researchers for a while. Advising Older Patients The answer may be too complex and multifaceted to pinpoint Experts agree that rising STD rates do not mean seniors cause, but Jena suspects the trend is simply linked to a should be pressed into abstinence. A study presented at The change in social norms. “It’s not like there were massive Endocrine Society’s 94th Annual Meeting, ENDO 2012, in advertising campaigns or things like Facebook that only Houston, Texas, found that testosterone levels remain high applied to older folks,” Jena said. Experts say doctors should in healthy sexually active men between the ages of 35 and be prepared to advise their older patients about how to carry on a healthy sex life even as they age, and to remind them of the basic safety tip they learned years ago in high school: Always use a condom. ■

Mapes is a freelance writer in Washington, D.C.

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22_31 F1_Cover_Sept2012.indd 25 8/10/12 11:49 AM HER FIRST $50/MONTH CO-PAY* OSTEOPOROTIC FRACTURE COULD LEAD NOW IS THE TIME FOR TO ANOTHER ANABOLIC ACTION

INDICATIONS AND USAGE FORTEO CONNECT OFFERS PERSONALIZED SUPPORT TO HELP PATIENTS THROUGHOUT THEIR TREATMENT • FORTEO® (teriparatide [rDNA origin] injection) is indicated for the treatment of postmenopausal women with R T E O [rDNA origi O ® • tide n] i osteoporosis at high risk for fracture, to increase bone mass in men with primary or hypogonadal osteoporosis at high Patients can choose to sign up for an insurance investigation, injection training, F ra nje a ct rip io e n risk for fracture, and for the treatment of men and women with osteoporosis associated with sustained, systemic and/or ongoing support for up to 24 months (t )

t r glucocorticoid therapy (daily dosage equivalent to 5 mg or greater of prednisone) at high risk for fracture o p • Now with the FORTEO Co-pay Card, eligible commercially insured patients p u S Y g ou in r C ngo • High risk for fracture is defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who will pay no more than a $50/month co-pay* onnection to O have failed or are intolerant to other available osteoporosis therapy *This offer may be terminated, rescinded, revoked, or amended by Lilly USA, LLC at any time without notice. Patient should provide the card to his/her pharmacist, along with a valid prescription from the physician. FORTEO is administered as a 20 microgram once daily dose and is available in a 2.4 mL prefilled delivery device for subcutaneous injection over 28 days. FORTEO SELECT SAFETY INFORMATION Prescribe FORTEO only for patients for whom the potential benefits are considered to outweigh the potential WARNING: POTENTIAL RISK OF OSTEOSARCOMA risks. FORTEO should not be prescribed for patients at increased baseline risk for osteosarcoma, including See the Important Safety Information for Complete Boxed Warning. those with Paget’s disease of bone, unexplained elevations of alkaline phosphatase, pediatric and young adult • In rats, teriparatide caused an increase in the incidence of osteosarcoma, a malignant bone tumor. patients with open epiphyses, or prior external beam or implant radiation therapy. Additionally, patients with bone metastases or a history of skeletal malignancies, metabolic bone diseases other than osteoporosis, or pre-existing • Because of the uncertain relevance of the rat osteosarcoma finding to humans, prescribe FORTEO only for patients hypercalcemia should not receive FORTEO. for whom potential benefits outweigh potential risk. Use of FORTEO for more than 2 years during a patient’s lifetime is not recommended. • FORTEO should not be prescribed for patients at increased baseline risk for osteosarcoma (eg, those with Paget’s disease of bone or unexplained elevations of alkaline phosphatase, pediatric and young adult patients with open Please see Important Safety Information, including Boxed Warning regarding osteosarcoma, and Brief epiphyses, or prior external beam or implant radiation therapy involving the skeleton). Summary on following pages. See Full User Manual that accompanies the delivery device.

Find out how FORTEO helps form new bone at www.FORTEOhcp.com

22_31 F1_Cover_Sept2012.indd 26 8/10/12 11:49 AM

Job Number: 15741 152_32560 SS KYMC Revision No: 0 Date: 07/26/12 HER FIRST $50/MONTH CO-PAY* OSTEOPOROTIC FRACTURE COULD LEAD NOW IS THE TIME FOR TO ANOTHER ANABOLIC ACTION

Find out how FORTEO helps form new bone at www.FORTEOhcp.com

22_31 F1_Cover_Sept2012.indd 27 8/10/12 11:49 AM

Job Number: 15741 152_32560 SS KYMC Revision No: 0 Date: 07/26/12 FORTEO® (teriparatide [rDNA origin] 20 mcg for it did not preclude continued treatment. Drug Interactions Hypercalcemia may INDICATIONS AND USAGE predispose patients to digitalis toxicity. Because FORTEO transiently increases injection) serum calcium, patients receiving digoxin should use FORTEO with caution. • FORTEO® (teriparatide [rDNA origin] injection) is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture, to increase bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture, and Brief Summary Consult the package insert for complete ADVERSE REACTIONS for the treatment of men and women with osteoporosis associated with sustained, systemic glucocorticoid therapy (daily dosage prescribing information. Clinical Trials Experience Because clinical studies are conducted under equivalent to 5 mg or greater of prednisone) at high risk for fracture widely varying conditions, adverse reaction rates observed in the clinical studies WARNING: POTENTIAL RISK OF OSTEOSARCOMA of a drug cannot be directly compared to rates in the clinical studies of another • High risk for fracture is defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed In male and female rats, teriparatide caused an increase in the incidence drug and may not reect the rates observed in practice. Treatment of Osteoporosis or are intolerant to other available osteoporosis therapy of osteosarcoma (a malignant bone tumor) that was dependent on dose in Men and Postmenopausal Women The safety of FORTEO in the treatment FORTEO is administered as a 20 microgram once daily dose and is available in a 2.4 mL prefilled delivery device for subcutaneous and treatment duration. The effect was observed at systemic exposures of osteoporosis in men and postmenopausal women was assessed in two injection over 28 days. to teriparatide ranging from 3 to 60 times the exposure in humans randomized, double-blind, placebo controlled trials of 1382 patients (21% men, given a 20-mcg dose. Because of the uncertain relevance of the rat 79% women) aged 28 to 86 years (mean 67 years). The median durations of osteosarcoma nding to humans, prescribe FORTEO® only for patients the trials were 11 months for men and 19 months for women, with 691 patients IMPORTANT SAFETY INFORMATION for whom the potential bene ts are considered to outweigh the potential exposed to FORTEO and 691 patients to placebo. All patients received 1000 mg of risk. FORTEO should not be prescribed for patients who are at increased calcium plus at least 400 IU of vitamin D supplementation per day. The incidence baseline risk for osteosarcoma (including those with Paget’s disease of of all cause mortality was 1% in the FORTEO group and 1% in the placebo group. WARNING: POTENTIAL RISK OF OSTEOSARCOMA bone or unexplained elevations of alkaline phosphatase, pediatric and In male and female rats, teriparatide caused an increase in the incidence of osteosarcoma (a malignant bone tumor) that was dependent on The incidence of serious adverse events was 16% in FORTEO patients and young adult patients with open epiphyses, or prior external beam or 19% in placebo patients. Early discontinuation due to adverse events occurred dose and treatment duration. The effect was observed at systemic exposures to teriparatide ranging from 3 to 60 times the exposure in implant radiation therapy involving the skeleton). humans given a 20-mcg dose. Because of the uncertain relevance of the rat osteosarcoma nding to humans, prescribe FORTEO® (teriparatide in 7% of FORTEO patients and 6% of placebo patients. Percentage of Patients with Adverse Events Reported by at Least 2% of FORTEO-Treated Patients [rDNA origin] injection) only for patients for whom the potential bene ts are considered to outweigh the potential risk. FORTEO should not be INDICATIONS AND USAGE and in More FORTEO-Treated Patients than Placebo-Treated Patients from prescribed for patients who are at increased baseline risk for osteosarcoma (including those with Paget’s disease of bone or unexplained FORTEO is indicated: for the treatment of postmenopausal women with elevations of alkaline phosphatase, pediatric and young adult patients with open epiphyses, or prior external beam or implant radiation osteoporosis at high risk for fracture; to increase bone mass in men with the Two Principal Osteoporosis Trials in Women and Men Adverse Events therapy involving the skeleton). primary or hypogonadal osteoporosis at high risk for fracture; for the treatment are Shown Without Attribution of Causality(FORTEO, N=691, Placebo, of men and women with osteoporosis associated with sustained, systemic N=691): Body as a Whole: Pain (21.3%, 20.5%), Headache (7.5%, 7.4%), Asthenia (8.7%, 6.8%), Neck Pain (3.0%, 2.7%); Cardiovascular: Hypertension CONTRAINDICATIONS glucocorticoid therapy at high risk for fracture. High risk for fracture is de ned Hypersensitivity to teriparatide or to any of its excipients. Reactions have included angioedema and anaphylaxis. as a history of osteoporotic fracture, multiple risk factors for fracture, or patients (7.1%, 6.8%), Angina Pectoris (2.5%, 1.6%), Syncope (2.6%, 1.4%); Digestive who have failed or are intolerant to other available osteoporosis therapy. System: Nausea (8.5%, 6.7%), Constipation (5.4%, 4.5%), Diarrhea (5.1%, 4.6%), WARNINGS AND PRECAUTIONS Dyspepsia (5.2%, 4.1%), Vomiting (3.0%, 2.3%), Gastrointestional disorder The following categories of patients have increased baseline risk of osteosarcoma and therefore should not be treated with FORTEO: Paget’s disease of bone, pediatric populations CONTRAINDICATIONS (2.3%, 2.0%), Tooth disorder (2.0%, 1.3%); Musculoskeletal: Arthralgia and young adults with open epiphyses, or prior external beam or implant radiation therapy. Do not use FORTEO in patients with Hypersensitivity to teriparatide or to any (10.1%, 8.4%), Leg cramps (2.6%, 1.3%); Nervous System: Dizziness Patients should be encouraged to enroll in the voluntary FORTEO Patient Registry, which is designed to collect information about any potential risk of osteosarcoma in patients of its excipients. Reactions have included angioedema and anaphylaxis. (8.0%, 5.4%), Depression (4.1%, 2.7%) Insomnia (4.3%, 3.6%), Vertigo (3.8%, 2.7%); Respiratory System: Rhinitis (9.6%, 8.8%), Cough increased who have taken FORTEO. Enrollment information can be obtained by calling 1-866-382-6813, or by visiting www.forteoregistry.rti.org. WARNINGS AND PRECAUTIONS (6.4%, 5.5%), Pharyngitis (5.5%, 4.8%), Dyspepsia (3.6%, 2.6%), Pneumonia Osteosarcoma In male and female rats, teriparatide caused an increase in Osteosarcoma occurs in about 4 out of every million older adults each year. Cases of bone tumor and osteosarcoma have been reported rarely in people taking FORTEO in the (3.9%, 3.3%); Skin and Appendages: Rash (4.9%, 4.5%), Sweating the incidence of osteosarcoma (a malignant bone tumor) that was dependent on post-marketing period. The causality to FORTEO use is unclear. (2.2%, 1.7%). Immunogenicity In the clinical trial, antibodies that cross-reacted dose and treatment duration. FORTEO should not be prescribed for patients at Use of FORTEO for more than 2 years during a patient’s lifetime is not recommended. increased baseline risk of osteosarcoma. These include Paget’s disease of bone with teriparatide were detected in 3% of women (15/541) receiving FORTEO. Patients with the following conditions also should not receive FORTEO: bone metastases or a history of skeletal malignancies, metabolic bone diseases other than osteoporosis, (unexplained elevations of alkaline phosphatase may indicate Paget’s disease Generally, antibodies were rst detected following 12 months of treatment and or hypercalcemic disorders. of bone); pediatric and young adult patients with open epiphyses; prior external diminished after withdrawal of therapy. There was no evidence of hypersensitivity reactions or allergic reactions among these patients. Antibody formation did not FORTEO may increase serum calcium, urinary calcium, and serum uric acid. beam or implant radiation therapy involving the skeleton. Patients should be encouraged to enroll in the voluntary FORTEO Patient Registry, which is designed appear to have effects on serum calcium, or on bone mineral density (BMD) Use with caution in patients with active or recent urolithiasis because of risk of exacerbation. If active urolithiasis or pre-existing hypercalciuria are suspected, measurement of to collect information about any potential risk of osteosarcoma in patients response. Laboratory Findings Serum Calcium: FORTEO transiently increased urinary calcium excretion should be considered. who have taken FORTEO. Enrollment information can be obtained by calling serum calcium, with the maximal effect observed at approximately 4 to 1-866-382-6813, or by visiting www.forteoregistry.rti.org. Treatment Duration 6 hours post-dose. Serum calcium measured at least 16 hours post-dose was Transient orthostatic hypotension may occur with initial doses of FORTEO. In short-term clinical pharmacology studies, transient episodes of symptomatic orthostatic hypotension not different from pretreatment levels. In clinical trials, the frequency of at were observed in 5% of patients. FORTEO should be administered initially under circumstances where the patient can sit or lie down if symptoms of orthostatic hypotension occur. The safety and ef cacy of FORTEO have not been evaluated beyond 2 years of treatment. Consequently, use of the drug for more than 2 years during a patients’ least 1 episode of transient hypercalcemia in the 4 to 6 hours after FORTEO Patients receiving digoxin should use FORTEO with caution because FORTEO may transiently increase serum calcium and hypercalcemia may predispose patients to digitalis toxicity. lifetime is not recommended. Bone Metastases and Skeletal Malignancies administration was increased from 2% of women and none of the men treated with placebo to 11% of women and 6% of men treated with FORTEO. The number ADVERSE REACTIONS Patients with bone metastases or a history of skeletal malignancies should not The most common adverse reactions in clinical trials include: arthralgia (10.1 FORTEO vs. 8.4 placebo), pain (21.3 FORTEO vs. 20.5 placebo), and nausea (8.5 FORTEO vs. be treated with FORTEO. Metabolic Bone Diseases Patients with metabolic of patients treated with FORTEO whose transient hypercalcemia was veri ed 6.7 placebo). Other adverse reactions include: dizziness, leg cramps, joint aches, and injection site reactions. bone diseases other than osteoporosis should not be treated with FORTEO. on consecutive measurements was 3% of women and 1% of men. Urinary Hypercalcemia and Hypercalcemic Disorders FORTEO has not been studied Calcium: FORTEO increased urinary calcium excretion, but the frequency of USE IN PREGNANCY/NURSING MOTHERS in patients with pre-existing hypercalcemia. These patients should not be hypercalciuria in clinical trials was similar for patients treated with FORTEO and FORTEO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Based on animal studies, FORTEO may cause fetal harm. treated with FORTEO because of the possibility of exacerbating hypercalcemia. placebo. Serum Uric Acid: FORTEO increased serum uric acid concentrations. It is not known whether teriparatide is excreted in human milk. Breastfeeding mothers should discontinue nursing or FORTEO, taking into account the importance of treatment Patients known to have an underlying hypercalcemic disorder, such as primary In clinical trials, 3% of FORTEO patients had serum uric acid concentrations to the mother. hyperparathyroidism, should not be treated with FORTEO. Urolithiasis or above the upper limit of normal compared with 1% of placebo patients. However, Pre-existing Hypercalciuria In clinical trials, the frequency of urolithiasis the hyperuricemia did not result in an increase in gout, arthralgia, or urolithiasis. INSTRUCTIONS FOR FORTEO USE Renal Function: No clinically important adverse renal effects were observed in FORTEO is provided as a fixed-dose, prefilled delivery device that can be used for up to 28 days, including the first injection. The delivery device contains 28 daily doses of 20 mcg was similar in patients treated with FORTEO and placebo. However, FORTEO has not been studied in patients with active urolithiasis. If active urolithiasis clinical studies. Assessments included creatinine clearance; measurements of each. Do not transfer the contents of the delivery device into a syringe. The FORTEO Delivery Device should be stored under refrigeration at 36° to 46° F (2° to 8° C) at all times. blood urea nitrogen (BUN), creatinine, and electrolytes in serum; urine speci c Do not use FORTEO if it has been frozen. or pre-existing hypercalciuria are suspected, measurement of urinary calcium excretion should be considered. FORTEO should be used with caution in patients gravity and pH; and examination of urine sediment. Studies in Men and Women For more safety information, please see Brief Summary of Prescribing with active or recent urolithiasis because of the potential to exacerbate this with Glucocorticoid-Induced Osteoporosis The safety of FORTEO in the treatment Information, including Boxed Warning regarding osteosarcoma, on condition. Orthostatic Hypotension FORTEO should be administered initially of men and women with glucocorticoid-induced osteoporosis was assessed in following pages. See Full User Manual that accompanies the delivery device. under circumstances in which the patient can sit or lie down if symptoms of a randomized, double-blind, active-controlled trial of 428 patients (19% men, TE HCP ISI 07Apr2011 orthostatic hypotension occur. In short-term clinical pharmacology studies 81% women) aged 22 to 89 years (mean 57 years) treated with ≥ 5mg per day with teriparatide, transient episodes of symptomatic orthostatic hypotension prednisone or equivalent for a minimum of 3 months. The duration of the trial was were observed in 5% of patients. Typically, an event began within 4 hours 18 months with 214 patients exposed to FORTEO and 214 patients exposed TE-79237 0712 PRINTED IN USA ©Lilly USA, LLC 2012. All rights reserved. FORTEO is a registered trademark of Eli Lilly and Company. of dosing and spontaneously resolved within a few minutes to a few hours. to oral daily bisphosphonate (active control). All patients received 1000 mg When transient orthostatic hypotension occurred, it happened within the rst of calcium plus 800 IU of vitamin D supplementation per day. The incidence several doses, it was relieved by placing the person in a reclining position, and of all cause mortality was 4% in the FORTEO group and 6% in the active

FORTEO® (teriparatide [rDNA origin] 20 mcg for injection) PA097FSAM01 FORTEO® (teriparatide [rDNA origin] 20 mcg for injection) PA097FSAM01

FORTEO TE HCP BS 28JUN2012 PA097FSAM01 BRF SUMMARY 7.125 X 9.875 PRINTER VERSION page 1 of 2 22_31 F1_Cover_Sept2012.indd 28 8/10/12 11:49 AM

Job Number: 15741 152_32560 KYMC Revision No: 0 Date: 07/26/12 Job Number: 15741 152_32560 P1 BW Revision No: 0 Date: 07/30/12 FORTEO® (teriparatide [rDNA origin] 20 mcg for it did not preclude continued treatment. Drug Interactions Hypercalcemia may INDICATIONS AND USAGE predispose patients to digitalis toxicity. Because FORTEO transiently increases injection) serum calcium, patients receiving digoxin should use FORTEO with caution. • FORTEO® (teriparatide [rDNA origin] injection) is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture, to increase bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture, and Brief Summary Consult the package insert for complete ADVERSE REACTIONS for the treatment of men and women with osteoporosis associated with sustained, systemic glucocorticoid therapy (daily dosage prescribing information. Clinical Trials Experience Because clinical studies are conducted under equivalent to 5 mg or greater of prednisone) at high risk for fracture widely varying conditions, adverse reaction rates observed in the clinical studies WARNING: POTENTIAL RISK OF OSTEOSARCOMA of a drug cannot be directly compared to rates in the clinical studies of another • High risk for fracture is defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed In male and female rats, teriparatide caused an increase in the incidence drug and may not reect the rates observed in practice. Treatment of Osteoporosis or are intolerant to other available osteoporosis therapy of osteosarcoma (a malignant bone tumor) that was dependent on dose in Men and Postmenopausal Women The safety of FORTEO in the treatment FORTEO is administered as a 20 microgram once daily dose and is available in a 2.4 mL prefilled delivery device for subcutaneous and treatment duration. The effect was observed at systemic exposures of osteoporosis in men and postmenopausal women was assessed in two injection over 28 days. to teriparatide ranging from 3 to 60 times the exposure in humans randomized, double-blind, placebo controlled trials of 1382 patients (21% men, given a 20-mcg dose. Because of the uncertain relevance of the rat 79% women) aged 28 to 86 years (mean 67 years). The median durations of osteosarcoma nding to humans, prescribe FORTEO® only for patients the trials were 11 months for men and 19 months for women, with 691 patients IMPORTANT SAFETY INFORMATION for whom the potential bene ts are considered to outweigh the potential exposed to FORTEO and 691 patients to placebo. All patients received 1000 mg of risk. FORTEO should not be prescribed for patients who are at increased calcium plus at least 400 IU of vitamin D supplementation per day. The incidence baseline risk for osteosarcoma (including those with Paget’s disease of of all cause mortality was 1% in the FORTEO group and 1% in the placebo group. WARNING: POTENTIAL RISK OF OSTEOSARCOMA bone or unexplained elevations of alkaline phosphatase, pediatric and In male and female rats, teriparatide caused an increase in the incidence of osteosarcoma (a malignant bone tumor) that was dependent on The incidence of serious adverse events was 16% in FORTEO patients and young adult patients with open epiphyses, or prior external beam or 19% in placebo patients. Early discontinuation due to adverse events occurred dose and treatment duration. The effect was observed at systemic exposures to teriparatide ranging from 3 to 60 times the exposure in implant radiation therapy involving the skeleton). humans given a 20-mcg dose. Because of the uncertain relevance of the rat osteosarcoma nding to humans, prescribe FORTEO® (teriparatide in 7% of FORTEO patients and 6% of placebo patients. Percentage of Patients with Adverse Events Reported by at Least 2% of FORTEO-Treated Patients [rDNA origin] injection) only for patients for whom the potential bene ts are considered to outweigh the potential risk. FORTEO should not be INDICATIONS AND USAGE and in More FORTEO-Treated Patients than Placebo-Treated Patients from prescribed for patients who are at increased baseline risk for osteosarcoma (including those with Paget’s disease of bone or unexplained FORTEO is indicated: for the treatment of postmenopausal women with elevations of alkaline phosphatase, pediatric and young adult patients with open epiphyses, or prior external beam or implant radiation osteoporosis at high risk for fracture; to increase bone mass in men with the Two Principal Osteoporosis Trials in Women and Men Adverse Events therapy involving the skeleton). primary or hypogonadal osteoporosis at high risk for fracture; for the treatment are Shown Without Attribution of Causality(FORTEO, N=691, Placebo, of men and women with osteoporosis associated with sustained, systemic N=691): Body as a Whole: Pain (21.3%, 20.5%), Headache (7.5%, 7.4%), Asthenia (8.7%, 6.8%), Neck Pain (3.0%, 2.7%); Cardiovascular: Hypertension CONTRAINDICATIONS glucocorticoid therapy at high risk for fracture. High risk for fracture is de ned Hypersensitivity to teriparatide or to any of its excipients. Reactions have included angioedema and anaphylaxis. as a history of osteoporotic fracture, multiple risk factors for fracture, or patients (7.1%, 6.8%), Angina Pectoris (2.5%, 1.6%), Syncope (2.6%, 1.4%); Digestive who have failed or are intolerant to other available osteoporosis therapy. System: Nausea (8.5%, 6.7%), Constipation (5.4%, 4.5%), Diarrhea (5.1%, 4.6%), WARNINGS AND PRECAUTIONS Dyspepsia (5.2%, 4.1%), Vomiting (3.0%, 2.3%), Gastrointestional disorder The following categories of patients have increased baseline risk of osteosarcoma and therefore should not be treated with FORTEO: Paget’s disease of bone, pediatric populations CONTRAINDICATIONS (2.3%, 2.0%), Tooth disorder (2.0%, 1.3%); Musculoskeletal: Arthralgia and young adults with open epiphyses, or prior external beam or implant radiation therapy. Do not use FORTEO in patients with Hypersensitivity to teriparatide or to any (10.1%, 8.4%), Leg cramps (2.6%, 1.3%); Nervous System: Dizziness Patients should be encouraged to enroll in the voluntary FORTEO Patient Registry, which is designed to collect information about any potential risk of osteosarcoma in patients of its excipients. Reactions have included angioedema and anaphylaxis. (8.0%, 5.4%), Depression (4.1%, 2.7%) Insomnia (4.3%, 3.6%), Vertigo (3.8%, 2.7%); Respiratory System: Rhinitis (9.6%, 8.8%), Cough increased who have taken FORTEO. Enrollment information can be obtained by calling 1-866-382-6813, or by visiting www.forteoregistry.rti.org. WARNINGS AND PRECAUTIONS (6.4%, 5.5%), Pharyngitis (5.5%, 4.8%), Dyspepsia (3.6%, 2.6%), Pneumonia Osteosarcoma In male and female rats, teriparatide caused an increase in Osteosarcoma occurs in about 4 out of every million older adults each year. Cases of bone tumor and osteosarcoma have been reported rarely in people taking FORTEO in the (3.9%, 3.3%); Skin and Appendages: Rash (4.9%, 4.5%), Sweating the incidence of osteosarcoma (a malignant bone tumor) that was dependent on post-marketing period. The causality to FORTEO use is unclear. (2.2%, 1.7%). Immunogenicity In the clinical trial, antibodies that cross-reacted dose and treatment duration. FORTEO should not be prescribed for patients at Use of FORTEO for more than 2 years during a patient’s lifetime is not recommended. increased baseline risk of osteosarcoma. These include Paget’s disease of bone with teriparatide were detected in 3% of women (15/541) receiving FORTEO. Patients with the following conditions also should not receive FORTEO: bone metastases or a history of skeletal malignancies, metabolic bone diseases other than osteoporosis, (unexplained elevations of alkaline phosphatase may indicate Paget’s disease Generally, antibodies were rst detected following 12 months of treatment and or hypercalcemic disorders. of bone); pediatric and young adult patients with open epiphyses; prior external diminished after withdrawal of therapy. There was no evidence of hypersensitivity reactions or allergic reactions among these patients. Antibody formation did not FORTEO may increase serum calcium, urinary calcium, and serum uric acid. beam or implant radiation therapy involving the skeleton. Patients should be encouraged to enroll in the voluntary FORTEO Patient Registry, which is designed appear to have effects on serum calcium, or on bone mineral density (BMD) Use with caution in patients with active or recent urolithiasis because of risk of exacerbation. If active urolithiasis or pre-existing hypercalciuria are suspected, measurement of to collect information about any potential risk of osteosarcoma in patients response. Laboratory Findings Serum Calcium: FORTEO transiently increased urinary calcium excretion should be considered. who have taken FORTEO. Enrollment information can be obtained by calling serum calcium, with the maximal effect observed at approximately 4 to 1-866-382-6813, or by visiting www.forteoregistry.rti.org. Treatment Duration 6 hours post-dose. Serum calcium measured at least 16 hours post-dose was Transient orthostatic hypotension may occur with initial doses of FORTEO. In short-term clinical pharmacology studies, transient episodes of symptomatic orthostatic hypotension not different from pretreatment levels. In clinical trials, the frequency of at were observed in 5% of patients. FORTEO should be administered initially under circumstances where the patient can sit or lie down if symptoms of orthostatic hypotension occur. The safety and ef cacy of FORTEO have not been evaluated beyond 2 years of treatment. Consequently, use of the drug for more than 2 years during a patients’ least 1 episode of transient hypercalcemia in the 4 to 6 hours after FORTEO Patients receiving digoxin should use FORTEO with caution because FORTEO may transiently increase serum calcium and hypercalcemia may predispose patients to digitalis toxicity. lifetime is not recommended. Bone Metastases and Skeletal Malignancies administration was increased from 2% of women and none of the men treated with placebo to 11% of women and 6% of men treated with FORTEO. The number ADVERSE REACTIONS Patients with bone metastases or a history of skeletal malignancies should not The most common adverse reactions in clinical trials include: arthralgia (10.1 FORTEO vs. 8.4 placebo), pain (21.3 FORTEO vs. 20.5 placebo), and nausea (8.5 FORTEO vs. be treated with FORTEO. Metabolic Bone Diseases Patients with metabolic of patients treated with FORTEO whose transient hypercalcemia was veri ed 6.7 placebo). Other adverse reactions include: dizziness, leg cramps, joint aches, and injection site reactions. bone diseases other than osteoporosis should not be treated with FORTEO. on consecutive measurements was 3% of women and 1% of men. Urinary Hypercalcemia and Hypercalcemic Disorders FORTEO has not been studied Calcium: FORTEO increased urinary calcium excretion, but the frequency of USE IN PREGNANCY/NURSING MOTHERS in patients with pre-existing hypercalcemia. These patients should not be hypercalciuria in clinical trials was similar for patients treated with FORTEO and FORTEO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Based on animal studies, FORTEO may cause fetal harm. treated with FORTEO because of the possibility of exacerbating hypercalcemia. placebo. Serum Uric Acid: FORTEO increased serum uric acid concentrations. It is not known whether teriparatide is excreted in human milk. Breastfeeding mothers should discontinue nursing or FORTEO, taking into account the importance of treatment Patients known to have an underlying hypercalcemic disorder, such as primary In clinical trials, 3% of FORTEO patients had serum uric acid concentrations to the mother. hyperparathyroidism, should not be treated with FORTEO. Urolithiasis or above the upper limit of normal compared with 1% of placebo patients. However, Pre-existing Hypercalciuria In clinical trials, the frequency of urolithiasis the hyperuricemia did not result in an increase in gout, arthralgia, or urolithiasis. INSTRUCTIONS FOR FORTEO USE Renal Function: No clinically important adverse renal effects were observed in FORTEO is provided as a fixed-dose, prefilled delivery device that can be used for up to 28 days, including the first injection. The delivery device contains 28 daily doses of 20 mcg was similar in patients treated with FORTEO and placebo. However, FORTEO has not been studied in patients with active urolithiasis. If active urolithiasis clinical studies. Assessments included creatinine clearance; measurements of each. Do not transfer the contents of the delivery device into a syringe. The FORTEO Delivery Device should be stored under refrigeration at 36° to 46° F (2° to 8° C) at all times. blood urea nitrogen (BUN), creatinine, and electrolytes in serum; urine speci c Do not use FORTEO if it has been frozen. or pre-existing hypercalciuria are suspected, measurement of urinary calcium excretion should be considered. FORTEO should be used with caution in patients gravity and pH; and examination of urine sediment. Studies in Men and Women For more safety information, please see Brief Summary of Prescribing with active or recent urolithiasis because of the potential to exacerbate this with Glucocorticoid-Induced Osteoporosis The safety of FORTEO in the treatment Information, including Boxed Warning regarding osteosarcoma, on condition. Orthostatic Hypotension FORTEO should be administered initially of men and women with glucocorticoid-induced osteoporosis was assessed in following pages. See Full User Manual that accompanies the delivery device. under circumstances in which the patient can sit or lie down if symptoms of a randomized, double-blind, active-controlled trial of 428 patients (19% men, TE HCP ISI 07Apr2011 orthostatic hypotension occur. In short-term clinical pharmacology studies 81% women) aged 22 to 89 years (mean 57 years) treated with ≥ 5mg per day with teriparatide, transient episodes of symptomatic orthostatic hypotension prednisone or equivalent for a minimum of 3 months. The duration of the trial was were observed in 5% of patients. Typically, an event began within 4 hours 18 months with 214 patients exposed to FORTEO and 214 patients exposed TE-79237 0712 PRINTED IN USA ©Lilly USA, LLC 2012. All rights reserved. FORTEO is a registered trademark of Eli Lilly and Company. of dosing and spontaneously resolved within a few minutes to a few hours. to oral daily bisphosphonate (active control). All patients received 1000 mg When transient orthostatic hypotension occurred, it happened within the rst of calcium plus 800 IU of vitamin D supplementation per day. The incidence several doses, it was relieved by placing the person in a reclining position, and of all cause mortality was 4% in the FORTEO group and 6% in the active

FORTEO® (teriparatide [rDNA origin] 20 mcg for injection) PA097FSAM01 FORTEO® (teriparatide [rDNA origin] 20 mcg for injection) PA097FSAM01

FORTEO TE HCP BS 28JUN2012 PA097FSAM01 BRF SUMMARY 7.125 X 9.875 PRINTER VERSION page 1 of 2 22_31 F1_Cover_Sept2012.indd 29 8/10/12 11:49 AM

Job Number: 15741 152_32560 KYMC Revision No: 0 Date: 07/26/12 Job Number: 15741 152_32560 P1 BW Revision No: 0 Date: 07/30/12 control group. The incidence of serious adverse events was 21% in FORTEO OVERDOSAGE patients and 18% in active control patients, and included pneumonia Incidents of overdose in humans have not been reported in clinical trials. (3% FORTEO, 1% active control). Early discontinuation because of adverse Teriparatide has been administered in single doses of up to 100 mcg and in events occurred in 15% of FORTEO patients and 12% of active control patients, repeated doses of up to 60 mcg/day for 6 weeks. The effects of overdose that and included dizziness (2% FORTEO, 0% active control). Adverse events reported might be expected include a delayed hypercalcemic effect and risk of orthostatic at a higher incidence in the FORTEO group and with at least a 2% difference hypotension. Nausea, vomiting, dizziness, and headache might also occur. In in FORTEO-treated patients compared with active control-treated patients postmarketing spontaneous reports, there have been cases of medication were: nausea (14%, 7%), gastritis (7%, 3%), pneumonia (6%, 3%), dyspnea errors in which the entire contents (up to 800 mcg) of the FORTEO delivery (6%, 3%), insomnia (5%, 1%), anxiety (4%, 1%), and herpes zoster (3%, 1%), device (pen) have been administered as a single dose. Transient events reported respectively. Postmarketing Experience: The following adverse reactions have have included nausea, weakness/lethargy and hypotension. In some cases, no been identied during postapproval use of FORTEO. Because these reactions adverse events occurred as a result of the overdose. No fatalities associated are reported voluntarily from a population of uncertain size, it is not always with overdose have been reported. Overdose Management There is no specic possible to reliably estimate their frequency or establish a causal relationship antidote for teriparatide. Treatment of suspected overdose should include to drug exposure. Osteosarcoma: Cases of bone tumor and osteosarcoma discontinuation of FORTEO, monitoring of serum calcium and phosphorus, and have been reported rarely in the postmarketing period. The causality to FORTEO implementation of appropriate supportive measures, such as hydration. use is unclear. Long term osteosarcoma surveillance studies are ongoing. DOSAGE FORMS AND STRENGTHS Hypercalcemia: Hypercalcemia greater than 13.0 mg/dL has been reported Multi-dose prelled delivery device (pen) for subcutaneous injection with FORTEO use. Adverse events reported since market introduction that were containing 28 daily doses of 20 mcg. temporally (but not necessarily causally) related to FORTEO therapy include the following: Allergic Reactions: Anaphylactic reactions, drug hypersensitivity, PATIENT COUNSELING INFORMATION angioedema, urticaria; Investigations: Hyperuricemia; Respiratory System: Patients should read the FDA-approved Medication Guide and delivery Acute dyspnea, chest pain; Musculoskeletal: Muscle spasms of the leg or back; device (pen) User Manual before starting therapy with FORTEO and re-read them Other: Injection site reactions including injection site pain, swelling and bruising; each time the prescription is renewed. Patients need to understand and follow oro-facial edema. the instructions in the FORTEO delivery device User Manual. Failure to do so may result in inaccurate dosing. USE IN SPECIFIC POPULATIONS 06/15/2012 Pregnancy Category C. There are no adequate and well-controlled studies of FORTEO in pregnant women. In animal studies, teriparatide increased skeletal PLEASE SEE FULL PRESCRIBING INFORMATION OR WWW.FORTEOHCP.COM deviations and variations in mouse offspring at doses more than 60 times the FOR ADDITIONAL INFORMATION. equivalent human dose and produced mild growth retardation and reduced motor activity in rat offspring at doses more than 120 times the equivalent human dose. FORTEO should be used during pregnancy only if the potential benet justies the potential risk to the fetus. In animal studies, pregnant mice received teriparatide during organogenesis at subcutaneous doses 8 to 267 times the human dose. At doses ≥ 60 times the human dose, the fetuses showed an increased incidence of skeletal deviations or variations (interrupted rib, extra vertebra or rib). When pregnant rats received subcutaneous teriparatide during organogenesis at doses 16 to 540 times the human dose, the fetuses showed no abnormal ndings. In a perinatal/postnatal study, pregnant rats received subcutaneous teriparatide from organogenesis through lactation. Mild growth retardation in female offspring at doses ≥120 times the human dose (based on surface area, mcg/m2). Mild growth retardation in male offspring and reduced motor activity in both male and female offspring occurred at maternal doses 540 times the human dose. There were no developmental or reproductive effects in mice or rats at doses 8 or 16 times the human dose, respectively. Exposure multiples were normalized based on body surface area (mcg/m2). Actual animal doses: mice (30 to 1000 mcg/kg/day); rats (30 to 1000 mcg/kg/day). Nursing Mothers: It is not known whether teriparatide is excreted in human milk. Because of the potential for tumorigenicity shown for teriparatide in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and efcacy of FORTEO have not been established in any pediatric population. FORTEO should not be prescribed in patients at an increased baseline risk of osteosarcoma which include pediatric and young adult patients with open epiphyses. Therefore, FORTEO is not indicated for use in pediatric or young adult patients with open epiphyses. Geriatric Use: Of the patients receiving FORTEO in the osteoporosis trial of 1637 postmenopausal women, 75% were 65 years of age and over and 23% were 75 years of age and over. Of the patients receiving FORTEO in the osteoporosis trial of 437 men, 39% were 65 years of age and over and 13% were 75 years of age and over. No overall differences in safety or effectiveness were Literature revised: March 21, 2012 observed between these subjects and younger subjects, and other reported Marketed by: Lilly USA, LLC clinical experience has not identied differences in responses between the Indianapolis, IN 46285, USA elderly and younger patients, but greater sensitivity of some older individuals www.forteo.com cannot be ruled out. Hepatic Impairment: No studies have been performed Copyright © 2002, 2012, Eli Lilly and Company. in patients with hepatic impairment. Renal Impairment: In 5 patients with All rights reserved. severe renal impairment (CrCl<30 mL/min), the AUC and T1/2 of teriparatide PA097FSAM01 were increased by 73% and 77%, respectively. Maximum serum concentration Rx only. of teriparatide was not increased. TE HCP BS 28JUN2012 PA097FSAM01

FORTEO® (teriparatide [rDNA origin] 20 mcg for injection) PA097FSAM01 FORTEO® (teriparatide [rDNA origin] 20 mcg for injection) PA097FSAM01

FORTEO TE HCP BS 28JUN2012 PA097FSAM01 BRF SUMMARY 7.125 X 9.875 PRINTER VERSION page 2 of 2

22_31 F1_Cover_Sept2012.indd 30 8/10/12 11:49 AM

Job Number: 15741 152_32560 P2 BW Revision No: 0 Date: 07/30/12 control group. The incidence of serious adverse events was 21% in FORTEO OVERDOSAGE patients and 18% in active control patients, and included pneumonia Incidents of overdose in humans have not been reported in clinical trials. (3% FORTEO, 1% active control). Early discontinuation because of adverse Teriparatide has been administered in single doses of up to 100 mcg and in events occurred in 15% of FORTEO patients and 12% of active control patients, repeated doses of up to 60 mcg/day for 6 weeks. The effects of overdose that and included dizziness (2% FORTEO, 0% active control). Adverse events reported might be expected include a delayed hypercalcemic effect and risk of orthostatic at a higher incidence in the FORTEO group and with at least a 2% difference hypotension. Nausea, vomiting, dizziness, and headache might also occur. In in FORTEO-treated patients compared with active control-treated patients postmarketing spontaneous reports, there have been cases of medication were: nausea (14%, 7%), gastritis (7%, 3%), pneumonia (6%, 3%), dyspnea errors in which the entire contents (up to 800 mcg) of the FORTEO delivery (6%, 3%), insomnia (5%, 1%), anxiety (4%, 1%), and herpes zoster (3%, 1%), device (pen) have been administered as a single dose. Transient events reported respectively. Postmarketing Experience: The following adverse reactions have have included nausea, weakness/lethargy and hypotension. In some cases, no been identied during postapproval use of FORTEO. Because these reactions adverse events occurred as a result of the overdose. No fatalities associated are reported voluntarily from a population of uncertain size, it is not always with overdose have been reported. Overdose Management There is no specic possible to reliably estimate their frequency or establish a causal relationship antidote for teriparatide. Treatment of suspected overdose should include to drug exposure. Osteosarcoma: Cases of bone tumor and osteosarcoma discontinuation of FORTEO, monitoring of serum calcium and phosphorus, and have been reported rarely in the postmarketing period. The causality to FORTEO implementation of appropriate supportive measures, such as hydration. use is unclear. Long term osteosarcoma surveillance studies are ongoing. DOSAGE FORMS AND STRENGTHS Hypercalcemia: Hypercalcemia greater than 13.0 mg/dL has been reported Multi-dose prelled delivery device (pen) for subcutaneous injection with FORTEO use. Adverse events reported since market introduction that were containing 28 daily doses of 20 mcg. temporally (but not necessarily causally) related to FORTEO therapy include the following: Allergic Reactions: Anaphylactic reactions, drug hypersensitivity, PATIENT COUNSELING INFORMATION angioedema, urticaria; Investigations: Hyperuricemia; Respiratory System: Patients should read the FDA-approved Medication Guide and delivery Acute dyspnea, chest pain; Musculoskeletal: Muscle spasms of the leg or back; device (pen) User Manual before starting therapy with FORTEO and re-read them Other: Injection site reactions including injection site pain, swelling and bruising; each time the prescription is renewed. Patients need to understand and follow oro-facial edema. the instructions in the FORTEO delivery device User Manual. Failure to do so may result in inaccurate dosing. Looking for MOC Points? USE IN SPECIFIC POPULATIONS 06/15/2012 Pregnancy Category C. There are no adequate and well-controlled studies of FORTEO in pregnant women. In animal studies, teriparatide increased skeletal PLEASE SEE FULL PRESCRIBING INFORMATION OR WWW.FORTEOHCP.COM deviations and variations in mouse offspring at doses more than 60 times the FOR ADDITIONAL INFORMATION. equivalent human dose and produced mild growth retardation and reduced motor activity in rat offspring at doses more than 120 times the equivalent human dose. FORTEO should be used during pregnancy only if the potential benet justies the potential risk to the fetus. In animal studies, pregnant NOW AVAILABLE mice received teriparatide during organogenesis at subcutaneous doses 8 to 267 times the human dose. At doses ≥ 60 times the human dose, the fetuses showed an increased incidence of skeletal deviations or variations (interrupted THE EVALUATION OF THYROID NODULES rib, extra vertebra or rib). When pregnant rats received subcutaneous teriparatide during organogenesis at doses 16 to 540 times the human dose, the fetuses showed no abnormal ndings. In a perinatal/postnatal study, pregnant rats Practice Improvement Module (PIM) received subcutaneous teriparatide from organogenesis through lactation. Mild growth retardation in female offspring at doses ≥120 times the human dose (based on surface area, mcg/m2). Mild growth retardation in male offspring and reduced motor activity in both male and female offspring occurred at The rst endocrine-speci c Practice Improvement Module (PIM), is a Web-based, self-evaluation maternal doses 540 times the human dose. There were no developmental or tool designed to assist you in evaluating your care of patients with thyroid nodules. Using data reproductive effects in mice or rats at doses 8 or 16 times the human dose, respectively. Exposure multiples were normalized based on body surface area from your practice, including patient charts, our PIM allows you to: (mcg/m2). Actual animal doses: mice (30 to 1000 mcg/kg/day); rats (30 to 1) Evaluate your performance in evaluating thyroid nodules; 1000 mcg/kg/day). Nursing Mothers: It is not known whether teriparatide is excreted in human milk. Because of the potential for tumorigenicity shown for 2) Compare your performance to ATA and AACE/AME/ETA clinical guidelines through teriparatide in animal studies, a decision should be made whether to discontinue personalized reports; nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and efcacy of FORTEO 3) Create and implement an individualized improvement plan; and have not been established in any pediatric population. FORTEO should not be 4) Reassess the impact of that improvement plan on your practice. prescribed in patients at an increased baseline risk of osteosarcoma which include pediatric and young adult patients with open epiphyses. Therefore, FORTEO is not indicated for use in pediatric or young adult patients with open Complete the PIM, either individually or as a part of a practice team, and earn 20 points toward epiphyses. Geriatric Use: Of the patients receiving FORTEO in the osteoporosis the Self-Evaluation of Practice Performance (Part 4) requirement of Maintenance of Certi cation trial of 1637 postmenopausal women, 75% were 65 years of age and over and 23% were 75 years of age and over. Of the patients receiving FORTEO in the (MOC) and claim up to 20 AMA PRA Category 1 Credits™. osteoporosis trial of 437 men, 39% were 65 years of age and over and 13% were Literature revised: March 21, 2012 75 years of age and over. No overall differences in safety or effectiveness were Evaluation of Thyroid Nodules PIM Task Force observed between these subjects and younger subjects, and other reported Marketed by: Lilly USA, LLC clinical experience has not identied differences in responses between the Indianapolis, IN 46285, USA Erik Alexander, MD | Carol Greenlee, MD, FACP, FACE | Susan Mandel, MD, MPH elderly and younger patients, but greater sensitivity of some older individuals www.forteo.com cannot be ruled out. Hepatic Impairment: No studies have been performed Copyright © 2002, 2012, Eli Lilly and Company. For more information visit endoselfassessment.org. in patients with hepatic impairment. Renal Impairment: In 5 patients with All rights reserved. severe renal impairment (CrCl<30 mL/min), the AUC and T1/2 of teriparatide PA097FSAM01 were increased by 73% and 77%, respectively. Maximum serum concentration Rx only. of teriparatide was not increased. TE HCP BS 28JUN2012 PA097FSAM01

FORTEO® (teriparatide [rDNA origin] 20 mcg for injection) PA097FSAM01 FORTEO® (teriparatide [rDNA origin] 20 mcg for injection) PA097FSAM01

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Job Number: 15741 152_32560 P2 BW Revision No: 0 Date: 07/30/12 FEATURE

Treating Children with TYPE 2 DIABETES By Eric Seaborg he alarming increase in type 2 diabetes mellitus (T2DM) among children and adolescents has researchers scrambling for effective treatments. Amid growing evidence that the disease progresses more quickly in children than in adults, some doctors are advocating aggressive drug treatment, and nearly all experts are stressing prevention as a priority to combat the condition. 2012 “The time to intervene with major lifestyle changes is not after diabetes has happened,” said Kenneth Copeland, M.D., a pediatric endocrinologist at the University of Oklahoma. SEPTEMBER “Our focus needs to be on the kids who are at risk before • they develop diabetes because effecting a major lifestyle

NEWS change—enough to change the course of established diabetes in youth—is exceedingly difﬁcult to do.” Copeland is a co-author of the recent study, “Treat-

ENDOCRINE NEWS • SEPTEMBER 2012 ment Options for type 2 Diabetes in Adolescents and Youth 32

32_35 F2 T2DM Sept2012B.indd 32 8/10/12 11:51 AM FEATURE FEATURE

(TODAY),” the first major trial to compare the effective- to 1,000 mg twice daily to attain glycemic control, defined ness of three treatments for T2DM in young people. Results as a glycated hemoglobin level less than 8 percent for at published in June in The New England Journal of Medicine least two months. showed that none of the treatments controlled glycemic Because insulin sensitivity declines in all children dur- levels in more than 61 percent of patients. ing puberty and then improves at puberty’s end, researchers These findings are important, considering the increasing wanted to test whether aggressive steps to maintain insulin number of American youth with T2DM; from 2001 to 2009, sensitivity might offer patients a safe passage through the number of cases rose 21 percent. Some 3,700 children this period, Zeitler said. But they found that the failure are diagnosed with the condition every year. Twenty years rate of metformin monotherapy was higher in the children ago, T2DM was almost nonexistent among children, accord- than in adults. ing to Philip Zeitler, M.D., Ph.D., a pediatric endocrinologist at Children’s Hospital Colorado in Aurora and professor of Faster Progression of the Disease pediatrics and clinical science at the University of Colorado One of the reasons for this lack of efficacy could be School of Medicine. He is another co-author of the TODAY trial. that T2DM seems to progress more quickly in young peo- The incidence of the disease is likely to continue to ple than adults, the researchers said in a presentation at grow because of the obesity epidemic. Seventeen percent of the American Diabetes Association’s Scientific Sessions in children between the ages of 2 and 19 are obese. This puts June. By the end of the TODAY study, nearly one-third of a large segment of the population at risk for developing the participants exhibited high blood pressure (compared high blood pressure, high cholesterol, and T2DM. Develop- with 12 percent at the beginning), 10 percent–30 percent ing T2DM at a young age also increases the risk of heart had dyslipidemia, about 17 percent exhibited elevated disease, retinopathy, and kidney disease. urinary albumin levels (compared Children With such dire medical complications facing the nation’s with 6 percent at the start), and youth, TODAY researchers compared the efficacy of three 13 percent had retinopathy. treatments in maintaining glycemic control for a four-year These numbers represent a period. One protocol used metformin, the standard treat- much faster progression of “It might be good ment for children with T2DM; another treatment combined the complications of the to start with a more metformin with lifestyle intervention; and the third used disease than in adults. metformin in combination with the insulin-sensitizing In light of these re- aggressive drug treat- drug rosiglitazone. Failure of control was defined as the sults, “it might be good ment approach,” said glycated hemoglobin, or A1C, level rising to 8 percent or to start with a more ag- more for six months. gressive drug treatment ap- Philip Zeitler, M.D. Treatment with metformin alone failed 52 percent of the proach,” Zeitler said. “The time, compared with a 47 percent failure rate for metformin good news is nearly 50 percent plus lifestyle intervention and 39 percent for metformin and of the kids did well on metformin rosiglitazone combined. The researchers deemed the addi- therapy.” Fortunately, patients who tion of lifestyle intervention not significantly different from will respond well to metformin can be identified early on metformin alone, but the two-drug combination led to a 25 based on their A1C level, he said. “Those kids who had percent improvement. an A1C in the normal range did The 700 patients in much better than those kids who the study were ages 10 got their A1C down but did not to 17 years and had had get a normal A1C. The kids you T2DM for less than 2 years can get under control quickly at study outset. Although and easily stay that way,” Zeitler the enrollment criteria explained. The median time to specified that they have a loss of glycemic control was a body mass index (BMI) less than a year. If the drug is at or above the 85th per- not going work, physcians will centile for age and sex, know fairly quickly. participants exceeded A question arises about this requirement, with where to turn when metformin, an average BMI in the the only oral drug approved by mid-30s, putting them the U.S. Food and Drug Admin- in the 98th percentile. istration (FDA) for treatment After being weaned from of children, fails to ameliorate any other diabetes medi- T2DM. Rosiglitazone, used in the cations, they were given study’s combination treatment,

a metformin dose of up is not an option; in September ENDOCRINE NEWS • SEPTEMBER 2012 33

32_35 F2 T2DM Sept2012B.indd 33 8/10/12 11:51 AM FEATURE CSOM230B2406 (Seascape): Investigating Pasireotide in

2010 the FDA imposed prescribing restrictions after studies metformin plus lifestyle intervention significantly decreased linked it to a higher risk of heart attacks and stroke in adults. percent overweight, this did not translate into sustained the Treatment of Active Cushing’s Disease (Those concerns arose after the TODAY trial was designed glycemic control, as compared with metformin monotherapy,” and inaugurated, and the study was allowed to continue the study said. Zeitler was surprised that the intervention was An open-label, multicenter, expanded-access study of with careful monitoring of participants.) Whether other not able to budge the patients out of their overall environ- drugs in the thiazolidinedione family, such as pioglitazone, ment of excess calories and a sedentary lifestyle enough to pasireotide sc in patients with Cushing’s disease would be salutary without the risks of rosiglitazone requires make a long-term difference. more research. The fact remains that rosiglitazone still “The key message from this Enrolling now. failed for many of these patients. study wasn’t so much about US health care professionals: please call (800) 340-6843 for more information. Health care professionals For now, the “only other well-studied option the need for add-on medica- outside the US: please contact Novartis Oncology by visiting www.pasporttrials.com “The key message tions as it was about the wasn’t so much about need for prevention,” Da- Screening Treatmenta vid Allen, M.D., head of the need for add-on med- pediatric endocrinology ications as it was about the at the University of Wis- Pasireotide sc 900 µg bidb consin School of Medicine, need for prevention,” told Endocrine News. “By said David Allen, M.D. demonstrating that a large proportion of children were not retrievable by medical in- Day -21 Day 1 1wk 2wk 3wk 1 mo 2 mo 3 mo 4 mo 5 mo 6 mo 12 mo tervention, as well as the acceler- ated rate at which they deteriorated aPatients will be followed at 12-week intervals between Months 6 and 12. in spite of medical intervention, this study bDose may be reduced to 600 µg bid and 300 µg bid upon sustained disease control, or in the case of tolerability concerns. The starting dose for patients with impaired glucose metabolism will be 600 µg bid. should add a tremendous impetus to focusing our energy on correcting the dangerous mismatch of calories con- ELIGIBLE PATIENTS: PRIMARY END POINT: sumed versus energy expended that these children experi- • Adult patients with a confirmed diagnosis of • The proportion of patients with drug-related ence.” The focus on looking for more drug therapies could Cushing’s disease grade 3 or 4 AEs or serious AEs be a distraction from the need for prevention, he added. — Mean UFC >ULN Allen’s call for prevention echoed The Endocrine Soci- — Morning plasma ACTH within or above the ety’s pediatric obesity clinical treatment guideline, which normal range recommends physicians become much more active as community advocates for healthier school lunches, policies — MRI confirmation of pituitary adenoma to ban advertising of unhealthful foods to children, and (≥0.6 cm) or positive inferior petrosal design of neighborhoods that emphasize walking instead sinus gradient for patients with a of driving. School food programs are an important target microadenoma <0.6 cm because children who participate in the school lunch and — Histopathological confirmation of an breakfast programs consume one-third to one-fifth of their ACTH-staining adenoma in postsurgical patients daily recommended caloric intake in school. is combination with insulin,” Zeitler said. The loss of insulin The Society’s guidelines also note that pediatricians are • Patients with de novo Cushing’s disease secretion was very rapid in the patients who lost glycemic lax in complying with the American Academy of Pediatri- who are nonsurgical candidates control, and physicians may, therefore, want to move to cians guidelines on obesity. Clinicians in general should insulin therapy quickly because the faster progression to be more proactive in screening for obesity and become comorbidities underscores the need to keep glycemic control involved with the entire family in prescribing dietary, in the adolescent age group. physical activity, and behavioral modifications in pursuit The PASPORT Research Program of a healthier lifestyle. PASireotide clinical trial PORTfolio: Evaluating pasireotide in patients with Increase Efforts to Modify Lifestyle Allen compared the challenge of the obesity epidemic pituitary and gastroenteropancreatic neuroendocrine tumors The TODAY researchers and other experts agreed that the with that of coping with climate change. Both issues, he failure of the lifestyle modification efforts should not be said, are “so complex, embedded in culture and econom- seen as reason to abandon them, but instead to redouble ics, and intertwined with conflicts between individual their efforts to help children adopt healthier habits. The freedom and societal health that solutions are difficult Pasireotide (SOM230) is an investigational new drug. Efficacy and safety have not been lifestyle intervention treatment model required assigning a to envision.” established. There is no guarantee that pasireotide will become commercially available. behavioral interventionist called a “pal” to each participant. The pals held weekly meetings with the children, advised Seaborg is a freelance writer in Charlottesville, Virginia. Abbreviations: ACTH, adrenocorticotropic hormone; AEs, adverse events; bid, twice a day; MRI, magnetic resonance imaging; SC, subcutaneous; UFC, urinary free cortisol; ULN, upper limit of normal. their families on being role models, chaperoned trips to For additional links related to this feature, the gym to exercise, and more. please visit Endocrine News Online at In general, the results were similar to previous adoles- www.endo-society.org/endo_news. ClinicalTrials.gov Identifier: NCT01582061 ENDOCRINE NEWS • SEPTEMBER 2012 cent weight-loss efforts and T2DM development. “Although 34

Novartis Pharmaceuticals Corporation East Hanover, NJ 07936-1080 ©Novartis 2012 6/12 SOM-1045462

32_35 F2 T2DM Sept2012B.indd 34 8/10/12 11:51 AM FEATURE CSOM230B2406FEATURE (Seascape): Investigating Pasireotide in the Treatment of Active Cushing’s Disease An open-label, multicenter, expanded-access study of pasireotide sc in patients with Cushing’s disease Enrolling now. US health care professionals: please call (800) 340-6843 for more information. Health care professionals outside the US: please contact Novartis Oncology by visiting www.pasporttrials.com

Screening Treatmenta

Pasireotide sc 900 µg bidb

Day -21 Day 1 1wk 2wk 3wk 1 mo 2 mo 3 mo 4 mo 5 mo 6 mo 12 mo

aPatients will be followed at 12-week intervals between Months 6 and 12. bDose may be reduced to 600 µg bid and 300 µg bid upon sustained disease control, or in the case of tolerability concerns. The starting dose for patients with impaired glucose metabolism will be 600 µg bid. ELIGIBLE PATIENTS: PRIMARY END POINT: • Adult patients with a confirmed diagnosis of • The proportion of patients with drug-related Cushing’s disease grade 3 or 4 AEs or serious AEs — Mean UFC >ULN — Morning plasma ACTH within or above the normal range — MRI confirmation of pituitary adenoma (≥0.6 cm) or positive inferior petrosal sinus gradient for patients with a microadenoma <0.6 cm — Histopathological confirmation of an ACTH-staining adenoma in postsurgical patients • Patients with de novo Cushing’s disease who are nonsurgical candidates

The PASPORT Research Program PASireotide clinical trial PORTfolio: Evaluating pasireotide in patients with pituitary and gastroenteropancreatic neuroendocrine tumors

Pasireotide (SOM230) is an investigational new drug. Efficacy and safety have not been established. There is no guarantee that pasireotide will become commercially available.

Abbreviations: ACTH, adrenocorticotropic hormone; AEs, adverse events; bid, twice a day; MRI, magnetic resonance imaging; SC, subcutaneous; UFC, urinary free cortisol; ULN, upper limit of normal.

ClinicalTrials.gov Identifier: NCT01582061 ENDOCRINE NEWS • SEPTEMBER 2012 35

Novartis Pharmaceuticals Corporation East Hanover, NJ 07936-1080 ©Novartis 2012 6/12 SOM-1045462

32_35 F2 T2DM Sept2012B.indd 35 8/10/12 11:51 AM FACT SHEET PRACTICE RESOURCES

tems. Importantly, this psychologi- cal mechanism affects most people, whether obese or not. Knowing that our consumption Downsizing Supersizes patterns have a distinctly psycho- By Kelly Horvath logical nature in addition to the physiologic drive, has an upside. We can “trick” ourselves into eating less f New York City Mayor Michael (USDA) and U.S. Food and Drug Ad- almost as easily as we succumb to Bloomberg’s proposal to ban sug- ministration standard portions. Small overconsuming. Research presented Iary drinks larger than 16 ounces wonder that 66 percent of Americans in July at the Annual Meeting of the passes this month, health advocates are now overweight or obese, com- Society for the Study of Ingestive Proven hope obese New Yorkers and other pared to 47 percent 30 years ago. Behavior shows that cutting food into Americans as well will get the push Research supports Bloomberg’s smaller pieces can reduce intake by they need to go from supersized to reasoning about portion control. creating the appearance of more food, Weight Loss healthy portions. Studies show that we tend to con- which induces more rapid and in- Since the 1970s, American waist- sume in units; if the food package is creased satiety than single portions. lines have been steadily increasing in large, we consume the entire amount. At the Hormone Health Network Methods direct proportion with food portion We also tend to eat more when (www.hormone.org), health care sizes in restaurants, food stores, served more. “The more food you providers offer a list of practical and homes. Many food items have have in front of you, the more you strategies for losing weight. A com- increased two to five times in size. are likely to eat,” George A. Bray, mon theme among the items listed Outside the home, almost all food M.D., chief of the Division of Clinical is changing what and how we eat, WHAT CAN WEIGHT LOSS WHAT CHANGES IN EATING HABITS CAN portion sizes have increased, some— Obesity and Metabolism at Penning- including eating less. Eating more DO FOR YOU? HELP YOU LOSE WEIGHT? such as sodas and cookies—up to ton Biomedical Research Center in slowly, for example, helps us eat less Most people need to change what they eat and how much they eight times. These sizes also exceed Baton Rouge and a leading obesity because it takes 20 minutes for the Losing weight can improve your health in a number of ways. It eat in order to lose weight. Your health care provider can help U.S. Department of Agriculture researcher, told Endocrine News. full signal from gut hormones, such can lower your risk for type 2 diabetes, high blood pressure, you decide how to change your eating habits. Choices include “This will be heightened as glucagon-like peptide-1 (GLP-1), stroke, and heart disease. Losing weight can also help you feel • Eating fewer calories than usual. This strategy helped people if the foods are ones that cholecystokinin (CKK), and pancreatic better. in the DPP study lose weight. Outside the home, you particularly like.” polypeptide (PPY) among others, to • Eating a low-carbohydrate diet. The psychology at reach the satiety center in the hypo- There are proven ways to lose weight. You can find what works • Eating less fat. People in the DPP study cut down on fat. almost all food changing eating habits work here contributes to thalamus. Slowing down allows time for you. Research has proven that and • Choosing more foods that aren’t high in calories and low in increasing physical activity (exercising) portion sizes have overconsumption; people for these hormones to do their work help people lose weight. nutrients. Eating foods such as non-starchy vegetables, some increased, some— often don’t realize they before those last forkfuls are taken. Other strategies also can help. For example, you might find fruits, and broth soups help you feel full, even though you’re are eating more and they In addition, said Caroline M. Apo- that rewarding yourself for exercising every day helps keep you eating fewer calories. such as cookies and don’t necessarily feel vian, M.D., director of the Nutrition motivated. Choose a non-food reward. • Using meal replacements, such as shakes or bars. They control sodas—up to eight fuller. In a 2003 “bot- and Weight Management Center at serving sizes, eliminate decisions about food choices, and are tomless bowl” study, 54 Boston Medical Center and profes- easy to keep on hand. times. participants ate soup sor of medicine at Boston University from either a normal School of Medicine, “Eating slowly DID YOU KNOW? Other healthy diets, such as the low-sodium DASH diet, also can bowl or a bowl rigged to in- can increase the response of PYY help. The DASH diet is designed to lower blood pressure but you conspicuously and automati- and GLP-1 as compared to eating Once you start eating, it takes 20 minutes can also use it to lose weight. It includes fruits, vegetables, whole cally refill. The refilling bowl fast.” It can also reduce levels of the for digestive hormones to tell your brain that grain foods, low-fat or non-fat dairy foods, nuts, seeds, and lean subjects ate a whopping 73 so-called “hunger hormone” ghrelin. you are full. For many people, eating slowly meats, poultry, and fish. percent more than those “Compared with 15 chews, 40 chews can help them eat less and still feel full. with the normal bowl. The results in lower caloric intake, lower WHAT KINDS OF EXERCISE CAN HELP researchers concluded that postprandial ghrelin concentrations, YOU LOSE WEIGHT? a large portion size sends a and higher GLP-1 and CCK concentra- subliminal message to our tions,” Apovian explained. In general, many kinds of exercise will help you lose weight, brains that this is the ac- Other tips include getting ad- THE DIABETES PREVENTION especially when you exercise daily or most days of the week. cepted norm, making it ap- equate support, such as in a weight PROGRAM (DPP) Walking briskly (for about 30 minutes a day) is a good way to propriate, even expected, for loss group, and keeping a food diary, exercise. To help you stick with your plan, you should choose a us to consume that amount. both of which involve controlling In this large study, researchers looked at what worked best type of exercise you enjoy. People in the DPP study exercised a Such visual cues also tend portion size and, in turn, eating less. for preventing type 2 diabetes. All of the people in the study total of 150 minutes each week, or about 20 minutes each day. to reduce our reliance on were overweight. Results showed that people who lost a

ENDOCRINE NEWS • SEPTEMBER 2012 our own self-monitoring sys- Continued on page 38 modest amount of weight through diet and exercise sharply However, exercise alone (without limiting calories) usually isn’t 36 lowered their risk for developing type 2 diabetes. enough to cause weight loss. But exercise plays an important part in helping people who have lost weight keep that weight off.

FS_CMD_Proven_Weight_Loss_EN 6-12.indd 1 6/5/12 3:21 PM 36_39 PractRes Sept2012.indd 36 8/10/12 11:51 AM FACT SHEET

Proven Weight Loss Methods

WHAT CAN WEIGHT LOSS WHAT CHANGES IN EATING HABITS CAN DO FOR YOU? HELP YOU LOSE WEIGHT? Most people need to change what they eat and how much they Losing weight can improve your health in a number of ways. It eat in order to lose weight. Your health care provider can help can lower your risk for type 2 diabetes, high blood pressure, you decide how to change your eating habits. Choices include stroke, and heart disease. Losing weight can also help you feel • Eating fewer calories than usual. This strategy helped people better. in the DPP study lose weight. • Eating a low-carbohydrate diet. There are proven ways to lose weight. You can find what works • Eating less fat. People in the DPP study cut down on fat. changing eating habits for you. Research has proven that and • Choosing more foods that aren’t high in calories and low in increasing physical activity (exercising) help people lose weight. nutrients. Eating foods such as non-starchy vegetables, some Other strategies also can help. For example, you might find fruits, and broth soups help you feel full, even though you’re that rewarding yourself for exercising every day helps keep you eating fewer calories. motivated. Choose a non-food reward. • Using meal replacements, such as shakes or bars. They control serving sizes, eliminate decisions about food choices, and are easy to keep on hand. DID YOU KNOW? Other healthy diets, such as the low-sodium DASH diet, also can help. The DASH diet is designed to lower blood pressure but you Once you start eating, it takes 20 minutes can also use it to lose weight. It includes fruits, vegetables, whole for digestive hormones to tell your brain that grain foods, low-fat or non-fat dairy foods, nuts, seeds, and lean you are full. For many people, eating slowly meats, poultry, and fish. can help them eat less and still feel full. WHAT KINDS OF EXERCISE CAN HELP YOU LOSE WEIGHT? In general, many kinds of exercise will help you lose weight, THE DIABETES PREVENTION especially when you exercise daily or most days of the week. PROGRAM (DPP) Walking briskly (for about 30 minutes a day) is a good way to exercise. To help you stick with your plan, you should choose a In this large study, researchers looked at what worked best type of exercise you enjoy. People in the DPP study exercised a for preventing type 2 diabetes. All of the people in the study total of 150 minutes each week, or about 20 minutes each day. were overweight. Results showed that people who lost a modest amount of weight through diet and exercise sharply However, exercise alone (without limiting calories) usually isn’t lowered their risk for developing type 2 diabetes. enough to cause weight loss. But exercise plays an important part in helping people who have lost weight keep that weight off.

FS_CMD_Proven_Weight_Loss_EN 6-12.indd 1 6/5/12 3:21 PM 36_39 PractRes Sept2012.indd 37 8/10/12 11:51 AM WHAT OTHER STRATEGIES CAN HELP YOU LOSE WEIGHT? Questions to ask your doctor These actions also help: • Weighing yourself every day • What is a healthy weight for me? • Keeping daily food records of everything you eat and drink • Can you recommend a diet plan for me? • Eating breakfast every day • Keeping the same eating patterns weekdays and weekends • Should I see a registered dietitian? • Should I see a diabetes educator? Many people ﬁnd that having support from other people helps them lose weight. You can get support by attending weekly • What kind of exercise is best for me? group meetings or from weekly visits with a health care provider, • How long will it take to reach my weight such a registered dietitian. goal?

CAN MEDICINES HELP WITH WEIGHT LOSS? RESOURCES Studies show that anti-obesity medicines can help people • Find-an-Endocrinologist: www.hormone.org or call lose more weight when combined with lifestyle changes (diet, 1-800-HORMONE (1-800-467-6663) exercise, and behavior change) than they can with lifestyle • Find a registered dietitian (Academy of Nutrition and changes alone. Dietetics): www.eatright.org/programs/rdﬁnder • Find a diabetes educator (American Association of Diabetes IS WEIGHT LOSS HARDER FOR PEOPLE Educators): www.diabeteseducator.org/DiabetesEducation/ WITH DIABETES? Find.html • Hormone Health Network information about hormones and Some studies show that weight loss is harder for people who obesity: www.hormone.org/Other/upload/hormones-and- have diabetes than for people who don’t. But you can still lose obesity-bilingual-042010.pdf weight, even if you have diabetes. • Mayo Clinic: www.mayoclinic.com/health/weight-loss/ NU00616 WHAT SHOULD YOU DO IF YOU WANT • National Institutes of Health: TO LOSE WEIGHT? —Weight-control Information Network: www.win.niddk.nih. gov or call (toll-free) 1-877-946-4627 Tell your doctor, dietitian, or diabetes educator that you’d like —Diabetes Prevention Program (DPP): diabetes.niddk.nih. to lose weight. Work with your provider to make a plan. Make gov/dm/pubs/preventionprogram and sure you’ve included a way to change what you eat a way to —DASH Diet: www.nhlbi.nih.gov/health/public/heart/hbp/ exercise. To get ready, choose a date to start. Decide how you’ll dash/new_dash.pdf reward yourself for doing what you’ve said you’ll do.

Most importantly, focus on what you can control. You can control what you eat and whether you go for a walk. But you can’t control how fast you lose weight. If you ﬁnd that your plan isn’t working, it doesn’t mean you’ve failed. Instead, it means you should change your plan. Find a plan that works for you.

EDITORS The Hormone Health Network offers free, online resources based on the most advanced clinical and scientiﬁc knowledge from Caroline M. Apovian, MD The Endocrine Society (www.endo-society.org). The Network’s goal Judith Korner, MD, PhD is to move patients from educated to engaged, from informed to active partners in their health care. This fact sheet is also available in Spanish at www.hormone.org/Spanish.

July 2012 Proven Weight Loss Methods Fact Sheet www.hormone.org

FS_CMD_Proven_Weight_Loss_EN 6-12.indd 2 6/5/12 3:21 PM 36_39 PractRes Sept2012.indd 38 8/10/12 11:51 AM WHAT OTHER STRATEGIES CAN HELP Continued from page 36 YOU LOSE WEIGHT? Questions to ask your doctor These actions also help: PRACTICE RESOURCES • Weighing yourself every day • What is a healthy weight for me? And, we can or placemat into appropriate serving • Keeping daily food records of everything you eat and drink • Can you recommend a diet plan for me? benefit from plain sizes and pictorially compares serv- • Eating breakfast every day and simple education ing sizes in many food categories to • Keeping the same eating patterns weekdays and weekends • Should I see a registered dietitian? as well to remedy everyday items to facilitate remem- • Should I see a diabetes educator? the all-too-common bering these sizes (for instance, 1.5 Many people find that having support from other people helps disconnect between ounces of hard cheese = 3 dice.) • What kind of exercise is best for me? them lose weight. You can get support by attending weekly portion size and serv- WebMD offers downloadable template group meetings or from weekly visits with a health care provider, • How long will it take to reach my weight ing size. Using vessels versions of a Portion Size Plate® in such a registered dietitian. goal? that show measure- various sizes that can be carried in ments is becoming wallets or stuck to the front of the CAN MEDICINES HELP WITH WEIGHT a popular strategy fridge. The USDA also provides similar LOSS? to reduce intake. services as part of their MyPlate pro- RESOURCES Measuring serving gram (www.choosemyplate.gov/). Studies show that anti-obesity medicines can help people • Find-an-Endocrinologist: www.hormone.org or call sizes and seeing what A similar strategy involves re- lose more weight when combined with lifestyle changes (diet, 1-800-HORMONE (1-800-467-6663) a cup, for example, packaging foods into smaller-volume exercise, and behavior change) than they can with lifestyle • Find a registered dietitian (Academy of Nutrition and really contains is an containers, as Bloomberg seeks changes alone. Dietetics): www.eatright.org/programs/rdfinder eye-opening experi- to do. If the supersize soda ban • Find a diabetes educator (American Association of Diabetes ence for many people proposal becomes law and Big Apple IS WEIGHT LOSS HARDER FOR PEOPLE Educators): www.diabeteseducator.org/DiabetesEducation/ who previously esti- residents shrink their drinks and WITH DIABETES? Find.html mated the capacity of their waistlines, it will be an inspira- • Hormone Health Network information about hormones and a cup to be consider- tion for people across the nation to Some studies show that weight loss is harder for people who obesity: www.hormone.org/Other/upload/hormones-and- ably larger. mind their plates. ■ ® have diabetes than for people who don’t. But you can still lose obesity-bilingual-042010.pdf The Portion Plate Hovarth is a free-lance writer and editor in Baltimore. weight, even if you have diabetes. • Mayo Clinic: www.mayoclinic.com/health/weight-loss/ demarcates a plate NU00616 WHAT SHOULD YOU DO IF YOU WANT • National Institutes of Health: TO LOSE WEIGHT? —Weight-control Information Network: www.win.niddk.nih. gov or call (toll-free) 1-877-946-4627 Tell your doctor, dietitian, or diabetes educator that you’d like —Diabetes Prevention Program (DPP): diabetes.niddk.nih. to lose weight. Work with your provider to make a plan. Make gov/dm/pubs/preventionprogram Register Now and Save! and sure you’ve included a way to change what you eat a way to —DASH Diet: www.nhlbi.nih.gov/health/public/heart/hbp/ exercise. To get ready, choose a date to start. Decide how you’ll dash/new_dash.pdf reward yourself for doing what you’ve said you’ll do. Endocrine Board Review

Most importantly, focus on what you can control. You can control SEPTEMBER 11–12, 2012 | MIAMI, FLORIDA what you eat and whether you go for a walk. But you can’t control how fast you lose weight. If you ﬁnd that your plan isn’t working, Are you prepared? Test your medical knowledge of it doesn’t mean you’ve failed. Instead, it means you should endocrinology at the Endocrine Board Review Course (EBR). change your plan. Find a plan that works for you. • Experience the most in-depth board preparation available • Assess your knowledge in each topic-specific area of the ABIM’s Endocrinology, Diabetes, and Metabolism Certification Examination • Get real-time feedback on your performance with the interactive mock-exam

Register by August 15 for discounted rates at www.endo-society.org/ebr or call Society Services at 1.888.363.6762 (toll-free in the U.S.) or 1.301.941.0210.

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July 2012 Proven Weight Loss Methods Fact Sheet www.hormone.org

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FS_CMD_Proven_Weight_Loss_EN 6-12.indd 2 6/5/12 3:21 PM 36_39 PractRes Sept2012.indd 39 8/10/12 11:51 AM SPOTLIGHT ON POLICY

s part of ongoing efforts to support a diverse and produc- Ative biomedical research workforce, The Endocrine Society recently The Society Supports NIH’s contributed to a National Institutes of Health (NIH) initiative to in- Workforce Diversity Effort crease support for underrepresented minorities in the biomedical research By Katie Moore, Ph.D. workforce. NIH sought feedback from the to bolster the success of minority groups. Student outreach and pro- scientific community after an August grant applicants, including funding fessional development programs, 2011 Science article titled, “Race, support for mentoring and career mentoring and networking activities, Ethnicity, and NIH Research Awards” development programs. The Society and comprehensive summer research raised concerns about opportunities also advocated for the development training programs are a few examples for minorities. The article, which of a tracking system to monitor the of the Society’s diversity portfolio. presents data correlating NIH R01 progress of trainees throughout their A second NIH ACD working group applicants’ race or ethnicity and the careers. These recommendations was charged with recommending probability of receiving an award, are included in the working group’s actions NIH could take to enhance shows that underrepresented minori- final report to NIH. In addition, the training for all biomedical research- BYDUREON: ties—including African Americans, report encouraged NIH to establish ers—not just underrepresented Hispanics, and Na- minorities—while reducing overall the first and only once-weekly tive Americans—with training time. The Society’s response doctorates in science to this working group highlighted treatment for type 2 diabetes and engineering make the importance of recognizing up less than 9 percent scientific work outside of academia. of occupations in these The Society encouraged NIH to assist fields. Compared to their institutions in providing training and white colleagues, Asian career development opportunities To learn more about BYDUREON through our Professional Education Programs, scientists are 4 percent- to prepare trainees for a variety of please visit www.BYDUREONHCP.com/ProfEd age points less likely to careers, specifically recommending receive R01 funding from the inclusion of training related to Indication and Usage NIH, the article said. For business management, mentoring, BYDUREON is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in African-American scien- and teaching science. multiple clinical settings. tists, the probability of These recommendations were • Because of the uncertain relevance of the rat thyroid C-cell tumor ndings to humans, prescribe only to patients for whom potential receiving funding is included in the working group’s final bene ts are considered to outweigh potential risk. even less likely, falling report to NIH, along with calls for the • Not recommended as rst-line therapy for patients who have inadequate glycemic control on diet and exercise. at 13 percentage points development of a more permanent • Not a substitute for insulin, should not be used in patients with type 1 diabetes or diabetic ketoacidosis, and cannot be recommended below whites (see http:// research staffing model, for increases for use with insulin. www.sciencemag.org/ in the number of early career awards • BYDUREON and BYETTA® (exenatide) injection both contain the same active ingredient, exenatide, and should not be used together. content/333/6045/1015). that NIH issues, and for limits on the • Exenatide has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, based on In response to the amount of investigator, student, and postmarketing data. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using BYDUREON; consider other antidiabetic therapies for these patients. article the NIH Advi- postdoc salaries that can be charged sory Committee to the to grants. The group also proposed BOXED WARNING: RISK OF THYROID C-CELL TUMORS Director (ACD) created a that NIH undertake a closer examina- Exenatide extended-release causes an increased incidence in thyroid C-cell tumors at clinically relevant exposures in rats working group to examine diversity an Office of Diversity and a new ACD tion of physician-scientist training. compared to controls. It is unknown whether BYDUREON causes thyroid C-cell tumors, including medullary thyroid carcinoma in the biomedical research work- working group to further examine The Society will continue to work (MTC), in humans, as human relevance could not be determined by clinical or nonclinical studies. BYDUREON is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). with its members and the scientific force. Acting on the working group’s methods for reducing disparities in Routine serum calcitonin or thyroid ultrasound monitoring is of uncertain value in patients treated with BYDUREON. Patients request, the Society sent a letter research awards. community to advocate for equity in should be counseled regarding the risk and symptoms of thyroid tumors. recommending specific actions that The Society has long been a biomedical research and to develop NIH can take to improve the partici- proponent of programs to increase programs and awards that support For additional safety pro le and other important prescribing pation and success of minorities in opportunities for minorities in the a sustainable, diverse biomedical considerations, please see the adjacent pages for the field. Focusing on concepts that biomedical research workforce and research workforce. ■ Brief Summary of Prescribing Information. could enhance diversity throughout maintains a broad array of career the biomedical research workforce development activities and programs Moore is the manager of science policy at The Endocrine Society. ENDOCRINE NEWS • SEPTEMBER 2012 pipeline, the Society suggested ways specifically for underrepresented 08-10-10680-B ©2012 AMYLIN PHARMACEUTICALS, INC. PRINTED IN USA. ALL RIGHTS RESERVED. 40 The BYDUREON mark and BYDUREON design mark are registered trademarks of Amylin Pharmaceuticals, Inc. BYETTA is a registered trademark of Amylin Pharmaceuticals, Inc.

21866_pamlar_jrnl_ad_EndocrineNews.indd 1 8/6/12 3:52 PM 40_43 Spotlight Sept2012.indd 40 8/10/12 11:51 AM PALIO Date: 8.03.12 • Client: Amylin • Product: Bydureon • File Name: 21866_pamlar_jrnl_ad_EndocrineNews.indd Endocrine News Ad Page Trim: 8.125” x 10.875” • Bleed: 8.375” x 11.125” • Live: 7.875” x 10.625” BYDUREON: the ﬁrst and only once-weekly treatment for type 2 diabetes

To learn more about BYDUREON through our Professional Education Programs, please visit www.BYDUREONHCP.com/ProfEd Indication and Usage BYDUREON is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings. • Because of the uncertain relevance of the rat thyroid C-cell tumor ndings to humans, prescribe only to patients for whom potential bene ts are considered to outweigh potential risk. • Not recommended as rst-line therapy for patients who have inadequate glycemic control on diet and exercise. • Not a substitute for insulin, should not be used in patients with type 1 diabetes or diabetic ketoacidosis, and cannot be recommended for use with insulin. • BYDUREON and BYETTA® (exenatide) injection both contain the same active ingredient, exenatide, and should not be used together. • Exenatide has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, based on postmarketing data. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using BYDUREON; consider other antidiabetic therapies for these patients. BOXED WARNING: RISK OF THYROID C-CELL TUMORS Exenatide extended-release causes an increased incidence in thyroid C-cell tumors at clinically relevant exposures in rats compared to controls. It is unknown whether BYDUREON causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be determined by clinical or nonclinical studies. BYDUREON is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Routine serum calcitonin or thyroid ultrasound monitoring is of uncertain value in patients treated with BYDUREON. Patients should be counseled regarding the risk and symptoms of thyroid tumors.

For additional safety pro le and other important prescribing considerations, please see the adjacent pages for Brief Summary of Prescribing Information.

08-10-10680-B ©2012 AMYLIN PHARMACEUTICALS, INC. PRINTED IN USA. ALL RIGHTS RESERVED. The BYDUREON mark and BYDUREON design mark are registered trademarks of Amylin Pharmaceuticals, Inc. BYETTA is a registered trademark of Amylin Pharmaceuticals, Inc.

21866_pamlar_jrnl_ad_EndocrineNews.indd 1 8/6/12 3:52 PM 40_43 Spotlight Sept2012.indd PALIO Date:41 8.03.12 • Client: Amylin • Product: Bydureon • File Name: 21866_pamlar_jrnl_ad_EndocrineNews.indd 8/10/12 11:51 AM Endocrine News Ad Page Trim: 8.125” x 10.875” • Bleed: 8.375” x 11.125” • Live: 7.875” x 10.625” BYDUREON® (exenatide extended-release for injectable suspension) There have been postmarketing reports of altered renal function with exenatide, including increased serum A total of 246 patients with antibodies to exenatide in the BYETTA and BYDUREON clinical trials were tested USE IN SPECIFIC POPULATIONS creatinine, renal impairment, worsened chronic renal failure and acute renal failure, sometimes requiring for the presence of cross-reactive antibodies to GLP-1 and/or glucagon. No treatment-emergent cross reactive Initial U.S. Approval: 2012 Pregnancy hemodialysis or kidney transplantation. Some of these events occurred in patients receiving one or more antibodies were observed across the range of titers. Pregnancy Category C Brief Summary: For complete details, please see full Prescribing Information pharmacologic agents known to aect renal function or hydration status such as angiotensin converting enzyme Other Adverse Reactions There are no adequate and well-controlled studies of BYDUREON use in pregnant women. In rats, exenatide

inhibitors, nonsteroidal anti-inammatory drugs, or diuretics. Some events occurred in patients who had been Monotherapy extended-release administered during the major period of organogenesis reduced fetal growth and produced WARNING: RISK OF THYROID C-CELL TUMORS experiencing nausea, vomiting, or diarrhea, with or without dehydration. Reversibility of altered renal function In a 26-week trial, treatment-emergent adverse reactions reported in ≥5% of BYDUREON-treated pat ients skeletal ossication decits in association with maternal eects; exenatide extended-release was not teratogenic in

Exenatide extended-release causes an increased incidence in thyroid C-cell tumors at clinically relevant exposures has been observed in many cases with supportive treatment and discontinuation of potentially causative agents, (N = 248) vs sitagliptin (N = 163), pioglitazone (N = 163) and metformin (N = 246), respectively, were nausea rats. In animal developmental studies, exenatide, the active ingredient of BYDUREON, caused cleft palate, irregular

in rats compared to controls. It is unknown whether BYDUREON causes thyroid C-cell tumors, including medullary including exenatide. Exenatide has not been found to be directly nephrotoxic in preclinical or clinical studies. (11.3% vs 3.7%, 4.3%, and 6.9%), diarrhea (10.9% vs 5.5%, 3.7%, and 12.6%), injection-site nodule (10.5% skeletal ossication and an increased number of neonatal deaths. BYDUREON should be used during pregnancy only

thyroid carcinoma (MTC), in humans, as human relevance could not be determined by clinical or nonclinical studies. Gastrointestinal Disease vs 6.7%, 3.7%, and 10.2%), constipation (8.5% vs 2.5%, 1.8%, and 3.3%), headache (8.1% vs 9.2%, 8.0%, and if the potential benet justies the potential risk to the fetus.

BYDUREON is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Exenatide has not been studied in patients with severe gastrointestinal disease, including gastroparesis. 12.2%), and dyspepsia (7.3% vs 1.8%, 4.9%, and 3.3%). Patients in the sitagliptin, pioglitazone, and metformin Fetuses from pregnant rats given subcutaneous doses of exenatide extended-release at 0.3, 1 or 3 mg/kg on

Endocrine Neoplasia syndrome type 2 (MEN 2). Routine serum calcitonin or thyroid ultrasound monitoring is of Because exenatide is commonly associated with gastrointestinal adverse reactions, including nausea, vomiting, arms received weekly placebo injection. gestation days 6, 9, 12 and 15 demonstrated reduced fetal growth at all doses and produced skeletal ossication

uncertain value in patients treated with BYDUREON. Patients should be counseled regarding the risk and symptoms and diarrhea, the use of BYDUREON is not recommended in patients with severe gastrointestinal disease. decits at 1 and 3 mg/kg in association with maternal eects (decreased food intake and decreased body weight gain). Combination therapy of thyroid tumors [see Contraindications and Warnings and Precautions]. There was no evidence of malformations. Doses of 0.3, 1 and 3 mg/kg correspond to systemic exposures of 3, 7 and Immunogenicity 26-week add-on to metformin 17-times, respectively, the human exposure resulting from the reco mmended dose of 2 mg/week, based on area INDICATIONS AND USAGE Patients may develop antibodies to exenatide following treatment with BYDUREON. Anti-exenatide antibodies Treatment-emergent adverse reactions reported in ≥5% of BYDUREON-treated patients (N = 160) vs sitagliptin under the time-concentration curve (AUC). BYDUREON is an extended-release formulation of exenatide, administered as an injection once every seven days (weekly). were measured in all BYDUREON-treated patients in the ve comparator-controlled 24-30 week studies of (N = 166) and pioglitazone (N = 165), respectively, were nausea (24.4% vs. 9.6% and 4.8%), diarrhea (20.0% vs BYDUREON. In 6% of BYDUREON-treated patients, antibody formation was associated with an attenuated glycemic 9.6% and 7.3%), vomiting (11.3% vs 2.4% and 3.0%), headache (9.4% vs 9.0% and 5.5%), constipation (6.3% vs Female mice given subcutaneous doses of exenatide, the active ingredient of BYDUREON, at 6, 68, or 760 mcg/kg/ Type 2 Diabetes Mellitus response. If there is worsening glycemic control or failure to achieve targeted glycemic control, alternative 3.6% and 1.2%), fatigue (5.6% vs 0.6% and 3.0%), dyspepsia (5.0% vs 3.6% and 2.4%), decreased appetite (5.0% day beginning 2 weeks prior to and throughout mating until gestation day 7, had no adverse fetal eects. At the BYDUREON is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 antidiabetic therapy should be considered. vs 1.2% and 0.0%), and injection-site pruritus (5.0% vs 4.8% and 1.2%). Patients in the sitagliptin and pioglitazone maximal dose, 760 mcg/kg/day, systemic exposures were up to 148 times the human exposure resulting from the diabetes mellitus in multiple clinical settings. recommended dose of 2 mg/week, based on AUC. Hypersensitivity arms received weekly placebo injection. Important Limitations of Use In developmental toxicity studies, pregnant animals received exenatide, the active ingredient of BYDUREON, There have been postmarketing reports of serious hypersensitivity reactions (e.g. anaphylaxis and angioedema) 26-week add-on to metformin or metformin plus sulfonylurea Because of the uncertain relevance of the rat thyroid C-cell tumor ndings to humans, prescribe BYDUREON only subcutaneously during organogenesis. Specically, fetuses from pregnant rabbits given subcutaneous doses of in patients treated with exenatide. If a hypersensitivity reaction occurs, the patient should discontinue BYDUREON Treatment-emergent adverse reaction reported in ≥5% of BYDUREON-treated patients (N = 233) vs titrated to patients for whom the potential bene ts are considered to outweigh the potential risk. exenatide at 0.2, 2, 22, 156, or 260 mcg/kg/day from gestation day 6 through 18 experienced irregular skeletal and other suspect medications and promptly seek medical advice. insulin glargine (N = 223), respectively, were nausea (12.9 vs 1.3), headache (9.9 vs 7.6), diarrhea (9.4 vs 4.0), and BYDUREON is not recommended as rst-line therapy for patients who have inadequate glycemic control on diet and exercise. injection-site nodule (6.0 vs 0.0). ossications from exposures 4 times the human exposure resulting from the recommended dose of 2 mg/week, Macrovascular Outcomes BYDUREON is not a substitute for insulin. BYDUREON should not be used in patients with type 1 diabetes or for 24-30 week monotherapy or as add-on to metformin, sulfonylurea, thiazolidinedione or combination of oral agents based on AUC. Fetuses from pregnant mice given subcutaneous doses of exenatide at 6, 68, 460, or 760 mcg/kg/day There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with the treatment of diabetic ketoacidosis, as it would not be eective in these settings. In the 24-week trial, treatment-emergent adverse react ions reported in ≥5% of BYDUREON-treated patients from gestation day 6 through 15 demonstrated reduced fetal and neonatal growth, cleft palate and skeletal eects BYDUREON or any other antidiabetic drug. The concurrent use of BYDUREON with insulin has not been studied and cannot be recommended. (N = 129) vs BYETTA (N = 123), respectively, were nausea (14.0% vs 35.0%), diarrhea (9.3% vs 4.1%), and at systemic exposure that is equivalent to the human exposure resulting from the recommended dose of 2 mg/ BYDUREON and BYETTA® (exenatide) injection both contain the same active ingredient, exenatide, and therefore ADVERSE REACTIONS injection-site erythema (5.4% vs 2.4%). In the 30-week trial, treatment-emergent adverse reactions reported in week, based on AUC. should not be used together. Clinical Trial Experience ≥5% of BYDUREON-treated patients (N = 148) vs BYETTA (N = 145), respectively, were nausea (27.0% vs 33.8%), Lactating mice given subcutaneous doses of exenatide, the active ingredient of BYDUREON, at 6, 68, or 760 mcg/ Based on postmarketing data, exenatide has been associated with acute pancreatitis, including fatal and Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the diarrhea (16.2% vs 12.4%), vomiting (10.8% vs 18.6%), injection-site pruritus (18.2% vs 1.4%), constipation kg/day from gestation day 6 through lactation day 20 (weaning), experienced an increased number of neonatal non-fatal hemorrhagic or necrotizing pancreatitis. BYDUREON has not been studied in patients with a history of clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reect (10.1% vs 6.2%), gastroenteritis viral (8.8% vs 5.5%), gastroesophageal reux disease (7.4% vs 4.1%), dyspepsia deaths. Deaths were observed on postpartum days 2-4 in dams given 6 mcg/kg/day, a systemic exposure that is pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while the rates observed in practice. (7.4% vs 2.1%), injection-site erythema (7.4% vs 0.0%), fatigue (6.1% vs 3.4%), headache (6.1% vs 4.8%), and equivalent to the human exposure resulting from the recommended dose of 2 mg/week, based on AUC. using BYDUREON. Other antidiabetic therapies should be considered in patients with a history of pancreatitis. The safety of BYDUREON was assessed in ve comparator-controlled trials, in patients who entered the studies not achieving injection-site hematoma (5.4% vs 11.0%). Pregnancy Registry CONTRAINDICATIONS adequate glycemic control on their current therapy. In a double-blind 26 week trial, patients on diet and exercise were treated Nausea was the most common adverse reaction associated with initiation of treatment with BYDUREON, and Amylin Pharmaceuticals, Inc. maintains a Pregnancy Registry to monitor pregnancy outcomes of women exposed with BYDUREON 2 mg once every seven days (weekly), sitagliptin 100 mg daily, pioglitazone 45 mg daily, or metformin 2000 Medullary Thyroid Carcinoma usually decreased over time. to exenatide during pregnancy. Physicians are encouraged to register patients by calling (800) 633-9081. mg daily. In a double-blind 26 week trial, patients on metformin were treated with BYDUREON 2 mg once every seven days BYDUREON is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in Injection Site Reactions Nursing Mothers (weekly), sitagliptin 100 mg daily, or pioglitazone 45 mg daily. In an open-label 26 week trial, patients on metformin or patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). In the ve comparator-controlled 24-30 week trials, injection site reactions were observed more frequently in Exenatide is present in the milk of lactating mice at concentrations less than or equal to 2.5% of the concentration metformin plus sulfonylurea were treated with BYDUREON 2 mg once every seven days (weekly) or optimized insulin glargine. Hypersensitivity patients treated with BYDUREON (17.1%) than in patients treated with BYETTA (12.7%), titrated insulin glargine in maternal plasma following subcutaneous dosing. It is not known whether exenatide is excreted in human In two open-label 24 to 30 week studies, patients on diet and exercise or metformin, a sulfonylurea, a thiazolidinedione or (1.8%) or those patients who received placebo injections (sitagliptin (10.6%), pioglitazone (6.4%), and metformin milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for BYDUREON is contraindicated in patients with a prior serious hypersensitivity reaction to exenatide or to any of the combination of oral agents were treated with BYDUREON 2 mg once every seven days (weekly) or BYETTA 10 mcg twice daily. product components. (13.0%) treatment groups). These reactions for patients treated with BYDUREON were more commonly observed in exenatide extended-release in animal studies, a decision should be made whether to discontinue nursing or to Withdrawals antibody-positive patients (14.2%) compared with antibody-negative patients (3.1%), with a greater incidence in discontinue BYDUREON, taking into account the importance of the drug to the mother. WARNINGS AND PRECAUTIONS The incidence of withdrawal due to adverse events was 4.9% (N=45) for BYDUREON-treated patients, 4.9% (N=13) those with higher titer antibodies. Incidence of injection site reactions for patients treated with BYETTA was similar Pediatric Use Risk of Thyroid C-cell Tumors for BYETTA-treated patients and 2.0% (N=23) for other comparator-treated patients in the ve comparator-controlled for antibody positive pat ients (5.8%) and antibody negative patients (7.0%). One percent of patients treated with Safety and eectiveness of BYDUREON have not been established in pediatric patients. BYDUREON is not In both genders of rats, exenatide extended-release caused a dose-related and treatment-duration-dependent 24-30 week trials. The most common adverse reactions leading to withdrawal for BYDUREON-treated patients were BYDUREON withdrew due to injection site adverse reactions (injection site mass, injection site nodule, injection site recommended for use in pediatric patients. increase in the incidence of thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures nausea 0.5% (N=5) versus 1.5% (N=4) for BYETTA and 0.3% (N=3) for other comparators, injection site nodule 0.5% pruritus, and injection site reaction). Geriatric Use compared to controls. A statistically signi cant increase in malignant thyroid C-cell carcinomas was observed in (N=5) versus 0.0% for BYETTA and 0.0% for other comparators, diarrhea 0.3% (N=3) versus 0.4% (N=1) for BYETTA Small, asymptomatic subcutaneous injection site nodules are seen with the use of BYDUREON. In a separate 15-week In the ve comparator-controlled 24-30 week trials, BYDUREON was studied in 132 patients (16.6%) who female rats receiving exenatide extended-release at 25-times clinical exposure compared to controls and higher and 0.3% (N=3) for other comparators, injection site reaction 0.2% (N=2) versus 0.0% for BYETTA and 0.0% for other study in which information on nodules were collected and analyzed, 24 out of 31 subjects (77%) experienced at were at least 65 years old and 20 patients who were at least 75 years old. No dierences in safety (N = 152) and incidences were noted in males above controls in all treated groups at ≥2-times clinical exposure. The potential comparators and headache 0.2% (N=2) versus 0.0% for BYETTA and 0.0% for other comparators. least one injection site nodule during treatment; 2 subjects (6.5%) reported accompanying localized symptoms. ecacy (N = 52) were observed between these patients and younger patients, but the small sample size for of exenatide extended-release to induce C-cell tumors in mice has not been evaluated. Other GLP-1 receptor The mean duration of events was 27 days. The formation of nodules is consistent with the known properties of the Hypoglycemia patients ≥75 years old limits conclusions. agonists have also induced thyroid C-cell adenomas and carcinomas in male and female mice and rats at clinically microspheres used in BYDUREON. The incidence (% of subjects) and rate (episodes/subject year) of minor hypoglycemia in the ve comparator- In separate trials, BYETTA was studied in 282 patients at least 65 years old and in 16 patients at least 75 years old. relevant exposures. It is unknown whether BYDUREON will cause thyroid C-cell tumors, including medullary thyroid controlled 24-30 week trials of BYDUREON used as monotherapy or as add-on to metformin, a sulfonylurea, a Post-Marketing Experience carcinoma (MTC), in humans, as the human relevance of exenatide extended-release-induced rodent thyroid C-cell No dierences in safety and ecacy were observed between these patients and younger patients, but the small thiazolidinedione or combination of these oral antidiabetic agents were as follows. In these trials, an event was BYETTA sample size for patients ≥75 years old limits conclusions. tumors could not be determined by clinical or nonclinical studies. Serum calcitonin was not assessed in the clinical classi ed as minor hypoglycemia if there were symptoms of hypoglycemia with a concomitant glucose <54 mg/dL The following additional adverse reactions have been reported during post-approval use of BYETTA. Because trials supporting the approval of BYDUREON [see Boxed Warning]. Because elderly patients are more likely to have decreased renal function, use caution when initiating BYDUREON and the patient was able to self-treat. these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably in the elderly. Serum calcitonin is a biological marker of MTC. Patients with MTC usually have calcitonin values >50 ng/L. In the 26-week monotherapy trial: BYDUREON, 2.0% (0.05) [N = 248]; sitagliptin, 0.0% (0.00) [N = 163]; estimate their frequency or establish a causal relationship to drug exposure. Hepatic Impairment Patients with thyroid nodules noted on physical examination or neck imaging should be referred to an pioglitazone, 0.0% (0.00) [N = 163]; and metformin, 0.0% (0.00) [N = 246]. In the 26-week add-on to metformin Allergy/Hypersensitivity: injection-site reactions, generalized pruritus and/or urticaria, macular or papular rash, No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic hepatic impairment. endocrinologist for further evaluation. Routine monitoring of serum calcitonin or using thyroid ultrasound is of trial: BYDUREON, 1.3% (0.03) [N = 160]; sitagliptin, 3.0% (0.12) [N = 166]; and pioglitazone, 1.2% (0.03) [N = 165]. angioedema; anaphylactic reaction. Because exenatide is cleared primarily by the kidney, hepatic impairment is not expected to aect blood concentrations uncertain value for early detection of MTC in patients treated with BYDUREON. Such monitoring may increase the In the 26-week add-on to metformin or metformin plus sulfonylurea trial: with concomitant sulfonylurea, Drug Interactions: increased international normalized ratio (INR), sometimes associated with bleeding, with of exenatide. risk of unnecessary procedures, due to the low speci city of serum calcitonin testing for MTC and a high background BYDUREON, 20.0% (1.11) [N = 70] and titrated insulin glargine, 43.9% (2.87) [N = 66]; without concomitant concomitant warfarin use. incidence of thyroid disease. If serum calcitonin is measured and found to be elevated, the patient should be sulfonylurea, BYDUREON, 3.7% (0.11) [N =163] and titrated insulin glargine, 19.1% (0.64) [N = 157]. Insulin Gastrointestinal: nausea, vomiting, and/or diarrhea resulting in dehydration; abdominal distension, abdominal OVERDOSAGE referred to an endocrinologist for further evaluation. glargine was dosed to a target fasting glucose concentration of 72 to 100 mg/dL. The mean dose of insulin glargine pain, eructation, constipation, atulence, acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes There were no reports of overdose in the ve comparator-controlled 24-30 week trials of BYDUREON. Eects of Acute Pancreatitis was 10 Units/day at baseline and 31 Units/day at endpoint. resulting in death. overdoses with BYETTA in clinical studies included severe nausea, severe vomiting, and rapidly declining blood glucose Based on postmarketing data, exenatide has been associated with acute pancreatitis, including In the 24-30 week trials of BYDUREON as monotherapy or add-on to metformin, sulfonylurea, thiazolidinedione or Neurologic: dysgeusia; somnolence concentrations, including severe hypoglycemia requiring parenteral glucose administration. In the event of overdose, fatal and non-fatal hemorrhagic or necrotizing pancreatitis. After initiation of BYDUREON, observe any combination of these oral agents, incidence (% of subjects) and rate (episodes/subject year) of minor hypoglycemia Renal and Urinary Disorders: altered renal function, including increased serum creatinine, renal impairment, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms. patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, were as follows. In the 24-week trial: with concomitant sulfonylurea, BYDUREON, 12.5% (0.72) [N = 40] and BYETTA, worsened chronic renal failure or acute renal failure (sometimes requiring hemodialysis), kidney transplant and Manufactured by Amylin Pharmaceuticals, Inc., San Diego, CA 92121 sometimes radiating to the back, which may or may not be accompanied by vomiting). If pancreatitis 11.8% (0.31) [N = 34]; without concomitant sulfonylurea, BYDUREON, 0.0% (0.00) [N = 89] and BYETTA, 0.0% (0.00) kidney transplant dysfunction. 1-877-700-7365 is suspected, BYDUREON should promptly be discontinued and appropriate management should be [N = 89]. In the 30-week trial: with concomitant sulfonylurea, BYDUREON, 14.5% (0.55) [N =55] and BYETTA, 15.4% Skin and Subcutaneous Tissue Disorders: alopecia http://www.bydureon.com initiated. If pancreatitis is con rmed, BYDUREON should not be restarted. Consider antidiabetic (0.37) [N = 52]; without concomitant sulfonylurea, BYDUREON, 0.0% (0.00) [N = 93] and BYETTA, 1.1% (0.02) [N = 93]. DRUG INTERACTIONS Literature Revised January 2012 therapies other than BYDUREON in patients with a history of pancreatitis. There were no reported events of major hypoglycemia in these ve comparator-controlled 24-30 week Orally Administered Drugs BYDUREON and BYETTA are registered trademarks of Amylin Pharmaceuticals, Inc. trials. Major hypoglycemia was de ned as loss of consciousness, seizure or coma (or other mental status Hypoglycemia Exenatide slows gastric emptying. Therefore, BYDUREON has the potential to reduce the rate of absorption of U.S. Patent Nos. 5,424,286, 6,858,576, 6,872,700, 6,956,026, 7,456,254, 6,479,065, 6,495,164, 6,667,061, change consistent with neuroglycopenia in the judgment of the investigator or physician) which resolved after The risk of hypoglycemia is increased when exenatide is used in combination with a sulfonylurea. Therefore, orally administered drugs. Use caution when administering oral medications with BYDUREON. 6,824,822, 7,223,440, 7,563,871 and 7,612,176. administration of glucagon or glucose or required third party assistance to resolve because of severe impairment in patients receiving BYDUREON and a sulfonylurea may require a lower dose of the sulfonylurea to minimize In patients with type 2 diabetes, BYDUREON did not aect the absorption of orally administered acetaminophen © 2012 Amylin Pharmaceuticals, Inc. All rights reserved. 832001-JJ consciousness or behavior. Patients were to have a concomitant glucose <54 mg/dL. the risk of hypoglycemia. It is also possible that the use of BYDUREON with other glucose-independent insulin to any clinically relevant degree. 08-11-12866-B secretagogues (e.g. meglitinides) could increase the risk of hypoglycemia. Immunogenicity Warfarin Anti-exenatide antibodies were measured at prespeci ed intervals (4-14 weeks) in all BYDUREON-treated patients Renal Impairment BYDUREON has not been studied with warfarin. However, in a drug interaction study, BYETTA did not have a (N=918) in the ve comparator-controlled studies of BYDUREON. In these ve trials, 452 BYDUREON-treated patients (49%) BYDUREON should not be used in patients with severe renal impairment (creatinine clearance < 30 mL/min) signicant eect on INR. There have been postmarketing reports for BYETTA of increased INR with concomitant use had low titer antibodies (≤125) to exenatide at any time during the trials and 405 BYDUREON-treated patients (45%) or end-stage renal disease and should be used with caution in patients with renal transplantation. In patients of warfarin, sometimes associated with bleeding. In patients taking warfarin, the INR should be monitored more had low titer antibodies to exenatide at study endpoint (24-30 weeks). The level of glycemic control in these patients was with end-stage renal disease receiving dialysis, single doses of BYETTA 5 mcg were not well tolerated due to frequently after initiating BYDUREON. Once a stable INR has been documented, the INR can be monitored at the generally comparable to that observed in the 379 BYDUREON-treated patients (43%) without antibody titers. An additional gastrointestinal side eects. Because BYDUREON may induce nausea and vomiting with transient hypovolemia, intervals usually recommended for patients on warfarin. treatment may worsen renal function. Use BYDUREON with caution in patients with moderate renal impairment 107 BYDUREON-treated patients (12%) had higher titer antibodies at endpoint. Of these patients, 50 (6% overall) had an (creatinine clearance 30 to 50 mL/min). BYDUREON has not been studied in patients with end-stage renal disease attenuated glycemic response to BYDUREON (<0.7% reduction in HbA1c); the remaining 57 (6% overall) had a glycemic or severe renal impairment. response comparable to that of patients without antibodies. In the 30-week trial in which anti-exenatide antibody assessments were performed at baseline and at 4-week intervals from week 6 to week 30, the mean anti-exenatide antibody titer in the BYDUREON-treated patients peaked at week 6 then declined by 56% from this peak by week 30.

21866_pamlar_jrnl_ad_EndocrineNews.indd 2 8/6/12 3:52 PM 21866_pamlar_jrnl_ad_EndocrineNews.indd 3 8/6/12 3:52 PM 40_43 Spotlight Sept2012.inddPALIO Date: 42 8.03.12 • Client: Amylin • Product: Bydureon • File Name: 21866_pamlar_jrnl_ad_EndocrineNews.indd 8/10/12 11:51 AM PALIO Date: 8.03.12 • Client: Amylin • Product: Bydureon • File Name: 21866_pamlar_jrnl_ad_EndocrineNews.indd Endocrine News Endocrine News BS Page 1 Trim: 8.125” x 10.875” • Bleed: 8.375” x 11.125” • Live: 7.875” x 10.625” BS Page 2 Trim: 8.125” x 10.875” • Bleed: 8.375” x 11.125” • Live: 7.875” x 10.625” Save the Date for ENDO 2013 DID YOU Join us for ENDO 2013, The Endocrine Society’s 95th Annual Meeting & Expo, in the beautiful city by the bay. KNOW? You can post your CV, post an open position or look for your next career opportunity in the targeted EndoCareers™ site.

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Teaching Experience Can Expand especially true in the current climate of focus should remain on science and Your Career Options tight budgets and reduced state fund- research. Acquiring teaching expe- ing for public colleges and universities. rience can be accomplished at the By Robert K. Dearth Effective teaching may also provide an same time. Teaching should serve to added level of career security in the strengthen your training portfolio For many doctoral candidates competitive environment of acquiring and create more career opportuni- and postdoctoral trainees, securing external research funding. ties. Teaching can also provide you a tenure-track faculty position at a Data from the U.S. Department of with insight and knowledge that can college or university is essential. The Education Integrated Postsecondary Ed- advance your research. reality is that you will be competing ucation Data System (IPEDS; www.nces. for an ever-decreasing number of fac- ed.gov/ipeds/datacenter) show that of Attend ENDO’s Trainee Day ulty positions. Having prior college the 4,371 new tenure track hires from The most opportune time to gain teaching experience is one way to gain 2006–2010, 75 percent (3,285) of the valuable teaching experience is prob- a competitive advantage. Yet acquir- new hires were at “teaching universi- ably during your graduate training. ing teaching experience is not always ties” with 1,086 new tenure track hires One of the easiest ways to learn how accommodated in doctoral and post- at “research universities.“ At “research teaching can impact your career is doctoral programs where the priority universities,” your research experience to attend the Endocrine Trainee Day must be given to mastering the skill-set and success will make you a desirable at The Endocrine Society’s Annual needed to become a successful inde- hire. At “teaching universities,” re- Meeting. ENDO’s Trainee Day provides pendent researcher. After all, that is search may still be an important com- valuable informational sessions about why you spend countless hours in the ponent, but a strong emphasis will be teaching and research in academia. For lab, living off caffeine or energy drinks. placed on your ability to teach. Many of individuals who are in graduate stud- College teaching experience, however, these universities will not give serious ies at undergraduate degree–granting can set you apart and expand your attention to candidates without prior universities, being a teaching assistant career options. college teaching experience. Clearly, (TA) for a deﬁned length of time (at At many, if not most, post-second- adding teaching experience to your least a semester) is a great way to gain ary institutions, entry-level tenure- basic science training will make you experience and might be a requirement track assistant professor positions more competitive in your quest for a for the degree. Being a TA can also expect faculty to teach, do research, faculty position. help support your graduate studies.

ENDOCRINE NEWS • SEPTEMBER 2012 and engage in service activities. This is As a science trainee your primary For individuals in a graduate pro- 44

44_48 TraineeCorner Sept2012.indd 44 8/10/12 1:38 PM gram at institutions that don’t have gain valuable teaching experience as and it is not his or her responsibility, an undergraduate program (such as you progress in your training. If you nor the institution’s, to help you gain medical schools and health science are looking for a postdoctoral position teaching experience. My advice is first schools) getting in front of the class and have decided that you want some to establish yourself in the lab, stay can be a little more difficult. My best level of classroom teaching, you should committed to your research, mentor advice, if teaching is not a part of try to get teaching experience before students, continue to publish, and your program, is to talk to your men- accepting the position. Being honest seek funding. Once you are comfort- tor and other professors about your and upfront with your potential men- able with your research progress, talk desire to assist in a course, perhaps tor will be beneficial to both of you. to your mentor about your desire to as a guest lecturer. Getting some level take on a teaching load and assure of classroom experience can help you Adjunct Teaching Opportunities him it will not detract from your re- decide if this is a desirable aspect of Several institutions now offer post- sponsibilities in the lab. your training. Furthermore, some un- doctoral training programs specifically Overall, adding teaching to your dergraduate universities and colleges for basic scientists that include class- training portfolio will make you a will hire recently granted Ph.D.s with room teaching. These programs include more rounded potential hire. Better little or no postdoctoral training if adjunct teaching positions at area yet, you may actually discover that they have had teaching experience as universities and community colleges one of your biggest contributions to a graduate student. Understand that and are the best training program for science is teaching future scientists. ■ if you do accept a primary teaching individuals wishing to obtain a tenure position, with little or no research track position that requires a heavy Robert K. Dearth, Ph.D., is requirement, you must be sure that teaching load. an assistant professor of biology at the University of you want a career with a focus on If you are a current postdoctoral Texas-Pan American in teaching. The longer you are away fellow and chose the position based Edinburg, Texas. from the bench, the more difficult on the research opportunity, remem- it is to transition back into research. ber your mentor is there to facilitate It becomes increasingly difficult to your desire to become a researcher

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44_48 TraineeCorner Sept2012.indd 45 8/10/12 1:38 PM CYCLOSET®: First-in-class therapy for type 2 diabetes in adults Improved glycemic control* • 0.6% to 0.9% A1C reductions seen when added to other oral agents† Demonstrated CV safety profile‡ • 42% relative risk reduction for composite CVD endpoint§ vs placebo. Hazard ratio=0.58 (95% CI, 0.35-0.96); P<.05

5.0

4.5

4.0 Placebo 3.5

3.0

2.5 CYCLOSET 2.0

1.5

1.0 Cumulative % Experiencing CVD Endpoint

0.5 P<.05

0 1 2 3 4 5 6 7 8 9 10 11 12 13 Month

Important Safety Information CYCLOSET is a dopamine receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. CYCLOSET is contraindicated in patients with hypersensitivity to heavy machinery if symptoms of somnolence occur. Concomitant *Preclinical studies suggest that appropriately timed daily administration of bromocriptine, the active ingredient of CYCLOSET, may positively affect hypothalamic activities associated with insulin resistance and glucose intolerance. In clinical studies, morning administration of CYCLOSET improved glycemic control in adults with type 2 diabetes without increasing plasma insulin concentrations. The precise ergot-related drugs, bromocriptine, or any of the excipients in use with dopamine antagonists such as neuroleptic agents is not mechanism of action of CYCLOSET is unknown. CYCLOSET. Do not use in patients with syncopal migraines. It may recommended. † Findings from a 52-week, randomized controlled trial to evaluate the safety and ef cacy of CYCLOSET. Data shown are from a prospective 24-week assessment for treatment differences in the change from precipitate hypotension. Do not use in nursing women. It may There have been no clinical studies establishing conclusive evidence of baseline to Week 24 in A1C among subjects with a baseline A1C ≥7.5% (average baseline A1C of 8.3%), taking 1 or 2 OADs, and completing 24 weeks of therapy. In the intent-to-treat, LOCF population, inhibit lactation. There are postmarketing reports of stroke in this macrovascular risk reduction with CYCLOSET or any other antidiabetic A1C reductions in the CYCLOSET arm vs placebo were 0.5% for patients failing any OAD, 0.5% for patients failing metformin ± OAD, 0.5% for patients failing metformin + SU ± OAD, and 0.6% for patients patient population. failing TZD ± OAD. drug. CYCLOSET does not increase the risk of macrovascular events. ‡In a 52-week, randomized clinical trial of 3,070 patients, CYCLOSET was not associated with an increased risk for adverse cardiovascular events. CYCLOSET can cause orthostatic hypotension and syncope, particularly In controlled clinical trials, adverse reactions reported in ≥5% of §Prespeci ed composite CVD endpoint of time to rst MI, stroke, coronary revascularization, hospitalization for unstable angina, or hospitalization for CHF. upon initiation or dose escalation. Use with caution in patients taking patients treated with CYCLOSET, and reported more commonly than antihypertensive medications. CYCLOSET may exacerbate psychotic in patients treated with placebo, included nausea, fatigue, dizziness, Reference: Data on File. Santarus, Inc. disorders or reduce the effectiveness of drugs that treat psychosis. vomiting, and headache. Use in patients with severe psychotic disorders is not recommended. Safety and effectiveness have not been established in pediatric patients. CV=cardiovascular; CVD=cardiovascular disease; OAD=oral antidiabetic therapy; LOCF=last observation carried forward; CYCLOSET may cause somnolence. Advise patients not to operate SU=sulfonylurea; TZD=thiazolidinedione; MI=myocardial infarction; CHF=congestive heart failure. CYCLOSET is a registered trademark of VeroScience, LLC, Tiverton, RI 02878. Manufactured for: VeroScience, LLC, Tiverton, RI. CYCLOSET is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Distributed and Marketed by: Santarus, Inc., San Diego, CA. Please see adjacent Brief Summary of Prescribing Information. Please visit www.cycloset.com for more information. Full Prescribing Information available at www.cycloset.com. © 2012 Santarus, Inc. 1-CYC12172 July 2012 Printed in the USA

44_48CYCLO-4740_M01_Journal_Ad_A-SIZE.indd TraineeCorner Sept2012.indd 46 1-2 8/10/12 1:38 PM 7/27/12 12:51 PM CYCLOSET®: First-in-class therapy for type 2 diabetes in adults Improved glycemic control* • 0.6% to 0.9% A1C reductions seen when added to other oral agents† Demonstrated CV safety profile‡ • 42% relative risk reduction for composite CVD endpoint§ vs placebo. Hazard ratio=0.58 (95% CI, 0.35-0.96); P<.05

5.0

4.5

4.0 Placebo 3.5

3.0

2.5 CYCLOSET 2.0

1.5

1.0 Cumulative % Experiencing CVD Endpoint

0.5 P<.05

0 1 2 3 4 5 6 7 8 9 10 11 12 13 Month

CYCLO-4740_M01_Journal_Ad_A-SIZE.indd 1-2 44_48 TraineeCorner Sept2012.indd 47 7/27/128/10/12 12:51 1:38 PM Table 1 (continued) protein-bound therapies (eg, salicylates, sulfonamides, chloramphenicol and probenecid), Adverse Events Reported in Phase 3 Clinical Trials of CYCLOSET (≥5% of Patients which may alter their effectiveness and risk for side effects. and Numerically More Frequent in CYCLOSET-Treated Patients than in Placebo- CYCLOSET is a dopamine receptor agonist. Concomitant use of dopamine receptor antagonists, Treated Patients, Regardless of Investigator Assessment of Causality*) such as neuroleptics (eg, phenothiazines, butyrophenones, thioxanthenes), or metoclopramide may diminish the effectiveness of CYCLOSET and CYCLOSET may diminish the effectiveness Adjunct to Sulfonylurea of these other therapies. The concurrent use of CYCLOSET with these agents has not been (2 pooled 24 week studies) studied in clinical trials and is not recommended [see Warning and Precautions (5.4)]. N = 494 N = 244 N = 250 CYCLOSET in combination with ergot-related drugs may cause an increase in the occurrence Nausea 62 (25.4) 12 (4.8) Brief Summary of Prescribing Information of ergot-related side effects such as nausea, vomiting, and fatigue, and may also reduce the Asthenia 46 (18.9) 20 (8.0) effectiveness of these ergot therapies when used to treat migraine. The concurrent use of these 1 INDICATIONS AND USAGE Headache 41 (16.8) 40 (16.0) ergot agents within 6 hours of CYCLOSET dosing is not recommended. 1.1 Type 2 Diabetes Mellitus Flu syndrome 23 (9.4) 19 (7.6) CYCLOSET is extensively metabolized by the liver via CYP3A4. Therefore, potent inhibitors or CYCLOSET is indicated as an adjunct to diet and exercise to improve glycemic control in adults inducers of CYP3A4 may increase or reduce the circulating levels of CYCLOSET, respectively. Constipation 24 (9.8) 11 (4.4) with type 2 diabetes mellitus. Use caution when co-administering drugs that are strong inhibitors, inducers, or substrates of 1.2 Important Limitations of Use Cold 20 (8.2) 20 (8.0) CYP3A4 (eg, azole antimycotics, HIV protease inhibitors) [See Phamacokinetics (12.3)]. • CYCLOSET should not be used to treat type 1 diabetes or diabetic ketoacidosis. Dizziness 29 (11.9) 14 (5.6) There are postmarketing reports of hypertension and tachycardia when bromocriptine was • Limited efficacy data in combination with thiazolidinediones Rhinitis 26 (10.7) 12 (4.8) co-administered with sympathomimetic drugs (eg, phenylpropanolamine and isometheptene) • Efficacy has not been confirmed in combination with insulin. Sinusitis 18 (7.4) 16 (6.4) in postpartum women. There are limited clinical trial data supporting the safety of co- Somnolence 16 (6.6) 5 (2.0) administering sympathomimetic drugs and CYCLOSET for more than 10 days. Therefore, 4 CONTRAINDICATIONS concomitant use of these agents with CYCLOSET for more than 10 days duration is not CYCLOSET is contraindicated in Vomiting 13 (5.3) 8 (3.2) recommended. Also, there are limited clinical trial data supporting the safety of selective • Patients with known hypersensitivity to bromocriptine, ergot-related drugs, or any of the Amblyopia 13 (5.3) 6 (2.4) 5-hydroxytryptamine1B (5-HT1B) agonists (eg, sumatriptan) used concurrently with CYCLOSET excipients in CYCLOSET. 52-Week Safety Trial† and the concomitant use of these agents with CYCLOSET should be avoided. • Patients with syncopal migraine. Bromocriptine increases the likelihood of a hypotensive N = 3070 N = 2054 N = 1016 8 USE IN SPECIFIC POPULATIONS episode among patients with syncopal migraine. Loss of consciousness during a migraine Nausea 661 (32.2) 77 (7.6) 8.1 Pregnancy may reflect dopamine receptor hypersensitivity. CYCLOSET is a dopamine receptor agonist, Pregnancy Category B and may, therefore, potentiate the risk for syncope in these patients. Dizziness 303 (14.8) 93 (9.2) Two strains of pregnant rats were dosed orally with 3, 10, and 30 mg/kg/day (up to 72 times • Women who are nursing their children. CYCLOSET may inhibit lactation. There are Fatigue 285 (13.9) 68 (6.7) the human 4.8 mg daily dose, based on mg/m2 comparison) from gestation day 6-15 and with postmarketing reports of stroke in this patient population although causality has not been Headache 235 (11.4) 84 (8.3) a single dose of 10 mg/kg on gestation day 5. Implantation was inhibited at 10 and 30 mg/ 2 proven [See Nursing Mothers (8.3)]. Vomiting 167 (8.1) 32 (3.1) kg (24 and 72 times the human 4.8 mg daily dose, based on mg/m comparison). When rats were dosed with 3, 10, and 30 mg/kg/day from gestation day 8-15 there was an increase 5 WARNINGS AND PRECAUTIONS Diarrhea 167 (8.1) 81 (8.0) 5.1 Hypotension: Hypotension, including orthostatic hypotension, can occur, particularly in resorptions at 10 and 30 mg/kg. These effects were probably due to the dependence of upon initiation of CYCLOSET therapy and with dose escalation. In a 52-week, randomized Constipation 119 (5.8) 52 (5.1) implantation and the maintenance of gestation on prolactin in the rat and are not relevant clinical trial of 3070 patients, hypotension was reported in 2.2% of patients randomized to *All randomized subjects receiving at least one dose of study drug for humans in which these events are not dependent on prolactin but on luteinizing hormone. CYCLOSET compared to 0.8% of patients randomized to placebo. Among CYCLOSET-treated †The Safety Trial enrolled patients treated with diet or no more than 2 anti-diabetic medications (metformin, insulin There was no evidence of teratogenic effects in the rat. patients reporting symptomatic hypotension, 98% were on at least one blood pressure secretagogues such as a sulfonylurea, thiazolidinediones, alpha glucosidase inhibitors, and/or insulin) In a small study in macaque monkeys given oral doses of 2 mg/kg/day (10 times the human 2 medication compared to 73% on such medication in the total study population. In this trial, Hypoglycemia 4.8 mg daily dose, based on mg/m comparison) during organogenesis no embryotoxic or six CYCLOSET-treated patients (0.3%) reported an adverse event of orthostatic hypotension In the monotherapy trial, hypoglycemia was reported in 2 CYCLOSET-treated patients (3.7%) teratologic effects were observed. compared to 2 (0.2%) placebo-treated patients. All six patients were taking anti-hypertensive and 1 placebo-treated patient (1.3%). In the add-on to sulfonylurea trials, the incidence of When male rats given oral doses of 2, 10 or 50 mg/kg/day (up to 120 times the human 4.8 medications. Hypotension can result in syncope. In this trial, syncope due to any cause hypoglycemia was 8.6% among the CYCLOSET-treated patients and 5.2% among the mg daily dose, based on mg/m2 comparison) were mated with untreated females, there was a was reported in 1.6% of CYCLOSET-treated patients and 0.7% of placebo-treated patients placebo-treated patients. In the CYCLOSET safety trial, hypoglycemia was defined as slight increase in pup loss in the 10 and 50 mg/kg/day groups (24-120 times the human 4.8 [See Adverse Reactions (6.1)]. As a precaution, assessment of orthostatic vital signs is any of the following: 1) symptoms suggestive of hypoglycemia that promptly resolved with mg daily dose, based on mg/m2 comparison). recommended prior to initiation of CYCLOSET and periodically thereafter. During early appropriate intervention, 2) symptoms with a measured glucose <60 mg/dL or 3) measured In two strains of pregnant rabbits treated from gestation day 6-18 with oral doses of 3, 10, treatment with CYCLOSET, patients should be advised to make slow postural changes and to glucose below 49 mg/dL regardless of symptoms. In the 52-week safety trial, the incidence 30, 100, and 300 mg/kg/day (up to 1400 times the human 4.8 mg daily dose, based on mg/ avoid situations that could lead to serious injury if syncope was to occur. Use caution in patients of hypoglycemia was 6.9% among the CYCLOSET-treated patients and 5.3% among the m2 comparison) there was maternal toxicity and embryolethality at doses ≥10 mg/kg/day (48 taking anti-hypertensive medications. placebo-treated patients. In the safety trial, severe hypoglycemia was defined as an inability to times the human 4.8 mg daily dose, based on mg/m2 comparison). Low incidences of fetal 5.2 Psychotic Disorders: In patients with severe psychotic disorders, treatment with a self-treat neurological symptoms consistent with hypoglycemia that occurred in the setting of a abnormalities were observed at maternally toxic doses of 100-300 mg/kg/day (480-1400 dopamine receptor agonist such as CYCLOSET may exacerbate the disorder or may diminish measured blood glucose <50 mg/dl (or evidence of prompt resolution of these symptoms with times the human 4.8 mg daily dose, based on mg/m2 comparison). There were no treatment- the effectiveness of drugs used to treat the disorder. Therefore, the use of CYCLOSET in administration of oral carbohydrates, subcutaneous glucagon, or intravenous glucose if blood related fetal abnormalities at doses ≤30 mg/kg/day (140 times the human 4.8 mg daily dose, patients with severe psychotic disorders is not recommended. glucose was not measured). In this trial, severe hypoglycemia was reported among 0.5% of based on mg/m2 comparison). Implantation was not affected in rabbits treated from gestation 5.3 Somnolence: CYCLOSET may cause somnolence. In a 52-week, randomized clinical CYCLOSET-treated patients and 1% of placebo-treated patients. day 1-6 with oral doses of 100-300 mg/kg/day (480-1400 times the human 4.8 mg daily trial, 4.3% of CYCLOSET treated-patients and 1.3% of placebo-treated patients reported Syncope dose, based on mg/m2 comparison). somnolence as an adverse event. None of these events were reported as serious and the In combined phase 2 and 3 clinical trials, syncope was reported in 1.4% of the 2,500 Studies in pregnant women have not shown that bromocriptine increases the risk of majority of patients reported resolution of somnolence over time. Patients should be made CYCLOSET-treated patients and 0.6% of the 1,454 placebo-treated patients. Among the abnormalities when administered during pregnancy. Information concerning 1,276 aware of this potential side effect, particularly when initiating therapy with CYCLOSET. Patients 3,070 patients studied in the 52-week safety trial, 33 CYCLOSET-treated patients (1.6%) and pregnancies in women taking bromocriptine has been collected. In the majority of cases, experiencing somnolence should refrain from driving or operating heavy machinery. 7 placebo-treated patients (0.7%) reported an adverse event of syncope. The cause of syncope bromocriptine was discontinued within the first 8 weeks of pregnancy (mean 29 days); 5.4 Interaction with Dopamine Receptor Antagonists: Dopamine receptor antagonists, is not known in all cases [See Warnings and Precautions (5.1)]. In this trial, electrocardiograms however, 8 patients received the drug continuously throughout pregnancy. The mean daily including neuroleptic agents that have dopamine D2 receptor antagonist properties (eg, were not available at the time of these events, but an assessment of routine electrocardiograms dose for all patients was 5.8 mg (range 1-40 mg). Of these 1,276 pregnancies, there were Clozapine, Olanzapine, Ziprasidone), may reduce the effectiveness of CYCLOSET and obtained during the course of the trial did not identify arrhythmias or QTc interval prolongation 1,088 full-term deliveries (4 stillborn), 145 spontaneous abortions (11.4%), and 28 induced CYCLOSET may reduce the effectiveness of these agents. CYCLOSET has not been studied in among the CYCLOSET-treated patients reporting syncope. abortions (2.2%). Twelve extrauterine gravidities and 3 hydatidiform moles (twice in the same patients taking neuroleptic drugs. The concomitant use of CYCLOSET and dopamine receptor Central Nervous System patient) caused early termination of pregnancy. These data compare favorably with the abortion antagonists, including neuroleptic drugs, is not recommended. In the 52-week safety trial, somnolence and hypoesthesia were the only adverse events within rate (11-25%) cited for pregnancies induced by clomiphene citrate, menopausal gonadotropin, 5.5 Other Dopamine Receptor Agonists: Other dopamine receptor agonists are the nervous system organ class that were reported at a rate of < 5% and ≥ 1% and that and chorionic gonadotropin. Although spontaneous abortions often go unreported, especially indicated for the treatment of Parkinson’s disease, hyperprolactinemia, restless leg syndrome, occurred at a numerically greater frequency among CYCLOSET-treated patients (CYCLOSET prior to 20 weeks of gestation, their frequency has been estimated to be 10-15% in the general acromegaly, and other disorders. The effectiveness and safety of CYCLOSET in patients who 4.3% vs. Placebo 1.3% for somnolence; CYCLOSET 1.4% vs. Placebo 1.1% for hypoesthesia). population. The incidence of birth defects in the general population ranges from 2% to 4.5%. are already taking one of these other dopamine receptor agonists is unknown. Concomitant use Serious Adverse Events and Cardiovascular Safety The incidence of birth defects in 1,109 live births from patients receiving bromocriptine was is not recommended. The primary endpoint of the 52-week safety trial was the occurrence of all serious adverse 3.3%. There is no suggestion that bromocriptine contributed to the type or incidence of birth 5.6 Macrovascular outcomes: There have been no clinical studies establishing conclusive events. A secondary endpoint was the occurrence of the composite of myocardial infarction, defects in this group of infants. evidence of macrovascular risk reduction with CYCLOSET or any other anti-diabetic drug. In a stroke, coronary revascularization, hospitalization for angina, and hospitalization for congestive A review of 4 different multicenter surveillance programs analyzed 2,351 pregnancies 52-week, randomized clinical trial, CYCLOSET use was not associated with an increased risk for heart failure. of 2,185 women treated with bromocriptine. In 583 children born of these women and adverse cardiovascular events [See Adverse Reactions (6.1)]. All serious adverse events and cardiovascular endpoints were adjudicated by an independent followed for a minimum of 3-12 months, there was no suggestion of any adverse effect of 6 ADVERSE REACTIONS event adjudication committee. Serious adverse events occurred in 176/2054 (8.5%) intra-uterine exposure to bromocriptine on post-natal development. Most (≥75%) women 6.1 Clinical Trials Experience CYCLOSET-treated patients and 98/1016 (9.6%) placebo-treated patients. The hazard ratio had taken bromocriptine for 2-8 weeks and at 5-10 mg per day. Among 86 women having Because clinical trials are conducted under widely varying conditions, the adverse reaction comparing CYCLOSET to placebo for the time to first occurrence of a serious adverse event 93 pregnancies and treated with bromocriptine throughout pregnancy or from week 30 of rates reported in one clinical trial may not be easily compared to those rates reported in another was 1.02 (upper bound of one-sided 96% confidence interval, 1.27). None of the serious pregnancy onwards (mostly for treatment of prolactinoma), there was only 1 spontaneous clinical trial, and may not reflect the rates actually observed in clinical practice. adverse events grouped by System-Organ-Class occurred more than 0.3 percentage points abortion. Similar results have been obtained in a Japanese hospital survey of 442 children born to 434 patients treated with bromocriptine during pregnancy and followed for at least one year. In the pooled CYCLOSET phase 3 clinical trials (CYCLOSET N = 2298; placebo N = 1266), higher with CYCLOSET than with placebo. The composite cardiovascular endpoint occurred adverse events leading to discontinuation occurred in 539 (24%) CYCLOSET-treated patients in 31 (1.5%) CYCLOSET-treated patients and 30 (3.0%) placebo-treated patients. The hazard Because the studies in humans cannot rule out the possibility of harm, CYCLOSET should be and 118 (9%) placebo-treated patients. This between-group difference was driven mostly by ratio comparing CYCLOSET to placebo for the time-to-first occurrence of the prespecified used during pregnancy only if clearly needed. gastrointestinal adverse events, particularly nausea. composite cardiovascular endpoint was 0.58 (two-sided 95% confidence interval, 0.35 – 8.3 Nursing Mothers The CYCLOSET safety trial was a 52-week, placebo-controlled study that included patients 0.96). Therefore, the incidence of this composite endpoint was not increased with CYCLOSET CYCLOSET is contraindicated in women who are nursing their children. CYCLOSET contains treated only with diet therapy or with other anti-diabetic medications. A total of 3,070 patients relative to placebo. bromocriptine which inhibits lactation. The indication for use of bromocriptine for inhibition of were randomized to CYCLOSET (titrated to 1.6 to 4.8 mg daily, as tolerated) or placebo. The 6.2 Postmarketing Experience postpartum lactation was withdrawn based on postmarketing reports of stroke in this setting study population had a mean baseline age of 60 years (range 27-80) and 33% were 65 years The active agent in CYCLOSET (bromocriptine mesylate) has been used in other formulations [See Contraindications (4) and Adverse Reactions (6.2)]. of age or older. Approximately 43% of the patients were female, 68% were Caucasian, 17% and often multiple times per day to treat hyperprolactinemia, acromegaly, and Parkinson’s 8.4 Pediatric Use were Black, 13% were Hispanic, and 1% were Asian. The mean baseline body mass index disease. The following adverse reactions have been identified during postapproval use of The safety and effectiveness of CYCLOSET in pediatric patients have not been established. was 32 kg/m2. The mean duration of diabetes at baseline was 8 years and the mean baseline bromocriptine mesylate for these indications, generally at doses higher than those approved 8.5 Geriatric Use HbA1c was 7.0% with a mean baseline fasting plasma glucose of 142 mg/dL. At baseline, for the treatment of type 2 diabetes. Because these reactions are reported voluntarily from a In the two clinical trials of CYCLOSET add-on to sulfonylurea therapy and in the monotherapy 12% of patients were treated with diet only, 40% were treated with one oral anti-diabetic agent, population of uncertain size, it is generally not possible to reliably estimate their frequency or trial, a total of 54 patients randomized to CYCLOSET were ≥65 years old. In the 52-week 33% were treated with two oral anti-diabetic agents, and 16% were treated with insulin alone establish a causal relationship to drug exposure. safety trial, 601 of the 2,054 CYCLOSET-treated patients (29%) were ≥65 years old. No overall or insulin in combination with an oral anti-diabetic agent. At baseline, 76% of patients reported Hallucinations differences in safety or effectiveness were observed between the elderly and younger patients, a history of hypercholesterolemia, 75% reported a history of hypertension, 11% reported a Hallucinations and mental confusion including delusions have been reported with but greater sensitivity of some older individuals cannot be ruled out. [See Clinical Studies (14)]. history of revascularization surgery, 10% reported a history of myocardial infarction, 10% bromocriptine. To date, there have been no reported cases of hallucinations or delusions 10 OVERDOSAGE reported a history of angina, and 5% reported a history of stroke. Forty-seven percent of the among CYCLOSET-treated patients (n = 2500) in combined Phase 2 and 3 clinical trials of With another formulation of bromocriptine mesylate, the most commonly reported signs and CYCLOSET-treated patients and 32% of the placebo-treated patients prematurely discontinued CYCLOSET. symptoms associated with acute overdose were nausea, vomiting, constipation, diaphoresis, treatment. Adverse events leading to discontinuation of study drug occurred among 24% of Fibrotic - Related Complications dizziness, pallor, severe hypotension, malaise, confusion, lethargy, drowsiness, delusions, the CYCLOSET-treated patients and 15% of the placebo-treated patients. This between-group Fibrotic complications, including cases of retroperitoneal fibrosis, pulmonary fibrosis, pleural hallucinations, and repetitive yawning. The lethal dose has not been established. difference was driven mostly by gastrointestinal adverse events, particularly nausea. effusion, pleural thickening, pericarditis and pericardial effusions have been reported. These Treatment of overdose consists of removal of the drug by emesis (if conscious), gastric lavage, Table 1 summarizes the adverse events reported in ≥5% of patients treated with CYCLOSET complications do not always resolve when bromocriptine is discontinued. Among several activated charcoal, or saline catharsis. Careful supervision and recording of fluid intake and in the phase 3 clinical trials regardless of investigator assessment of causality. The most studies investigating a possible relation between bromocriptine exposure and cardiac output is essential. Hypotension should be treated by placing the patient in the Trendelenburg commonly reported adverse events (nausea, fatigue, vomiting, headache, dizziness) lasted a valvulopathy, some events of cardiac valvulopathy have been reported, but no definitive position and administering intravenous fluids. If satisfactory relief of hypotension cannot median of 14 days and were more likely to occur during the initial titration of CYCLOSET. None association between bromocriptine mesylate use and clinically significant (moderate to severe) be achieved by using the above measures to their fullest extent, vasopressors should be of the reports of nausea or vomiting were described as serious. There were no differences in cardiac valvulopathy could be concluded. considered. the pattern of common adverse events across race groups or age groups (<65 years old vs. To date, there have been no reported cases of retroperitoneal fibrosis, pulmonary infiltrates, 13 NONCLINICAL TOXICOLOGY >65 years old). In the 52-week CYCLOSET safety trial, 11.5% of CYCLOSET-treated women pleural effusion, pleural thickening, pericarditis or pericardial effusions among the CYCLOSET- 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility compared to 3.6% of placebo-treated women reported vomiting. In this same trial, 5.4% of treated patients (n=2500) in combined Phase 2 and 3 controlled clinical trials of CYCLOSET. Carcinogenesis CYCLOSET-treated men compared to 2.8% of placebo-treated men reported vomiting. There was one unconfirmed case (0.04% event rate) of an adverse event of pulmonary fibrosis In a 74-week dietary study in mice at doses up to 50 mg/kg/day (56 times the human 4.8 mg Table 1: classified as non-serious in a CYCLOSET-treated patient. daily dose, based on mg/m2 comparison) there was no evidence of tumorigenicity. Adverse Events Reported in Phase 3 Clinical Trials of CYCLOSET (≥5% of Patients No cases of cardiac valvulopathy have been reported in any of the clinical studies to date In a 100-week dietary carcinogenicity study in rats at doses of 1.8, 9.9 and 44.5 mg/kg/ and Numerically More Frequent in CYCLOSET-Treated Patients than in Placebo- with CYCLOSET. day (up to 106 times the human 4.8 mg daily dose, based on mg/m2 comparison) there was Treated Patients, Regardless of Investigator Assessment of Causality*) Psychotic and Psychiatric Disorders a significant increase in the incidence of malignant uterine neoplasms in the mid- and high 2 Monotherapy CYCLOSET Placebo Psychotic disorders have been reported with bromocriptine. Additionally, pathological gambling dose groups (24-106 times the human 4.8 mg daily dose, based on mg/m comparison). 1.6 mg – 4.8 mg has been reported with bromocriptine used to treat patients with Parkinson’s disease. To The increase in uterine neoplasms was probably due to the inhibition of prolactin-stimulated date, there have been no reported cases of psychoses or pathological gambling among the progesterone secretion resulting in estrogen domination and endometrial stimulation in the N (%) N (%) CYCLOSET-treated patients (N=2500) in combined Phase 2 and 3 controlled clinical trials aging rat. Because prolactin does not play a role in human progesterone production this finding N = 159 N = 80 N = 79 of CYCLOSET. is unlikely to be clinically relevant. Nausea 26 (32.5) 6 (7.6) Stroke Mutagenicity Rhinitis 11 (13.8) 3 (3.8) The indication for use of bromocriptine for inhibition of postpartum lactation was withdrawn Bromocriptine was not mutagenic in the in vitro Ames bacterial mutation assay, the V79 based on postmarketing reports of stroke. Causality of bromocriptine use and the occurrence Chinese hamster fibroblast mutagenity test, the in vivo bone marrow micronucleus test in mice Headache 10 (12.5) 7 (8.9) of stroke in this patient population has not been proven. Based on the CYCLOSET clinical and the in vivo Chinese hamster bone marrow chromosomal aberration test. Asthenia 10 (12.5) 5 (6.3) trials, there is no evidence of increased risk for stroke when CYCLOSET is used to treat type Impairment of Fertility Dizziness 10 (12.5) 6 (7.6) 2 diabetes. In female rats treated with oral doses of 1 and 3 mg/kg (2 to 7 times the human 4.8 mg daily Constipation 9 (11.3) 3 (3.8) Neuroleptic - like Malignant Syndrome dose, based on mg/m2 comparison) from 2 weeks prior to mating through 2 weeks post mating Sinusitis 8 (10.0) 2 (2.5) A neuroleptic-like malignant syndrome (manifested by high fever and increase in or throughout lactation there was no effect on fertility. Postnatal pup weight gain was reduced Diarrhea 7 (8.8) 4 (5.1) creatinine phosphokinase) has been reported upon cessation of bromocriptine treatment dose-dependently in treated groups probably due to lactation inhibition. in patients with advanced Parkinson’s disease or patients with secondary Parkinsonism. Amblyopia 6 (7.5) 1 (1.3) In male rats treated with oral doses of 2, 10, and 50 mg/kg/day (up to 120 times the human To date, there have been no reported cases of neuroleptic-like malignant syndrome in 4.8 mg daily dose, based on mg/m2 comparison) there was no effect on mating or fertility. Dyspepsia 6 (7.5) 2 (2.5) combined Phase 2 and 3 controlled clinical trials of CYCLOSET, including the Safety Trial Manufactured for: VeroScience, LLC, Tiverton, RI. Vomiting 5 (6.3) 1 (1.3) (N = 2500). In the CYCLOSET Safety Trial, there were no reports of neuroleptic-like malignant Distributed and Marketed by: Santarus, Inc., San Diego, CA. Infection 5 (6.3) 4 (5.1) syndrome during the 30 days of follow-up after cessation of CYCLOSET (N = 2054). Anorexia 4 (5.0) 1 (1.3) 7 DRUG INTERACTIONS The active ingredient in CYCLOSET, bromocriptine mesylate, is highly bound to serum proteins. ©2010 Santarus, Inc. 1-CYC10442 September 2010 continued Therefore, CYCLOSET may increase the unbound fraction of other concomitantly used highly CYCLOSET® is a registered trademark of VeroScience, LLC, Tiverton, RI 02878

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➤ The following studies will be pub- Fini JB, Le Mével S, Palmier K. Thy- cancer and osteoporosis. lished in Endocrine Society journals. roid hormone signaling in the Xeno- Matthews CE, Fortner RT, Xu X, Han- Before print, they are edited and pus laevis embryo is functional and kinson SE, Eliassen AH, Ziegler RG. posted online in each journal's Early susceptible to endocrine disruption. Association between physical activity Release section. You can access the and urinary estrogens and estro- journals via www.endo-society.org. gen metabolites in premenopausal The Journal of Clinical women. Endocrinology & Metabolism Endocrinology ➤ Sedation and anesthesia can in- Molecular Endocrinology ➤ Males with familial hypertro- duce a significant rise in cortisol phic cardiomyopathy should avoid in children. ➤ Using small molecules or IGF-I/ phytoestrogens. Hsu AA, von Elten K, Chan D. IGF-II antibodies might aid in Haines CD, Harvey PA, Luczak ED, Characterization of the cortisol stress avoiding anti-IGF-IR resistance in et al. Estrogenic compounds are not response to sedation and anesthesia EWS patients. always cardioprotective and can be in children. Garofalo C, Mancarella C, Grilli A, lethal in males with genetic heart et al. Identification of common and disease. ➤ The need for hormone re- distinctive mechanisms of resistance placement therapy should be to different anti-IGF-1R agents in Ew- ➤ This new stem cell methodology re-evaluated three months after ing’s sarcoma. could provide future therapies for surgical correction of NPH because patients with adrenal insufficiency. most endocrine dysfunctions are ➤ New molecular mechanisms Sonoyama T, Sone M, Honda, et al. reversed in this time. are suggested for the functional Differentiation of human embry- Moin T, Bergsneider M, Vespa P, withdrawal of progesterone at onic stem cells and human induced Heaney A. Pituitary function in term labor. pluripotent stem cells into steroid- patients with normal pressure hydro- Xie N, Liu L, Li Y, et al. Expression producing cells. cephalus before and after neurosur- and function of myometrial PSF sug- gical correction. gest a role in progesterone withdraw- ➤ AMH knock-down may have al and initiation of labor. therapeutic value in infertile ➤ Runt-related transcription fac- women who respond poorly to tor 2 potentiates the migration ➤ Lung cancer incidence and ovarian stimulation. and invasive capacity of thyroid treatment approach could be pre- Campbell BK, Clinton M, Webb R. tumor cells. dicted by NR expression. The role of anti-müllerian hormone Sancisi V, Borettini G, Maramotti Jeong Y, Xie Y, Lee W, et al. Diag- (AMH) during follicle development in S, et al. Runx2 isoform I controls a nostic and therapeutic potential of a monovulatory species (sheep). panel of pro-invasive genes driving nuclear receptor expression in lung aggressiveness of papillary thyroid cancer. ➤ PPARγ expression in pancreatic carcinomas. β-cells is unlikely to be directly essential for normal β-cell func- ➤ Circulating myostatin levels in Hormones and Cancer tion or the insulin-sensitizing men are associated with seasonal actions of rosiglitazone. changes, age, body mass index, fat ➤ Endometrial cancer risk is not Welters HJ, El Ouaamari A, Kawamori mass, smoking, and 25-hydroxy- associated with migraine history D, et al. Rosiglitazone promotes cholecalciferol levels. and NSAID use. PPARγ-dependent and independent Szulc P, Schoppet M, Goettsch C, et Phipps AI, Anderson GL, Cochrane alterations in gene expression in al. Endocrine and clinical correlates BB, et al. Migraine history, nonsteroi- mouse islets. of myostatin serum concentration in dal anti-inflammatory drug use, and men—the STRAMBO study. risk of postmenopausal endometrial ➤ TH signaling in tadpoles is cancer. ■ active even before thyroid forma- ➤ Physical activity promotes tion, suggesting an early sensi- favorable estrogen metabolism tivity to endocrine-disrupting that could lead to prevention of

chemicals. chronic diseases such as breast ENDOCRINE NEWS • SEPTEMBER 2012 49

49 ResBriefs Sept2012.indd 49 8/10/12 11:54 AM endocrinologists and for primary care ENDOCRINE physicians treating endocrine-related diseases. Endocrine Essentials Pro, chaired by Lisa Fish, M.D., is designed for endocrinologists and focuses on metabolic bone disease and adrenal disorders. Endocrine Essentials for Primary Care, chaired by Rocio Pereira, M.D., is a diabetes program platform that provides a comprehen- for internists, general practitioners, HHN Joins Forces with sive review of best practices and diabetes educators, and other pri- Menopause the Musical® evidence-based strategies in the ﬁeld mary care providers. of endocrinology. Attendees will gain These programs are scheduled insight into the evaluation and man- for the following towns and dates: agement of patients with endocrine Minneapolis on September 29, Kansas disorders and diseases. Presented by City, Missouri, on October 20, India- world-renowned faculty, the 2012 napolis on October 27, and New York program will include female repro- City on November 10. duction and pituitary, thyroid, and These concurrent half-day adrenal disorders. The faculty is com- programs provide state-of-the-art up- prised of Past President Janet Hall, dates on current practice challenges M.D., past Annual Meeting Steering from expert faculty. More information Committee Chair Lynnette Nieman, and registration is available online at M.D., David Cooper, M.D., and David www.endo-society.org/eelive. ■ For women going through the Clemmons, M.D. “change of life,” managing menopausal symptoms is no laughing FLARE Ignites Careers matter: A recent national survey by of Young Professionals the Hormone Health Network found calendar that 72 percent of women experiencing troublesome symptoms have not received treatment, and another 60 SEPT 11–15: MIAMI percent are not discussing treatment Endocrine Board Review and options with their doctor. To help Clinical Endocrinology Update bridge this conversation gap, the The Endocrine Society is pleased www.endo-society.org/miami Network teamed up with Menopause to announce the launch of the Future SEPT 19–23: QUEBEC CITY, CANADA the Musical®, a light-hearted look Leaders Advancing Research in En- American Thyroid at four women coping with their docrinology (FLARE) program, which Association 82st Annual Meeting www.thyroid.org/ann_mtg/index.html menopausal symptoms, at the Warner will provide leadership development Theater in August to introduce the training to senior graduate students SEPT 20–24: SAN ANTONIO Menopause Map to its Washington, and postdoctoral and clinical fellows The Obesity Society’s 30th Annual Scientiﬁc Meeting D.C., audience. Attendees had the from underrepresented communities. www.obesity.org/meetings-and events/ opportunity to complete the online, The FLARE program is funded by a annual-meeting.htm interactive Map on-site, and received grant from the National Institute of OCT 13–17: NEW ORLEANS the Networks’ patient fact sheets on Diabetes and Digestive and Kidney Society for Neuroscience menopause. Diseases. More information can be 42nd Annual Meeting found at www.endo-society.org/FLARE. www.sfn.org/am2012 Third Annual Endocrine OCT 17–19: PHILADELPHIA Summit in India Endocrine Education American Academy of On September 30, The Endocrine in Your Backyard Family Physicians (AAFP) www.aafp.org/online/en/home/cme/aaf- Society will present the third Annual The Endocrine Society brings top- pcourses/conferences/assembly.html Endocrine Summit in India. This quality clinical updates to your area program, held in Mumbai, will bring with Endocrine Essential Live. This See more events at www.endosociety.org, on the Worldwide Endocrine together more than 200 of India’s new regional series features two pro- Events Calendar. ENDOCRINE NEWS • SEPTEMBER 2012 endocrinologists for an interactive grams designed for both professional 50

50 SocUpdate Sept2012.indd 50 8/10/12 11:55 AM CLASSIFIEDS If you are interested in submitting classiﬁed advertising to Endocrine News, please contact Christine Whorton at [email protected] or 800-361-3906.

School are seeking an Endo- position includes a faculty Endocrinologist Needed crinologist at the Assistant appointment, teaching op- in Growing Philadelphia or Associate Professor rank portunities and a com- Suburb (tenure track). The candidate petitive salary and beneﬁt will participate in clinical package. Previous experi- Need to hire an Gateway Medical Endocri- and educational activities of ence with thyroid ultrasound nology Associates is seeking the division, and will have preferred. The search endocrinologist? a BC/BE Endocrinologist to completed an endocrinology committee will also consider join well-established group. fellowship and be BC/BE in applicants with an active re- Join three endocrinologists, Internal Medicine and En- search program focused on EndoCareers one diabetologist, two nurse docrinology. Opportunities aspects related to diabetes practitioners, and a diabetes for program development or thyroid disease. There are is the answer. educator. This respected include diabetes education, excellent laboratory facilities practice is located in West inpatient glucometrics and available and possible start Chester Pennsylvania, an thyroid cancer management. up package. The historic Advertise here outstanding place to live We are seeking an indi- port city of Norfolk is cen- for great results! and work. Allscripts EMR. vidual to join our group with trally located in the 1.8 mil- Competitive Salary! Email CV interests in quality and the lion person Hampton Roads to mdyson@gatewaydoctors. development of innovative area on the Chesapeake www.endocareers.org com. clinical programs focusing Bay, a short drive from the 800-361-3906 on early intervention. The Virginia Beach oceanfront. Endocrinologist successful candidate will Forward CV to: HRapps@ become an integral part of a evms.edu. EVMS is an Equal The Strelitz Diabetes Center system of care, working with Opportunity/Afﬁrmative Ac- and Division of Endocrinol- our primary care network tion Employer/M/F/D/V and ogy and Metabolism, at the and multiple specialties to a Drug and Tobacco Free Eastern Virginia Medical enhance diabetes care. The workplace. ■

People. Passion. Community. Board Certiﬁed/Board Eligible Endocrinologist It all comes together here.

There’s a simple reason you chose a career in medicine. We invite you to practice it. Head-To-Toe Medications We welcome your enthusiasm for compassionate medicine as you change lives with some of the most inspiring people you will ever meet. Join a team of two Endocrinologists and 2 Nurse By Jacqueline Ruttimann, Ph.D., Interim Editorw Practitioners who practice 100% consultative endocrinology and enjoy excellent physician support, flexible scheduling, and 1:4/5 call with Hospitalist support. We offer an above average compensation package that includes income guarantee, production bonuses, and relocation/ residency stipend/loan repayment options. Your practice and your family will flourish in Wausau, WI; a safe and friendly community that offers a low cost of living. In return, we promise to treat you with the same dignity and respect you give to your patients. Respecting your work/life balance is a big part of the Aspirus culture. We will surround you with a highly qualified nursing and support staff, an extensive network of outstanding specialists, and a medical culture that shares an unyielding commitment to excellence. A practice model like this could only happen in a place like this. It’s a place where kayakers and theatergoers live in harmony. A place of adventure through all four seasons. A place good natures and great schools call home.

Details at AspirusProviderOpps.org. Contact Dawn Decker at [email protected] Erin Connell or 800.792.8728. ENDOCRINE NEWS • SEPTEMBER 2012 PHYREC-052 51

51_53 Classifieds Sept2012.indd 51 8/10/12 11:55 AM DIVISION CHIEF OF PEDIATRIC ENDOCRINOLOGY The Nemours/Alfred I. DuPont Hospital for Children in Wilmington, Delaware seeks a Division Chief of Endocrinology to join their team. Interested candidates must be board certi ed in Pediatric Endocrinology, be ranked at the Associate Professor level, and have a track record of Lexington Clinic is seeking a full-time federal funding. Management and prevention of pediatric BC/BE Endocrinologist to join obesity is a major area of investigation. Nemours is one of the nation’s premier pediatric health care a thriving practice. systems. The Nemours/Alfred I. DuPont Hospital for Children • 100% clinical endocrinology oers intensive and acute inpatient and outpatient services • Outpatient only with limited o ce call • Large internal/external referral base covering more than 30 pediatric specialties. They care for • Favorable payer mix approximately a quarter of a million children annually and have done so for more than 70 years. Lexington Clinic is the largest and oldest private multi-specialty group practice in the Commonwealth of Kentucky, consisting of primary care Position oers a competitive income along with a full and physicians, surgical specialists and allied health professionals. We o er comprehensive bene ts package. a competitive salary, plus bonus; excellent bene ts; CME and relocation To learn more visit: Nemours.org allotment. Partnership available after one year. Nemours is a registered trademark of the Nemours Foundation. Nemours is an Equal Opportunity Employer. Interested candidates please contact: Audra Davidson To learn more, please contact either Manager, Physician Services and Recruitment Danise Cooper Beth Briggs [email protected] 800-678-7858 x63006 800-678-7858 x64454 p. 859.258.4135 c. 859.230.4417 [email protected] [email protected] LexingtonClinic.com

j ID#139877A15 ce kasearch.com Lexington Clinic is an Equal Opportunity Employer.

Endocrine News September 2012 1/4 page DAC 139877 PENDO

ENDOCRINOLOGIST

OCHSNER HEALTH SYSTEM in New Orleans is searching for a BC/BE ENDOCRINOLOGIST to join The Ochsner Health System is comprised of 8 our staff at Ochsner Baptist Medical Center. Can- hospitals and more than 38 clinics across southeast didates with experience or directly from training are Louisiana which sees over 1.5 million clinic patient welcomed to apply. Areas of interest should include visits annually. Ochsner is a major provider of gradu- general endocrine disorders, diabetes, and endocrine ate medical education with 23 ACGME accredited disorders as related to pregnancy. This position is residency and fellowship programs including our Endo- mainly outpatient-based but will serve a large Ob/Gyn crinology fellowship program. group with signiﬁcant inpatient consultation. Salary is New Orleans is a cosmopolitan, historic city with a competitive and commensurate with experience and pleasant climate, unique architecture, multiple medical training. schools and academic centers, professional sports Ochsner Baptist Medical Center, with a deep- teams, world-class dining and cultural interests, and rooted history in Uptown New Orleans, is a fully world-renowned live entertainment and music. accredited, full-service hospital staffed by more than Please email CV to: ochsnerphysiciancv@gmail. 390 physicians. We have all private rooms, an ICU, com Ref. # ABENDO1 or call 800-488-2240 for thirteen operating rooms, and a state-of-the art imag- more information. EOE. ing center. We are proud to be distinguished by our excellence in specialty care and high patient satisfac- tion scores. Our newly renovated 24-hour full-service emergency department is staffed by a team of board- certiﬁed ER physicians. Sorry, no J-1 visa opportunities available. ENDOCRINE NEWS • SEPTEMBER 2012 52

51_53 Classifieds Sept2012.indd 52 8/10/12 11:55 AM Division Director, Division of Endocrinology Department of Internal Medicine The Ohio State University The Department of Internal Medicine of the Ohio State University College of Medicine seeks to recruit a Director for the Division of Endocrinology, Diabetes and Metabolism. The ideal candidate will be a visionary leader interested in building upon the division’s strengths to expand its tripartite mission in clinical care, medical education and research excellence. The new Division Director would be expected to lead the division in achieving its vision of translating knowledge to improved care of endocrine and metabolic disease, mentoring faculty to support their career success, and collaborating across divisions, departments, centers and colleges at one of the nation’s most comprehensive universities and one of the largest academic health sciences campuses.

The Department is interested in strong candidates who have demonstrated commitment to excellence by providing leadership in teaching, research, and clinical service. Experience in building and/or supporting innovative clinical programs would be a strength. Applicants with mature research programs in basic, clinical or translational research are encouraged to apply. A track record of mentoring trainees for successful academic careers or supporting the career development of faculty is desirable as recruitment of additional faculty aligned with research, clinical and educational missions is anticipated.

The Division currently consists of 15 faculty whose clinical expertise spans a broad scope of general endocrinology and diabetes while supporting individuals focusing in diabetes, obesity, thyroid cancer, adrenal disorders, and bone health. Areas of research excellence include strong multidisciplinary research programs in thyroid cancer, diabetes, neuroendocrine tumors and women’s musculoskeletal health. In addition, Ohio State offers many unique opportunities for collaboration including the Comprehensive Cancer Center, The Center of Clinical and Translational Science, The Davis Heart and Lung Research Institute, Transplant Medicine and Bariatric Surgery among others. High quality clinical care is maintained through focused quality improvements, optimized electronic health records, cross-disciplinary teams and support staff. Post-graduate training includes a GME accredited fellowship program, and rotating residents in outpatient clinics and inpatient consultative services. The division is active in Ohio State’s innovative Lead.Serve.Inspire Curriculum for the medical students. The division is currently ranked in the top 20 by the U.S. News & World Report.

Candidates should be eligible for Associate Professor rank or above. To apply for the Division Director for the Division of Endocrinology at the Ohio State University Wexner Medical Center, submit a confidential inquiry, nomination, referral, or application to: Dan Dolan, Director of Senior Leader Recruitment for the OSU Medical Center 660 Ackerman Road, P.O. Box 183100, Columbus, OH 43218-3100. [email protected] 614-293-4513 To build a diverse workforce, the Ohio State University Wexner Medical Center encourages applications from individuals with disabilities, minorities, veterans, and women. Ohio State is an EEO/AA Employer.

We have used EndoCareers on several occasions and More for You from found the system ef cient, easy, and a successful way to screen and interview news ® prospective recruits.

— Ronald Swerdloff, MD Endocrine News Online has a fresh, new look each Chief, Division of Endocrinology Associate Chair, Department of Medicine month to bring you even more content. Our expanded Harbor UCLA Medical Center, Torrance, CA Web site is updated frequently and carries additional information you don’t want to miss.

e-Edition: An interactive PDF with pages you can turn, carrying links to videos, audios, and more.

The Finest Endocrinology Online Exclusives: Career Resources Available! Summaries of late-breaking research. The Hormone Health Network news: Print, Web, and Bulk Advertising Links to the latest patient information Free CV Database about endocrine disorders. Free Tips/How To Resources

Go to www.endo-society.org/endo_news or scan this QR Code with your smartphone’s QR Reader to see the many new online features, headlines, news briefs, interactive text,

Contact: Christine Whorton, EndoCareers ENDOCRINE NEWS • SEPTEMBER 2012 photos, and links, among other enhancements. [email protected] | 1.800.361.3906 | www.endocareers.org 53

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51_53 Classifieds Sept2012.indd 53 8/10/12 2:14 PM Back Story

sic level. Often called the first modern war, the Civil War was fought with technologically advanced weaponry that left young men with A Second Look at the Military horrible new injuries that taxed the ingenuity of field surgeons. More Medical Museum than anything the museum dem- By Marian Smith Holmes onstrates how the horrors of war created urgency in the development of medicine. “This is the place death delights to help the living,” a sign on one NMHM wall proclaims. “It was essentially the first government-sponsored medical research project in the United States,”

“It was essentially the rst government- sponsored medical research project in the United States,” says Laura Cutter, the museum’s archivist.

says Laura Cutter, the museum’s archivist. The battlefield collection eird. Quirky. Eeew! Such Army museum became the basis are the knee-jerk assess- dedicated to for the six-volume Wments people often make the study Medical and Surgical when they hear about the National of military History of the War of Museum of Health and Medicine medicine and the Rebellion, 1861– (NMHM). Yes, the exhibitions in- surgery. 65, a government clude a massive human hair ball, a “I have publication detailing huge elephantiasis leg and diverse numerous tens of thousands of organs preserved in formaldehyde. specimens for diseases, wounds, and But the 150-year-old museum, just you,” a Union surgeries. Not only outside Washington, D. C., is in surgeon replied. was it “highly valuable” truth an extensive collection of “Have put them to doctors for practi- medical artifacts and an impres- in ale barrels with cal information, Cutter sive educational facility. Even those some whisky & chlori- Dr. Mary Edwards Walker says, but it also statistically exhibits that sound creepy are nated soda.” Bone frag- documented the occurrence of grounded in real science. ments, pieces of tissue and other diseases. Based on the compilation, Scientific research was the specimens from the battlefields “the primary cause of military death museum founder’s original intent poured in along with photos of during the war was diarrhea and when it was established during the wounded soldiers and handwritten dysentery,” she adds. Civil War. “Forward… all specimens accounts of case studies and surgical In addition to housing 25 million of morbid anatomy,” U.S. Army Sur- procedures. artifacts, which include thousands of geon General William A. Hammond As gruesome as the collecting preserved organs and skeletal speci- instructed field doctors in 1862, may seem to modern sensibilities, it mens, the museum showcases nar-

ENDOCRINE NEWS • SEPTEMBER 2012 soliciting contributions to the new represented research at its most ba- ratives about individuals who made 54

54_56 Back Story Sept2012.indd 54 8/10/12 11:56 AM BACK STORY the years to get war includes the Sept. 11 tragedy. amputees function- Over the years, the museum a difference. An exhibition about Dr. ing again; a similar display has undergone name changes Mary Edwards Walker, a surgeon in charts the history of and numerous reloca- Union battlefield hospitals, contains facial reconstruction. tions. From 1971 to her surgical kit, a small leather case Though steeped in Civil 2011 it was housed in about the size of a make-up bag. The War history, the muse- the Walter Reed Army Army’s first female surgeon, she was um continues to collect, Medical Center, which once captured by the Confederates creating exhibitions of was then located in but she returned to the battlefield recent military medi- Washington, D.C. A soon after she was released. She was cal innovations. One year ago NMHM moved later awarded the Medal of Honor, the installation features a into its own brand first and only woman to ever receive section of an emergency new building in Silver it. Also on display is the beautifully room tent used in Iraq. Spring, Maryland. It crafted leather and gold microscope of A traumatic brain injury remains a destination 17th century scientist Robert Hooke, exhibition displays com- for researchers, but is a who used it to observe organisms that puterized equipment favorite of families he described and illustrated in his alongside instruments and, yes, curiosity book, Micrographica, a revolutionary from the 1800s, and a seekers. ■ scientific text at the time. Fascinated forensics exhibition trac- by the microscopic images, he coined ing the evolution of Holmes is the managing editor of the biological use of the word “cell.” the science so criti- Endocrine News. A display of prosthetic limbs cal to identifying illustrates the advances made over the fallen in battle

Now Available Evaluation & Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline

Developed independently by a team of experts, evidence based, and Endocrine Society Clinical Guidelines ALSO AVAILABLE vetted through a rigorous, multi-step peer review process, the Evaluation & Treatment of Hypertriglyceridemia guideline addresses: • Maternal Thyroid Dysfunction UPDATED • Osteoporosis in Men • Diagnosis and deﬁnitions of hypertriglyceridemia • Management of Hyperglycemia in Hospital- ized Patients in Non-Critical Care Setting • Causes of elevated triglycerides • Continuous Glucose Monitoring • Secondary causes of hyperlipidemia • Vitamin D • Adult Growth Hormone Deﬁciency • Treatment goals in patients with moderate hypertriglyceridemia • Pituitary Incidentaloma • Hyperprolactinemia • Post-Bariatric Surgery Patient • Congenital Adrenal Hyperplasia • Testosterone Therapy in Adult Men • Endocrine Treatment of Transsexual Persons • Adult Hypoglycemic Disorders • Pediatric Obesity • CVD and Type 2 Diabetes in Patients at Metabolic Risk • Patients with Primary Aldosteronism • The Diagnosis of Cushing’s Syndrome To purchase available guidelines visit: www.endo-society.org/ guidelines/Current-Clinical-Practice-Guidelines.cfm. • Hirsutism in Premenopausal Women • Androgen Therapy in Women

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54_56 Back Story Sept2012.indd 56 8/10/12 11:56 AM NEW! Endo Pubs App The Endocrine Society’s Full-Text Multi Journal App

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