HIGH RATE OF SUCCESS IN AN NIH- STUDY

of hypertensive patients- highest

percentage - remained on itial therapy 83% with NORVASC#{174}(amlodipi besylate) after 4 years; nearly all pati were on the 5-mg starting dose’

LOW RATE DISCONTINUATION ONLY 1.5%of patients in placebo studies (n= 1730) discontinued due to adverse effects2

PROVEN

No negative inotropic effects clinical doses in hemodyna m ic stud 2* No clinically significant effect on cardiac conduction or heart rate2

*S1IflH,jr fiernodynamic findings, hcvever fiave been agents possessing significant neqafive notropic ebecto

and 10-mg tablets Once-Daily NORV (ambdipine

EFFICACY AND SAFETY THAT’S EASY TO WITH Br$e(Summary NORVASC(amlodlpine besylate) Tablets For Oral Use CONTRAINDICATIONS: NORVASC is contraindicated in patients with known sensitivity to arniodipirre. In hypertension WARNINGS: Increased Angina and/or MyOcardIal Infarction: Rarely, patients, particulady those with severe obstruc5ve coronary artery disease, have developed documented increased frequency,durationand/or severity of angina or acute myocardial infarction on starhng cafrium channel blocker therapy or attire time of dosage increase. The mechanism of this effect has not been elucidated. PRECAUTIONS: General: Since the vasoditation induced by NORVASC is gradual in onset, acute hypotension has rarely been reported after oraladministrationof NORVASC. Nonethetuss, caution should be exercised when admin- or angina, convenient istering NORVASC as with any other penpherio vasodilator particularly in pahentswithsevere aortic stenoros. Usein Patients with CongestIve Heart Failure: In general, csicium channelbiockersshouldbe used with caution in patients with heart failure. NORVASC (5-10 mg per day) has been studied in a placebo-cnotrolledtrialof 1153 pabents with NYHA Class Ill or IV hearifailure on stable doses oIACE inhibitor,dtgooin,and diuretics.Follow-upwas at least 6 months, with a mean of about 14 months.There was nooveralladverse effecton survivalor cardiac morbidity as once-daily dosing defined by life-threateningarrhythmia,acute myocardialinfarction,or hospitalizationfor worsened heart failure). NORVASC has been compared to placebo in four 8-12 week studiesof patientswith NYHA Class llll heart failure, involving a totalof697 pahents.In these studies,there was no evidence ofworsened heart failurebased on measuresof eoercisetolerance,NY1IAclassification,symptoms,or LVEF. Beta#{149}BlockerWithdrawal: NORVASC is not a beta-blocker and thereforegives no protection against the dangers of abrupt beta-blocker withdrawal, any such withdrawal should be by gradual reduction of the dose ofthe beta-blocker. #{149}The usual starting dose is5 mg in hypertension Patients wIth Hepatic Failure: Since NORVASC is extensively metabolized by theliverand the plasma elimination hail- Ide 1J) is 56 hoursinpatients with impaired hepatic function, caution should be enercised when administering or angina NORVASC to patientswithsevere hepatic impairment Drug kiteractions: In vitro data in human plasma indicate that NORVASC has no effect on the proteinbinding of drugs tested )digooin, phenytoin, warfarin, and indomethacin) Special studies have indicated thatthe co-administrationof - In hypertension, small, fragile, or elderly individuals NORVASC with digooindid not change serum digooinlevelsor digooinrenal clearance in normal volunteers; thatco- or patients with hepatic insufficiency may be started on administrationwithcimetidinedid not abet the pharmacokinetics of amlodipine,and that co-administrationwithwarfarin did not change the warfarmnprothrornbtn response time. 2.5 mg once daily2 In clinicaltrials,NORVASChas been safely administered with thiazide diuretics,beta-blockers,angiotensin converting enzyme inhibitors,long-actingnitrates,sublingualnitroglycerin,digooin,warfarin,non-steroidalanti- inflammatory drugs,antibiotics,and oralhypoglycemicdrugs. #{149}litration can proceed to 10 mg DruglLaborator.j Test Interactions: None known. Carcinogenesis, NUtagSnesIs,ImpSIrm.M of Fertility: Rats and mice treated with amlodipine in the dietfor two years, at concentrationscalculatedto providedaily dosage levels of0.5, 1.25, and 2 5 mg/kg/day showedno evidenceof - Most angina patients will require 10 mg carcinogen-city. The highesr dose for mice, similarto,and forratstwice the maximum recommended clinicaldose of 10 mg on a mg/mi basis), was close to the maximum tolerated dose for mice but notfor rats. Mutagenicdy studws revealed no drug related effects ateIther the gene or chromosome levels. #{149}Can be taken with or without food There was no effecton the fertilityof ratstreated with amlodipine males for64 days and females 14 days prior to mating) at dosesup to 10 mg/kg/day )8 times the maximumrecommended humandose of 10 mg on a mg/m2 basis) Pregnancy Category C: No evidence ofteratogenicity or otherembryo/fetal toxicitywasfound whenpregnant ratsor #{149}The most common side effects are headache rabbits were treated orally with up to 10 mg/kg amlodipine respectively8 times’ and 23 tirnes the maximum recom- mended human dose of 10 mg on a mgJm basis)duringtheir respective periods of major organogenesis However, litter size was signiticantlydecreased by about 50%) and the number of intrauterinedeaths was significantly increased about 5-fold)in rats administered10 mg/kg amlodipinefor 14 days before matingand throughoutmetingand and edema gestation. Amlodipine has been shown to prolongboth the gestationperiod and the durationof labor in rats at this dose. There are no adequate and well-controlled studies in pregnant women. Arniodipine should be used during pregnancy only it the potential benefitjustihes the potentialrisk to the fetus. Nursing Mothers: Itis not known whether amlodipine is excreted inhuman milk.In the absence of thisinformation,it is recommended thatnursingbe disconbnued WhileNORVASC is administered Pediatric Use: Safety and effectiveness of NORVASCin childrenhave not been established. ADVERSE REACTIONS: NORVASC has been evaluated for safety inmore than 11,000 pahentsin U S. and foreign clinical trials. In general,treatmentwithNORVASC was well-tolerated at doses up to 10 mg daily Most adverse reactions reported duringtherapywithNORVASC were of mildor moderate severity.In controlledclinicaltrials directly comparing NORVASC )N =1730)in doses up to 10 rn9to placebo)N =1250), discontinuation of NORVASC due to adverse reactions was requiredin onlyabout 1 5% of patientsand was notsignificantlydifferentfromplacebo )about 1%). The most common side effects are headache and edema. The incidence)%) ofside effects which occurred in a dose related manner are as follows:edema )1.8% at 2.5 mg, 3.0% at 5.0 mg, and 10.8% at 10.0 mg, compared with 0.6% placebo); dizziness 1.1% at 2.5 mg, 3.4% at 5.0 mg, and 3.4% at 10.0 mg, compared with 1.5% placebo); flushing 0.7% at 2.5 mg, 1.4% at 5.0 mg, and 2.6% at 10.0 mg, compared with0.0% placebo); and palpitation 0.7% at 2.5 mg, 1.4% at 5 0 mg, and 4 5% at 10.0 mg, compared with0.6% placebo) Other adverse experiences which were notclearlydose relatedbut whichwere reportedwithan incidence greater fl9/tct.,. than 10% in placebo-controlled clinical tnals include the following headache 7.3%, compared with 7.8% placebo); fatigue 4.5%, compared with 2.8% placebo); nausea 2.9%, compared with 1.9% placebo); abdominal pain )1.6%, compared with 0.3% placebo);and sornnolence)1.4%, compared with0.6% placebo). For severaladverseexperiences that appear to be drug and dose related, there was a greater incidence inwomen than men associated with amlodipine treatment as follows: edema 5.6% in men, 14.6% in women,compared with a placebo incidence inmen of 1.4% and 5.1% in women);flushing 1.5% in men, 4.5% in women,compared with a placebo incidence of 0.3% in men and 0.9% in women),palpitations 1.4% in men, 3.3% in women,compared witha placebo incidenceof 0.9% in men and 0.9% in women);and somnolence)1.3% in men, 1.6% inwomen, compared with a placebo incidenceof0.8% in men and 0.3% in women). The followingevents occurredin l% but >0.1% of patientsin controlledclinicaltrialsorunder conditionsof open Once-Daily 5-mg and 10-mg tablets trialsor marketingeoperiencewhere a causal relationshipis uncertain;they are listedtoalart thephysicianto a possible relationship:cardiovascular: arrhythmia includingventriculartachycardia and atrialfibrillation),bradycardia, chest pain, hypotensiori, peripheral ischemia, syncope, tachycardla, posturaldizziness, postural hypotension; central and psrthsral nervous system: hypoestfiesia, paresthesia, fremor, vertigo; gastrointestinal: anorexia, constipation, dyspepsla, dysphagia, diarrhea, flatulence, vomiting, gingival hyperplasla; general: asthenia,’ back pain, hotfiushes. malaise, pain, rigors, weight gain;musculo-skeletal system: arthralgia, arthrosis. muscle cramps, rnyalgla; psychiatric: sexual dysfunction )male and female), msomnla,nervousness,depression, abnormal dreams, anmety,depersonalization; respIratory systim: dyoprea,’ epistaxis;skIn and appendages: pruritus, rash, rasherythematous, rash maculopapular;specIal senses: abnormalviolas,conlunctivitis, diplopia, eye pam, tinnitus;urinary system: micturthon frequency, micturitiondisorder,nocturia;autonomic nsrvous system: dry mouth, sweating increased; mitabolic and nutrttlon: thirst; hemopoletic: purpura. The following events occurredin O.1% of patients:cardiac failure,pulse irregularity,extrasystoles,skin discoloration, NORVASC#{174}urticaria, skindryness,alopecia, dermatitis,muscleweakness,twitching,ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis,increasedappetite, loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia. Other reactionsoccurredsporadicallyand cannot be distinguishedfrommedicationsorconcurrentdisease states (amlodipinebesylate) such as myocardial infarction and angina. NORVASC therapy has notbeen associatedwith clinically significant changes in routine laboratory tests.No clinically relevantchangeswere noted in serum potassium, serum glucose,totaltriglycerides,total cholesterol,HDL cholesterol, uricacid, blood urea nitrogen, creatinlne or liver function tests. NORVASC has been used safely inpabentswithchroisc obstructive pufrnonary disease, wall compensated live heart failure,peripheralvasculardisease, diabetes mellitus,and abnormallipidprofiles. 0 GE: Single oral doses of 40 mg/kg and 100 mg/kg in mice and rats, respectively,caused deaths. A single oraldose of 4 mg/kg or higher indogs caused a marked peripheral vasodilation and hypotension. Overdosage mightbe expected to cause excessivepenpheral vasodilabonwith marked hypotenroon and possiblya reflextachycardia.In humans,experience with intentional overdosage of NORVASC is limited.Reports of intentional overdosage include a patient who ingested250 mg and was asymptomaticand was not hospitalized;another )120 mg) was hospitalized,underwentgastriclavage and remainednorrnotensive;the third 105 mg) was hospitalizedand had hypotension)90/50 mmHg) whichnormalizedfollowingplasma expansion. A patientwho took 70 mg amlodipine and an unknown quantity of benzodiazepine in a suicideattempt, developed shockwhichwas refractorytotreatmentand died the followingday with abnormally highbenzodiazepine plasma concentration. A case of accidental drug overdose has been documentedin a 19 month oldmale who ingested30 mg amlodipine)about 2 mg/kg). Duringthe emergency room presentation, vital signswere stable with no evidence of hypotension,but a heart rate of 180 bpm. Ipecac was administered3.5 hoursafter ingestionand on subsequent observation oversight)no sequelae were noted. 1. Neaton JD, Gnmm RH Jr, Pnneas RJ, et a for the Treatment of MUdHerteneton Study Research Group. If massiveoverdoseshouldoccur,active cardiac and respiratorymonitoring should be instituted. Frequentblood Treatment of MUdHypertension Stud ansi results. JAW. 199327713-724. pressuremeasurementsare essential.Shouldhypotension occur, cardiovascular support includingelevationof the 2. Data on file. Pfizer Inc. New York, NY. extremities and the judicious administration of fluidsshouldbe initiated.If hypotension remains unresponsive to these conservative measures, administrationofvasopressors such as phenylephrine),shouldbe consideredwithattention to circulatingvolumeand urine output.Intravenouscalciumgluconatemay helpto reversetIreeffectsof calcium entry blockade. As NORVASCis highlyproteinbound, hemodialysis isnot likelyto be of benefit. * Based on patientweightof 50kg. lhese eventsoccurredin less than 1%in placebo controlledtrials,but the incidenceof theseside effectswas between Labs #{149}NHO #{149}Pratt#{149} 1%and 2% inall multipledose studies W U.S. Pharmaceuticals Group More detailed professional information availableon request Revised June 1996 0 0 0

There’s More To EPOGEN#{174}(Epoetin alfa) Than Epoetin Alfa.

When you specify EPOGEN#{174}(Epoetin Support Services. Your Amgen Professional alfa), you get more than a product. You also Sales Representative can tell you more about get a comprehensive support system. That’s the ways these programs can satisfy your needs. important, because the depth and quality of There simply is no comparable source of professional support is a significant element professional support. That’s not surprising, in long-term clinical success. because EPOGEN#{174}is a lot more than just a EPOGEN#{174}support encompasses the drug. It’s a way of life. Amgen Reimbursement Hotline, the Amgen For more information, please call SAFETY NET#{174}Program, Professional Services, 1-800-77-AMGEN. Professional Education Programs, and Clinical

EPEN Priigr.uiisav-aitable exclusively for diatysis patients and providers. (EPOETIN ALFA) 01994 Amgeii tic. R1(( )MiSINAN T In Adult Patients...

HELP E ICATE H Use the a

40 mcg/

toHeip B

RECOMBIVAX HB is contraindicated in the presence of hypersensitivity to yeast or to any component of the Patients who develop symptoms suggestive of hypersensitivity after an injection should not receive further injections vaccine. RECOMBIVAX HB Dialysis Formulation (40 mcg/mL) is intended only for adult predialysis/dialysis patients. A booster dose or revaccination may be considered if the anti.HBs level is less than 10 mlU/mL 1-2 months the third dose. Please read the Brief Summary of the Prescribing Information accompanying this advertisement.

MERCK Copyright © 1997 by Merck & Co., Inc. Vaccine Dwion All rights reserved. BRIEF SUMMARY Incidence Less Than 1% of Injections BODYASA WHOLE Sweating; achiness; sensation of warmth; lightheadedness; chills; and RECOMBI VAX HB#{174} flushing HEPATITIS B VACCINE (RECOMBINANT) DIGESTIVE SYSTEM Vomiting; abdomina) pains/cramps; dyspepsia; and diminished appetite Please read the full Prescribing Information for complete details. RESPIRATORY SYSTEM Rhinitis; influenza; and cough INDICATIONS AND USAGE RECOMBIVAX HB is indicated for vaccination against infection caused by all NERVOUS SYSTEM known subtypes of hepatitis B virus. RECOMBIVAX HB Dialysis Formulation Vertigo/dizziness; and paresthesia is indicated for vaccination of adult predialysis and dialysis patients against INTEGUMENTARY SYSTEM infection caused by all known subtypes of hepatitis B virus. Pruritus; rash (non-specified); angioedema; and urticaria

CONTRAINDICAT1ONS MUSCULOSKELETAL SYSTEM Arthralgia including monoarticular; myalgia; back pain; neck pain; shoulder pain; Hypersensitivity to yeast or any component of the vaccine. and neck stiffness

WARNINGS HEMIC/LYMPHATIC SYSTEM Patients who develop symptoms suggestive of hypersensitivity after an Lymphadenopathy injection should not receive further injections ofthe vaccine (see CONJTRAINDICAT1ONSL PSYCHIATRIC/BEHAVIORAL Because of the long incubation period for hepatitis B, it is possible for Insomnia/disturbed sleep unrecognized infection to be present at the time the vaccine is given. The vaccine SPECIAL SENSES may not prevent hepatitis B in such patients. Earache PRECAUTIONS UROGENITAL SYSTEM General Dysuria As with any percutaneous vaccine, epinephrine should be available for CARDIOVASCULAR SYSTEM immediate use should an anaphylactoid reaction occur. Hypotension Any serious active infection is reason for delaying use of the vaccine except when in the opinion of the physician, withholding the vaccine entails a greater risk. Marketed Experience Caution and appropriate care should be exercised in administering the vaccine The following additional adverse reactions have been reported with use of the to individuals with severely compromised cardiopulmonary status or to others in marketed vaccine. In many instances, the relationship to the vaccine was whom a febrile or systemic reaction could pose a significant risk. unclear. Pregnancy Hypersensitivity Pregnancy Category C: Animal reproduction studies have not been conducted Anaphylaxis and symptoms of immediate hypersensitivity reactions including with the vaccine. It is also not known whether the vaccine can cause fetal harm rash, pruritus, urticaria, edema, angioedema. dyspnea, chest discomfort, bronchial when administered to a pregnant woman or can affect reproduction capacity. The spasm, palpitation, or symptoms consistent with a hypotensive episode have vaccine should be given to a pregnant woman only if clearly needed. been reported within the first few hours after vaccination. An apparent hypersensitivity syndrome (serum-sickness-like) of delayed onset has been reported Nursing Mothers days to weeks after vaccination, including; arthralgia/arthritis (usually transient), fever, It is not known whether the vaccine is excreted in human milk. Because many and dermatologic reactions such as urticaria, erythema multiforme, ecchymoses and drugs are excreted in human milk, caution should be exercised when the vaccine is erythema nodosum (see WARNINGS and PRECAUTIONS). administered to a nursing woman. Digestive System Pediatric Use Elevation of liver enzymes; constipation. RECOMBIVAX HB has been shown to be usually well-tolerated and highly immunogenic in infants and children of all ages. Newborns also respond Nervous System well; maternally transferred antibodies do not interfere with the active immune Guillain-Barr#{233}Syndrome; multiple sclerosis; myelitis including transverse response to the vaccine. See DOSAGE AND ADMINISTRATION in full Prescribing myelitis; peripheral neuropathy including Bell’s Palsy; radiculopathy; herpes zoster; migraine; muscle weakness; hypesthesia. Information for recommended pediatric dosage and for recommended dosage for infants born to HBsAG positive mothers. Integumentary System The safety and effectiveness of RECOMBIVAX HB Dialysis Formulation in chil- Stevens-Johnson Syndrome; petechiae. dren have not been established. Musculoskeletal System Arthritis. ADVERSE REACTIONS Hematologic RECOMBIVAX HB and RECOMBIVAX HB Dialysis Formulation are generally Increased erythrocyte sedimentation rate; thrombocytopenia. well-tolerated. No serious adverse reactions attributable to the vaccine have been reported during the course of clinical trials. No adverse experiences were Immune System reported during clinical trials which could be related to changes in the titers of Lupus-like syndrome. antibodies to yeast. As with any vaccine, there is the possibility that broad use of Psychiatric/Behavioral the vaccine could reveal adverse reactions not observed in clinical trials. Irritability; agitation; somnolence. In a group of studies, 1636 doses of RECOMBIVAX HB were administered to 653 Special Senses healthy infants and children (up to 10 years of age) who were monitored for 5 days Optic neuritis; tinnitus; conjunctivitis; visual disturbances. after each dose. Injection site reactions (including erythema and swelling) and systematic complaints were reported following 8% and 17% of the injections, Cardiovascular System respectively. The most frequently reported systemic adverse reactions Syncope, tachycardia. (>1% injections), in decreasing order of frequency, were irritability, tiredness, fever The following adverse reaction has been reported with another Hepatitis B (>1O1’F oral equivalent), crying, diarrhea, vomiting. diminished appetite and insomnia In a group of studies, 3258 doses of RECOMBIVAX HB were administered to Vaccine (Recombinant) but not with RECOMBIVAX HB: keratitis. 1252 healthy adults who were monitored for 5 days after each dose. Injection site and systemic complaints were reported following 17% and 15% of the injections, respectively. The following adverse reactions were reported:

Incidence Equal to or Greater Than 1% of Injections LOCAL REACTION (INJECTION SITE) Injection site reactions consisting principally of soreness, and including pain, ten- derness, pruritus, erythema, ecchymosis, swelling, warmth, and nodule formation. BODYASA WHOLE The most frequent systemic complaints include fatigue/weakness; headache; 0 M5adDtby INC., West Point, PA 19486, USA fever (100’F); and malaise. Syringes of RECOMBIVAX HB are also manufaciured by: Evans Medical Lid. DIGESTIVE SYSTEM Gaskill Road, Speke, Liverpool L24 9CR. England Nausea; and diarrhea RESPIRATORY SYSTEM Issued February 1996 7462214 Pharyngitis; and upper respiratory infection J6254-1296 PRINTED IN U.S.A. CONTAINS 50% RECYCLED MATERIAL#{174} the of Hypertension... Bring down the pre ure withease

ONCE-DAILY mg #{149}160 mg TM

asu es

ONCE-D#{193}IL 80 mg #{149}160 mg art v Isartan capsules NOW- NOT the power of leading

#{149}Starting delivers efficacy of: 5 mg 20 mg2 10 mg34 BUT ALSO the tolerability of placebo... #{149}Overall of side effects comparable to at both dosage strengths4* PLUS once-daily dosing #{149}Start 80mg qd #{149}Dosage be titrated to 160 mg qd for additional effect at no extra cost45 about 2 6 and 6 times, respectively. the maximum recommended human dose on a mg/m2 basis DiovanTM (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.) valsartan Mutagenicity assays did not reveal any valsartan-related effects at either the gene or chromosome level These assays included bacterial mutagenicity tests with Salmonella (Ames) and E colc a gene Capsules mutation test with Chinese hamster V79 cells; a cytogenetic test with Chinese hamster ovary cells; and a rat micronucleus test BRIEF SUMMAFIY(FOR COMPLETE PRESCRIBING INFORMATION, SEE PACKAGE INSERT) Valsartar had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day. This dose is 6 times the maximum recommended human dose on a mg.’m2 basis Calculations assume an oral dose of 320 mg/day and a 60-kg patient I USE IN PREGNANCY When used in pregnancy during the second and third trimesters, drugs that act directly on Pregnancy Categories C Ifirst trimesterl and 0 lsecond and third trimestersl the renin-anglotensin system can caase Injary and even death to the developing fetus. When See WARNINGS, Fetal/Neonatal Morbidity and Mortality pregnancy is detected, Diovan should be discontinued as soonas possible. See WARNINGS: Nursing Mothers Fetal/tleonatal MorbidIty and Modality. It is not known whether valsartan is eocreted in human milk, but valsartan was excreted in the milk of lactating rats Because of the potential fur adverse effects on the nursing infant. a decision should be INDICATIONS AND USAGE made whether to discontinue nursing or discontinue the drug. taking into account the importance of Diovan is indicated for the treatment of hypertension It may be used alone or in combination with the drug to the mother other antihypertenoive agents Pediatric Use CONTRAINDICATIONS Safety and effectiveness in pediatric patients have not been established. Diovan is contraindicated in patients who are hypersensitive to any component of this product Geriatric Use WARNINGS In the controlled clinical trials of valsartan, 1214 36.2%) of patients treated with valsartan were Fetal/Neonatal Morbidity and Modality 65 years and 265 (7 9%) were > 75 years. No overall difference in the efficacy or safety of valsartan Drags that act directly on the renin-angioterrsin system can cause fetal and neonatal morbidity and was observed in this patient population, but greater sensitivity of some older individuals cannot be deathwhen administered to pregnant women. Several ruled out dozencases have been reported in the world literature ADVERSE REACTIONS in patients who were taking angiotenoin’converring Diovan has been evaluated for safety in more than enzyme inhibitors. When pregnancy is detected, Diovan 4000 patients including over 400 treated for over should be discontinued as soon as possible 6 months. and more than 160 for over 1 year. Adverse The use of drugs that act directly on the renin- evpeniences have generally been mild and transient in angiotensin system during the second and third fri nature and have only infrequently required discon- mestersof pregnancyhas been associatedwith fetal tinuation of therapy The overall incidence of adverse and neonatal injury, including hypotension, neonatal evpeniences with Diovan was similar to placebo. skull hypoplasia, anuria, reversible or irreversible renal The overall frequency of adverse experiences was failure, and death. Oligohydramnios has also been neither dose-related nor related to gender, age. race. reported. presumably resulting from decreased fetal or regimen Discontinuation of therapy due to side renal function; oligohydramnios in this setting has effects was required in 2.3% of valsartan patients and been associated with fetal limb contractures, cranis- 2.0% of placebo patients. The most common reasons facial deformation,and hypoplastic lung development for discontinuation of therapy with Diovan were head- Prematurity. intrauterine growth retardation. and patent valsartan capsules ache and dizziness ductus arteriosus have also been reported, although it The adverse eoperiences that occurred in placebo- is not clear whether these occurrences were due to controlled clinical trials in at least 1% of patients eoposure to the drug. treated with Diovan and at a higher incidence in These adverse effects do not appear to have resulted from intrauterine drug exposure that has been valsartan )n2316) than placebo )n=888) patients included viral infection (3% vs. 2%), fatigue (2% limited to the first trimester, Mothers whose embryos and fetuses are exposed to an angiotensin II vs. 1”,), and abdominal pain (2”, vs. 1%). receptor antagonist only during the first trimester should be so informed Nonetheless, when patients Headache, dizziness, upper respiratory infection, cough. diarrhea, rhinitis, sinusitis. nausea, phar- become pregnant, physicians should advise the patient to discontinue the use of valsartan as soon as yngitis, edema, and arthralgia occurred at a more than 1” rate but at about the same incidence in possible. placebo and valsartan patients Rarely (probably less often than once in every thousand pregnancies). no alternative to a drug acting in trials in which valsartan was compared to an ACE inhibitor with or without placebo, the incidence on the renin-angiotensin system will be found In these rare cases, the mothers should be apprised of of dry cough was significantly greater in the ACE-inhibitor group (7.9%) than in the groups who the potential hazards to their fetuses. and serial ultrasound eoaminations should be performed to received valsartan (2.6”.) or placebo (1 5%). In a 129-patient trial limited to patients who had had dry assessthe intra-amniotic environment. cough when they had previously received ACE inhibitors, the incidences of cough in patients who If oligohydramnios is observed, valsartan should be discontinued unless it is considered life-saving received valsartan, HCTZ, or lisinopril were 20’/,, 19%, and 69% respectively (p.cO.001). for the mother. Contraction stress testing (CST), a nonstress test INST) or biophysical profiling (BPPI Dose-related orthostatic effects were seen in less than 1% of patients. An increase in the incidence may be appropriate, depending upon the week of pregnancy Patients and physicians should be aware, of dizziness was observed in patients treated with Diovan 320 mg (8%) compared to 10 to 160 mg however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury 12’, to 4”. 1 Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely Diovan has been used concomitantly with hydrochlorothiazide without evidence of clinically impor- observed for hypotension. oliguria. and hyperkalemia. If oliguria occurs, attention should be directed ant adverse interactions. toward support of blood pressure and renal perfusion Enchange transfusion or dialysis may be reguired Other adverse experiences that occurred in controlled clinical trials of patients treated with Diovan as means of reversing hypotension and/or substituting for disordered renal function 1>0.2’:, of valsartan patients) are listed below It cannot be determined whether these events were No teratogenic effects were observed when valsartan was administered to pregnant mice and rats at causally related to Diovan oral doses up to 600 mg/kglday and to pregnant rabbits at oral doses up to 10 mglkglday However, Body as a Whole Allergic reaction and asthenia significant decreases in fetal weight, pup birth weight. pap survival rate, and slight delays in develop- Cardiovascular. Palpitations mental milestones were observed in studies in which parental rats were treated with valsartan at oral, Dermatologic: Pruritus and rash maternally tonic (reduction in body weight gain and food consumption) doses of 600 mg/kg/day during Digestive. Constipation dry mouth, dyspepsia. and flatulence organogenesis or late gestation and lactation. In rabbits, fetotonicity (i.e . resorptions, liter loss, abor- Musculoskeletal. Back pain. muscle cramps, and myalgia lions, and low body weight) associated with maternal tooicity (mortality) was observed at doses of Neurologic and Psychiatric: Anxiety. insomnia, paresthesia. and somnolence 5 and 10 mg/kg/day The no observed adverse effect doses of 600. 200 and 2 mg/kgiday in mice. rats Respiratory Dyspnea and rabbits represent 9. 6. and O.t times, respectively. the manimum recommended human dose on a Special Senses Vertigo mglm2 basis. (Calculations assume an oral dose of 32t mg/day and a 60.kg patient I Urogenital. Impotence Hypotenaion in Volume- and/or Salt-Depleted Patients Other reported events seen less frequently in clinical trials included chest pain. syncope, anoreoia. Excessive reduction of blood pressure was rarely seen (0 1%) in patients with uncomplicated hyper- vomiting. and angiuedema tension. In patients with an activated renin-angiotensin system. such as volume and/or salt’depleted Clinical LaboratoryTestFindings patients receiving high doses of diuretics, symptomatic hypofension may occur. This condition should in controlled clinical trials, clinically important changes in standard laboratory parameters were rarely be corrected prior to administration of Diovan, or the treatment should start under close medical associated with administration of Diovan. supervision. Creatinine: Minor elevations in creatinine occurred in 0.8% of patients taking Diovan and 0.6’/, given If hypotension occurs, the patient should be placed in the supine position and, if necessary. giver placebo in controlled clinical trials an intravenous infusion of normal saline A transient hypotensive response is not a contraindication Hemoglobin and Hematocrit Greater than 20” decreases in hemvglobin and hematocrit were observed to further treatment, which usually can be continued without difficulty once the blood pressure has in 0 4”, and 0.8’:,, respectively. of Diovan patients, compared with 0.1% and 0.1’/, in placebo-treated stabilized. patients One valsartan patient discontinued treatment for microcytic anemia PRECAUTIONS Liver function tests Occasional elevations greater than 150’/) of liver chemistries occurred in Diovan- General treated patients Three patients )< 0.1%) treated with valsartan discontinued treatment for elevated Impaired Hepatic Function: As the majority of valsartan is eliminated in the bile, patients with mild- liver chemistries. to-moderate hepatic impairment, including patients with biliary obstructive disorders, showed lower Neutropenia. Neutropenia was observed in 1 .9% of patients treated with Oiovan and 0 B’i, of patients valsartan clearance (higher AUCO( Care should be eoercised in administering Dinvan to these patients treated with placebo. Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system. Serum Potassium Greater than 20% increases in serum potassium were observed in 4.4’/, of Diovan- changes in renal function may be anticipated in susceptible individuals. In patients whose renal func- treated patients compared to 2.9% of placebo-treated patients. No patient treated with valsartan dis- lion may depend on the activity of the renin-ungiotensin-aldosterone system Ic g . patients with severe continued therapy for hyperkalemia. congestive heart failure(. treatment with angiotensin-conver’ting enzyme inhibitors and angiotensin Store below 30’C l86’Fl Protect from moisture receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with Dispense in tight container )USP). acute renal failure and/or death Diovan would be expected to behave similarly In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis. increases in 666751 C97-6 (Rev. 4/97) serum creatinine or blood urea nitrogen have been reported In a 4day trial of valsartan in 12 patients with unilateral renal artery stenosis, no significant increases in serum creatinine or blood urea nitrogen were observed.There has been no long-term use of Diovan in patients with unilateral or bilateral renal artery stenosis, but an effect similar to that seen with ACE inhibitors should be anticipated Information for Patients Pregnancy: Female patients of childbearing age should be told about the consequences of second- and third-trimester enposure to drugs that act on the renin-angiotensin system, and they should also Dist by be told that these consequences do not appear to have resulted from intrauterine drug eoposure that Ciba-Geigy Corporation has been limited to the first trimester. These patients should be asked to report pregnancies to their Pharmaceuticals Division physicians as soon as possible Summit. New Jersey 07901 Drag Interactions No clinically significant pharmacokinetic interactions were observed when valsartan was coadminis- tered with amlodipine, ateno(ol, cimetidine, digooin, furosemide, glyburide. hydrochlorothiazide, or indomethacin. The valsartan-atenolol combination was more antihyperfensive than either component. References: 1. Corea1,(ardoni 0, Fogari R,eI al. Volsorton,a newongiolensin II antagonist for the treat- but it did not lower the heart rate more than atenolol alone Coadministration of valsartan and warfanin did not change the pharmacokinefics of valsartan or the meet of essentialhypertension: a comparative study of the efficacy and safety against amlodipine. (lie time-course of the anticoagulant properties of warfarin PharmacolTher 1996;60:341-346. 2. HolwerdaNJ, Fogari R,Angeli P,et aL Valsartan,a new angiotensin II cv 450 Interactions: The enzyme(s( responsible for valsartan metabolism have not been identified but do not seem to be CYP 450 isozymes The inhibitory or induction potential of valsartan on CYP 450 antagonistfor the treatment of essentialhypertension: efficacy and safety comparedwith placeboand is also unknown. enalapril. J Hypertens. 1996;14:l 147-) 151. 3. Bl&k FIR,Graff A, Shute D, et al. Valsartan,a new Carcinogenesis, Motagenesis, Impairment of Fertility angiotensin II antagonist for the treatment of essentialhypertension: efficacy,tolerability and safety compared There was no evidence of carcinogenicity when valsartan was administered in the diet to mice and rats for up to 2 years at doses up to 160 and 200 mg/kg/day. respectively These doses in mice and rats are to an angiotensinconverting enzyme inhibitor lisinopril. J Hum Hyperlens. 1997;1 1:483-489. 4. Data on file, Novartis. 5. RedBool{ UPDATE.September 1997. . #{149}:T - ilamti ‘) NOVARTIS ©1998 Novart’ts Printed in USA (1/98) DIO-0799 #{174}Printedon RecycledPaper Chromagen Forte Liquid-Iron Gelcaps

I Contains 151 mg of elemental I Reduces the need for and risks iron-the most elemental iron associated with IV iron5 available in an oral hematinic today #{149}livers liquid iron to the site of I Supplies the essential amount of optimal absorption for iron for successful Epogen#{174}t enhanced GI tolerability and therapy2’4 excellent patient compliance

Recommendthe most wdyprescrthed ? G#{220}ROMI4GEN

formulatedto meetthe needsof thosewho need ]FIT]I The strength of liquid iron in a soft gelcap

Pleaseseefull presctibing information adjacentto thisad, Basedona nationwide survey of nephrologists.Dataonfile,SavageLaboratories. Bosed on INS National PrescriptionAud’d,September1997. © 1998 SavageLaboratories tEpogen (epoetin silo) is a registered trademark of AmgenInc. g&tl PRECAUTIONS Folic acid should not be prescribed until the diagnosis of pernicious ane- mia has been eliminated, since it can alleviate the hematologic manifes- tations, while allowing neurological damage to continue undetected.23 ADVERSE REACTIONS Average capsule doses in sensitive individuals or excessive dosage may cause nausea, skin rash, vomiting, diarrhea, precordial pain, or flushing of the face and extremities. #1 DOSAGE AND ADMINISTRATION *\ ‘1 c23? Usual adult dose is 1-2 soft gelatin capsules daily, or as directed by a physician. HOW SUPPLIED Capsules: NDC 0281 -0262-18, Unit Dose Box 100 CAUTION: Federal law prohibits dispensing without prescription. BIBLIOGRAPHY CHROMAGEN#{174} IITI ‘Berk, MS. and Novich, MA.: “Treatment of Iron Deficiency Anemia With SOFT GELATIN CAPSULES Ferrous Fumarate,” Am. J. Obst. & Gynec., 203-206, 1962. 2Shapleigh, J.B., and Montgomery, A.:Am. Pract. & Dig.Treat. 10-461, 1959. ‘Brise, H. DESCRIPTION and Hallberg, L.: “Effect of Ascorbic Acid on Iron Absorption’ Acta. Med. CONTENTS: Each brown soft gelatin capsule contains: ferrous fumarate Scand.171:376, 51-58, 1962. ‘New Drugs, p. 309, AMA, Chicago, 1966. usP, 460 mg (151 mg elemental iron), ascorbic acid USP, 60 mg, folic acid 5Mazur, A., Green, S. and Carleton, A,: “Mechanism of Plasma Iron usP, 1 mg, cyanocobalamin USP, 10 mcg. Incorporation into Hepatic Ferritin,” J. Bio. Chem. 3:595-603, 1960. #{176}Greenberg,SM., Tucker, A. E., Mathues, H and J.D.: “Iron Absorption and DISCUSSION: The amount of elemental iron and the absorption of the Metabolism, I. Interrelationship of Ascorbic Acid and Vitamin E’ J. Nutrition iron components of commercial iron preparations vary widely. It is further 63:19-31, 1957. 7Moore, CV. and Dubach, R. “Observations on the established that certain accessory components” may be included to Absorption of Iron from Foods Tagged with Radioiron” Trans. Assoc. Amer. enhance absorption and utilization of iron. Chromagen#{174}Forte Capsules Physic. 64:245, 1951 . eSteinkamp, A. Dubach, A. and Moore, CV.: are formulated to provide the essential factors for a complete, versatile “Studies in Iron Transportation and Metabolism’Arch. Int. Med. 95:181, hematinic. 1955. #{176}Gorten,M. K. and Bradley, J. E.: “The Treatment of Nutritional ACTiONS Anemia in Infancy and Childhood with Oral Iron and Ascorbic Acid’ J. HIGH ELEMENTAL IRON CONTENT: Ferrous fumarate, used in Pediatrics, 45:1, 1954. ‘#{176}Mazur,A.: “Role of Ascorbic Acid in the Chromagen#{174} Forte Capsules, is an organic iron complex which has the Incorporation of Plasma Iron into Ferritin’ Ann. N.Y. Acad. Sci, 92:223-229, highest elemental iron content of any hematinic salt - 33%. This compares 1961 . “Cox, E.V. et at.: “The Anemia of Scurvy’ Amer. J. Med. 42:220- with 20% for ferrous sulfate (heptahydrate) and 13% for ferrous glu- 227, 1967. ‘#{176}McEvoy,G.K., Ed.: AHFS Drug Information, p. 2667-2669, 2 Chromagen#{174} Forte contains 151 mg of elemental iron. Am. Soc. Hosp. Pharm., Bethesda, 1996. “Franken DG, Boers GH, Blom MORE COMPLETE ABSORPTION: It has been repeatedly shown that HJ, Trijbels JM. “Effect of various regimens of vitamin B6 and folic acid on ascorbic acid, when given in sufficient amounts, can increase the absorp- mild hyperhomocysteinemia in vascular patients’ J. Inherit. Metab. Dis. tion of ferrous iron from the gastrointestinal tract.” The absorption-pro- 1994; 17:159-62. “Brattstrom L, Israelsson B, Norrving B, et al. “Impaired moting effect is mainly due to the reducing action of ascorbic acid within homocysteine metabolism in early-onset cerebral and peripheral occlusive the gastrointestinal lumen, which helps to prevent or delay the formation of disease - effects of pyridoxine and folic acid treatment” Atherosclerosis insoluble or less dissociated ferric compounds.’ 1990; 81 : 2004-6. “Kang S. Wong PWK, Norusis M. “Homocysteinemia PROMOTES MOVEMENT OF PLASMA IRON: Ascorbic acid also plays due to folate deficiency.” Metabolism 1987; 36: 458-62. “AlIen RH, Stabler an important role in the movement of plasma iron to storage depots in the SP, Savage DG, Lindernbaum J. “Dia9nosis of cobalamin deficiency.” IL tissues.’#{176}The action, which leads to the transport of plasma iron to ferritin, usefulness of serum methylmalonic acid and total homocysteine concen- presumably involves its reducing effect, converting transferrin iron from the trations. Am. J. Hematol. 1990; 34: 90-98. ‘7Dekker GA, de Vries JI, ferric to the ferrous state. There is also evidence that ascorbic acid Doelitzsch PM, Huijgens PC, von Blomberg BM, Jakobs, C, van Geijn HP. improves iron utilization, presumably as a further result of its reducing 1 985. “Underlying disorder associated with severe early-onset preeclamp- action,” and some evidence that it may have a direct effect upon erythro- sia” Am. J. Obstet. Gynecol. 173: 1042-1048. ‘“Mills JL, McPartlin JM, poiesis. Ascorbic acid is further alleged to enhance the conversion of folic Kirke PN, Lee YJ, Conley MR, Weir DG, Scott JM. 1995. “Homocysteine acid to a more physiologically active form, folinic acid, which would make metabolism in pregnancies complicated by neural-tube defects.” Lancet. it even more important in the treatment of anemia since it would aid in the 345: 149-151 . ‘“Steegers-Theunissen AR Boers GH, Blom HJ, Nijhuis JG, utilization of dietary folic acid.” Thomas CM, Borm GF, Eskes TK. 1995. “Neural tube defects and elevat- ed homocysteine levels in amniotic fluid” Am. J. Obstet. Gynecol. 172: EXCELLENT ORAL TOLERATION: Ferrous fumarate is used in 1436-1441 . ‘#{176}LandgrenF, Israelsson B, Lindgren A, Hultberg B, Andersson Chromagen#{174} Forte Capsules because it is less likely to cause the gastric A, Brattstrom L. 1995. “Plasma homocysteine in acute myocardial infarc- disturbances so often associated with oral iron therapy. Ferrous fumarate tion: Homocysteine-lowering effect of folic acid.” J. Intern. Med. 237: 381- has a low ionization constant and high solubility in the entire pH range of 388. 2’Mayer EL, Jacobsen DW, Robinson K. 1996. “Homocysteine and the gastrointestinal tract. It does not precipitate proteins or have the astrin- Coronary Atherosclerosis” J. Am. CoIl. Cardiol. 27: 517-27. tmBerenbaum, gency of more ionizable forms of iron, and does not interfere with MC. et al.: Blood, 15:540, 1960. tmDrug Information for the Health Care proteolytic or diastatic activities of the digestive system. Because of excel- Professional, p.1365-1368, U. S. Pharmacopeial Conven., Rockville, 1995. lent oral toleration, Chromagen#{174} Forte Capsules can usually be adminis- tered between meals when iron absorption is maximal. REFERENCES 1 . Drug Facts and Comparisons#{174}. 1 993 Facts and Comparisons St. Louis, FOLIC ACID SUPPLEMENTATION: The use of supplemental folic acid Mo; 208-236. 2. Dunea G, Swagel MA, Bodiwala U, et at, Intradialytic oral may be indicated in patients with increased requirements for this vitamin, iron therapy. mt J Artif Organs. 1994;17:261-264. 3. Kirlin LF. Case man- such as iron deficiency anemia. Folic acid administration may reduce the agement of the anemic patient epoetin atfa-focus on iron supplementation. risk of neural tube defects in the developing fetus.2 Folic acid has also ANNA Journal. 1 993; 20:678-681 . 4. Wingard RL, Parker RA, Ismail N. et been shown to reduce circulating homocysteine levels in the blood.” al. Efficacy of oral iron therapy in patients receiving recombinant human Folate as 5-methyltetrahydrofolate and B,2 as methylcobalamin are erythropoietin. Am J Kidney Dis. 1995;25:433-439. 5. Data on file, Savage involved in the remethylation reaction of homocysteine to methionine.’ ‘ Laboratories. Elevated homocysteine plasma levels are associated with increased risk of preeclampsia, neural tube defects, myocardial infarction and artherosclerosis.” TOXICITY: Ferrous fumarate was found to be the least toxic of three pop- ular oral iron salts, with an oral LD00of 630 mg/kg. In the same report, the LD00 of ferrous gluconate was reported to be 320 mg/kg and ferrous sul- fate 230 mg/kg.’ 22 INDICATiONS For the treatment of all anemias responsive to oral iron therapy, such as hypochromic anemia associated with pregnancy, chronic or acute blood loss, dietary restriction, metabolic disease and post-surgical convales- cence. #{174}Manufactured for: CONTRAINDICATIONS SAVAGE LABORATORIES#{174} Hemochromatosis and hemosiderosis are contraindications to iron therapy. a division of Altana Inc. Folic acid is contraindicated in patients with pernicious anemia (see PRE- MELVILLE, NEWYORK 11747 CAUTIONS). WARNING I by: R.P. Scherer Corporation, St. Petersburg, Florida 33702 Accidental overdose of iron-containing products is a leading cause of fatal I poisoning in children under 6. Keep this product out of reach of children. I In case of accidental overdose, call a doctor or poison control center I 1F7O262C immediately. ] 01997 SAVAGE LABORATORIES#{174} R9/97

CALCIJEX#{174} CALCITRIOI. INJECTiON 1 meg and 2 meg/niL

BRIEF SUMMARY INDICATIONS AND USAGE Catcijex#{174}(catcitriol injectiont is indicated in the management of hypocaicemia in patients undergoing chronic renal dialysis. It has been shown to signiticantty reduce elevated parathyroid hormone tenets. Reduction of PTH has been shown to result in an improvement in renal osteodystrophy CONTR.NJNOICAT1ONS Catcijes#{174}lcaicitrioi injectiont should net be given to patients with hypercatcemia or evidence of vitamin D toxicity. WARNINGS Since cafcitriot is the most potent metabolite of vitamin 0 available, vitamin 0 and its derivatives should be withheld during treatment. A non-aluminum phosphate-binding compound should be used to control serum phosphorus levels in patients undergoing dialysis. Overdosage of any form of vitamin 0 is dangerous see also OVERDOSAGE). Progressive hypercalcemia due to overdosage of vitamin D and its metabofites may be so severe as to require emergency attention. Chronic hypercalcemia can lead to generalized vascular calcification, nephrocalcinosis and other soft-tissue calcification. The serum calcium times phosphate ICa x Pt product should not be allowed to exceed 70. Radiographic evaluation of suspect anatomical regions may be useful in the early detection of this condition. PRECAUTiONS 1. General Excessive dosage of Calciies#{174}(calcitriol iniectionl induces hypercalcemia and in some instances hypercalciuria; therefore. early in treatment during dosage adjustment. serum calcium and phosphorus should be determined at feast twice weekly. Should hypercalcemia develop, the drug should be discontinued immediately. Calcijes should be given cautiously to patients on digitalis, because hypercalcemia in such patients may precipitate cardiac arrhythmias. 2. Information toe the Patient The patient and his or her parents should be informed about adherence to instructions about diet and calcium supplementation and avoidance of the use of unapproved non-prescription drugs, including magnesium- containing antacids. Patients should also be carefully informed about the symptoms of hypercalcemia see ADVERSE REACTIONSI. 3. Essential Laboratory Tests Serum calcium, phosphorus, magnesium and alkaline phosphatase and 24-hour urinary calcium and phosphorus should be determined periodically. During the initial phase of the medication, serum calcium and phosphorus should be determined more frequently (twice weeklyl Adynamic bone disease may develop if PIN levels are suppressed to abnormal levels. If biopsy is not being done for other diagnostic) reasons, PTH levels may be used to indicate the rate of bone turnover. If PTH levels copy of 3ASN to your department or institutiona’ library. tall below recommended target range lt.5 to 3 times the upper limit of normall, in patients treated with Calcijex, the Calcites dose should be reduced or therapy discontinued. Discontinuation of Calcije’t therapy may result in rebound effect, therefore, appropriate titration downward to a maintenance dose is recommended. 4. Drug Ineeractiouia ------Magnesium-containing antacid and Calcijen should not be used concomitantly, because such use may lead so the development of hypermagnesemia. 5. C.rcinogeneaia. Mutagenesis. knp.inment of Fertility Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Calcijex Icalcitriol iniectioni. There was no evidence of mutagenicity as studied by the Ames Method. No significant To: Collections Development Librarian effects of calcitriol on fertility were reported using oral calcitriol. I I 6. Use in Pregnancy: Pregnancy Category C: Calcitniot given oralty has been reported to be teratogenic in rabbits when given in doses 4 and I I 15 times the dose recommended for human use. All 15 fetuses in 3 litters at these doses showed external and skeletal abnormalities. However, none of the I Name of library I other 23 litters 1156 fetusesl showed significant abnormalities compared with controls. Teratology studies in rats showed no evidence of teratogenic potential. There are no adequate and well- I Name of institution I controlled studies in pregnant women. Calcijeo should be used during pregnancy only if the potential benefit ustihes the potential risk to the fetus. I I 1. Nursing Mothera ft is not known whether this drag is excreted in human milk. Because many drugs are excreted in human milk I Street address I and because of the potential for serious adverse reactions in nursing infants from calc’itriol, a decision should be made whether to discontinue nursing or to discontinue the drug. taking into account the importance of the City, State, Zip drug to the mother. I I o_ Pediatric Uee Safety and efficacy of Calcijes in pediatric patients have not been established. AD VERSE REACTiONS From: Adverse effects of Calciiex#{174}Haicitriol injectiont are, in general, similar to those encountered with excessive I I vitamin 0 intake. The catty and tate signs and symptoms of vitamin D intoxication associated with hypercalcemia include: I Your name I 1. Early weaknens. headache, somnolence, nausea, vomiting, dry mouth, constipation, muscle pain, bone pain and I Street address I metallic taste. 2. Late I I Polyuria, potydipsia. anorexia, weight loss, nocturia, conjunctivitis (calcifict, pancreatitis, photophobia, rhinorrhea, pruritus, hyperthermia, decreased libido, elevated BUN, albuminuria, hypercholesterolemia, I City, State. Zip I elevated 5601 and SGPT, ectopic calcification, hypertension, cardiac arrhyttsmias and, rarely, overt psychosis. Occasional mild pain on injection has been observed. I My colleagues and I would like to have access to JASN and request that I OVEROOSAGE Administration of Calcijex#{174}Icalcitriol injectiont to patients in excess of their requirements can cause our library subscribe to it. hypercalcemia, hypercalciuria and hyperphosphatemia. High intake of calcium and phosphate concomitant with Calcijex may lead to similar abnormalities. I Signature Date I t_ Treatment of Hypercalcemua and Overdosage in Patients on Hemodialysis General treatment of hypercalcemia Igreater than t mg/dL above the upper limit of normal rangel consists xl Reasons why thisjournal would be a valuable addition to our collection on immediate discontinuation of Calciiex therapy, institution of a low calcium diet and withdrawal of calcium I I supplements. Serum calcium levels should be determined daily until normocalcemia ensues. Hypercalcemia usually resotves in two to seven days. V/hen serum calcium levels have returned to within normal limits, Calcijex I this subject. Check the appropriate box(es): I therapy may be reinstituted at a dose 0.5 mc less than prior therapy. Serum calcium levels should be obtained at leant twice weekly after all dosage changes. I andNews clinicalabout advancesscientific LILi StudentReference/citationassignments for Persistent or markedly elevated serum calcium levels may be corrected by dialysis against a calcium-tree diatysate. I Reports on major research I 2. Treatment of Accidental Overdos.ge of Calcitniol Injection The treatment ofacute accidental overdosage of Calcijeo should consist of general supportive measures. Serial I professional meetings El Track trends in the specialty I serum electrolyte determinations lespecially calcium), rate of urinary calcium excretion and assessment of electrocardiographic abnormalities due to hypercalcemia should be obtained. Such monitoring is critical in I Information on licensing LI Continuing medical education patients receiving digitalia. Discontinuation of supplemental calcium and low calcium diet are also indicated in and certification Li Other ______accidental overdosage. Due to the relatively short duration of the pharmacological action of calcitriol, further measures are probably unnecessary. Should, however. persistent and markedly elevated serum calcium levels I 3ournal of the American Society of Nephrology I occur, there are a variety of therapeutic alternatives which may be considered, depending on the patients’ underlying condition. These include the use of drags such as phosphates and corticosteroids as well as I ISSN 1046-6673 / Published monthly I measures to induce an appropriate forced diuresis. The use of peritoneal dialysis against a calcium’tree dialysate has also been reported. I Institutional rate $389/yr. / Add $65/yr. for postage outside the U.S. I HOWSUPPLIED Calcijes#{174})calcitriol iniection) is supplied in 1 ml ampuls containing 1 mcg list No. t200) and 2 mcg List No. t210). Protect train light. I 4EASYWAYSTOORDER I Store at controlled room temperature 15” to 30”C 59” to 86”F). #{149} CALL 1-800-638-6423 E-MAiL Caution: Federal IUSAI law prohibits dispensing without prescription. . Outside the U.S.: 410-528-8555 [email protected] ©Abbots 1997 Reference O6-9656R8Rev. Jun., 1997 I London: 171-543-4848 I I Hong Kong: 852-2610-2339 MAIL order form today to: 1 Uach F, Hervax J. Cerezo S: The importance of dosing intravenous calcitriol in diatysis patients with severe hyperparathyroidism. Am .1 Kidney Dia 26)5):845-85t, t995. #{149} Tokyo: 03-5689-5400 WilliTflS & Wilkins 2 DressIer R, Laut J, Lynn R, Ginsberg N: Long-term high dose intravenous calcitriol therapy in end-stage renal I p.o. Box 23291 disease patients with severe secondary hyperparathyroidism. Clia Nephrol 43)31:324-331, 1995. F*,x 410-528-8596 Baltimore, MD 21203-9990 3 Cannella 13,Bonuicci E, Roll. 0. Ballanti P. Monero E, DeGrandi R, Augeri C, Claudiani F,DiMaio 6: Evidence of healing of secondary hyperparathyroidism in chronically hemodiatyzed uremic patients treated with longterm I IASNLIBBI I intravenous calcitriol. Kid 1nt46:1124-1132. 1994. L ------.1 Introducing Spectra Renal Management. Diagnostic and management services for the future of patient care.

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References: 1. Eschbach JW, Haley NA. Adamsvn JW. New insights into the treatment of the anemia of chronic renal failure with erythropvietin Semirr Dial. 1990:3)2) 1 12-121 .2. Van Wyck DB. Stivelman JC. Auiz J, Kirlin LF, Katz MA, Ogden DA. Iron status in patients receiving erythropoietin for dialysis-associated anemia. Kidneylnt. 1989;35:712’716 3. Van Wyck 08. Iron management during recombinant human erythropvietin therapy. Am JKidrtey Dis. 1989:14(2))suppl 1):9-13. 4. Van Wyck DO. Iron deficiency in patients with dialysis-associated anemia during erythropoietin replacement therapy. strategies for assessment and management. Semin Nephrol t989;9)1)(suppl 2):21-24. 5. Prescribing Information for EPOGEW )epoetin alfa). Amgen Inc., Thousand Oaks, Ca. 6. Daugirdas JT, log IS, eds. Handbook olDialysis. 2nd ed. Boston, Mass: Little, Brown and Co. 1994:445-457. 7. Wingard AL, Parker AA. Ismail N, Hakim AM. Efficacy of oral iron therapy in patients receiving recombinant human erythropoietin Am J Kidney Dis. 1995:25(31:433-439. 8. Fishbane 5, Ungureanu V-D, Maesaka JK, et al. A multicenter study of the safety of intravenous iron dextran )IVFe) in hemodialysis patients AmjKidneyDis. 1996:27(4):A6. INFeD” (IRON DEXTRAN INJECTION, USP) be valid in patients on chronic renal dialysis who are also receiving iron deotran complev. Athough there are significant variations in body build and weight distribution among males and temales, the accompanying table WAluIM . ThE PARENTERAL USE OF COMPLEXES OF IRON AND CARBOHYDRATESHAS RESULTED IN ANAPHYLACTlC- and formula represent a convenient means for estimating the total iron required This total iron requirement reflects the amount TYPE REACTIONS.DEAThS ASSOCIATED WITh SUCH ADMINISTRATiON HAVE BEEN REPORTED, ThEREFORE, INFeD of iron needed to restore hemoglobin concentration to normal or near normal levels plus an additional allowance to provide ade- SHOULD BE USED ONLY IN THOSE PATiENTS IN WHOM ThE INDICATIONS HAVE BEEN CLEARLY ESTABUSHED AND quate replenishment of iron stores in most individuals with moderately or severely reduced levels ot hemoglobin It should be LABORATORYINVESTIGATiONSCONFIRM AN IRON DEFICIENTSTATE NOTAMENABLETO ORAL IRON THERAPY. remembered that iron deficiency anemia will not appear until essentially all iron stores have been depleted Therapy, thus, should aim at not only replenishment of hemoglobin iron but iron stores as well DESCRIPTiON: INFeD (iron dextran inlection. USP) is a dark brown, slightly viscous sterile liquid complex of ferric hydroxide and Factors contributing to the formula are shown below. dextran for intravenous or intramuscular use Each mL contains the equivalent of 50 mg of elemental iron (as an iron devlran complex), appronimately 0.9’/ sodium chloride. mg blood iron ml blood v ghemoglobin v mg iron in water for inteclion. Sodium hydroxide and/or hydrochloric acid may have been used to adjust pH. The pH of the solution is lbtiOd5’iQht lb body weight mL blond g hemoglobin between 5.2 and 6.5. a) Blood volume 65 mI/kg of body weight The iron deetran cnmpleo has an average apparent molecular weight of 165.000 b) Normal hemoglobin (males and females) Therapeutic Class: Hemalinic over 15 kg (33 ho) 14.8 g/dI CLINICAL PHARMACOLOGY: General: After intramuscular inlection, iron deotran is absorbed from the inlection site into the is kg 33 Ibs) or less 12.0 g/dl capillaries and the lymphatic system Circulating iron deotran is removed from the plasma by cells of the reticuloendothelial sys- c) Iron content of hemoglobin 0.34’!, em, which split the complex into its components of iron and deotran. The iron is immediately bound to the available protein moi- d) Hemoglobin deficit elms to form hemnsiderin or ferritin, the physiological forms of iron, or to a lesser enfent to transferrin This iron which is subject to physiological control replenishes hemoglobin and depleted iron stores. ft Weight Deotran, a polyglucose, is either metabolized or excreted Negligible amounts of iron are lost via the urinary or alimentary path- BaSedvnthe above factors, individuals with normal hemoglobin levels will have approvimately 33 mg of blood iron per kilogram ways after administration of iron deetran of body weight (15 mg/tb) The manr portion of intramuscular in)ections of iron dextran is absorbed within 72 hours, must of the remaining iron is ab- Note: the table and accompanying formula are applicable for dosage determinations only in patients with iron dehciency anemia, sorbed overthe ensuing 3 to 4 weeks they are notto be used for dosage determinations in patients requinng iron replacementfor blood loss. Various studies involving intravenously administered ‘Fe iron dextran to iron deficient subtects. some of whom hadcoevisting TOTAL INFeD” RFOUIRFMFNT FOR HEMOGLOBIN RESTORATION AND IRON STORES REPI.ACFMENT diseases, have yielded half-life values ranging from 5 hours to more than 20 hours. The 5-hour value was determined for 5tFe Milliliter Reuiremenf of INFeD Based On Observed Hemoglobin of iron dextran from a study that used laboratory methods to separate the circulating 59Feiron deotran from the transferrin-bound PATIENT 59Fe The 20-hour value reflects a half-life determined by measuring total ‘9Fe, both circulating and bound It should be under- LEANBUD V WEIGHT 10 stood that these half-life values do not represent clearance of iron from the body. Iron is not easily eliminated from the body and gJdI) (g/dl) (g/dI) (gJdIl (g/dI) (g/dIl (g/dl) Ig/dI) accumulation of iron can be toxic kg lh INDICATIONS AND USAGE: Intravenous or intramuscular inlectlvns of iron deotran are indicated for treatment of patients with 5 11 documented iron deficiency in whom oral administration is unsatisfactory or impossible to 22 CONTRAINDICATIONS: Hypersensitivity to the product All anemias not associated with iron deficiency. 15 33 10 WARNINGS: See BOXED WARNING 20 44 16 15 14 13 12 10 A risk of carcinogenesis may attend the intramuscular inlection of iron-carbohydrate complexes Such complenes have been 25 55 20 18 17 16 15 14 13 12 found under eoperimental conditions to produce sarcoma when large doses or small doses Inlected repeatedly at the same site 30 66 23 22 21 19 18 17 15 14 were given to rats, mice, and rabbits, and possibly in hamsters. 35 77 27 26 24 23 21 20 18 17 The long latent period between the inlection of a potential carcinogen and the appearance of a tumor makes it impossible to mea- 40 88 31 29 28 26 24 22 21 19 sure accurately the risk in man There have, however, been several reports in the literature describing tumors at the inlection site 45 99 35 33 31 29 27 25 23 21 in humans who had previously received intramuscular injections of iron-carbohydrate complexes. 50 110 39 37 35 32 30 28 26 24 Large intravenous doses, such as used with total dose infusions )TDI), have beenassociated with an increased incidence of 55 121 43 41 38 36 33 31 28 26 adverseeffects The adverse effects frequently are delayed 1-2 days) reactions typified by one or more of the following symp- 60 132 47 44 42 39 36 34 31 28 toms. arlhralgia. backache, chills, dizziness, modnrateto high fever, headache, malaise, mvalgia. nausea, and vomiting. The 65 143 51 48 45 42 39 36 34 31 onset is usually 24-48 hours after administration and symptoms generally subside within -4 days. These symptoms have also 70 154 55 52 49 45 42 39 36 33 been reporlod following intramuscular injection and generally subside within 3’7 days. The etiology of these reactions is not 75 165 59 55 52 49 45 42 39 35 known. The potential for a delayed reaction must be considered when estimating the risk/benefit of treatment 80 176 63 59 55 52 48 45 41 38 The maximum daily dose should nut exceed 2 mL undiluted iron deotran. 85 187 66 63 59 55 51 48 44 40 This preparation should be used with extreme care in patients with serious impairment of liver function. 90 198 70 66 62 58 54 50 46 42 It should not be used during the acute phase of infectious kidney disease 95 209 74 70 66 62 57 53 49 45 Adverse reactions eoperienced following administration of INFetI may exacerbate cardiovascular complications in patients with 100 220 78 74 69 65 60 56 52 47 pre-eoisling cardiovascular disease. 105 231 82 77 73 68 63 59 54 50 PRECAUTIONS:General:Unwarranted therapy with parenteral iron will cause excess storage of iron with the consequent possi- 110 242 86 81 76 71 67 62 57 52 bility of exogenous hemosiderosis. Such iron overload is particularly apt to occur in patients with hemoglobinopathies and other 115 253 90 85 80 75 70 64 59 54 refractory anemiasthat might be erroneously diagnosed as iron deficiency anemias. 120 264 94 88 83 78 73 67 62 57 INFeD should be used with caution in individuals with histories of signihcant allergies and/or asthma. Anaphylaxis and other hypersensitivity reactions have been reported after uneventful test doses as well as therapeutic doses of Table values were calculated based on a normal adult hemoglobin of 14 8 g/dl for weights greater than 15 kg 33 Ibs) and a iron deotran inlection Therefore, administration of subsequent test doses during therapy should be considered See DOSAGE hemoglobin of 12.0 g/dl for weights less than or equal to 15 kg 33 Ibs) AND ADMINISTRATION Administration I The total amount of INFeD in mL required to treat the anemia and replenish iron stores may be approximated as follows Epinephrine should be immediately available in the event of acute hypersensitivity reactivns. Usual adult dose 0 5 mL of a Adults andChildren over 15kg (331bs): See Dosage Table. Alternatively the total dose may be calculated 1.1000 solution, by subcutaneous or intramuscular injection.) Nate: Patients using beta-blocking agents may not respond ade- Dose )mL) 0.0442 Desired Hb ‘Observed Hb) o LBW + 0.26 v LBW) quately to epinephrine. )soproterenol or similar beta-agonist agents may be required in these patients. Based on Desired Hb = the target Hb in g/dl Patients with rheumatoid arthritis may have an acate eoacerbatinn of loot pain and swelling following the administration of INFeD Observed Hb the patient’s current hemoglobin in g/dl Reports in the literature from countries outside the United States in particular, New Zealand) have suggested that the use of intra- LBW = Lean body weight in kg. A patient’s lean body weight 0’ actual body weight if less than lean body weight) should muscular iron dextran in neonateshasbeenassociatedwith an increasedincidence of gram’negative sepsis, primarily due toE. Coli. be utilized when determining dosage. Informatioe For Patients: Patients should be advised of the potential adverse reacbuns associated with the use of INFeD For males LBW = 50 kg v 2 3 kg for each inch of patient’s height over 5 feet Drag/Laboratory Test Interactions: Large doses of iron deotran 5 ml or more) have been reported to give a brown color to For females: LBW = 45.5 kg v 2 3 kg for each inch of patients height over 5 feet serum from a blood sample drawn 4 hours after administration To calculate a patient’s weight in kg when lbs are known: patient’s weight in pounds = weight in kilograms The drug may cause falsely elevated values of serum bilirubin and falsely decreased values of serum calcium 2 2 Serum iron determinations especially by colorimeiric assays) may not be meaningful for 3 weeks following the administration of Cblldran 5 - l5kg(11 - 33Ibs): See Dosage Table. iron deofran. INFeD should not normally be given in the first tour months of Ide See PRECAUTIONS: Pediafric Use) Serumferntin peaks approximately 7 to 9 days after an intravenous dose of INFeD and slowly returns to baseline after about 3 weeks Afternatively the total dose may be calculated. Euamination 01the bone marrow for iron stores may not be meaningful for prolonged periods following iron deofran therapy Dnse )mL) = 0 0442 Desired Hb - Observed Hb) v W v 0 26 oW) because residual iron deotran may remain in the reticuloendothelial cells Based on: Desired Hb = the target Hb in g/dl. Normal Hb for Children 15 kg or less is 12 g/dl.) Bone scans involving 99m Tc-diphosphnnate have been reported to show a dense, crescentic area of activity in the buttocks. nI- W Weight in kg. lowing the contour of the iliac crest, 1 to 6 days after intramuscular in)ections of iron deofran To calculate a pafient’s weight in kg when lbs are known patient’s weight in pounds = weight in kilograms Bone scans with 99m Tc-labeled bone seeking agents. inthe presenceof high serumferritin levelsorfollowing iron deotran infusions, 2 2 have been reportedto show reductionof bony uptake, marked renalactivity, and excessive blood pool and soft tissue accumulation Carcinogenesig, Matagenesin, Impairment Of Fertility: See WARNINGS Iron ReplacementforBloodLoss:Some individuals sustain blood moses on an intermisent or repetitive basis. Such blood Pregnancy: PregnancyCategoryC Iron deotran has been shown to be teratogenic and embryvcidal in mice, rats, rabbits, dogs. losses may occur periodically in patients with hemorrhagic diatheses familial telangiectasia: hemophilia: gastrointestinal bleed- and monkeys when given in doses of about 3 times the maximum human dose. ing) and on a repetitive basis mm procedures such as renal hemodialysis. No consistent adverse fetal eftects were observed in mice. rats. rabbits, dogs and monkeys at doses of 50 mg iron/kg or less. Iron therapy in these patients should be directed toward replacement xl the equivalent amount of iron represented in the blood Fetaland maternal toxicity has been reported in monkeys at a total intravenous dose of 90 mg iron/kg over a 14 day period. loss. The table and formula described under I, Iron OeflclencyAnem!aare notapplicable for simple iron replacement values Similar eftects were observed in mice and rats on administration of a single dose of 125 mg iron/kg. Fetalabnormalities in rats Quantitative estimates of the individual’s penodic blood loss and hemalocrit during the bleeding episode provide a convenient and dogs were observed at doses of 250 mg iron/kg and higher The animals used in these tests were not iron deficient. There method fur the calculation of the required iron dose. are no adequate and well-controlled studies in pregnant women. INFeD should he used during pregnancy only if the potential The formula shown below is based on the approximation that 1 mL xl normvcytic, normnchromic red cells contains 1 mg of ele- benefit buttes the potential risk to the fetus. mental iron. Placental Transfer: Various animal studies and studies in pregnant humans have demonstrated incnnclusive results with Replacement iron in mg) Blood loss (in mL) n hematocrit respect to the placental transler of iron deotran as iron dextran It appears that some iron does reach Ihe fetus, but the form in EXOmple Blood loss of 500 mL with 20x1, hematvcrit which it crosses the placenta is not clear Replacement Iron = 500 o 0.20 100mg Naming Mothers: Caution should be exercised when INFeD is administered to a nursing woman Traces of unmetabolized iron INFeD dose 100mg 2 mL deotran are excreted in human milk. 50 Pediatric tine: Not recommended for use in infants under 4 months of age. See DOSAGE AND ADMINISTRATION ) Administration: The total amount of INFeD required for the treatment of iron deficiency anemia or iron replacement for blvod ADVERSE REACTiONS: Severe/Fatal: Anaphytactic reactions have been reported with the use of iron dextran in)ectlon: on occa- loss is determined from the table or appropriate formula. See Dosage sions these reactions have beenfatal. Such reactions. which occur most often within the first several minutes of administration, 1, IntravenouslnJectlon- PRIOR TO RECEIVING THEIR FIRST INFeD ‘IHERAPEUTIC DOSE, ALL PATIENTS SHOULD BE GIVEN have been generally characterized by sodden onset of respiratory difficulty and/or cardiovascular collapse ISee booed WARN- AN INTRAVENOUS TEST DOSE OF 0.5 mL. See PRECAUTIONS: General.) THE TEST DOSE SHOULD BE ADMINISTERED AT A ING and PRECAUTIONS. General, pertaining to immediate availability of epinephrine.) GRADUAL RATE OVER AT LEAST 30 SECONDS. Although anaphylactic reactions known to occur following INFeD administration Cardiovascolar:Chest pain, chest tightness, shock, hypotension. hypertension, tachycardia, flushing, arrhyfhmias. (Flushing are usually evident within a few minutes, or sooner, it is recommended that a period of an hour or longer elapse before the and hypotension may occur from too rapid inlecti005 bythe intravenous route I remainder ofthe initialtherapeulic dose is given. Oermatologic: Ur’ticania, pruritus. purpura, rash Individual doses of 2 mL or less may be given on a daily basis until the calculated total amount required has been reached. INFeD Gastrointestinal: Abdominal pain, nausea, vomiting, diarrhea ‘ given undiluted ata slow gradual rate notto exceed 50 mg 1 mL) per minute. Hematologlc/tymphatlc: Leucocylosis. fymphadenopathy 2, Intramuscularlnjection - PRIOR TO RECEIVING THEIR FIRST INFeD THERAPEUTIC DOSE, ALL PATIENTS SHOULD BE Musculoakeletal/saft tIssue: Arthralgia. arthritis may represent reactivation in patients with quiescent rheumatoid arthritis - GIVEN AN INTRAMUSCULAR TEST DOSE OF 0.5 mL See PRECAUTIONS General.) The test dose should be administered in the See PRECAUTIONS General), myalgia: backache: sterile abscess. atrophy/fibrosis intramuscular inlection site), brown skin same recommended test site and by the same technique as descrihed in the last paragraph of this section. Although anaphylactic and/or underlying tissue discoloration (staining). soreness or painat or near intramuscular Inlection sites: cellulitis, swelling, reactions known to occur following INFeD administration are usually evident within a few minutes or sooner. it is recommended inflammation; local phlebitis at or near intravenous injection site. that at least an hour or longer elapse before the remainder of the initial therapeutic dose is given. Neoralogic:Convulsions, seizures, syncope. headache, weakness. unresponsiveness. paresthesia, febrile episodes, chills, dizzi- If no adverse reactions are observed. INFeD can he given according to the following schedule until the calculated total amount ness, disorientation, numbness. required has been reached. Each day’s dose should ordinarily not exceed 0.5 mL (25 mg of iron) for infants under 5 kg 1 1 Ibs), Respiratory: Respiratory arrest, dyspnea. bronchoopasm 1 0 mL (50 mg of iron) for children under 10 kg (22 Ibs), and 2.0 mL (100 mg xl iron) br other patients Urologic: Hematunia INFeD should be inlected only into the muscle mass of the upper outer quadrant of the buttock - never into the arm or other Delayed reactions: At’thralgia, backache, chills, dizziness, fever, headache, malaise. myalgia. nausea. vomiting See WARNINGS I eoposed areas and should be Inlected deeply, with a 2-inch or 3-inch 19 or 20 gauge needle. If the patient is standing, he/she Miscellaneous: Febri)e episodes, sweating, shivering, chills, malaise, altered taste. should be bearing‘ his/her weight nn the leg opposite the inlection ode, or if in bed, he/she should be in the lateral position with OVERDOSAGE: Overdosage with iron deotran is unlikelyto be associated with any acute manifestations. Dosages of iron deotran injection site uppermost. To avoid injection or leakage into the subcutaneous tisrue, a ZIracklechnique displacement of the in excess of the requirements for restoration of hemoglobin and replenishment of iron stores may lead to hemosiderosis skin laterally prior to inlection) is recommended Periodic monitoring of serum fernitin levels may be helpful in recognizing a deleterious progressive accumulation of iron re- NOTE: Do not mix INFeD with other medications or add to parenteral nutrition solutions for intravenous infusion suIting from impaired uptake xl iron from the reticulsendothelial system in concurrent medical conditions such as chronic renal Parenteral drug products should be inspected visually for particulate maser and discoloration pnor to administration, whenever failure, Hodgkin’s disease, and rheumatoid arthritis The LOw of iron deotran is not less than 500 mg/kg in the mouse the solution and container permit. DOSAGE AND ADMINISTRATION: Oral iron should be discontinued prior to administration of INFeD HOW SUPPLIED: INFeD’ (Iron Deotran Injection, USP) containing 50 mg of elemental iron per mL, is availablein 2 ml single Dosage: dose amber vials (for intramuscular or intravenous use) in cartons of 10 )NDC 0364-3012’47) I, Iron OeflclancyAnemia: Periodic hematologic determination (hemoglobin and hematocnrt) is a simple and accurate technique Store at controlled room temperature 15’ - 30’ C 59’ - 86” F) for monitoring hematological response. and should be used as a guide in therapy It should be recognized that iron storage may CAUTION: Federal law prohibits dispensing without prescription. lag behind the appearance of normal blood morphology Serum iron, total iron binding capacity (TIBC) and percent saturation of Literature revised July 1995 Iransfernin are other important tests for detecting and monitoring the iron deficient stale Product No 1001-02 695310010364’El IF1O reticulocyte count SCHEINPHARMACEUTiCAL,INC. Vi SCIiIEIN After administration of iron dextran compleo, evidence of a therapeutic response can be seen in a few days as an increase in the Although serum ferritin is usually a good guide to hedy iron stores, the correlation of body iron stores and serum ferritin may not Florham Park, NJ 07932 USA p H A e N A C F U T I C A

When a hypertensive patient doesn’t adequately respond to any dihydropyridine CCB or any ACEI Lotrel provides superior BP control at low doses vs its components*

. Greater decrease in BP

. Higher responder rate

. Full, smooth 24-hour control

Lotrel is a single therapy with complementary CCB/ACEI actions, resulting in superior control and an excellent side effect profile LOTREL amlodipine/benazepril HCI 2.5/10 #{149}5/10 #{149}5/20-mg capsules

. Patients with congestive heart failure (with or without associated renal insufficiency) should be monitored for the first 2 weeks whenever Lotrel therapy is started or the dosage is changed

. In non-African-American patients, the complementary mechanisms of action of Lotrel produce a BP-lowering effect that is additive and in some cases synergistic

*ln African-American patients, virtually all of the antihypertensive effect could be attributed to the

amlodipine component, but all patient groups benefit from the reduction in amlodipine-induced edema.

Pregnancy Warning: ACE inhibitors should be discontinued as soon as pregnancy is detected (see Warnings). Angioedema and cough have been reported in patients receiving ACE inhibitors. Headache and edema are the most common side effects in patients receiving amlodipine.

Please consult the brief summary of Prescribing Information on next page.

!) NOVARTIS

88 1997, NOVARTIS. LTR-0597 Exchange transfusion or penitoneal dialysis may be required as means of myers- Mutagenicity studies with amlodipine revealed no drug-related effects at Lotrel#{174} ing hypotension and/or substituting for disordered renalfunction. Benazepnil, either the gene or chromosome levels. which crosses the placenta, can theoretically be removed from the neonatal There was no effect on the fertility of rats treated with amludipine males for amlodipine and benazepril hydrochloride circulation by these means, there are occasional reports of benefit from these 64 days and females for 14 days prior to mating) at doses up 10 10 mg/kg/day Combination Capsules maneuvers, but eopenience is limited. 8 times the maximum recommended human dose of 10 mg on a mg/m#{176}basis, Lotmel has not been adequately studied in pregnant women. When mats assuming a 88-kg person). 2,SmgllOmg received benazepnl:amlodipine at doses ranging from 5:2.5 to 50:25 mg/kg/day, No adverse effects on fertility occurred when the benazepril:amlodipine core- Smg/lOmg dystocia was observed with increasing dose-related incidence at all doses tested bination was given orally to ratu of either sex at dose ratios up to 15:7.5 mg/kg/day 5 mg/20 mg On a mg/m2 basis, the 2.5 mg/kg/day dose of amlndipine is 3.6 times the )benazepril:amlodipine), prior to mating and throughout gestation. amlodipine dose delivered when the maximum recommended dose of Lotmel is Pregnancy given to a 50-kg wxman. Similarly, the 5 mg/kg/day dose of benazepnil is appmox- PrgeancyCataporlas C(Ilrsttrlmest.r)and O(socond and third trimest.rs): BRIEFSUM*I4RY(FOR COMPLETEPRESCRIBING INFORM4T1ON, imately 2 times the benazeprii dose delivered when the maximum recommended See WARNINGS. Fetallheonatai Morbidity and Mortality SEE PACKAGE INSER F) dose of Lntmel is given to a 50-kg woman. Nursing Mothers No teratogenic effects were seen when beoaznpnil and amlodipine were Minimal amounts of unchanged benazepnil and of benazeprilat are excreted into USE IN PREGNANCY administered in combination to pregnant rats or rabbits. Rats received dose the breast milk of lactating women treated with bnnazepril, so that a newborn Wh.n void In pregnancy during the second and third tnimesturs, ACE ratios up to 50:25 mg/hg/day )benazepnl:amlodipinel 124 times the maximum child ingesting nothing but breast milk would receive less than 0 1% of the inhIbitors can cause inlury and even death to the developing Isles, When recommended human dose on a mg/m? basis, assuming a 50’kg woman) maternal doses of benazepnl and benazeprilat pregnancy is detected, Lotrel should be discontinued as soon as possible. Rabbits received doses of up to 1 .5:0.75 )benazepnil:amlodipine) mg/kg/day: It is not known whether amlodipine is excreted in human milk. In the See Warniugs, Fetal/Neonatal MorbidIty and Modality. on a mg/m? basis, this is 0.97 times Ito size of a maximum recommended absence ofthis information, it is recommended that nursing be discontinued dose of Lotrel given to a 50-kg woman while Lotrel is administered. INDICATIONS AND USAGE Similar results were seen in animal studies involving benazepnil alone and Geriatric Use Lotrel is indicated for the treatment of hypertension. amlodipine alone. Of the total number of patients who received Lotmel in U.S. clinical siudies of This fixed comhinatlon drug is not indicated br the initial therapy at Hepatic Failare Lotmel, 19% were 65 or older while about 2’!, were 75 or older. Overall differ- hypeduuaiou tees DOSAGE AND ADMINISTRATIONI, Rarely, ACE inhibitors have been associated with a syndrome that siarts with ences in effectiveness or safety were not observed between these patients and In using Lotrot, consideration should be given to the foot that an ACE cholestatic jaundice and progresses to fulminant hepatic necrosis and some- younger patients. Clinical experience has not identified differences in responses inhibitor, captopnil, has caused agranalocytosis, particularly in patients with times) death. The mechanism ofthis syndrome is not understood. Patients between the elderly and younger patients. but greater sensitivity of some older renal impairment or collagen’vascuiar disease Available data are insufficient to receiving ACE inhibitors wtio develop laundice or marked elevations of tiepatic individuals cannot be ruled out. show that benazepni does not havn a similar risk (see WARNINGS, Neutnopeniu/ enzymes should discontinue the ACE inhibitor and receive appropriate medical Pediatric Use Agranulxcyfoxisl. follow-up. Safety ond effectiveness in pediatric patients have not been established. Black patients receiving ACE inhibitors have been reported in have a higher PRECAUTIONS ADVERSE REACTIONS incidence of angixedema compared to nonblacks General Lotmel has been evaluated for safety in over 1600 patients with hypertension: CONTRAINDICAT1ONS ImpalrudRinal FunctIon: Lotrel should be used with caution in patients with over 500 ofthese patients were treated for at least 6 months, and over 400 Lotrel is contnaindicated in patients who are hypersensilivo to benaznpnl, to any severe renal disease. were treated for morn than 1 year. other ACE inhibitor, or to amiodipine When the mnnin-angiotensin-aldosterone system is inhibited by benazepril. The reported side effects were generally mild and transient, and there was WARNINGS changes in renal function may be anticipated in susceptible individuals. In no relationship between side effects and age, sex. mace,or duration of therapy. Anaphylactoitt and Possihly Related Reactions patients with severe congestive heart failure. whose renal function may depend Discontinuation oftherapy due to side effects was required in appmnoimately Presumably becauseangiotonsin-convnrting enzyme inhibitors affect the on the activity ofthe menin-angintensin-aldostnrone system, treatment with ACE 4% of patients treated with Lotmel and in 3% of patients treated with placebo. metabolism of oicosanoids and polypeptides, including nndognnous bradykinin. inhibitors including benazepnil) may be associated with oligunia and/or progmes- The mostcommon reasons for discontinuation ofttierapy with Lotmel in patients receiving ACEinhibitors (including Lotrel) may be subtect to a variety sine azotemia and Inanely) with acute ronal failure and/or death. U.S. studies were cough and edema. of adverse reactions, some ofthem serious. Those reactions usually occur after In a small study of hypertensive patients with unilateral or hilateral renal The side effects considered possibly or probably related to study drug that one of the first few doses of the ACE inhibitor, but they sometimes do not appear artery stenosis, treatment with benazepnl was associated with increases in occurred in U.S. placebo’contmolled trials in more than 1x,, of patients treated unftl after months nttherupy. blood urea nitrogen and serum creatinine: these increases were reversible upon with Lotmelare shown in the table below. Anglo..d.ma: Anginedema ofthnface, eutrnmibes, lips, tongue, glottis, and discontinuation of benazeprii therapy, concomitant diuretic therapy, or both. PERCENT INCIDENCE IN U.S. PLACEBO-CONTROLLED TRIALS larynx has beenreported in patients treated with ACE inhibitors. In U.S. clinical When such patients are treated with Lotrel, renal function should be monitored trials, symptoms consistent with angixedema wore seen in none ofthe subiects during the first few weeks of therapy Benazepnil/ who received placebo and in about 0.5% of tIre subiects who received benaznpnil. Some benazopniltreated hypertensive patients with nu apparent preexisting Amindipine Benazepril Amlodipine Placebo Angioedema associated with laryngeal edema can be fatal iflaryngeal stridor or renal vascular disease have developed increases in blood urea nitrogen and N760 N=554 N=475 N’408 angioedoma nftbe face, tongue, or glottis occurs, tneatmentwith LoIrnI should serum creatinine, usually minor and transient, especially when benazepril has cough 3.3 1.0 04 5.2 be disconbnued and appropriate therapy instituted immediately. ws,en involve’ been given concomitantly with a diuretic. Dosage reduction of Loimel may be Headache 2.2 3.8 2.9 5.6 mentolthe fongue, gloWs, orla,ynxappoarslikely to cause airway obstruction, required. Evaluation otthe hypertensive patient should alwayu include assess- Dizziness 1.3 1.6 2.3 1.5 appmpnate Therapy, e.g., subcutaneous epinephnne injection 1:1000(0.3-0.5 mL), meet at renat function see DOSAGE AND ADMINISTRATION) Edema 2.1 0.9 5 1 2 2 ohouldbepromptlyadminiotered(0oeADVERSE REACTIONS). Hyperkalimla: In U.S placebo-controlled trials of Lotrel, hyperkalemia serum AnaphyfactoldRoactlora During 0.s.nslt!zaflon: Two patients undergoing potassium at least 0.5 mtq/L greater than the upper limit of normal) not present Edema refers to all edemx, such as dependent edema, anginedema, facial edema. desensitizing treatment with hymenoptera venom while receiving ACE inhibitors at baseline occurred in approximately 1.5% of hypertensive patients receiving The incidence of edema was statistically greater in patients treated with sustained life-threatening anaphylacloid reactions. In the same patients, theun Lotrol. Increases in serum potassium were generally reversible. Risk factors for amlodipine monotherapy then in patients treated with the combination. Edema reactions were avoided when ACE inhibitors worn temporarily withheld, but they the development of hyperkalemia include renal insufficiency, diabetes mellitus. and certain other side effects are associated with amlodipine monotherapy in a reappeared upon inadvertent rechallange. and the concomitant use of potassium-sparing diuretics, potassium supple’ dose-dependent manner, and appear to affect women more than men. The addi- Anapbylacooldaactlons During Membrane Eosuve:Anaphylactoid reactions ments, and/or potassium-containing salt substitutes. tion of benazepril resulted in lower incidences as shown in the following table; have bean reported in patients dialyzed with high’flux membranes and treated PatIents WIth CongestIve Heart Fallere:Although hemodynamic studies and the protective effect of benazepnil was independent of race and within the range concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been a controlled trial in patients with NYI’IA Class ll’lll heart failure have shown that of doses tested) of dose reported in patients undergoing low-density lipoprotnin aphnresis with dexOran amlodipine did not lead to clinical deterioration as measured by exercise ruler- sulfate absorption. once, left ventricular election traction, and clinical symptomalology, studies have PERCENT INCIDENCE BY SEX OF CERTAIN ADVERSE EVENTS Incr,as#{149}dAnglrsaand/orMyocarlflallnlarct!on: Rarely, patients, particularly not beenperformed in patients with NYHA Class IV heart failure. In general, Benazepnil/ those with severe obstructive coronary artery disease, have developed docu- all calcium channel blockers should be used with caution in patients with heart Amlvdipine Benazepnil Amlodipino Placebo matted increased frequency, duration, and/or severity of angina or acute myo failure. Male Female Male Female Male Female Male Female cordial infarction on starting calcium channel blocker therapy or at the time of Patients With Hepat!c Failure: In patients with hepatic dysfunction due to N=329 N=431 N=269 N’285 N’277 N’198 N=217 N=191 dosage increase. The mechanism ofthix effect has not been elucidated cirrhosis, levels of benazeprilat are essentially unaltered. However, since Hypolannion amlxdipine is extensively metabolized by the liver and the plasma elimination Edema 0.6 3.2 0.0 1.B 2.2 9.1 1.4 3.1 Lotrel can cause symptomatic hypotension. Like other ACE inhibitors, benaznpril half-life It 112) is 56 hours in patients with impaired hepatic function, caution Flushing 0.3 0 0 0.0 0.7 0.4 2.0 0 5 0 0 has boon only rarely associated with hypotonsion in uncomplicated hypartensivo should be exercised when administering Lotmel to patients with severe hepatic Palpitations 0.3 0 5 0 4 t .4 0 4 2.0 0.5 0.5 pationts. Symptomatic hypxtension is most likely to occur in patients who have impairment see also WARNINGS) Somnolence 0.3 0 0 0 4 0 4 0 4 0 5 0 0 00 been volume and/or saltdepletad as a result of prolonged diuretic therapy, Cough: Presumably due to the inhibition ofthe degradation of endogenous Other side effects considered possibly or probably related to study drug that dietary salt restflction, dialysis, diarrhea, or vomiting. Volume and/or salt deple- bradykinin, persistent nonproductive cough has been reported with all ACE occurred in U.S. placebocontrulled trials of patients treated with Lotmel were the lion should be corrected before initiating therapy with Lotrel. inhibitors, always resolving after discontinuation of therapy ACE inhibitor- following Since the vasodilabon induced by amlodipine is gradual in onset, acute induced cough should be considered in the differential diagnosis of cough. Angiondama: Includes edema of the lips or face without other manifestations of hypotension has rarely been reported after oral administration of amiodipino. Surgany/Aocs.thula: in patients undergoing surgery or dunng anesthesia angixedema see wAeNING5. Angixedemal. Nonetheless. caution should be exercised when administering Lntrei as with any with agents that produce tiypotntsion, benazepnil will block the angiotensin ii Bodyas a Whole:Asthenia and fatigue There have been reports of gynecomas- other peripheral vasodilator, particularly in patients with severe axrtic stonosis. formation that could otherwise occur secondary to compensatory menin release. lix in patients receiving calcium channel blockers. In patients with congestive heartfailure, with or without associated renal Hypotension that occurs as a result ofthis mechanism can be corrected by CNS: Insomnia. nervousness, anxiety, tremor, and decreased libido. Insufficiency, ACE Inhibitor therapy may cause oxcessivo hypotension, which volume expansion. Darmatologic: Flushing, tiotliasties. rash, skin nodule, and dermatitis. There may be associated with oligunia, azntnmia, and rarely) with acote renal failure Drug Interactions have been rare reports of pemphigus in patients receiving ACE inhibitors. and death. In such patients, Lotrel therapy should be started under close medical DiuretIcs: Patients on diuretics, especially those in whom diuretic therapy Digestive: Dry mouth, nausea, abdominal pain, constipation, diarrhea, dyspep- supervision: they should be followed closely for the first 2 weeks of treatment was recently instituted, may occasionally nopenience an nocessive reduction sia, and esophagitis. There have been rare reports of pancreatitis in patients and whenever the dose xfthe bonazepnil component is increased or a diuretic of blood pressure after initiation otiherapy with Loirel The possibility of receiving ACE inhibitors. is added or its dose increased. hypotensive effects with Lotrel can be minimized by either discontinuing the Hamatologic:There have been rare reports of hemolytic anemia in patients If hypotension occurs, the patient should be placed in a supine position, and diuretic or increasing the salt intake pniorto initiation oftreatment with Lotrel. receiving ACE inhibitors if necessary. treated with intravenous infusion of physiologic saline. Lotrnl treat- Potassium Supplamonts and Potaulum-Sparlng Diuretics: Benazepnil Metabolic andNutritional: Hypokalemia mont usually can be continued fxllxwing restoration of blood pressure and volume. can attenuate potassium loss caused by ttiiazide diuretics. Potassium’sparing Musculoskeletal: Back pain, musculoskeletal pain, cramps, and muscle cramps. Neotropenia/Agranutocytonia diuretics )spimonolactone, amiloride, triamtemene, and others) or potassium Resplraloey: Pharyngitis. Another ACE inhIbitor, captopril. has bean shown to cause agronulocytosis and supplements can increase the risk of hyperkalemia If concomitant use of such Urogenital: Sexual problems such as impotence, and polyunia bone marrow depression, rarely in uncomplicated patients incidence probably agents is indicated, they should he given with caution, and ttie patient’s serum Other infrequently reported events were seen in clinical trials causal less that once per 10,000 exposures) but morn frequently incidence possibly as potassium should be monitored frequently. relationship unlikely). These included chest pain, ventricular entrasystole, gout, greatas once per 1000 exposures) in patients with renal impairment, especially LIthIum:lncreased serum lithium levels and symptoms of lithium toxicity have neuritis, and tinnitus. those who also have collagen-vascular diseases such as systemic lupos erythe- been moported in patients receiving ACE inhibitors during therapy wiih lithium. FatalflhaonatalMorbidityandMo,tality: See WARNINGS, Fetal/Neonatal matosus or sclerodorma. Available data from clinical trials of benazopril are Lotmel and lithium should be coadministemed with caution, and frequent monitor- Morbidity and Mortality. insufflciettto show that benazepril does tot cause agranulocytnsis at similar ing xl serum lithium levels is recommended. Monotherupins of benazepnii and amlodipine have been evaluated for safety rates Mnnitonng ofwhite blood cell counts should be considered in patients Other: Benazeprilhas been used concomitantly with oral anticoagulants, in clinical tnals in over 6000 and 11.000 patients, respectively The observed with collagen-vascular disease, especially if the disease is associated with beta’admenergic-blocking agents, calcium-blocking agents, cimetidine, diuretics, adverse reactions to the monniherapies in these trials were similar to those seen impaired renal function. dignoin, hydralazine. and nxpmoxen without evidence of clinically important in trials of Lotrel. in postmarketing experience with benazepril, there have been Fetal/Neonatal Morbidity and Modality adverse interactions rare reports of Stevens-Johnson syndrome and thrombocytopenia. Jaundice and ACE inhibitors can cause fetal and neonatal morbidity and death when adminis- In clinicaltrials, amlodipine has been safely administered with ttiiazide tiepatic enzyme elevations mostly consistent with cholestasis) severe enough to toned to pregnant women. Sevoral dozen cases have been reported in the world diuretics. beta blockers, ACE inhibitors, long-acting nitrates, sublingual nitmo- require hospitalization have been reported in association with use xl amlodipine literature. When pregnancy is detected, Lxtrel should be discontinued as soon glycerin, digoxin, warfann, nonstemoidal anti-inflammatory drugs, antibiotics, Clinical Laboratory Test Findings us possible. and oral hypoglycemic drugs. Serum Electrolytes: See PRECAUTIONS. The use of ACE Inhibitors dunng the second and third tnmextors of preg- In vitro data in human plasma indicate that amiodipine has no effect on the Creatinina: Minor reversible increases in serum creatinine were observed in nancy has heat associated with fetal and neonatal inlury, including hypotension. protein binding of drugs tested )digoxin. phenytoin, warfarin, and indomethacin). patients with essential hypertension treated with Lotrel increases in crealinine neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and Special studies have indicated that the coadministration of amlodipine with are more likely to occur in patients with renal insufficiency onthose pmetmeated death. Oligohydramnios has also beet reported, prosumably resulting from digoxin did not change serum dignoin levels or digoxin renal clearance in normal with a diuretic and, based on experience with other ACE inhibitors, would decreased fetal renal function: oligxhydramnixs in this setting has bean associ- volunteers: that coadministration with cimetidine did not alter the pharmacokinet- be expected to be especially likely in patients with renal artery stenosis see ated with fetal limb cxntractures, craniofacial deformation, and hypuplastic lung cs of amlodipine: and that coadministration with warfanin did not change the PRECAUTIONS. General). development. Prematurity, intrautenne growth retardation, and patent ductus warfanninduced prothmnmbin response time. Othar)causal relationships unknown). Clinically important changes in standard arteninsus have also been reported, athoagh it is notclear whether these occur- Carcinogenesis, Mutagenesis, Impairment of Fertility laboratory tests were rarely associated wiih Lotrol administration Elevations rences were due to the ACE inhibitor esposure No evidenceof carcinvgenicity was found when bnnazepril was given, via dietary of serum bilirubin and uric acid have been reported as have scanemed incidents These adverse effects dx not appear to have resulted from intrauterine ACE administration, to rats and mice for 104 weeks at doses up to 150 mg/kg/day. of elevations of liver enzymes. inhibitor noposure that has been limited to the first trimester. Mothers whoxe On a body-weight basis, this dose is over lottimes the maximum recommended embrynu and fetuses are exposed to ACE inhibitors only during the trot trimester human dose: on a body-surface-area basis, this dose is 18 times rats) and 865262 Printed in U 5.A C96-57 lRev. 11/90) should be so informed. Nonetheless, whet patients become pregnant. physicians g times Imicel the maximum recommended human dose. No mulagenic activity should make every eftxrttx discontinue the use of benazepni as seen as possible. was detected in the Ames test in bacteria, in an in vitro testfor forward muta’ Rarely (probubly less often that once in every thousand pregnancies), no lions in cultured mammalian cells. or in a nucleus anomaly test At doses of alternative to ACE inhibitors will be found. In these rare cases, the mothers 50500 mg/ kg/day 38-375 times the maximum recommended human dose should be apprised of the potential hazards to their fetuses, and serial ultrasound on a body-weight basis: 6-61 times the maximum recommended dose on a examinations shxuid be performed to assess the intruamnintic environment. body’surlace’area basis), benazepril had no adverse effect on the reproductive If oligohydramnixo is observed, benazepnil should be discontinued unless performance of male and female rats. it is considered lifesaving for the mother. Contraction stress testing )CST), a Rats and mice treated with amlodipine in the dietfor 2 years, at concentra’ nonstress test )NST). or biuphysical profiling )BPP) may be appropriate, depend- tions calculated to provide daily dosage levels of 0 5, 1 25. and 2.5 mg/kg/day. ing upon the week of pregnancy. Patients and physicians should be aware, how’ showed no evidence of carcinogenicity. For mice, but not for rats, the highest ever, that oligohydramnins may tot appear until after the fetus has sustained dose was close to the maximum tolerated dose. On a mg/m#{176}basis, this dose Dint by: irreversible injury given to mice was approximately equal to the maximum recommended clinical Ciba-Geigy Corporation infants with histnnies of in uteno expusure to ACE inhibitors should be dose. On the same basis, the same dose given to rats was approximately twice Pharmaceuticals Division closely observed for hypotension, oligunia, and hyperkalemia II oliguria occurs, the maximum recommendod clinical dose. Summit, New Jersey 07901 attention should be directed toward support of blood pressure and renal perfusion INSTRUCTIONS TO AUTHORS

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camitine ri eliminated in the urina Using plasma levels simon- Cathsogeneai mt*ageneei hnsnent at lorMItu CARNffORne)I rected for endogenoux lesocamitine, the mean distribution Metagenicity taxes performed in Safrnorse8a typlsknunxxrr, Pediatrics and adults: CARt-ATOP#{174}injection is administered half lIe was 0,585 hours and the mean apparent terminal Saccharomyces cereu’isiae, and Schizosaccharomyces intravenously. The recommended dose is 50 mg/kg given as elimination halt lie was ‘174 hours following a single iritra- pembe indicate that CARNfTOR#{174})Leraxcarn’rtine) is real a slow 2-3 minute bedus injection on by infusion. Often a venous dosa mutagenic. Long-term antirnal studies have not been con- loading dose is given in patients with severe metabolic crisis dusted to evaluate the carcinogenic polential of levocamitine. followed by an equivalent dose over the following 24 hours The absolute bioavariabehfy of L-camitine from CARNflOA#{174} ft should be administered q3h on q4h, and never less than lv . TABLETS . ORAL SOLUTION Tablets and Oral Solution wax determined compared to the Pregnancy q6h either by infusion on by inlravenous injection. Al subse- bioavailabii’ey of L-cam’itine from CARNIFOR#{174} injection Pregnancy Category B. quest daily doses are recommended to be in the range of 50 admirestered intievenousiy in 15 healthy male volunteers. After Reproductive studies have been performed en rats and rob- mg/kg on as therapy may require. The highest dose admin- correction Ion circulating endogenous levels of L-camitine in bits at doses up to 3,8 times the human dose on the basis of islered has been 300 mg/kg. surface area and have revealed no evidence of impaired fan- CARNflOR#{174} lLevocarrsitinel is IRI-3-carboxy-2-hydroxy- the plasma, absolute bioevaitabd’ity was 15.1% v 5.3% for L- tub on harm to the fetus due to CARNrTOR#{174}.There are, how- Ii is recommended that a plasma camitine level be obtained N,N,N-lrlmetfnyl-1-propanaminium hydroxide, inner salt. camitine from CARNTTOR#{174}Tablets and 15.9% u 4.9% from ever, no adequate and maO contrt9ed studies er pregnant prior 10 beginning this parenteral therapy. Weekly and month- Levocarnitine el a carrier rnolecuel tin the transport of kang- the Ods Solution. women. Because animal reproduction studies are not always ly monitonng is recommended as well This monitoring chain lofty acids across the inner mEtochondrial membrane. predictive of human respona this drug should be used tier- should include blood chemistries, vital signs, plasma carol- Aa a bsdk drug substance it IS a white powder with a melt- Total body clearance of L-camnitine IDose/AUC including log pregnancy only if clearly needed. tine concentrations lthe plasma free camitine level should ing point of 196-197CC and is readily aoiuble in water, hot endogenous baseline levels) wax a mean ot 4.00 LJhr. be between 35 and 60 pmnol/L) and overall clinical condition. alcohol, and insolubleinacetone. The pH ole aoietion 1 in Endogenous baseline levels were nol Subtracted since total NursIng mothers 20) ai between 6-8 and Is pKa value is a8. Itschenitcal body clearance of L-camitine does not distingusih between ft ix not known whether thIs drug is excreted in human milk. Parenteral drug products should be inspected visually for par- structure a: exogenous sources of L-camitine and endogenously syn- Because many drugs are excreted in human mdlx, a decision ticulale matter and discoloration pnionto administration, when- thesized L-camiftne. Vokirne of distribution of the intra- should be made whether to discontinue nursing on to discon- ever solution and container permit. CH3 venously administered dose above baseline eedogenous tinue the drug, taleng into account the mportance of the drug levels was calculated to be a mean of 29.0 L ± 7.1Llapprox- lv the mother. coeblety and StabilIty 0-13 - N - - CH - CH2- COO imately 0.39 l/1eg), which ix an under-estimate of tIne true CamitoitS injection is compatible and stable when raised in volume of distribution since plasma L-carnitine is known to PediatrIc use parenteral solutions of Sodium Chloride 0.9% on Lactated CH3 OH equdibmie slowly with, for instance, muscle L-camitine. See Dosage and Administration Ringers in concentrations ranging from 250 mg/500 mL(0.5 mg/mL) to 4200 mg/500 mL 18.0 mg/mtl and stored at Empirical Forrniia: CiHNO3 L-carnitine was floe bound to plasma protein or albumin when Mverse reacifona room lemperature l25Cl for up to 24 houm in PVC plastic Moiecuiar VN: 16120 tested at any concentistion on with any species including the Various mild gastrointestinal complaints have been bags. human.9 reported during the long-term administration of L - or DL- Each CARNrrOR#{174}ILevscamiflnel ibblet contains 330 mg ol camnitine; these include transient nausea and vomiting, How supplied levocamitine and the inacltva ingredlentu maeeksn uteeist MetaboNam and excreiton abdominal cramps, and diarrhea. Less frequent adverse CARNTTOR#{174})Leecicamnrine) Tablets are supplied as 330 mg nicnochw celkioee and povidona reactions are body odor, nausea, and gastnitis. An mci- Five normal adult male idunleers, administered a dose of limit dosel labtets embossed with CARNfl0R S-’r in indi- [3H-methyf]-L-carndine following 15 days of a hx camitne dence for these reactions is difficult to estimate due to vidual blislera packaged in boxes of 90 (NDC 54482-144-07 Each 118 mL container of the CARNfTOA#{174}ILevocamitine) diet and additional camitine stplemen excreted 58% to ihe confounding effects of the underlying pathology. Mild Siore at room temperature )25’C/77 F). Oral Solstice contains 1 g xl levocamitine/lO mL Also con- 65% of adnitnislered radioactive dose in 5 to 11 days in the myasthenia has been described only in anemic patients talus: Artificial Cherry Flavor, D&C Red N 33, D,L-Mabc urine and fecea Maxamum concentration of [3H-metbyj-L- receiving D,L-cumitirie. CARNIFOR#{174}Itevocamitinel Oral Solution is supplied in 118 Acid, FD&C Red No. 40, Purified Waler, Sucrose Snup. camitine in sersin occurred from 22 to 4S hr after drug mLI4 Ii. oz.l multiple-unit plastic containera.The multiple-unit Methyiparaben HF and Propylpareben NF are added as achlrinistmtiorL Mapir metaboIses buind were tiimeth4amine Decreasing the dosage often diminishes or eliminates drug- containers are packaged 24 per case (HOC 54482-145-08 preservatives. The pH is approximately 5. N-ordde, primarily in urine (8% to 49% of the administered related patient body odor on gastrointestinal symptoms when Store at room temperature I25C/77Fl. CARNITOR#{174} dose) and [3H)-g-bUttObetaine, primarily in laces (0.44% to present Tolerance should be monitored very closely during )Levocamitine) Oral Solution manufactured for: Sigma-Twa CARNITOR#{174}ILevocamitine) inon ic a sterile aqueous 45% of the admiritstneed dose Urinary excretion of camitine the first week of adminietration, and after arry dosage Pharmaceuticals, Inc. By: Barre-Nationat Inc. Baltimore, MD sekation containing 1 grain ol levocamitine per 5 mLampouie was 4% to 8% of the dose. Focal excretion of toed cannittine increases. Gastrointestinal adverse reactions with CARNI- 21207-2642 and Hi-TECH Pharmacal Co. Inc Amifyville, NY and 500 mg of levocamitine pen 2.5 mL ampoia The pH is was lass than 1% of total carnitine eocretion.#{176} TOR#{174})Levocarrnitinel Oral Solution dissolved in tiquids 11701 actyiaeed to 6.0 - 6.5 with hydrochionic acid. mixt be avoided by a slow consumption of the solution on After attainment of steady state lollowing 4 days of oral admin- by a greater dilution. CARNITOR#{174}ILevocarnitmnel Injection, 200 mg per 1 mL is al istiabon of L-camniflne with CARNflOR#{174}ibbiels 11980 mg available in 5 mL single-dose ampouleu packaged 5 CARNflOR#{174} lLevocamitirsel ri a naturally occurring sub- ql2h) on Oral Solution (2000 mg ql2h) to 15 healthy male ned- ampoules per carton INDC 54482-146-09) and as mL sin- stance reqs#{225}rndin mammahan energy metabolisrr ft has There have been no reports of toixcity from camnitrne rover- sideero, urinary excretion of L-camitine was a mean of 2107 gle-dose ampoules packaged 5 ampoules per cation INDC been shown to facitale lung-chain tetty acid entry into cease- dosage. The oral W50 of levocarrittine m mice a 192 glkg. and 2339 lamoles, respectively equivalent to 85% and 9A%, 54482-146-101. Made in Italy. Store ampoules at room tern- Ian mitochendnia, therefore delivering substrate for csddation respectively of the omay administered doses lunconrected Ion Camitine may cause diarrhea. Overdosage should be treated perature l25*C/7rFl in carton until their use to protect front and subsequent energy production. Fatty acids are uthzed as endogenous urinary excretion After a sine intravenous with cae- light Discard unused portion of an opened ampoule, as they an energy substrate rn an tissues ssmepl the beds. in skeletal dose (20 mg/kg) prior to multiple reel doses, urinary excretion contain no preservative. and card muscle they serva as ma4or keel Primary sm- of L-camitine was 6974 pmoleu, equivalent to 75.6% of the Doeage and adminlefradon temic camiltne deficiency in characterized by bee plasma, CAl7OR(Lasocarni&re) Thbteta, intravenously administered dose (uncorrected for endoge- Ceoiton RB and/or tissue lewis. ft has not been possible 10 deter- Adults: The recommended oral dosage Ion adults is 990 mg nuns urinary Federal IUSAI w prohifxits depensing without prescrtion mine which sTrptoma ate due to camitine deficiency and two on three times a day useng the 330 mg tablets, depending which ate dun to 8ie underlying ergac acidemla, as snnp- on dinmal response. dcone msd uaage Relorencee toivia xl bolts abnormaleles may be expected to irmnpecvewith CARMIOR#{174} lLevocamthnel Tablets and Oral Solution are 1. Bohmer ‘T Rynding A, Solberg HE: Camnitine levels in camitine. The liteislure imports that cannitine can promole the infants and children: The recoe’n’nended oral dosage Ion indicated in the saahmxent of primary systemic camitine del i- human serum in health and disease. ClIn Chim Acts 57: escemlion 01 excess organic or taffy acids in patients with infants and chddren is between 50 and 100 mg/leg/day in ciency In the reported cases, the clinical presentation con- 55-61, 1974. defects in laIty acid metabolism and/or specific oanic ad- divided doses, with a maxnnisim of 3 g/day. Dosage should sisted of recurrent episodes of Reye-iike encephatopatby 2. Brooks H, Goldberg L, Holland A at al.: Carnitine- dopathiea that bioaccumulate acyl-C0A esters. begin al 50 mg/kg/day The exact dosage will depend on clix- hypoketotic hypoglycemia, and/or cardiomyopathy. induced effects on cardiac and peripheral hemodynam- ical response. Associated symptoms included bypolonia, muscle weak- cs. J CIln Pharmacol 17: 561-578, 1977. Secondary levocarnitiee deficiency can be a consequence ness and failure to thrive. A diagnosis of primary camitine 3. Christiansen A, Bremen J: Active transport of butyro- ot inborn errors ol metaboiseft CARNITOR#{174}may alleviate Monitoring should include periodic blood chemistries, vital deficiency requires that serum, red cell and/on tissue cami- betaine and carnitine into isolated liver cells. Blochem the metabolic abnormahltes of patients with inborn errors that signs, plasma camitine concentrations and overall clinical tine levels be low and that the patient does not have a pa- Blophys Acts 448: 562-577, 1977. macit in accumulation of tosric organic acids. Conditions ton condthon many defect in fatty acid on organic acid oxidation see 4. Lindstedt S, Lindxtedl G: Distribution and excretion of which thai effect was demonstrated are: gkdanic addunia II, OnCal Pharmacology). in some patients, partiCularly those camnitine 14C02 in the rat. Acts Chem Scand 15: 701- methpl malerac acadoria, proponro acidemss, and mediam- CARNflOR(L. O Soluhon. presenting with cardiomyopathy camitine supplementation 701, 1961. chain fatty acy-COA delqylnogenase Auto- For osk use only. Not for perenteral use. rapidly alleviated signs and symptoms. Treahmxerrt should 5. Rebouche CJ, Engel AG: Carnitine metabolism and intosication occurs in these patients due to the accumula- include, in addition to camitine, supportive and other therapy deficiency syndromes. Mayo ClIn Proc 58: 533-540, hots cit acy4-COA compounds that disrupt intermediary Adults: The recommended dosage of levocamitine is 1 to 3 as indicated by the condition of the patient. CARNITOA#{174} 1983. metabolism. The subsequent hydrolysis xl the acyl-COA g/day Ion a 50 kg subject, which is equivalent to 10 to 30 (Levocamitine) Tablets and Oral Sokitioe are also indicated 6. Rebouche CJ, Paulson DJ: Cumnitine metabolism and compound to its free acid results in acidosis that can be life mL/day of CARNITOR#{174} (Levocamitmne( Oral Solution. Ion acute and chronic tmealmenl of patients with an inborn function in humans. Ann Rev Nub- 6: 41-68, 1956. threatenln Lavocarnitine dears the acyl-CoA compound by Hiser doses should be administered only with caution and error of metabolism that results in a secondary camitine 7. Scriver CR, Beaudet AL, Sly WS, Valle D: The formation of acyf carnitine, mt-itch is quickly excreted. only where clinical arid biochemical considerations make it deficiency Metabolic Basis of Inherited Disease. McGraw-Hill, New Levocamitine deficiancy is defined biochemically as abnor- seem likely that higher doses will be of benetit Dosage York, 1989. maey low plasma levels xl free camitine lions than 20 pmol/L should start at 1 9/day, 110 mLlduy), and be increased slow- a. Schaub J, Van Hoof F, Vis HL: Inborn Errors of at age greater than one week post term) and may be asso- CARNITOR#{174}ILevocamitinel Injection is ir’idicaled Ion the ly white assessing tolerance and therapeutic respenne. Metabolism. Raven Press, New York, 1991. dated wets hssue and/or urine levels. Further, axle condi- acute and chronic treatment of patients with an inborn error of Monitoring shouid include periodic blood chemistries, vital metabolism that results in secondary camnitine deficiency. 9. Marzo A, Arnigoni Martelli E, Mancmnelli A, Curdace 0, hen may be associated with a ratio of plasma aster/tree fey- signs, plasma camitine concentrations, and overall clinical Corbelleila C, Bassani E, Solbiati M: Prolein binding of ocarnitine levels greaten than OA or abnormally elevated 1ev- condition. L-camnitine family components. Eur J Drug Mel Pharma. ala ol netedhed levscarnihne in the urine. in premature infants Coelndlsallona: None keow cokln, Special issue iii: 364-368, 1992. and newborns, secondary deficiency el delined as plasma Infants and children: The recommended dosage of levocar- 10. Rebouche C: Quantitative estimation of absorption free lenrocamAne lomb below age related-nOrmal levels. Wsendnge. Nona nitine is 50 to 100mg/kg/day, which is equivalent to 0.5 and degradation of a camnitine supplement by human milkg/day CARNITOR#{174} ILevocumnitinel Oral Solution. adults. Metabolism: 1305-1310, 1991. Proceuns Higher doses should be administered only with caution and in a relative bioevaaabeity atuady in 15 healthy adult male ned- General only where clerical and biochemical considerations make it unlearn CARNflOA#{174}Tablnts were found to be blo-equiselent CARNflOA#{174}(Lewocamitine) Oral Solution is ton Oral/internal seem likely that higher doses will be of benefit Dosage to CARNFOA#{174}Otel Solutina Foeowing the adn*itSttetiOn of use only Not for perenteral use. should start at 50 mg/kg/day, and be increased slowly to a 16e0 mg bid. the maximum plasma concentistien level maoamum of 3 g/day 130 mudayl while assessing tolerance Gastrointestinal machens may result from too rapid consurnp- Icons_a)was 80 nmotlmL and the time to maramum concen- and therapeutic response. MOnitOring should include period- Delict (T) occurred at 3,3 hours. There were no signif i- hon of oral levecamitine. CARNITOR#{174}(Levecarnitine) Oel ic blood chemistries, vital signs, plasma camitine concentra- sigma-tau PHARMACEUTICALS, INC. card differences Ion M)C and urinary excretion deserved Solution may be consumed alone on dissolved in drinks on lions, and overall cbnical condition. other ltquid foods to reduce taste tatigue. 6 should be con- between these beinLifabuna 8oo S. Frederick Avenue - Suite 300 in the same bicevellabhty study ot 15 healthy adult melon, s&tned slowly and doses should be spaced evenly throusotd CARNfl’OR#{174}(Levocamnitine( Oral Solution may be consumed Gaithersburg, MD 20877 CARNflOA#{174}lLevocarnitinel Irechon administered as a slow the day to maximize tolerance. alone on dissolved in drink or other liquid food. Doses should TEL: (800) 447-0169 - FAX: (301) 948-1862 3-minute bolos intravenouS iniection at a dose xl 20 mgilsg be spaced evenly thnouolouI the day levery three on four showed that free leecicamihne plasma profiles are beet hr by CARNITOR#{174}(Levocamitinel Injection Is Ion intravenous use hours), preferably during on following meals and should be EMAIL: [email protected] a two-corrrpertment model. Apprrsdmateiy 76% of free lane- only. consumed slowly in oider to maximize tolerance. WEB: www.sigma-tau.it/na evi Reduce the Pressure of Hypertension

‘1 Effective as monotherapy’

, Effective in combination with other antihypertensive agents”2

Well Tolerated

, Like other alpha,-blockers, HYTRIN can cause marked lowering of blood pressure, especially postural hypotension and syncope.’

, Caution should be observed when HYTRIN is administered concomitantly with other antihypertensive agents, especially the calcium channel blocker verapamil, to avoid the possibility of developing significant hypotension. Dosage reduction and retitration of either agent may be necessary.’

, Adverse events occurring significantly more often than placebo in hypertension clinical trials were dizziness, asthenia, nasal congestion, peripheral edema, somnolence, nausea, palpitations and blurred vision.’

HYTRIN FREE START I PROGRAM I Freepatientsamplesavailable. TER42OSIN NC! Call: 1MN

moreinformation. Reduce the Pressure

R.f.reuces: Pleasesee adjacent page for brief summary of prescribing information. 1. HYTRINpockogejilted, AbbottLObOIOIOIIeS. 2. Luther IR GkissmanHN, JordanDC,SpecialWD. Efficacyo leruzosinason onhhyperienvive agent. AjnJMetL 1986;80(suppl 5B):73-76. a Abbott Laboratories Inc

North Chicago, IL 60064

©1997, Abbofl LaboratoriesInc December1997 Printedin U.S.A. BRIEF SUMMARY Drug Interactions: In controlled trials, terazosin has been added terazosin, as monolherapy or in combination with other antihy- CONSULT PACKAGE INSERT FOR FULL PRESCRIBING to diuretics, and several beta-adrenergic blockers; no unex- pertensive agents, at doses ranging from I to 40 mg. INFORMATION pected interactions were observed. Terazosin has also been used Adverse experiences in these trials where the prevalence rate HYTRIN#{174}(terszosin hydrochloride) Capsules in patients on a variety of concomitant therapies; while these in the terazosin group was at least 5%, where the prevalence rate were not formal interaction studies, no interactions were for the terazosin group was at least 2% and was greater than the INDICATIONS AND USAGE: HYTRIN is indicated for the treat- observed. Terazosin has been used concomitantly in at least prevalence rate for she placebo group, or where the reaction is of ment of hypertension. It can be used alone or in combination 50 patients on the following drugs or drug classes: I ) anal- with other antihypertensive agents such us diuretics or beta- particular interest are (TERAZOSIN [n859J - PLACEBO gesic/ansi-inflammatory (e.g., acetuminophen, aspirin, codeine, [n=5061): asthenia (11.3% - 4.3%), back pain (2.4% - 1.2%), adrenergic blocking agents. ibuprofen, indomethacin); 2) antibiotics (e.g., erythromycin, headache (16.2% - 15.8%), palpitations (4.3% - 1.2%), postural HYTRIN capsules are contraindicated in CONTRAINDICATIONS: trimelhoprim and sulfamethoxazole); 3) anticholinergic/sympa- hypotension (1.3% - 0.4%), tachycardia (1.9% - 1.2%), nausea patients known to be hypersensitive to terazosin hydrochloride. thomimetics (e.g., phenylephrine hydrochloride, phenyl- (4.4% - 1.4%), edema (09% . 0.6%), peripheral edema (5.5% - WARNINGS: Syncope and “First.dose” Effect: HYTRIN propanolamine hydrochloride, psuedoephedrine hydrochloride): 2.4%), weight gain (0.5% - 0.2%), pain-extremities (3.5% - capsules, like other slpha.adrenergic blocking agents, can 4) antigout (e.g., allopurinol); 5) antihistamines (e.g., chlor- 3.0%), depression (0.3% - 0.2%), dizziness (19.3% - 7.5%), cause marked lowering of blood pressure, especially pos. pheniramine): 6) cardiovascular agents (e.g., atenolol, libido decreased (0.6% - 0.2%), nervousness (2.3% - 1.8%), tural hypotension, and syncope in association with the first hydrochlorothiazide, methyclothiazide, propranolol); 7) corsi- paresthesia (2.9% - 1.4%), somnolence (5.4% - 2.6%), dyspnea dose or first few days of therapy. A similar effect can be costeroids; 8) gastrointestinal agents (e.g., antacids): 9) hypo- (3.1% - 2.4%), nasal congestion (5.9% - 3.4%), sinusitis (2.6% - anticipated if therapy is interrupted for several days and glycemics; 10) sedatives and tranquilizers (e.g., diazepam). 1.4%), blurred vision (1.6% - 0.0%), and impotence (1.2% - then restarted. Syncope has also been reported with other Use with Other Drugs: In a study (n=24) where terazosin and 1.4%). Asthenia includes weakness, tiredness, lassitude, and alpha-adrenergic blocking agents in association with rapid verapamil were administered concomitantly, terazosin’s mean fatigue. Asthenia, blurred vision, dizziness, nasal congestion, dosage increases or the introduction of another antihyper. AUC24 increased 1 1% after the first verapamil dose and after nausea, peripheral edema, palpitations, and somnolence were tensive drug. Syncope is believed to be due to an excessive 3 weeks of verapamil treatment it increased by 24% with associ- the only symptoms that were significantly (p < 0.05) more corn- postural hypotensive effect, although occaaionally the synco. ated increases in Cnun (25%) and Ce,n (32%) means. Terazosin mon in patients receiving terazosin than in patients receiving pal episode has been preceded by a bout of severe supraven. mean T,,.. decreased from 1.3 hours to 0.8 hours after 3 weeks placebo. Similar adverse reaction rates were observed in tricular tachycardla with heart rates of 120.160 beats per of verapamil treatment. Statistically significant differences were placebo-controlled monotherapy trials. minute. Additionally, the possibility of the contribution of not found in the verapamil level with and without terazosin. In a Additional adverse reactions have been reported, but these hemodilution to the symptoms of postural hypotension study (n=6) where terazosin and captopril were administered are, in general, not distinguishable from symptoms that might should be considered. concomitantly, plasma disposition of captopril was not influ- have occurred in the absence of exposure to terazosin, The fol- To decrease the likelihood of syncope or excessive enced by concomitant administration of terazosin and terazosin lowing additional adverse reactions were reported by at least 1% hypotension, treatment should always be initiated with a maximum plasma concentrations increased linearly with dose at of 1987 patients who received terazosin in controlled or open, 1 mg dose of terazosin, given at bedtime. The 2 mg, 5 mg steady-state after administration of serazosin plus capsopril (see short- or long-term clinical trials or have been reported during and 10 mg capsules are not indicated as initial therapy. Dosage and Administration). marketing experience: Body as a Whole: chest pain, facial Dosage should then be increased slowly, according to recom- edema, fever, abdominal pain, neck pain, shoulder pain; Cardio- Carcinogenesis, Mutagenesis, Impairment of Fertility: Tera- mendations in the Dosage and Administration section and s’ascular System: arrhythmia, vasodilasion; Digestive System: zosin was devoid of musagenic potential when evaluated in rico additional sntlhypertensive agents should be added with constipation, diarrhea, dry mouth, dyspepsiu, flatulence, vomit- and in s’itro (the Ames test, in s’is’o cytogenetics, the dominant caution. The patient should be cautioned to avoid situations, ing; MetaboliclNutritional Disorders: gout; Musculoskeletal lethal test in mice, in rico Chinese hamster chromosome aberra- such as driving or hazardous tasks, where injury could System: arthralgia, arthritis, joint disorder, myalgia; Neri’ous tion test and V79 forward mutation assay). result should syncope occur during initiation of therapy. System: anxiety, insomnia; Respirators’ System: bronchitis, cold Terazosin, administered in the feed to rats at doses of 8, 40, In early investigational swdies. where increasing single doses symptoms, epistaxis, flu symptoms, increased cough, phuryngi- and 250 mg/kg/day (70, 350, and 2100 mgfM2/day), for two up to 7.5 mg were given at 3 day internals, tolerance to the first tis, rhinitis; Skin and Appendages: pruritus, rash, sweating; Spe- years, was associated with a statistically significant increase in dose phenomenon did not necessarily develop and the first- cial Senses: abnormal vision, conjunctivitis, sinnitus; Urogenital benign adrenal medullary tumors of male rats exposed to the dose” effect could be observed at all doses. Syncopal episodes System: urinary frequency, urinary incontinence primarily 250 mg/kg dose. This dose is 175 times the maximum recom- occurred in 3 of the 14 subjects given terazosin at doses of reported in postmenopausal women, urinary tract infection. mended human dose of 20 mg (12 mg/M2). Female rats were 2.5, 5 and 7.5 mg, which are higher than the recommended initial Post-marketing experience indicates that in rare instances unaffected. Terazosin was not oncogenic in mice when adminis- dose; in addition, severe orthostatic hypotension (blood pressure patients may develop allergic reactions, including anaphyluxis, tered in feed for 2 years at a maximum tolerated dose of falling to 50/0 mmHg) was seen in two others and dizziness, following administration of terazosin hydrochloride. There have 32 mg/kg/day (I 10 mgfM2; 9 times the maximum recommended lachycardia, and lightheadedness occurred in most subjects. been reports of priapism during post-marketing surveillance. human dose). The absence of mutagenicity in a battery of tests, These adverse effects all occurred within 90 minutes of dosing. The adverse reactions were usually mild or moderate in inten- of tumorigenicity of any cell type in the mouse carcinogenicisy In three placebo-controlled BPH studies, the incidence of pos- sity bus sometimes were serious enough to interrupt treatment. assay, of increased total tumor incidence in either species, and tural hypotension in the terazosin treated patients was 5.1%, The adverse reactions that were moss bothersome, as judged by of proliferative adrenal lesions in female rats, suggests a male 5.2%, and 3.7% respectively. their being reported as reasons for discontinuation of therapy by rat species-specific evens. Numerous other diverse pharmaceuti- In multiple dose clinical trials involving nearly 2000 lsyper- at least 0.5% of the terazosin group and being reported more cal and chemical compounds have also been associated with tensive patients treated with terazosin, syncope was reported in often than in the placebo group (TERAZOSIN [n=859] - benign adrenal medullary tumors in male rats without support- about 1% of patients. Syncope was not necessarily associated PLACEBO [n=506]) are: asthenia (1.6% - 0.0%), headache ing evidence for carcinogenicity in man. only with the first dose. ( I .3% - 1.0%), palpitations ( I .4% - 0.2%), postural hypotension The effect of terazosin on fertility was assessed in a standard If syncope occurs, the patient should be placed in a (0.5% - 0.0%), syncope (0.5% - 0.2%), tachycardia (0.6% - fertility/reproductive performance study in which male and recumbent position and treated supportively as necesaary. 0.0%), nausea (0.8% - 0.0%), peripheral edema (0.6% - 0.0%), female rats were administered oral doses of 8, 30 and There is evidence that the orthostatic effect of tera.zosin is dizziness (3.1% - 0.4%), paresthesia (0.8% - 0.2%), somnolence 120 mg/kg/day. Four of 20 male rats given 30 mg/kg greater, even in chronic use, shortly after dosing. The risk of (0.6% - 0.2%), dyspnea (0.9% - 0.6%), nasal congestion (0.6% - (240 mg/M2; 20 times the maximum recommended human dose) the events is greatest during the initial seven days of treat- 0.0%), and blurred vision (0.6% - 0.0%). and five of 19 male rats given 120 mg/kg (960 mg/Nt2; 80 times ment, but continues at all time intervals. the maximum recommended human dose) failed to sire a litter. OVERDOSAGE: Should overdosage of HYTRIN lead to hypoten- Priapism: Rarely, (probably less than once in every several Testicular weights and morphology were unaffected by treat- sion, support of the cardiovascular system is of first importance. thousand patients) terazosin and other a1-antagonists have been ment. Vaginal smears at 30 and 120 mg/kg/day, however, Restoration of blood pressure and normalization of heart rate associated with priapism (painful penile erection, sustained for appeared to contain less sperm than smears from control mat- may be accomplished by keeping the patient in the supine posi- hours and unrelieved by sexual intercourse or masturbation). ings and good correlation was reported between sperm count tion. If this measure is inadequate, shock should first be treated Two or three dozen cases have been reported. Because this con- and subsequent pregnancy. with volume expanders. If necessary, vasopressors should then dition can lead to permanent impotence if not promptly treated, Oral administration of terazosin for one or two years elicited a be used and renal function should be monitored and supported patients must be advised about the seriousness of the condition statistically significant increase in the incidence of testicular as needed. Laboratory data indicate that serazosin is 90-94% (see PRECAUTIONS: Information for Patients). atrophy in rats exposed to 40 and 250 mg/kg/day (29 and protein bound: therefore, dialysis may not be of benefit. PRECAUTIONS: General: Prostatic Cancer: Carcinoma of the 175 times the maximum recommended human dose), but not in DOSAGE AND ADMINISTRATION: If HYTRIN administration is prostate and BPH cause many of the same symptoms. These two rats exposed to 8 mg/lcg/day (> 6 times the maximum recom- discontinued for several days, therapy should be reinstituted diseases frequently co-exist. Therefore, patients thought to have mended human dose). Testicular atrophy was also observed in using the initial dosing regimen. BPH should be examined prior to starting HYTRIN therapy to dogs dosed with 300 mg/kg/day (> 500 times the maximum rec- Hypertension: The dose of HYTRIN and she dose interval rule out the presence of carcinoma of the prostate. ommended human dose) for three months but not after one year (12 or 24 hours) should be adjusted according to the patient’s Orthostatic Hypotension: While syncope is the most severe when dosed with 20 mg/kg/day (38 times the maximum recom- individual blood pressure response. The following is a guide so orthostatic effect of terazosin (see Warnings), other symptoms of mended human dose). This lesion has also been seen with Mini- its administration: press#{174},another (marketed) selective-alpha-I blocking agent. lowered blood pressure, such as dizziness, lightheadedness and Initial Dose: I mg as bedtime is the starting dose for alt palpitations, were more common and occurred in some 28% of Pregnanc’e’: Teratogenic effects: Pregnancy Category C. Tera- patients, and this dose should not be exceeded. This initial dos- patients in clinical trials of hypertension. In BPH clinical trials, zosin was not teratogenic in either rats or rabbits when adminis- ing regimen should be strictly observed to minimize the poten- 21% of the patients experienced one or more of the following: tered as oral doses up to 280 and 60 times, respectively, the hal for severe hypotensive effects. dizziness, hypotension, postural hypotension, syncope, and ver- maximum recommended human dose. Fetal resorpsions Subsequent Doses: The dose may be slowly increased to tigo. Patients with occupations in which such events represent occurred in rats dosed with 480 mg/kg/day, approximately achieve the desired blood pressure response. The usual recom- potential problems should be treated with particular caution. 280 times the maximum recommended human dose. Increased mended dose range is I mg so 5 mg administered once a day: fetal resorptions, decreased fetal weight and an increased num- Information for Patients (see Patient Package Insert): Patients however, some patients may benefit from doses as high as should be made aware of the possibility of syncopal and orthosta- ber of supernumerary ribs were observed in offspring of rabbits dosed with 60 times the maximum recommended human dose. 20 mg per day. Doses over 20 mg do not appear to provide fur- tic symptoms, especially at the initiation of therapy, and to avoid ther blood pressure effect and doses over 40 mg have not been These findings (in both species) were most likely secondary to driving or hazardous tasks for 12 hours after the first dose, after a studied. BlOOd pressure should be monitored at the end of the maternal toxicity. There are no adequate and well-controlled dosage increase and after interruption of therapy when treatment dosing interval to sure control is maintained shroughous the studies in pregnant women and the safety of terazosin in preg- be is resumed. They should be cautioned to avoid situations where interval. Is may also be helpful to measure blood pressure injury could result should syncope occur during initiation of 1cm- nancy has not been established. HYTRIN is not recommended during pregnancy unless the potential benefitjustifies the poten- 2-3 hours after dosing to see if the maximum and minimum zosin therapy. They should also be advised of the need to sit or lie responses are similar, and to evaluate symptoms such as dizzi- down when symptoms of lowered blood pressure occur, although tial risk to the mother and fetus. Nonteratogenic effects: In a peri- and post-natal development ness or palpitations which can result from excessive hypotensive these symptoms are not always orthostatic, and to be careful when study in rats, significantly more pups died in the group dosed response. If response is substantially diminished at 24 hours an rising from a sitting or lying position. If dizziness, lightheaded- increased dose or use of a twice daily regimen can be consid- with 120 mg/kg/day (> 75 times the maximum recommended ness, or palpitations are bothersome they should be reported to the ered. If terazosin administration is discontinued for several physician, so that dose adjustment can be considered, human dose) than in the control group during the three-week postpartum period. days or longer, therapy should be reinstituted using the mi- Patients should also be told that drowsiness or somnolence tial dosing regimen. In clinical trials, except for the initial dose, can occur with terazosin, requiring caution in people who must Nursing Mothers: It is not known whether terazosin is excreted the dose was given in the morning. drive or operate heavy machinery. in breast milk. Because many drugs are excreted in breast milk, Use with Other Drugs: Caution should be observed when Patients should be advised about the possibility of priapism as a caution should be exercised when terazosin is administered so a HYTRIN is administered concomitantly with other antihyper- result of treatment with HYTRIN and other similar medications. nursing woman. tensive agents, especially the calcium channel blocker vera- Patients should know that this reaction to HYTRIN is extremely Pediatric Use: Safety and effectiveness in children have not pamil, to avoid she possibility of developing significant rare, but that if it is not brought to immediate medical attention, it been determined. hyposension. When using HYTRIN and other ansihypertensive can lead to permanent erectile dysfunction (impotence). ADVERSE REACTiONS agents concomitantly, dosage reduction and retitrasion of either Laboratory’ Tests: Small but statistically significant decreases in Hypertension: The prevalence of adverse reactions has been agent may be necessary (see Precautions). hematocris, hemoglobin, white blood cells, total protein and ascertained from clinical trials conducted primarily in the Ref. 03-4655-R3-Revised: October, 1996-1-IYP albumin were observed in controlled clinical trials. These labo- United States. All adverse experiences (events) reported during ratory findings suggested the possibility of hemodilution. Treat- these trials were recorded as adverse reactions. The prevalence 710-501-1652 MASTER ment with terazosin for up to 24 months had no significant rates presented below are based on combined data from fourteen El ABBOTT LABORATORIES 712-501-2019 effect on prostate specific antigen (PSA) levels. placebo-controlled trials involving once-a-day administration of NORTH CHICAGO, IL 60064, U.S.A. PRINTED IN U.S.A. 4

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FERRUM#{174} (IRON DEXTRAN INJECTION, USP)

WARNING Carclnegeneala, Matagenesia, Impairment 01 FertIlIty: See WARNINGS THE PARENTERAL USE OF COMPLEXES OF IRON AND CARBOHYDRATES HAS RESULTED tN Pregnancy: Teratvgonic Effects. Psegnancy Categwy C ton deotran has been shown iv be teratogenic and ANAPHYLACTIC.TYPE REACTtONS. DEATHS ASSOCtATED WtTH SUCH ADMtNISTRATION HAVE BEEN embryocidal in mice. rats, rabbits. dogs. and monkeys when given in doses of about 3 times the maximum human dose. REPORTED. THEREFORE, DEXFERRUM SHOULD BE USED ONLY IN THOSE PATIENTS IN WHOM THE INDICAT1ONS HAVE BEEN CLEARLY ESTABLISHED AND LABORATORY INVESTIGATIONS CONFIRM AN IRON N oconsis tent adverse fetal effects were observed in mice. rats. rabbits. dogs and monkeys at doses of 50 mg irvnkg DEFICIENT STATE NOT AMENABLE TO ORAL IRON THERAPY. or less. Fetal and maternal toxicity has been reported in monkeys at a total intravenous dose of 90 mg iron/kg over a f4 day period Similar eftects were observed in mice and rats on administration of a single dose of 25 mg iron/kg Fetal DESCRIPTION: DEXFERRUP.4#{174}(IRON DEXTRAN INJECTION. USP) a a dark brown, sbghtly v,scous ster,Ie bqs.d complen abnormalities in rats and dogs were observed at doses of 250 mg iron/kg and higher The animals used in these tests 51 lame suyhydrsxde and a low molecular wegert stentran der,vatn,e tsr ntr acenoususe Each mL c ontar,s 50 mg were not iron deficient There are no adequate and welicvntrviled studies in pregnant ovmen DexFerrum should be elemental ron as an run dexmran comple. Sodrum chlobde may have been added or tsnccty. Wamem or njectov q.s pH used during pregnancy only it the potential benefit ustifies the potential risk to the fetus . with hydmochlonc acid and, II necessary, sodjum hydrssule. Stenle, nonpyrogenic sdlusted to 5.2 6 5 Placental Tranaler: Various animal studies and studies in pregnant humans have demonstrated inconclusive results Therapeutic Class Hematin,c with respect to the placental transfer of iron deotran as iron dextran It appears that some iron does reach the fetus. but INDICATiONS AND USAGE: DexFemrum is ,ndrcated br treatment ot pat:ents with documented iron defictency fl whom the form in which it crosses the placenta is not cleat oral administration is unsattslactory or mpossrble Naralng Methera: Caution should be exercised when DexFettum is administered to a nursing woman Traces of CONTRAINDICATIONS: Hypemsensitto’ty to the product. AU anemias not associated with iron deI’c:ency unmetabvlized iron dentran are excreted in human milk WARNINGS: See BOXED WARNING Pediatric Uae: Not tecommended for useioin I antsiio de’ 4 months of age (See DOSAGE AND ADMINISTRATION). A nsk of carcinogenesis may attend the ntmamsscular Injection sI ron-carbohydrate complexes. Such complexes cave ADVERSE REACTIONS: Senere/Fatal: Anaphylacfic reactions have been teported with the use of iron deottan been sand under enpenmental conditions to produce sarcoma when large closes or small doses Inlected repeatedly at iniection; on occasions these reactions have been fatal Such reactions, which occur most often within the first several minutes of administration, have been generally characterized by sudden onset of respiratory difficulty and/or the same site were given to rats, mIce. and rabbits, and possibly in hamsters cardiovascular collapse (See boxed WARNING and PRtCAUTIONS General. pertaining to immediate availability of The lung latent period between the Inlectlon xl a potential carcinogen and the appearance xl a tumor makes t impossible epinephrine.) to measure accurately the risk n man There haoe, however. been several reports n the literalure descrtbng tumors at Cardlevaacalar: Chest pain. chest tightness. shock. hypotension.- hypertension, tachycatdia. flushing. arrhythmias the Inlection SttC Itt humans who had preotously received intramuscular Olections xl ron-carbohydrate complexes (Flushing and hypotension may occur from too rapid injections by the intravenous ‘oute ( Large ,ntraoenous doses. such as used wtth total dose nlussons TOll. have been assoc,ated w,th an ncreased ncdence xl adverse effects The adverse eBectslrequently are delayed lt’2 days) reactions typrlred by one or more olrhe tolloxng Dermaeeleglc: Urr:caria. pruritus, purpuru, ‘ash symptoms: arthralgra. backache, chIlls, dizzIness. moderate to hIgh fever, headache, malaise, myalgia. nausea. and Gaatrolnteatlnal: Abdominal pain, nausea. vomiting. diarrhea oxmtttng The onset s usually 24-40 hours after admlnlslrallon and symptoms generally subside withjn 3-4 days. The Hematologlcllpmphatlc: Leucocytvsis, (ymphadenopathy et:ology of these reactions Is not known. The potential for a delayed reaction must be considered when estjmating the rIsk/benefit of treatment Muecute.keletal/aelt tleaae: Arthraigia. arthritis (may represent reactivation in patients oith qu:escan t rheumatoid arthritis See PRECAUTIONS: General), myalgia: backache. steriie abscess; b,own skin anEor underlying tissue The maxImum daily dose should not exceed 2 mL undIluted ron deotran. discoloration (staining). ce(lulitis. swelling, infiammation, local ph(ebitis at or neat nt, avenvu S inlection site ThIs preparatton should be used with extreme care in patients with sertous impairment of liver function Nearologlc: Convulsions, seizures, syncope, headache, weakness. unresponsiveness, paresthesia. febrile episodes, It should not be used during the acute phase of infectious kidney disease chiiis. dizziness. disorientation. numbness Adverse reactions experienced following administration of DenFerrum may exacerbate cardiovascular complications in RespIratory: Respiratory a”est, dyspnea. bronchospusm patIents with pre-enisling cardiovascular disease Ureleglc: Hematutia PRECAUTIONS: General: Unwarranted therapy with parenteral iron will cause excess storage of iron with the Delayed reactlena: Arthraigia. backache. chills. di zziness . eve,, headache, naiaise, myaig:a. nausea , vomiting (See consequent possibility of coo genvus hemosiderosis Such iron overload is particularly apt to occut in patients with WARNINGS) hemoglobinopathies and other refractory anemcas that might be erroneously diagnosed as iron deficiency anemias. Mlecellaneoaa: Febri(e episodes, sweating, shivering. chills, malaise, altered taste DeoFerrum should be used with caution in individuals with histories of significant allergies andlor asthma. DOSAGE AND ADMINISTRATION: Ora( iron should be discontinued priv, to administration of DeoFerrum Anaphylanis and other hypersensitioity reactions have been reported after uneventful test doses as well as therapeutic doses of iron cleotran inlectlon Therefore, administration of subsequent test doses during therapy should be considered Intravenous Injection . PRIOR TO RECEIVING THEIR FIRST DEXFERRUM THERAPEUTIC DOSE. ALL PATIENTS (See DOSAGE AND ADMINISTRATION Administralion) SHOULD BE GIVEN AN INTRAVENOUS TEST DOSE OF 0 5 mL. (See PRECAUTIONS; Genera).) THE TEST DOSE SHOULD BE ADMINISTERED AT A GRADUAL RATE OVER AT LEAST 5 MINUTES Although anaphylactic meactions Epinephrine should be immediately available in the event of acute hypersensitivity reactions (Usual adult dose 0 5 mL known to occur following DeoFerrum administrati vnareusua liv evident within a few minutes. or sooner, it is xl a I t000 solution, by subcut anevus or intramuscular inlection.) Nela: Patients using betablocking agents may not tecommended that a period of an hour or longer elapse befote the remainde, of the initial thetapeutic dose is given respond adequately Iv epinephrine Isoprolerenol or similar beta-agonist agents may be required in these patients. Individual doses of 2 mL or less may be given on a daily basis until the calculated total amount required has been Patients with rheumatoid arthritis may have an acute exacerbatIon of loint pain and swelling following the administration reached DeoFerrum is given undiluted at a slow gradual rate not to exceed 50 mg (1 mL) per minute of DeaFerrum. If no adverse reactions are observed. DenFerrum can be given according to the following schedule until the calculated Inlormallen Per Paltasla: Patients should be advised of the potential adverse reactions associated with the use vf total amount required has been reached. Each day’s dose should ordinarily not exceed 0.5 mL (25 mg of iron) for infants DeoFerrum under 5 kg (tt Ibs); t mL (50 mg of iron) for children under 10 kg (22 lbs(, and 2 mL (100 mg of Iron) lot other patients. DruglLaboralerp Teat Inlaractlona: Large doses of iron dentran 5 mL or more) have been reported to give a brown NOTE: Do not mix DexFerrum with other medications ot add to parenteral nutrition solutions for intravenous infusion. color to serum from a blond sample drawn 4 hours after adminislration Parenteral drug ptvducts should be inspected visually for particulate matter and discoloration prior to administration. The drug may cause falsely elevated values of serum bilirubin and falsely decreased values of serum calcium whenever the solution and container permit Serum iron determinations especially by colorimetric assays) may not be meaningful for 3 weeks following the HOW SUPPUED: DeoFerrum#{174} (Iron Dentran Inlechon, USP) containing 50 mg of elemental iron per mL. is available in 2 mL administration of iron deotran single dose vials (for intravenous use( in cottons of to (NDC 05t7’0234’tO( and individually packaged )NDC 05t7’0234’Ot(. Serum ferritin peaks approximately 7 to 9 days after an intr avenvu 5 dose xl DeoFerrum and slowly returns to baseline Stote at controlled room temperature 15’ 30:C (59’ 86’F) after about 3 weeks ‘ ‘ CAUT1ON: Federal lam prohIbits dlepeneing mlthoat prescriptIon. Examination of the bane marrow for iron stores may not be meaningful for prolonged periods following iron deotran therapy because residual iron deotran may remain in the reticuloendothelial cells. This is a brief summary; see product package insen for full prescribing information Bone scans with 99m Tc-labeled bane seeking agents. in the presence of high serum ferritin levels or following iron BS0234 deotran infusions. have been reported to show reduction of bony uptake. marked renal activity, and excessive blood pool Rev 2/97 and soft tissue accumulation.

AMERICAN REGENT LABORATORIES, INC. SHIRLEY, NY 11967 4

/

The only liquid growth hormone.

Eliminates the need for reconstitution. Nutropin AQ is indicated for the treatment of growth failure due to a lack of adequate endogenous growth hormone secretion, growth failure associated with chronic renal insufficiency up to the time of renal transplantation, and short stature associated with Turner syndrome.

Important safety information Growth hormone should not be used in patients with closed epiphyses or active neoplasia. Growth hormone therapy should be discontinued if evidence of neoplasia develops.

From Genentech, Inc. Offering your patients the broadest line of growth hormone products and services.

For more information, call 1-800- 530-3083.

6th#{149} Science. Innovation. Service.

Please see brief summary of prescribing information for Nutropin AQ on adjacent page.

C l998Genentech,lnc. G7l143-R3 OVERDOSAGE MItIV*At The recommended dosage for GHD is up to 0.30 mg/kg (approximately 0.90 IU/kg( of body weight weekly. The rex- Emmm(#{188}Aa)EtctksJ BRIEF SUMMARY ummended dosage for CR1is up to 0.35 mg/kg (approximately 1.05 lU/kg( of body weight weekly. The recommend- The fsllswitg is a brief summaty. Before prescrIbIng, please consult full prescrIbIng itformatios, including DOSAGE ed dosage for Turner syndrome is up to 0.375 mg/kg (approolmately 1.125 lU/kg) of body weight weekly. Long-term averdosagecould result is signs and symptomsof gigantism and/or acromegalyconsistent with the known effects AND ADMINISTRATION. of excess human growth hormone. INDICATIONSAND USAGE Nutropin AD#{174}[somatrnpin (rONA urigis) injectionl IS indicated for the long-term treatment of growth failure duets G713l0-R0 a lack of adequateendugensusgrowth hormone secretion. Nutropia AD#{174} Nutropin AD#{174}[somatrspin (rONA origin) injectioni is also indicated for the treatment of growth failure associated [somatropin (rONA origin) inlection] (G48l09-Rl Revised March, 1997) with chronic renal issufficiency up to the time of renal transplantation. Nutrspin AQ therapy shauld be used in con- Manufactured by: junction with optimal management of chronic renal insufficiency. Genentech, lute. 01997 Genentech, Inc. 460 Potnt San Bruno Boulevard Notropin AQ [somatropin frOM origin) injectisol is also Indicated for the long-term treatment of short stature South Sas Franctsco, CA 94080-4990 associatedwith Turnersyndrome. CONTRAINDICATIONS Nutropin AQ should not be used in subjects with closed epiphyses.

Nutropln AQ should not be used It patIents with actIve neoplasla. Grnwth hormone )GHI therapy should be dlscon- tinued it evtdence of neoplasia develops. WARNINGS:Nene. PRECAUTIONS General: Nutrnpln AQshould be prescnbed by physlclan5 eoperienced in the diagnosis and management of patients with growth failure due to GH deficIency IGHD). Turner syndrome, or chronic renal insufficiency lCRl). No studies have been completed of Nutropln AQtherapy n patIents who have received renal transplants. Currently, treatment of patients with functioeiog renal allografts s not Indicated. BecauseNutroptn AU may reduce 15501)5 sensItIvIty, patients should be msnttored for evidence ofglacose intolerance. Patents wtth a hlstueystan IntracranIal leslse shoeld be esamlned freqaeetty for progression or mcurrenceofthe Iesn. Patients with growth failure secondaty to CR1should be examined periodically for evidence of progresslee of renal osteodystrophy. Slipped capital femoral eplphysis ar avascalar necrosis of the femoral head may be seen is children with advanced renal osteedystrophy, and it is uncertatn whether these problems are affected by GHtherapy.X-rays of the hips should be obtained prior to Initiating therapy for CR)patIents. PhysicIans and parents should be alert to the development of a limp or complaints of hip or knee pain in patients treated with Notropin AU. Slipped capital femoral epiphysis may also occur more frequently in patients with endocrine disorders or in patients undergoing rapid growth. Progressionof scol’etsis can occur in patients whoexperience rapid growth. Because GH increases grtveth rate, patients with a histolyofscoliosiswhoart treated with GHshould be monitored for pmgression of scoliosis. Growth hormonehas not been shownto increase the incidence of scoliosis. Skeletal abnormalities including scoliosis are commonly seen in untreated Turnersyndmme patients. Physicians should be ale) to these abnormalities, which may manifest during GHtherapy. Patteets with Turner syndrome should be evaluated carefully for otitis media and other ear disorders since these patients havean increasednsk of ear or hearingdisorders. In a randomized-coetmlledtrial, there was a statistically significant increase, as comparedto untreatedcontrels, in otitis media 143%vs. 26%) and ear disorders (18% vs. 5%) Itt patients receiving GH. In additioe, patients with Turner syndrome should be monitored closely tar cardis- vascular disorders (e.g., stroke, aoetic aneurysm, hypertensioe) as these patientsare alsoat risk far these conditions. Intracranial hypertension llH) with papilledema, visual changes, headache, nausea and/er vomiting has been reported 10 a small number of patients treated with GHprodacts.Symptoms osaaltyoccurred within the first eight (81weelss of the InItIatIon of GH therapy. In all reported cases, IN-assocIated 5IO5 and symptomsresolvedafter termination of therapy or a redacteetof the UN dose. Fanduscopi msaminat’ee of paheets is recommended at the initiahon and penodicalty during the course of GHtherapy.Patientswith CR1and Tamersyndrome may he at increased risk for devekapment of IN. As for any prntein, local or systemIc allergic reactions may occur. Pareets/Patieet should be informed that such mac- tlons are possible and that prnmpt medcaI attention should be sought If allergIc reactions occur. Laboratory Tests: Serum levels of Inorganic phosphorus, alkaline phosphatase, and parathyroid hormone (PTHI may increase with Notmpin AU therapy. Untreated hypothyrsidism prevents optimal response to Nutropin AU. Patients with Turner syndrome have an inher- ently increased risk of developing aotoimmuse thyrnid disease. Changes in thyroid hormone laboratory measure- ments may develop daring Nutropin AU treatment. Therefore, patients should have perisdic thyrnid function tests and should be treated with thyroid hormone when indicated. Drug Interaction The use of Nutrapin AU in patients with CR1receiving glucocorticoid therapy has not been evalu- ated. Concomitant glucocorticoid therapy may inhibit the growth.promoting effect of Nutropin AU. It glucocorticoid replacement is required, the glucocorticoid dose should be carefully adjusted. Therewas no evidence it the controlled studies of somatropin’s interaction with drugs commonly used in CR)patients. Limited published data indicate that GH treatment increases cytochrome P450 (CP450) mediated antipyrine clear- ancein man. There data suggest that GH administration may alter the clearance of compounds known to he metab- silted by CP450 liver enzymes (e.g., corticosteroids, set steroids, anticonvulsants, cyclosperin). Careful monitoring is advtsable when GHis administeredin combination with ether drugs known to be metabolized by CP4SOliver enzymes. Carcinogenesis,Mutagenesis,Impairment of Fertility: Carcinogeniclty, mutageniclty, and reproduction studies have not been conducted with Nutropin AU. Pregnancy: Pregnancy (Category C). AnImal reproductIon studIes have not been coedacted with Natropin AU. it is also not known whether Notropln AU can cause fetal harm when admInistered to a pregnant woman or can affect reprodactlon capacIty. Nutropln AUshould be givento a pregnantwomanonly It clearly needed.

NursIng Mothers: It is not known whether Natropis AU 15 escreted 5 human milk. Becaase manydregs are excreted In haman mIlk, caation should he exercised when Nutropln AU is administered to a nursing mother. InformatIon for Patients:Patientsbeingtreatedwith GHand/or their parents shouldbeinformed of the potential hen- eMs andrisks associated with treatment. If home use 5 determined to he desirable by the physician, instnactions on appropriateuse shouldhegiven, including a revtew of the contents of the Patient Information Insert. This information 15 intended to aid in the sate and effective administration of the medication. It IS nOt a disclesute of all possible adverseor intendedeffects. It home use 5 prescribed, a ponctare resistant contaIner for the disposal of used syringes and needlesshould he recommended to the patient. Patients and/or parents should he thoroughly instructed in the importance of prnper disposal and cautioned against any reuse of needles and syringes (see Patient Information Insert). ADVERSE REACTIONS As with all protein pharmaceuticals, a small percentage of patients may develnp antibodies to the pmtein. Growth hormone antibody binding capacities below 2 mg/I have not been associated with growth attenuation. In some cases when binding capacity euceeds 2 mg/I, growth attenuation has been observed. In clinical studies of patients that were treated with Notropin’ [somatropin (rONA origin) for injection] for the first time, 0/107 GHD patients, 0/125 CR1patients, and Oil 12 Turner syndrome patients screened for antibody prodaction developed antibodies with binding capacities 2 mg/L at six months. In a clinical study of patients that were treated with Natropin AU#{174} Isomatropin (tUNA origin) tnjection] for the first time, 0138GHDpatients screenedfor antibodyproduction,tar up to 15 months, developed antibodies with binding capacities 2 mg/I. AdditIonal short-term immunologic and renal function studies were carried out In a group of patients with CR1after approximately one year of treatment to detect other potential adverseeffects of antibodies to growth hormone. Testing Included measurements of Clq, C3, Cit. rheumatoId factor, creatinine, creatlnlne clearance, and BUN.No adverseeffects of growth hormone antibodies were noted. In addItion to an evaluatIon of compliance with the prescribed treatment program and thyroid status, testing for anttbedies to human growth hormone should he carrted out in any patient who fails to respond to therapy.

Inlection site dIscomfort has been reported. This 5 more commonly observed in children switched from another GH product to Nutropin AU. LeukemIa hasbeen reportedin a small numberof GHDpatIents treated with GH. It is uncertain whether this increased nsk is related to the pathology of GHDitself, GHtherapy, or other associated treatments such as radiation therapy for IntracranIal tumors. Onthe basis of current evidence, experts cannot concludethat GHtherapy is respoesibleforthese occerrences. The risk to GIlD,CR1,or Turnersyndromepatients, if any, remains to be established. Other adverse drug reactions that have been reported in GH-treated patients include the following: 1) Metahelic: Infrequent, mild, and transient peripheral edema. 2) Musculoskeletal: Arthralgias; rare carpal tunnel syndrome. 31 Skin: Rare increased growth of pee-existing nevi patients should he monitored carefully for malignant transfer- mation. 41 EndocrIne: Rare gynecomastia. Rare pancreatitis. of Renal Vitamins

THE STANDARD OF CARE IN VITAMIN REPLACEMENT THERAPY FOR RENAL PATIENTS

I renal failure patients, renal specific vitamin replacement is essen- tial. The Nephro-Vite#{174} family of renal vitamins is formulated to meet the spe- cial micronutrient replacement needs of renal failure patients. Nephro-Vite#{174} provides complete B and C vitamin replacement therapy, with increased amounts of folic acid and B6. It alSO includes Bi, B2, B12, biotin, pantothenic acid and macin.

Providing Leadership In the Nutritional and Pharmaceutical Management of Kidney Disease

R&D Laboratories, Inc. 4640 AdxniraltyWay, Suite 710, Marina del Rey, CA 90292 800/338-9066 #{149}310/305-8053 #{149}FAX 310/305-8103 E-Mail: [email protected] Internet: www.rndlabs.com Patient and professional education materials and product samples available on request. See accompanipng prescribing information. flinily of RenalVitamins It’s WW

THE STANDARD OF CARE IN VITAMIN REPLACEMENT THERAPY FOR RENAL PAri’rs

WRITEDO NOTNuo-ViRxSUBSTITIJTh 0 To AssuiYouii Pwrs GEr TU e RENAL Vrrsionr STinm or CAIu.

REIMBURSABLE Di 43 STATEs, BY INSURANCE PLANS. 0 EE MEDICAID, AND B Mosr Pniv Nephro.Vlte#{174} Rx

DIDIC&TIONS: Nephzo-Vite#{174} Rx is a vitamin B complex and C supplement for vitamin deS- S

hematologicalciencyneurologicalciencbea.lPRECAuTION:ofperisiciouadamagedamageFolic anemia,acidprogoessea.due maytowhilevitaminpartiallythe B12associatedcorrectdeS- the t WABNINO: Folic acid alone is improper therapy in the treatment ofperrticuous aitentiru and other megaloblastic anemias WhereVUtairtin B12 is deS- cient. Keep out ofieach of citildien. ADVERSE REACTION: Allergic sensitization has been reported following both oral and pasenoeral administration of folic acid. DOSAGE: One tablet daily or as prescribed by physician. Pbr patients on hemodialyaia, Nephro- Vite#{174}RXshould be taken after treatment on dialy- abe days HOW SUPPL: Round, yellow tablet, Sins coat- ed. NDC 54391-1002-01.Tablets in plastic bottles of 100. A child proofaafety cap is standard on each 100 tablet bottle as a safeguard against accidental CCC efficient, ingestion by childien. Store at controlied room temperature 15-30#{176}C(59-86#{176}F).The most recent and to comply revision of this labeling iaJU1y 1994.

Nephro.Vite#{174}+I with U.S. law. Through

WARNING: Accidental overdose of iron-containing our systems, products is a leading cause of fatal poisoning in children under 6. Keep this product out ofreach of children In case ofaccidental overdose#{149}call a doc- toe or poison control center intnsediately. INDICATIONS: For anypatieno needingvitansiit 1 .7 million titles over and iron supplementation for docUmented iron deficiency, Suitable for persons with end stage renal disease,certainpatienta undargoingtherapy 9,000 publishers. Whether it’s with erythropoietin or iron deficiency anemia. PRECAUTIONS: Eblic acid may partially coriect the hematological damage due to vitansinBl2 deS- photocopying, electronic use, ciency ofpernicious anemia while the associated neurological damage progiesses.Fblic acidis the emerging improper therapy in the treatment ofpernicious or anemia and other megaloblastic anemias where vitamin B12 is deficient. ADVERSE REACTION: Allergic sensitization has been reported following both oral and parenoeral administration of folic acid. Iron sensitivity to low CCC makes it easy. doses ofiron has been reported and high doses result in iron toxicity which is characterized by’. transient bloating, flatulence, constipation, and diarrhea, Ingestion of greater than 400 nig per day ofelemental iron caniesult innausea andvozniting. Call 1 -800-982-3887 ext. 700 DOSAGE: One tablet daily between meals or as presibed by the attending physician. EOWSUPPLTED: Film coated oval tablets manned tO find out how CCC can help RD23. NDC 54391-2213-08.Tablets in blister pack- aging, sealed in foil.Ten tablets per card. 3 cards total. Store at controlled room temperature, 15-30#{176}C you to Copy Right!SM (59-86#{176}Y).The most recent revision ofthis labeling isJuly 1997.

1. Kopplej: Nuthtion diet and the Itidney in Shils () Clearance Center#{174} ME andYouxsgVR (eda): Modern Nutrition in Health and Disease, Lea & Pbiger 1988, 1230-1263. Creating Copyright Solutions

Providing L.ad.rahip In the Nutritional and Pharmaceutical Management ofXidn.y Disease 222 Rosewood Drive

I$II1 Danvers,MA 01923 R&D Laboratories, Inc. 4640 AdmiraltyWay Suite 710, Marina del Rey CA 90292 Copyngtlt ClearanceCenter and the CCClogo are registered trademarks 000/338-9066 . 310/305-0053 - FAX 310/305-8103 of Copyngm ClearanceCenter, Inc. within the United States E-Mail: mdlabs©aoLcons Inoernet: www.rndlabs.com

(mycophenolate mofetil) 250 mg capsules and 500 mg tablets

Prevents renal allgg raft -rejection. % i. II

: Ii

k_l -

Reduces the incidence of treatment Improves combination failure and organ rejection. drug protocols. CeilCept in combination with cyclosporine and CellCept 1 g twice a day, with cyclosporine corticosteroids reduced the incidence of treatment and corticosteroids, with or without failure (statistically significant at the <0.05 level) over antithymocyte globulin induction therapy. azathioprine (AZA) or placebo within the first 6 months post-transpIant Available in CelICept substantially reduced the incidence of organ 250 mg capsules and 500 mg tablets. rejection within the first 6 months post-transplantation.

*Da) from three randomized, double-b(inci, muicenter trials of new]y transp(anted patients,

Roche Labomtories

S AMernbercEthOROcheGrOUp A safety profile proven in WARNING: Increased susceptibility to infec- patients worldwide. tion and the possible development of No incremental increase in nephrotoxicity, hepatotoxicity, lymphoma may result from immunosuppres- hypertension or neurotoxicity was reported with CelICept sion. Only physicians experienced in immuno- when used with cyclosporine and corticosteroids. suppressive therapy and management of renal transplant patients should use CelICept#{174}. The principal adverse events associated with CellCept Patients receiving the drug should be managed administration include diarrhea, leukopenia sepsis in facilities equipped and staffed with adequate (generally CMV viremia), vomiting and a higher frequency laboratory and supportive medical resources. of certain types of infections. The physician responsible for maintenance therapy should have complete information req- CelICeptshould not be used in pregnant women unlessthe uisite for the follow-up of the patient. potential benefitjusfies the potential sk to the fetus.Women of childbearingpotential should use effectivecontraception prior t Patients should be monitored for neutropenia. If neutropenia develops to, during and for 6 weeks after CellCepthas been stopped. (ANC <1 .3 x 103/pL), dosing with CetCept should be interrupted or the dose reduced. See brief summary of product information. (SeeWARNINGS,PRECAUTIONS:Pregnancyand Information Please see brief summary of product information on following pages. for Paflentsin brief summary of product informaon.) Copyright © 1997 by Roche Laboratories Inc. All rights reserved.

CeilCept. Making every kidney count. CeliCept#{174} (mycophenolate mofetil capsules) (mycophenolate mofetil tablets)

Before prescribing, please see complete product information, a summar,’ ofwhich follows: antacids with magnesium and aluminum hydroxides: Absorption of a single-dose of CeilCept#{174} mycophenolate mofetil (2.0 g) was decreased when administered to ten rheumatoid arthritis (mycophenotate mofetit capsules) patients also taking Maalox#{174}TC (10 mL q.i.d.). The Cmax and AUC024 for MPA were 33% and 1 7% lower, respectively, than when mycophenolate mofetil was administered alone under (mycophenolate mofetit tablets) fasting conditions. CellCept may be administered to patients who are also taking antacids containing magnesium and aluminum hydroxides; however, it is recommended that CeIlCept WARNING - Increased susceptibility to infection and the possible development of lym- phoma may result from immunosuppression. Only physicians experienced in immunosup- and the antacid not be administered simultaneously. pressive therapy and management of renal transplant patients should use CeIICept#{176}. cholestyramine: Following single-dose administration of 1.5 g mycophenolate mofetil to Patients receiving the drug should be managed in facilities equipped and staffed with ade- twelve healthy volunteers pretreated with 4 g lid. of cholestyramine for 4 days, MPA AUC quate laboratory and supportive medical resources. The physician responsible for mainte- decreased approximately 40%. This decrease is consistent with interruption of enterohepatic nance therapy should have complete information requisite for the follow-up ofthe patient. recirculation which may be due to binding of recirculating MPAG with cholestyramine in the intestine. CelICept is not recommended to be given with cholestyramine or other agents that INDICATIONS AND USAGE: CeliCept is indicated for the prophylaxis of organ rejection in may interfere with enterohepatic recirculation. patients receiving allogeneic renal transplants. CellCept should be used concomitantly with cyclosporine: Cyclosporine )Sandimmune#{174}) pharmacokinetics (at doses of 275 to 415 cyclosporine and corticosteroids. mg/day) were unaffected by single and multiple doses of 1 .5 g bid. of mycophenolate mofetil in ten stable renal transplant patients. The mean (±SD) AUC0.12 and Cmax of cyclosporine CONTRAtNDICATIONS: Allergic reactions to CeliCept have been observed; therefore, CellCept is contraindicated in patients with a hypersensitivity to mycophenolate mofetil, after 14 days of multiple doses of mycophenolate mofetil were 3290 (±822) ng.h/mL and 753 mycophenolic acid or any component of the drug product. (±161) ng/mL, respectively, compared to 3245 (±1088) ng.h/mL and 700 (±246) ng/mL, respectively, one week before administration of mycophenolate mofetil. The effect of WARNINGS: See boxed WARNING.) Patients receiving immunosuppressive regimens involv- cyclosporine on mycophenolate mofetil pharmacokinetics could not be evaluated in this study, ing combinations of drugs, including CeliCept, as part of an immunosuppressive regimen are however, plasma concentrations of MPA were similar to that for healthy volunteers. at increased risk of developing lymphomas and other malignancies, particularly of the skin. ganciclovir: Following single-dose administration to twelve stable renal transplant patients, no The risk appears to be related to the intensity and duration of immunosuppression rather than pharmacokinetic interaction was observed between mycophenolate mofetil (1 .5 g) and IV gan- to the use of any specific agent. Oversuppression of the immune system can also increase ciclovir (5 mg/kg). Mean (±SD) ganciclovir AUC and Cmax )n1O) were 54.3 (±19.0) ig.h/mL susceptibility to infection. CeilCept has been administered in combination with the following and 1 1 .5 (±1 .8) pg/mL, respectively after coadministration of the two drugs, compared to 51.0 agents in clinical trials: antithymocyte globulin (ATGAM#{174}),OKT3 Orthoclone OKT#{174}3), (±17.0) .ig’h/mL and 10.6 (±2.0) pg/mL, respectively after administration of IV ganciclovir alone. cyclosporine Sandimmune#{174}), and corticosteroids. The efficacy and safety of the use of The mean (±SD) AUC and Cmax of MPA )n=1 2) after coadministration were 80.9 (±21 .6) CellCept in combination with other immunosuppressive agents have not been determined. pg.h/mL and 27.8 ±13.9) pg/mL respectively compared to values of 80.3 (±16.4) pg.h/mL Lymphoproliferative disease or lymphoma developed in patients receiving CellCept with other and 30.9 (±1 1 .2) pg/mL, respectively after administration of mycophenolate mofetil alone. immunosuppressive agents in approximately 1 % of patients in the controlled studies of pre- vention of rejection. )See ADVERSE REACTIONS.) Because MPAG plasma concentrations are increased in the presence of renal impairment, as Adverse effects on fetal development (including malformations) occurred when pregnant rats are ganciclovir concentrations, the potential exists for the two drugs to compete for tubular and rabbits were dosed during organogenesis. These responses occurred at doses lower secretion and thus further increases in concentrations of both drugs may occur. than those associated with maternal toxicity, and at doses below the recommended clinical oral contraceptives: Following single-dose administration to fifteen healthy women, no phar- dose. There are no adequate and well-controlled studies in pregnant women. However, as macokinetic interaction was observed between mycophenolate mofetil (1 .0 g) and two tablets of CellCept has been shown to have teratogenic effects in animals, it may cause fetal harm when Ortho-Novum#{174} 7/7/7 (1 mg norethindrone [NET) and 35 pg estradiol ethin [EE]). This single- administered to a pregnant woman. Therefore, CellCept should not be used in pregnant dose study suggests the lack of a gross pharmacokinetic interaction, but cannot exclude the women unless the potential benefit justifies the potential risk to the fetus. possibility of changes in the pharmacokinetics of the oral contraceptive under long term dosing Women of childbearing potential should have a negative serum or urine pregnancy test with a condions with CelICept which might adversely affect the efficacy ofthe oral contraceptive. sensitivitiy of at least 50 mlU/mL within 1 week prior to beginning therapy. It is recommended trimethoprim/sulfamethoxazole: Following single dose administration of mycophenolate that CellCept therapy should not be initiated by the physician until a report of a negative preg- mofetil (1 .5 g) to twelve healthy male volunteers on day 8 of a 10 day course of Bactrirrt DS nancy test has been obtained. )trimethoprim 160 mg/sulfamethoxazole 800 mgI administered bid., no effect on the bioavail- Effective contraception must be used before beginning CelICept therapy, during therapy, and ability of MPA was observed. The mean )±SD) AUC and Cmax of MPA after concomitant for 6 weeks following discontinuation of therapy, even where there has been a history of infer- administration were 75.2 (±19.8) pg.h/mL and 34.0 (±6.6) pg/mL, respectively compared to tility, unless due to hysterectomy. Two reliable forms of contraception must be used simulta- 79.2 (±27.9) and 34.2 ±10.7), respectively after administration of mycophenolate mofetil alone. neously unless abstinence is the chosen method. If pregnancy does occur during treatment, other interactions: The measured value for renal clearance of MPAG indicates removal the physician and patient should discuss the desirability of continuing the pregnancy. (See occurs by renal tubular secretion as well as glomerular filtration. Consistent with this, coad- PRECAUT1ONS: Pregnancy and Information for Patients.) In the three controlled studies for prevention of rejection, similar rates of fatal infections/sepsis ministration of probenecid, a known inhibitor of tubular secretion, with mycophenolate mofetil (<2%) occurred in patients while receiving CelICept or control therapy in combination with in monkeys results in a 3-fold increase in plasma MPAG AUC and a 2-fold increase in plasma other immunosuppressive agents. (See ADVERSE REACTiONS.) MPA AUC. Thus, other drugs known to undergo renal tubular secretion may compete with Up to 2.0% of patients receiving CelICept for prevention of rejection developed severe neu- MPAG and thereby raise plasma concentrations of MPAG or the other drug undergoing tubu- tropenia [absolute neutrophil count )ANC) <0.5 x 103/pL]. (See ADVERSE REACTIONS.) lar secretion. Patients receiving CellCept should be monitored for neutropenia. (See PRECAUTIONS: Drugs that alter the gastrointestinal flora may interact with mycophenolate mofetil by disrupting Laboratory Tests.) The development of neutropenia may be related to CellCept itself, con- enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available comitant medications, viral infections, or some combination of these causes. If neutropenia for absorption. develops )ANC <1.3 x 103/pL), dosing with CeIlCept should be interrupted or the dose Carcinogenesis, Mutagenesis, Impairment of Fertility: In a 104-week oral carcinogenicity reduced, appropriate diagnostic tests performed, and the patient managed appropriately. study in mice, mycophenolate mofetil in daily doses up to 180 mg/kg was not tumorigenic. (See DOSAGE AND ADMINISTRATION.) Neutropenia has been observed most frequently in The highest dose tested was 0.5 times the recommended clinical dose (2 g/day) when cor- the period from 31 to 180 days post-transplant in patients treated for prevention of rejection. rected for differences in body surface area )BSA). In a 104-week oral carcinogenicity study in PRECAUTIONS: General: Gastrointestinal tract hemorrhage has been observed in approxi- rats, mycophenolate mofetil in daily doses up to 15 mg/kg was not tumorigenic. The highest mately 3% of patients treated with CeIlCept. Gastrointestinal tract perforations have rarely dose was 0.08 times the recommended clinical dose when corrected for BSA. While these been observed. Most patients receiving CeIlCept were also receiving other drugs known to be animal doses were lower than those given to patients, they were maximal in those species and associated with these complications. Patients with active peptic ulcer disease were excluded were considered adequate to evaluate the potential for human risk. (See WARNINGS.) from enrollment in studies with mycophenolate mofetil. Because CeIlCept has been associ- Mycophenolate mofetil was not genotoc, with or Mthout metabolic activation, in several assays: ated with an increased incidence of digestive system adverse events, including infrequent the bacterial mutation assay, the yeast mabtic gene conversion assay, the mouse micronucleus cases of gastrointestinal tract ulceration, hemorrhage, and perforation, CelICept should be aberration assay, or the Chinese hamster ovary cdl (CHO) chromosomal aberration assay. administered with caution in patients with active serious digestive system disease. Mycophenolate mofetil had no effect on fertility of male rats at oral doses up to 20 mg/kg/day. Subjects with severe chronic renal impairment )GFR <25 mLlmin/1 .73 m2) who have received This dose represents 0.1 times the recommended clinical dose when corrected for BSA. In a single doses of CeIlCept showed higher plasma MPA and MPAG AUCs relative to subjects female fertility and reproduction study conducted in rats, oral doses of 4.5 mg/kg/day caused with lesser degrees of renal impairment or normal healthy volunteers. No data are available on malformations (principally of the head and eyes) in the first generation offspring in the absence the safety of long-term exposure to these levels of MPAG. Doses of CellCept greater than 1 g of maternal toxicity. This dose was 0.02 times the recommended clinical dose when cor- administered twice a day should be avoided and they should be carefully observed. (See rected for BSA. No effects on fertility or reproductive parameters were evident in the dams or CUNICAL PHARMACOLOGY: Pharmacokinetics and DOSAGE AND ADMINISTRATiON.) in the subsequent generation. In patients with delayed graft function post-transplant, mean MPA AUC012 was comparable, Pregnancy: Category C: In teratology studies in rats and rabbits, fetal resorptions and maifor- but MPAG AUC0.12 was 2-3 fold higher, compared to that seen in post-transplant patients mations occurred in rats at 6 mg/kg/day and in rabbits at 90 mg/kg/day, in the absence of without delayed graft function. In the three controlled studies of prevention of rejection, there maternal toxicity. These levels are equivalent to o.o3-o.g2 times the recommended clinical dose were 298 of 1 483 patients (20%) with delayed graft function. Although patients with delayed on a BSA basis. In a female and reproduction study conducted rats, oral doses of 4.5 graft function have a higher incidence of certain adverse events (anemia, thrombocytopenia, fertility in mg/kg/day caused malformations (principally ofthe head and eyes) in the first generation offspring hyperkalemia) than patients without delayed graft function, these events were not more fre- in the absence of maternal toxicity. This dose was 0.02 times the recommended clinical dose quent in patients recelong CeIlCept than azathioprine or placebo. No dose adjustment is rec- when corrected for BSA. ommended for these patients, however, they should be carefully observed. (See CLINICAL There are no adequate and well-controlled studies in pregnant women. CellCept should not be PHARMACOLOGY: Pharmacolonetics and DOSAGE AND ADMINISTRATION.) It is recommended that CeIlCept not be administered concomitantly with azathioprine because used in pregnant women unless the potential benefitjustifles the potential risk to the fetus. Effective such concomitant administration has not been studied clinically. contraception must be used before beginning CeiCept therapy, during therapy and for 6 weeks In view of the significant reduction in the AUC of MPA by cholestyramine, caution should be after CeiCept has been stopped. (See WARNINGS, PRECAUTIONS: Information for Patients.) Studies in rats treated with mycophenolate mofetil have shown mycophe- used in the concomitant administration of CeIlCept with drugs that interfere with enterohepatic Nursing Mothers: recirculation because of the potential to reduce the efficacy of CellCept. (See PRECAUTiONS: nolic acid to be excreted in milk. It is not known whether this drug is excreted in human milk. Drug Interactions.) Because many drugs are excreted in human milk and because of the potential for serious Information for Patients: Patients should be informed of the need for repeated appropriate adverse reactions in nursing infants from mycophenolate mofetil, a decision should be made laboratory tests while they are receiving CelICept. Patients should be given complete dosage whether to discontinue nursing or to discontinue the drug, taking into account the importance instructions and informed of the increased risk of lymphoproliferative disease and certain other of the drug to the mother. malignancies. Women of childbearing potential should be instructed of the potential risks dur- Pediatric Patients: Safety and effectiveness in pediatric patients have not been established. ing pregnancy, and that they should use effective contraception before beginning CelICept Very limited pharmacokinetic data are available in pediatric patients. (See CLINICAL PHAR- therapy, during therapy and for 6 weeks after CellCept has been stopped. (See WARNINGS MACOLOGY: Pharmacokinetics.) and PRECAUTiONS: Pregnancy.) ADVERSE REACTIONS: The principal adverse reactions associated with the administration of Laboratory Tests: Complete blood counts should be performed weekly during the first CeIlCept include diarrhea, leukopenia, sepsis and vomiting, and there is evidence of a higher month, twice monthly for the second and third months of treatment, then monthly through the frequency of certain types of infections. first year. (See WARNINGS, ADVERSE REACT1ONS, and DOSAGE AND ADMINISTRATION.) The incidence of adverse events for CelICept was determined in three randomized compara- Drug Interactions: Drug interaction studies with mycophenolate mofetil have been conducted tive double-blind trials in prevention of rejection in renal transplant patients. Because of Ihe with acyclovir, antacids, cholestyramine, cyclosporine, ganciclovir, oral contraceptives, and trimethoprim/sulfamethoxazole. Drug interaction studies have not been conducted with other lower overall report:ng of events in the European placebo-controlled, prevention of rejection drugs that may be commonly administered to renal transplant patients. CelICept has not study, these data were not combined with the other two active-controlled prevention trials, but been administered concomitantly with azathioprine. are instead presented separately. acyclovir: Coadministration of mycophenolate mofetil (1 g) and acyclovir (800 mg) to twelve Safety data are summarized below for all patients in the double-blind prevention studies while healthy volunteers resulted in no significant change in MPA AUC and Cmax. However, MPAG receiving treatment; approximately 53% of these patients have been treated for more than 1 and acyclovir plasma AUC5 were increased 10.6% and 21 .9%, respectively. Because MPAG year. Adverse events that were reported in 10% of patients in either CellCepf treatment plasma concentrations are increased in the presence of renal impairment, as are acyclovir group are presented below for the two active-controlled studies combined (USA and concentrations, the potential exists for the two drugs to compete for tubular secretion further Europe/Canada/Australia) and for the one European placebo-controlled study. Opportunistic increasing the concentrations of both drugs. infections are summarized separately. CeliCept#{174} (mycophenolate mofetil capsules) CeilCept#{174} (mycophenolate mofetil capsules) (mycophenolate mofetil tablets) (mycophenotate mofetil tablets)

Adverse Events in Prevention of Renal Ailograft Rejection Malignancies Observed in Prevention of Renal Rejection Trials USA Study Combined with Eurooe/Canada/Australia Study Azathiopnine Azathioprine CellCept CeIlCept 1 -2 mg/kg/day or CellCept CeIlCept 1-2 mg’kg/day or 2 g/day 3 g/day Placebo 100-150 mg/day 2 g/day 3 g/day 100-1 50 mg/day (o,E5,Qj LflsA9.Q) LusJ) IDw QJw Lymphoma/lympho- 0.6% 1.0% 0.0% 0.3% Body as a Whole proliferative disease Pain 33.0% 31.2% 32.2% Non-melanoma skin 4.0 1 .6 0.0 2.4 Abdominal pain 24.7 27.6 23.0 carcinoma Fever 21.4 23.3 23.3 Headache 21.1 16.1 21.2 Other malignancy 0.8 1 .4 1 .8 1 .8 Infection 18.2 20.9 19.9 Sepsis 17.6 19.7 1S.6 Up to 2.0% of patients receiving CellCept for prevention of reiection have developed severe Asthenia 13.7 16.1 19.9 neutropenia [absolute neutrophil count (ANC) <0.5 x 10’/pL[. (See WARNINGS, PRECAU- Chest pain 13.4 13.3 14.7 liONS: Laboratory Tests, and DOSAGE AND ADMINISTRATiON.) Backpain 11.6 12.1 14.1 The following tables show the incidence of opportunistic infections that occurred in the trans- plant population in the prevention of relection trials: Hemic and Lymohatic Anemia 25.6 25.8 23.6 Opportunistic Infections in Prevention of Renal Rejection Trials Leukopenia 23.2 34.5 24.8 Thrombocytopenia 10.1 8.2 13.2 CellCeptCr, ,+ Hypochromic anemia 7.4 11.5 9.2 Azathioprine CetCept 1 -2 mg/kg/day or Leukocytosis 7.1 10.9 7.4 2 g/day 3 g/day 100-150 mg/day LDa Urogenital Urinary tract infection 37.2 37 0 33.7 Herpes simplex 16.7% 20.0% 19.0% Her’rtaturia 14.0 12.1 11.3 Kidney tubular necrosis 6.3 10.0 5.8 CMV viremia/syndrome 13.4 12.4 13.8 Cardiovascular tissue invasive disease 8.3 11.5 6.1 Hypertension 32.4 28.2 32.2 Herpes zoster 6.0 7.6 5.8 Metabolic and Nutritional Peripheral edema 28.6 27.0 28.2 Candida Hypercholesteremia 12.8 8.5 1 1.3 fungemia/disseminated 0.6 0.6 0.3 Hypophosphatemia 12.S 15.8 11 .7 tissue invasive 0.6 0.6 0.3 Edema 12.2 11.8 13.5 Hypokalemia 10.1 10.0 8.3 Aspergillus/Mucor 0.3 0.9 0.3 Hyperkalemia 8.g 10.3 16.9 invasive disease Hyperglycemia 8.6 12.4 1.0 Pneumocystis carinii 0.3 0.0 1.2

Diarrhea 31.0 36.1 20.9 Europe Study Constipation 22.g 18.S 22.4 CelICept CelICept 2 g/day Nausea ig.g 23.6 24.5 3 g/day Placebo Dyspepsia 17.6 13.6 13.8 LOaJ LOs1 Lus1il) Vomiting 12.5 13.6 9.2 Herpessimplex 15.2% 12.5% 6.0% Nausea and vomiting 10.4 9.7 10.7 11.3 Oral moniliasis 10.1 12.1 CMV viremia/syndrome 15.2 15.0 13.3 Respiratory tissue invasive disease 3.6 7.5 2.4 Infection 22.0 23.9 19.6 Dyspnea 15.5 17.3 16.6 Herpeszoster 6.7 6.9 2.4 Cough increased 15.5 13.3 15.0 Pharyngitis g.5 11.2 8.0 Candida fungernia/disseminated 0.0 0.6 0.0 Skin and Aopendages tissue invasive 0.0 0.6 0.0 Acne 10.1 9.7 6.4 Rash 7.7 6.4 10.4 Pneumocystis carinii 0.0 0.0 2.4 In the three controlled studies for prevention of rejection, similar rates of fatal infections/sepsis Nervous System Tremor 11.0 11.8 12 3 (<2%) occurred in patients while receiving CeIlCept or control therapy in combination with Insomnia 8.9 11.8 104 other immunosuppressive agents. (See WARNINGS.) Dizziness 5.7 11.2 1 1#{149}0 The following adverse events, not mentioned in any of the tables above, were reported with . 3% incidence in patients treated with CeilCept: BODY AS A WHOLE: abdomen enlarged, accidental injury, chills and fever, cyst, face edema, flu syndrome, hemorrhage, hernia, malaise, pelvic pain; HEMIC AND LYMPHATIC: ecchymosis, polycythemia; UROGENITAL: Eurooe Study albuminuria, dysuria, hydronephrosis, impotence, pain, pyelonephrffis, urinary frequency, un- CellCept CelICept nary tract disorder; CARDIOVASCULAR: angina pectons, atrial flbnllation, cardiovascular dis- 2 g/day 3 g/day Placebo order, hypotension, palpitation, peripheral vascular disorder, postural hypotension, Liis.i jas.ibo tachycardia, thrombosis, vasodilatation; METABOLIC AND NUTRITiONAL: acidosis, alkaline phosphatase increased, creatinine increased, dehydration, gamma glutamyl transpeptidase Both, as a Whole increased, hypercalcemia, hyperlipemia, hyperunicemia, hypervolemia, hypocalcemia, hypo- Sepsis 21.8% 17.5% 13.9% glycemia, hypoproteinemia, lactic dehydrogenase increased, SGOT increased, SGPT Infection 12.7 15.6 13.3 increased, weight gain; DIGESTIVE: anorexia, esophagitis, fatulence, gastnitis, gastroentenitis, Abdominal pain 1 2. 1 1 1 .9 1 1.4 gastrointestinal hemorrhage, gastrointestinal moniliasis, gingivitis, gum hyperplasia, hepatitis, ileus, infection, liver function tests abnormal, mouth ulceration, rectal disorder; RESPIRATORY: Hemic and Lymphatic asthma, lung disorder, lung edema, pleural effusion, rhinitis, sinusitis; SKIN AND Leukopenia 11.5 16.3 4.2 APPENDAGES: alopecia, fungal dermatitis, hirsutism, pruritis, skin benign neoplasm, skin dis- order, skin hypertrophy, skin ulcer, sweating; NERVOUS: anxiety, depression, hypertonia, paresthesia, somnolence; ENDOCRINE: diabetes mellitus, parathyroid disorder; MUSCULO- Urogenital SKELETAL: arthralgia, joint disorder, leg cramps, myalgia, myasthenia; SPECIAL SENSES: Urinary tract infection 45.5 44.4 37.3 amblyopia, cataract (not specified), conjunctivitis. Urinary tract disorder 6.7 10.6 4.2 CAUflON: Federal (USA) law prohibits dispensing without a prescription. Cardiovascular Hypertension 17.6 16.9 19.3 Manufactured by Syntex Puerto Rico, Inc., Humacao, Puerto Rico 00791 for

Destwe Diarrhea 16.4 18.8 13.9 Roche Laboratories C AMeniberottheRocheGroup Resoiratory Infection 15.8 13.1 9.0 Bronchitis 8.5 1 1 .9 8.4 Roche Laboratories Inc. Pneumonia 3.6 10.6 10.8 340 Kings)and Street The above data demonstrate that in three controlled tnals for prevention of resection, patients Nutley, New Jersey 07110-1199 receiving 2 g per day of CellCept had an overall better safety profile than did patients receiving 0654 JUNE 1997 3 g per day of CeilCept. Sepsis, which was generally CMV viremia, was slightly more common in patients treated with CeilCept, with an incidence of 18-22%, compatad to 16% in patients receiving azathioprine and 14% in patients receiving placebo. In the digestive system, diarrhea was most clearly increased in patients receiving CellCept, with an incidence of up to 36%, compared to 21 % for patients recelong azathioprine and 14% for patients receiving placebo. The incidence of malignancies among the 1 .483 patients enrolled in controlled trials for the prevention of rejection who were followed for 1 year was similar to the incidence reported in the literature for renal allograft recipients. There was a slight increase in the incidence of lym- phoproliferative disease in the CeIlCept treatment groups compared to the placebo and aza- thioprine groups. (See WARNINGS.) The following table summarizes the incidence of malignancies observed in the prevention of rejection trials.

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