In hypertension or angina every Tom, Dick, s effective control... Consider NORVASC the #1 branded agent for hypertension and/or angina*

Easy to start with and stay with2’3

Effective in all stages of hypertension, I-Ia r including severe hypertension4

Safely used in patients with common concomitant conditions, such as diabetes, COPD, and abnormal lipids4

No known drug interactions

No clinically significant effect on cardiac conduction or heart rate

In clinical trials, the most common side effects versus placebo were edema (8.3% vs 2.4%) headache (7.3% vs 7.8%) fatigue (4.5% vs 2.8%) dizziness (3.2% vs 3.4%)

Once-Daily S-mg and 10-mg tablets

NORVASC#{174}(amodpine besyHte)

‘Among branded cardiovascular agents indicated for

hypertension and/or angina.’ Please see brief summary of prescribing information on next page. Br$ef Summary NORVASC5(amlodI besylate)Tabfets In hypertension or angina... For Oral Use CONTRNNDICATIONS: NORVASC is contraindicated in patients with known sensitioity to amlodipine WARNINGS: Increased Angina and/er MyOcardial Infarction: Rarely, patients. particularly those with severe obstructive coronary artery disease, have developed documented increased frequency, duration and/or severity of Convenient angina or acute myocardial infarction on starting calcium channel blocker therapy or atthe time of dosage increase. The mechanism otthis effect has not been elucidated PRECAUTIONS: General: Since the vasodilation induced by NORVASCis gradual in onset, acute hypotension has rarely been reported aher oral administration of NORVASC Nonetheless, caution should be exercised when admin- islering NORVASCas with any other peripheral vasodilator particularly in patients with severe aortic stenosis once-daily dosing Use In Patients wtth Congestive Heart Faflure: In general, calcium channel blockers should be used with caution in patients with heart failure NORVASC(5-10 mg per day) has been studied in a placebo-controlled trial of t 153 patients with NYHA Class Ill or IV heart failure on stable doses of ACE inhibitor, digoxin, and diuretics Follow-up was at least 6 months, with a mean of about 14 months There was no overall adverse effect on survival or cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure) NORVASChas been compared to placebo in four 8-12 week studies of patients with NYHA Class Il/Il heart failure, The usual starting dose is 5 mg in involving a total of 697 patients In these studies, there was no evidence of worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or LVEF Beta.Slocker Wtthdraw&: NORVASC is not a beta-blocker and therefore gives no protection againstthe dangers of hypertension or angina abrupt beta-blocker withdrawal: any such withdrawal should be by gradual reduction of the dose of the beta-blocker Patients with Hepatic Failure: Since NORVASCis eotensively metabolized by the liver and the plasma elimination half- life )t if) is 56 hours in patients with impaired hepatic function. caution should be exercised when administering - In hypertension, small, fragile, or elderly individuals or NORVASCto patients with severe hepatic impairment. Drug Interac8ons: In vitrodata in human plasma indicate that NORVASChas no effect on the protein binding of drugs patients with hepatic insufficiency may be started on tested )digosin, phenytoin, warfarin, and indomethacin) Special studies have indicated that the co-administration of NORVASCwith digoxin did not change serum digosin levels or digooin renal clearance in normal volunteers, that co 2.5 mg once daily administration with cimetidine did not after the pharmacokinetics of amlodipine, and that co-administration with warfarin did not change the warfarin prothrombin response time In clinical trials, NORVASC has been safely administered with thiazide diuretics, beta-blockers, angiotensin converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin. digoxin. warfarin, non-steroidal anti- inflammatory drugs, antibiotics, and oral hypoglycemic drugs DruglLaboratory Test Interactions: None known Titration can proceed to 10 mg Carcinogenesis, Mutagenests, mpairment of Fertility: Rats and mice treated with amlodipine in the diet for two years. at coxcentrahons calculated to provide daily dosage levels of 0.5, 1 25, and 2 5 mg/kg/day showed no evidence of - Most angina patients will require 10 mg carcinogenicity. The highest dose (for mice, similar to, and for rats twice’ the maximum recommended clinical dose of 10 mg on a mg/m2 basis), was close to the maximum tolerated dose for mice but not for rats Mutagenicity studies revealed no drug related effects at either the gene or chromosome levels There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 14 days prior to meting) at doses up to 10 mg/kg/day (8 times’ the maximum recommended human dose of 10 mg on a mg/m2 basis) Pregnancy Category C: No evidence of teratogenicity or other embryo/fetaltoxicity was found when pregnant rats or Can be taken with or without food rabbits were treated orally with up to 10 mg/kg amlodipine (respectively 8 times’ and 23 times’ the maximum recom- mended human dose of 10 mg on a mg/mg basis) during their respective periods of muIr organogenesis. However, hOer size was significanty decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about S-fold) in rats administered 10 mg/kg amlodipine for 14 days before mating and throughout meting and gestation. Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose There are no adequate and well-controlled studies in pregnant women Amlvdipine should be used during pregnancy An excellent side-eftect profile only if the tentia) benefit (ustifies the potential risk to the fetus. Nursing : It is not known whether amlodipine is eocreted in human milk In the absence vfthis information, it is recommended that nursing be discontinued while NORVASCis administered Pediatric Use: Safety and effectiveness of NORVASC in children have not been established ADVERSE REACTIONS: NORVASChas been evaluated for safety in more than 11.000 patients in U S and foreign clinical trials. In general, treatment with NORVASCwas well-tolerated at doses up to 10 mg daily Most adverse reactions reported during therapy with NORVASCwere of mild or moderate severity In controlled clinical trials directly comparing NORVASC(N =1730) in doses up to 10 mg to placebo (N =1250), discontinuation of NORVASC due to adverse reactions was required in only about 15% of patients and was not significantly differentfrorn placebo (about 1%) The most common side effects are headache and edema The incidence (%( of side effects which occurred in a dose related manner ate 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 15% placebo), flushing (0 7% at 2 5 mg, 1.4% at 5 0 mg, and 2 6% at 10 0 mg, compared with 0 0% placebo), and palpitation (0 7% at 2 5 mg, 14% at 5.0 mg, and 4 5% at tO 0 mg, compared with 0 6% placebo) Other adverse eoperiences which were not clearly dose related but wInch were reported with an incidence greater than 1.0% in placebo-controlled clinical trials include the following headache (7.3%, compared with 7 8% placebo). tabgue (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 somnolence (1.4%, compared with 0 6% placebo) For several adverse experiences that appear to be drug and dose related, there was a greater incidence in women than men associated with amlodipine treatment asfollows edema (5 6% in men, 14 6% in women, compared with a placebo incidence in men of 14% 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 with a placebo incidence of 0.9% in men and 0 9% in women), and somnolence (1.3% in men, 16% in women, compared with a placebo incidence 010 8% in men and 0 3% in women) The following events occurred in t% but >0.1% of patients in controlled clinical trials or under conditions of open trials or marketin eoperience where a causal relationship is uncertain, they are listed to alert the physician to a possible relationship ovascular: arrhythmia (including ventricular tachycardia and atrialfibrillation), bradycardia, chest pain, hypotension, peripheral schema, syncope, tachycardia, postural dizziness, postural hypotension, central and peripheral nervous system: hypoesthesia, paresthesia, tremor, vertigo; gastroIntestinal: anorexia, constipation, dyspepsia,” dysphagia, diarrhea, flatulence, vomiting, gingival hyperplasia: general: asthenia,” back pain, hottlushes, malaise, pain, rigors, weight gain, musculoskeletal system: arthralgia, arthrosis, muscle cramps,” myalgia, psychiatric: sevual dysfunchon (mete” and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization, respiratory system: dyspnea,” epistaxis, skin and appendages: pruritus.” rash,” rash erythematous, rash maculopapular; special senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus, urinary system: micturition - - - Once-Daily 5-mg and 10-mg tablets hequency. micturition disorder, noctuna, autonomic nervous system: dry mouth, sweating increased, metabolic and nutritional: thirst, hemopoletic: purpura The following events occurred in 60 1% of patients’ cardiac failure, pulse irregularity, extraoystoles. skin discoloration, urticana, skin dryness, alopecia, dermatitis, muscle weakness. twitching. ataxia, hypertonia, migraine. cold and clammy skin, apathy, agitation. amnesia, gastritis. increased appetite, loose stools, coughing, rhinitis, dysuria, pvlyuria, parosmia. taste perversion, abnormal visual accommodation, and xerophthalmia. Other reactions occurred sporadically and cannot be distinguished from medications or concurrent disease states such as myocardia) infarction and angina. NORVASC#{174}NORVASCtherapy has not been associated with clinically significant changes in routine laboratory tests No clinically relevant changes were noted in serum potassium, serum glucose total triglycerides. total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, creatinine or liverfunction tests (amlodipinebesylate) NORVASChas been used safely in patients with chronic obstructive pulmonary disease, well compensated congestive heartfailure, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles OVERDOSAGE: Sing)e oral doses of 40 mg/kg and 100 mg/kg in mice and rats, respectively, caused deaths A single The #1 Branded Cardiovascular oral dose of 4 mg/kg or higher in dogs caused a marked peripheral vasvdilation and hypotension Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia In humans, experience with intentional overdosage of NORVASC is limited Repvrts of intentional Agent Worldwide1 overdosage include a patient who ingested 250 mg and was asymptomatic and was not hospitalized, another (120 mg) was hospitalized, underwent gastnc lavage and remained normotensive, the third (105 mgI was hospitalized and had hypotension (90)50 mmHg) which normalized following plasma eopansion A patient who took 70 mg amtodipine and an unknown quantity of benzodiazepine in a suicide affempt, developed shock which was refractory to treatment and died the following day with abnormally high benzodiazepine plasma concentration A case of accidental drug overdose has References: 1. IMS Midas sales data, 1Q98, and MS America prescription data, April 1998 2. Neaton been documented in a 19 month old male who ingested 30 rig amlodipine (about 2 mglkg( During the emergency room JO, Grimm RHJr. Prineas RJ, et al, for the Treatmentof Mild Hypertension Study Research Group. Treatment of presentation, vital signs were stable with no evidence of hypotension. but a heart rate of 180 bpm Ipecac was Mild Hypertension Study final results JAMA. 1993270 713-724 3. Hayduk K, Sauerbrey-Wullkopf N, Leverkus administered 3.5 hours after ingestion and on subsequent observation (overnight) no sequelae were noted F Initial dose finding of amlodipine in patients with essential hypertension, Eon HeartJ. 1994,15(suppl) 194A If massive overdose should occur, active cardiac and respiratory monitoring should be instituted Frequent blood pressure measurements are essential. Should hypotension occur, cardiovascular support including elevation of the 4. Data on tile Pfizer Inc. New York, NY extremffies and thejudicious administration offluids should be initiated. If hypvtension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine). should be considered with attention to circulating volume and urine output Intravenous calcium gluconate may help to reverse the effects of calcium entry blockade As NORVASCis highly protein bound, hemodialysis is not likely to be of benefit

‘ Based on patient weight of 50 kg. “These events occurred in less than 1%in placebo controlled trials, but the incidence ofthese side effects was between U.S. Pharmaceuticals 1% and 2% in alt multiple dose studies. More detailed professional information available on request. NC165A98 1011998, Pfizer Inc Revised June 1996 form

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MORE OF WHAT YOUR PATIENTS NEED, And less of what they don’t.

R&D Laboratories’ calcium carbonate line is formulated to meet the distinctive nutritional requirements of patients with renal disease. You will find a choice of forms and unique, high-strength formulations for medical food supplementation and phosphorus binding to optimize bone metabolism in ESRD. Our patient-friendly options mean greater benefit and greater compliance. Just how do we know? We’re a company focused on renal micronutrition. What you and your patients get out of our medical food supplements is all the years of expertise we put into them. For samples or more information, IDEAL FORMULATIONS. contact us at 800-338-9066, [email protected], or www.rndlabs.com IDEAL PARTNERS.

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Today, a growing consensus supports managing ESRD patients in the upper half of the 30-36% hematocrit range.

. New NKF-DOQI guidelines recommend hematocrits of 33-36%.’

I rpwo new studies suggest an association between hematocrits of 33-36% and reduced hospitalization.23 Reduced hospitalization --- NKF-DOQI may reduce the cost of care.

The future? Hematocrits higher in the target range mean more dialysis patients can be feeling better. Doing better.

And going stronger. H-’--- HCFA Anemia Project -

H EPOGENPackage Insert’-

Let’s keep it up. Recommended Hematocrit Ranges

ER1EN’ (EPOETIN AFA) RECOMBINANT

HIGHER HEMATOCRITS LEAD TO BETTER OUTCOMES.

*The EPOGEN#{174}package insert recommends a target hematocrit range of 30% to 36%.

EPOGEN#{174}is indicated for the treatment of anemia in dialysis patients with chronic renal failure.

Patients who receive EPOGEN#{174}may experience adverse effects such as hypertension or flu-like symptoms. Please see brief summary of prescribing information on following page.

(1) Natixxal Kidney Fxundatiox-Dials’sis OutcxnxesQuality Initialise (NKF-DOQ1)Clinical Practice Guidelines fxrthe Treatment of Anemia xf Chronic Renal Failure.1mJAdnet’ Dzs. 1997:30(44, suppl 3):S192-S237, (2) CollinsA, MaJ, EbfutxJ. hospital length xf stay is associated with hematncrit Ievel.J4m Soc Vephivi. 1997:8:1905.Abstract 50886. (3) Collins & MaJ. EbbenJ. Hemahocrit level is a predictive factor fxr future hospitalization esenls.J4m Soc Nepbrol. 1997:8:1905.Abstract 50885. EPOGEN Nut Modte,s Postnatal observations of the live offspring (Ft generation) of &mafe rats trealed EPOET1N ALFA with EF’OGEN during gestation arid lactation reveakd decreases in body weighl gain, delays in For Inon appearance of abdominal hair, eyelid opening, and decreases in the number of caudal vertebrae BRIFF SUMMARY OF PRESCRIBING INFORhtTION in the Fl fetuses of the 500 1)1kg group. INDICATIONS AND USAGE - EPOGEN is indicated for the treatment ot anemia associated wfth It is not known whether EPOGEN is excreted in human milk. Because many dwgr are excreted chronic renal failure (CRF), including patients on dialysis (end-stage renal disease) and patients n in human milk, caution should he exercised when EPOGEN is administered to a nursing woman. on dialysis. EPOGEN is indicated to elevate or maintain the red blood cell level has manifested atric Llte’ The saksty and effectiveness of EPOGEN in pediatric patients have not been established by the hematocrit (HCT) or hemoglobin deteeminationj and to decrease the need for transfusions in (see WARNINGS). these patients. L#{226}or Monit: The HG shouki he determined Iwice a week until it has stabdized in the CONTRAINDICAT1ONS - EPOGEN is contraindicated in patients with: 1) uncontrofled susted taiget rar and the maintenance dose has been established. Aher any dose adjustment, the hypertension; 25 known hypersensitivity to mammalian cell-derived products; ne 3) known HCT thouki also hedetem*sed twice weeldy for a least 2 m 6 weeks until ti has been detemned that the hypersensitivity to Albumin (Human). HCT has stliIized in resporse E thedose clsesge. The HCF shouk then he monikared at regular irae.va WARNINGS - Prdlatric U.e’ The multidow prese,wd formulation cotlains benzyl alcohol. Benzyl A complete blood count with differential and platelet count shotM he pedomied regularly. During alcohol has been reported to be associated with an increased incidence of neurological and other clinical trials, modest increases were seen in plalelets and white blood ceo counts. While these complicahons in premature infants which aer sometimes fatal. The safety and effectiveness of changes were statistically significant, they were not clinically significant and the values remained Epoetin aBa in pediatric patients have not been established. within normal ranges. Thrombodc Evenb aid Increaied Mortality: A randomized, prospective trial of 1265 hemodialysis In patients with CRF, serum chemistry values including blood urea nitrogen BUN), uric acid, patients with clinically evident cardiac disease (ischemic heart disease or congestive heart failure) creatinine, phosphorus, and potassiumh should he monitored regularly. During clinical trials in was conducted in which patients sswre assigned to EPOGEN treatment tateted to a maintenance patients on dialysis, modest increases were seen in BUN, creatinine, phosphorus, and potassium. HG of either 42 ± 3% ne 30 ± 3%. Increased modality was observed in 634 patients randomized In some patients with CRF not on dialysis treated with EPOGEN, modest increases in serum uric to a target HG of 42% 1221 deaths (35% mortality)h compared to 631 patients targeted to remain acid and phosphorus were observed. While changes were statistically significant, the values at a HG of 30% 1185 deaths (29% mortality)h. The reason for the increased mortality observed in remained within the ranges normafly seen in palients with CRF. these studis is unknown, however the inodence of non-fatal myocardial infairtions (3.1% vs 23%), Diet: As the HG increases and patients experience an improved sense of well-being and quality vascular access thromboses (39% vs 29%l. and all other thrombotic events (22% vs 18%) were of life, the importance of compliance with dtary and dialysis prescriptions shouid he reinforced. also higher in the group randomized to achieve a HCT of 42%. In particulai hyperkalemia is not uncommon in patients with CRF. In US studies in patients on dialysis, Hpertension: Patients with uncontrolled hypettension should not be treated with EPOGEN; hyperkalemia has occurred at an annualized rate of approximately 0.11 episodes per patient-year blood pressure (BP) should be controlled adequately before initiation of therapy. tip to 80% of EPOGEN therapy, often in association with poor comphance to medicalion, diet, and/or dialysis. ofpatientswithCRF haveahistoryofhypertension. Althoughtheredoesnotappeartobeany D1aI Management: Therapy with EPOGEN results in an increase in HCT and a decrease in direct pressor effects of EP()GEN, BP may rise during EPOGEN therapy. During the early phase plasma volume which could affect dialysis efficiency. In studies to dale, the resulting increase in of treatment when the H is increasing, approximately 25% of patients on dialysis may require HCT did not appear tri adversely affect dialyzer function” or the effloency of high flux heniodiaIs. initiation of, ix increases in, antihypertensive therapy. Hypertensive encephalopathy and seizures During hemodialysis, patients treated with EPOGEN may require increased anticoagulation with have been observed in pahents with CRF treated with EPOGEN. heparin to prevent clotting of the artificial kidney. Specialcare s!totiki be taken wa closely monitor and aggressively connol 8Pm patients treated with Patients who are maiinaIIy dialyzed may require adjustments in their dialysis prescription. As with EI#{174}XEM. Patients shouki be advised as to the importance of compliance with antihypertensive all patients on dialysis, the serum chemistry values (including BUN, crealinine, phosphorus, and therapy and dietary restrictions. If BP is difficult to control by initiation of appropriate measures, potassium) in patients treated with EPOGEN should he monitored regularly to assure the adequacy the HCT may be reduced by decreasing or wfthholdrng the dote of EPOGEN A clinically significant of the dialysis prescriwion. decrease in HG may nnt be observed for seseral weeks. ADVERSE REACTIONS - EIOGEN is generally well-tolerated. The adverse events reported are It is ieccrnmer,ckd that the *sw OIEPOGEM be decreased ifthe HCT increase exceeds 4 xsines frequent sequelae of CRF and are not necessarily attributable to EPOGEN therapy. In double- in any 2-week period. because of the possible association of excessive rate of rise of HG with an blind, placebo-controlkd studies involving over 300 patients with CRF, the events reported in exacerbation of hypertension. In CRF patients on hemodialysis with clinically evident ischemic greater than 5% of patients treated with EPOGEN during the blinded phase were: heart disease or congestive heart failure, H shouki be managed carefully, nnt to exceed 36% (see THROMBOTIC EVENTS). PERCENT OF PATIENTS REPORTiNG EVENT Seizures: Seizures have occurred in patients with CRF participating in EPOGEN clinical trials. Patients Treated with EPOGEN Placebo.Treated Patients In patients on dialysis, there was a higher incidence of seizures during the first 90 days of therapy Event (n-200) (n.135) (occurring in approximately 2.5% of patients) as compared with later timepoints. Hypertension 24% 19% Given the potential for an increased risk of swizures during the first 90 days of therapy, BP and the Headache 16% 12% presence of premonitory neurologic symptoms should be monitored closely. Pahents shouki he Arthralgias 11% 6% cautioned to avoid potentially hazardous activities such as driving or operating heavy machinery Nausea 11% 9% during this period. While the relationship between seizures and the rate of rise of HCT is uncertain, it is reconyv,enckd that the chase OIEPOGEM be kcreased i(the HCTincrease exceeds 4 points in Edema 9% 10’/ any 2-week od. Fatigue 9% 14% Throntholk Events: During hemodialysis, patients treated with EPOGEN may require increased Diarrhea 9% 6% anticoagulatwin with hepann to present cksting of the artificial kklriey (see ADVERSE REACTIONS kmiting 8% 5% for more information about thrombotic events). Chest Pain 7% 9% Other thronibotic events (eg myocardial infarction, cerebrovascular accident, transient ischemic attack) Skin Reaction (Administration Site) 7% 12% have occurred in clinical trials at an annualized rate of less than 0.04 events per patient year of EPOGEN therapy. These trials were conducted in patients with CRF (whether on dialysis or not) in Asthenia 7% 12% whom the target HG was 32% b 40%. However, the risk of thrombotic events, induding vascular Dizziness 7% 13% access thrombosis, was significantly increased in patients with ischemic heart disease or congestive Clotted Access 7% 2% heart failure receiving EFOGEN’ therapy with the goal of reaching a normal HO 142%) as compared Significant adverse events of concern in patients wilh CRF Irealed in double-blind, placebo- to a target HG of 30%. Patients with preexisting cardiovascular disease shouki be monitored closy. controlled trials occurred in 11w following percent of patients during the blinded phase of the studies: PRECAUTiONS - The parenteral administration of any biologic product should be attended by Seizure 1.1% 1.1% appropriate precautions in case allergic or other untoward reactions occur (see CONTRAINDICA- CVW11A 0.4% 0.6% lIONS). In clinical trials, while transient rashes were occasionally observed concurrently with MI 0.4% 1.1% EPOGEN#{149}therapy, no serkais allergic or anaphylactic reactions were reported (see ADVERSE REACTIONS for more information about allergic reactions). Death 0.0% 1.7% The safety and efficacy of EPOGEN therapy have nnt been established in patients with a known In the US EPOGEN studies in patients on dialysis (over 567 patients), the incidence number of history of a seizure disorder or underlying hematOiOgiC disease )eg sickle cell anemia, myelodys- events per patient-year) of the most frequently reported adverse events were: hypertension (0.75), plastic syndromes, or hypercoagulable disorders). headache (0.40), tachycardia 10.31 ), nause#{174}#s’omiting (0.26), clotted vascular access (0.25), short. ness of breath (0.14), hyperkalemia )0.I 1), and diarrhea (0.1 1 ). Other reported events occurred al In some femate patients, menses have resumed foikawing EPOGEN therapy; the possibility of a rate of less than 0.10 events per patient per year. pregnancy shouki be discussed and the need for contracephon evaluated, Events reported 10 have occurred within several hours of administration of EPOGEN were rare, Hematology: Exacerbation of porphyria has been observed rarely in patients with CRF treated mild, and transient, and included injection site stinging in dialysis patients and fluhike symptoms with EPOCEN’. However, EPOGEN has not caused increased urinary excretion of porphyrin metaboliles in normal wlunteers, even in the presence of a rapid erythropoietic response. such as arthralgias and myalgias. Nevertheless, EPOGEN should be used with caution in patients with known porphyria. H ‘ : Increases in BP have been reported in clinical trials, often during the first 90 days py. On occasion, hypertensive encephatopathy and seizures have been observed in patients In preclinical studies in dogs and rats; but not in monkeys, EPOGEN therapy was associated with with CRF treated with EPOGEN’. When data from all patients in the US Phase 3 multicenter trial subclinical bone marrow fibrosis. Bone marrow fibrosis is a known complication of CRF in were analyzed, there was an apparent trend of more reports of hypertensive adverse events in humans and may he related to secondary hyperparathyroidism or unknown factors. The incidence patients on dialysis with a faster rate of rise of HCT (greater than 4 HG poetts in any 2-week period). of bone marrow fibrosis was not increased in a study of patients on dialysis who were treated with However; in a double-blind, placebo-controlled trial, hypertensive adverse events were not reported EPOCEN’ for 12 Io 19 months, compared to the incidence of bone marrow fibrosis in a matched group of patients who had not been treated with EPOGEN. at an increased rate in the group treated with EPOGEN’ (1 50 UAcg TM)) relative to the placebo group. Hematocrit in CRF patients shouki he measured twice a week. In order to asoich reaching the Seizures: There have been 47 seizures in 1010 patients on dialysis treated with EPOGEN in clinical suggested target HCT too rapidly, or exceeding the suggested target range )HCT of 30% to 36%), trials, with an exposure of 986 patient-years for a rate of approximately 0.048 events per patient-year. the guidelines for dose and frequency of dose adjustments shouki he followed (see DOSAGE Howeve there appeared to be a higher rate of seizures during the first 90 days of therapy (occurring in approximately 25% of patients) when compared to subsequent 90-day periods. The baseline and ADMINISTRATION). incidence of seizures in the untreated dialysis population is difficult to determine; it appears lo he For pahents who respond to EPOGEN with a rapid increase in HG (egmore than 4 pcwists in in the range of 5% to 10% per palienlyear. any 2-week perkad), the dose of EPOGEN should be reduced because of the possible association of excessive rate of rise of HG with an exacerbation of hypertension. Thronthotic Events: In clinical trials where the maintenance HO was 35 ± 3% on EPOGEN, clotting ofthe vascular access A-V shunt) has occurred at an annualized rate of about 0.25 events The elevated bleeding lime characteristic ofCRF decreases toward nomial after correction of anemia per patient-year, and other lhrombotic events )eg, myocardial infarction, cerebral vascular accidenl, in patients treated with EPOGEN. ReductiOn of bleeding time also occurs after correction of anemia transient ischemic attack, and pulmonary embolism) occurred at a rate of 0.04 events per patient- by transfusion. year. In a separate study of till untreated dialysis patients, clotting of the vascular access occurred DeIa or Diininiied Reipome: If the patient fails to respond or to maintain a response 10 doses at a rate of 0.50 events per patient-year. However, in CRF patients on hemodialysis who also had within the recotrnsended dosing range, the kbwing etiologies shouki he considered and evaluated: clinically evident iscbemic heart disease or congestive heart failure, the risk of A-V shunt thrombosis I) iron deficiency: virtually all patients will eventually require supplemental iron therapy (see IRON was higher (39% vs 29%, p < 0.001), and myocardial infarctions, vascular ischemic events, and EVALUATION); 2) underlying infectious, in8amaio.y, or malignant processes; 3) occuk blood kws; venous thrombosis were increased, in patients laveeted to a HG of 42 ± 3% compared to Ihose 4) underIing hematotogic deeases se, thalassemi#{174}refractory anemia, or other myetodysplastic maintained at 30 ± 3% (see WARNINGS). disorders); S)vitamin de4icinmes: )ohc acid or vitamin B12; 6) hemolysis; 7) aluminum iososication; In patients treated with commercial EPOGEN, Ihere have been rare reports of serious or unusual 8) osleitis fibmsa cystica. thrombo.cmbok events including migratory thromboptsiebais, microvascular thrombosis, pulmonary Iron Evaluation: During EPOGEN therapy, absolute or functional iron deficiency may develop. embolus, and thrombosis of 11w retinal artery, and temporal and renal veins. A causal relationship Functional iron deficiency, with normal ferrilin levels but low transferrin saturation, is presumably has not been established. due to the inability lo mobilize iron stores rapidly enoug)i 10 support increased er4hropoiesis. . Reactio.: There have been no reports of serious allergic reactions or anaphylaxis associated Transferrin saturat,on should be at least 20% and ferritin should he at least 100 nghmL. with POGEN’ administration during clinical trials. Skin rashes and urticaria have been observed Prior to and during EPOGEN therapy, the patient’s iron status, including transferrin saturation rarely and when reported have generally been mild and transient in nature. (serum iron divided by iron binding capacity) and serum lerritin, should be evaluated. Virtually There have been rare reports of potentially serious allergic reactions including urticaria with associated all patients will eventually require supplemental iron to increase or maintain transferrin saturation respiratory symptoms or circumoral edema, or urticaria alone. Most reactions occurred in situations to tovels which will adequately support erplhropoiesis stimulated by EPOGEN where a causal relalionship could not he established. Symptoms recurred with rechallenge in a few Drug Interaction: No evidence of interaction of EPOGEN with other drugs was observed in the instances, suggesting that allergic reactivity may occasionally he associated with EPOGEN’ Iherapy. course of clinical trials. There has been no evidence for dev&opmenl of antibodies In erythropoietin in patients tested lo dale, Cardnogenesis, Mutagene#{252}, and InainnenI of Fertility: Carcinogenic potential of including those receiving EIOGEN for over 4 years Nevertheless, fan anaphylactoid reaction occurs, EPOGEN has not been evaluated. EPOGEN does not induce bacterial gene mutation (Ames EPOGEN should be immediately discontinued and appropriate therapy initiated. Test), chromosomal aberralions in mammalian cells, micronuclei in mice, or gene mutation at the DOSAGE AND ADMINISTRATION HGPRT locus. In female rats Irealed IV with EPOGEN, Ihere was a trend for slighlly increased Starting Dose: 50 to 100 U/kg TtW; IV or SC fetal wastage at doses of tOO and 500 Uilcg. Reduce Dose ‘Mien: 1 . HCT approaches 36% or, PrtWtancy Category C: EPOGEN has been shown to have adverse effects in rats when given in doses 5 times the human dose. There are no adequate and well-controlled studies in pregnant 2. HCT increases > 4 points in any 2-week tx’rxt women. EP(XEN’ thouki he used during pregnancy only if poenIial heneilt justifies the potential Increase Dose If: HO’ does not increase by 5 to 6 points after 8 weeks risk to the fetus. of therapy, and HG is below suggested largc’l range In StUdies in lemak’ rats, there were decreases in body weight g,in, delays in appearance of abdominal Maintenance Dose: Individually titrate hair, delayed eyelid opening, delayed ossification, and decreases in the number of caudal vertebrae Suggested Target HO Range: 30%, IC) 36% in 11w Ft teluses of the 500 liikg group. In femate rats Ireated IV, there was a trend for slightly ire reased fetal wastage at doses of 100 and 500 Uikg. Mantdaciutt’d by: An#{174}nInc., Arrgen Certer, Thousand (1s, California 91 320-1 789 Issue Dats’I3v97 Tm AMERICAN SocmTy OF NEPHROLOGY

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The only oral prophylaxis for CMV disease in solid organ transplantation.

iwo CYTOVENE 500 MG CAPSULES Monitoring of renal function during therapy is essential, have been shown to be bioequivalentto four 250 mg especially for patients receiving medications that may capsules in subjects who are seropositive for CMV cause nephrotoxicity. Please refer to the complete and human immunodeficiency virus.1 product information for dose modifications for patients with renal impairment. MANAGEABLE SAFETY PROFILE. The most common adverse events reported in a CONVENIENT ORAL DOSAGE. study (GAN 040) of liver transplant recipients included 1000 mg (two 500 mg capsules) tid with food. immune system disorders (graft rejection), infection, fever, abdominal pain, headache and diarrhea. There The clinical toxicity of CYTOVENE includes granulocy- was also a trend toward increased creatinine levels topenia, anemia and thrombocytopenia. In animal (2.5 mg/dL) in 16% of the 150 patients treated studies ganciclovir was carcinogenic and teratogenic with CYTOVENE capsules compared with 10% of the and caused aspermatogenesis. 154 patients receiving placebo; however, this was CYTOVENE should not be administered if the absolute not statistically significant.2 neutrophil count is less than 500 cells/pL or the platelet Please see summary of product information on the following pages. count is less than 25,000 cells/pL. References: 1. Data on file (Ref. 018-049), Hoffmann-La Roche Inc., Nutley, NJ 07110. 2. Data on file (Ref. 018-038), HoffmannLa Roche Inc., Nutley, NJ 07110. Copyright © 1998 by Roche Laboratories Inc. Al) rights reserved.

0*’ a / CYTOVE NE#{174} (I . cycovis (ganciclovircapsules) x#to,J.’. 0 250mg&SOOmg . tY5O SN

oil. 0 ORAL DEFENSE AGAINSTCMV /

0 Pharmaceuticals I CYTOVB(#{149}’IV(cIo* sodhim kr iIectIon) FOR PlTRMBOUS IIFUSION ONLY CY1OVEI(0-IV (ganciclcreir sodium for injection) and CYTOVENP (ganciclcwir capsules) CYTOVEIt#{149}(ganciclovir capsules) FOR ORAl. ADMINISTRAnON dovir AUC increased 53 ± 91% (range: -14% to 299%) in the presence of probenecid, 500 mg every Before prescribing, *ase see complete product informa6on, a summary of whhh fckms: 6 hours. Renal dearance of ganciclovir decreased 22 a 20% (range: -54% to -4%), which is consistent with an interaction involving competition for renal tubular secretion. Imipenem-cilastatin: Generalized WARNING: THE WNICAL TOWTY OF CYTOVENE AND CYTOVENEN INWJDES szures have been reported in patients who recaived gancicliir and imipenem-cilastatin. These drugs PENIA, ANEMIA AND THROMBOCY1OPENIA. IN ANIMAL STUDIES GANIXLOVIR WAS CARcINO- should not be used concomitantly usiess the potent benefits outwaigh the ricks. Ot1 Medications: ft is GENIC, TERAFOGENIC AND CAUSED ASPERMATOGENESIS. possible that drugs that inhibit replication of rapidly dividing call populations such as bone marrow, spec- CYIDVFJIE.N IS INDICATED FOR USE ONLY IN ThE TREATMENT OF CY1DMEGAI.OVIRUS (CMV) matogonla and germinal layers of skin and gastrointestinal mucous may have additive tcaicity when adminis- RET1NS IN NMUNOOMPROMISED PAT1ENIS AND FOR ThE PREVENTiON OF CMV DISEASE IN tered concomitantly with ganciclovir. Therefore, drugs such as dapsone, pentamidine, flucytosine, TRANSPLANT PATiENTS AT RISK FOR CMV DISEASE. vincds1in vinblastine, adtiamycln, amphoterutn B, thmethopdm/sutiarnefhoxazde combinations or other nucleoside analogues, should be considered for concomitant use with gancidovir onty if the potential hone- fits are iudged to outwgh the risks. No formal drug interaction studtes of CYTOVENE-lV or CYTtNENE and drugs commonly used in transtlant rectpients have been conducted Increases in serum creatinine were deserved in pahonts treated with CYlWENEV plus etiher cydosponne or arnphoteddn B, drugs with known potential for nephrottsucity (see AOVERSE EVENTS). In a retrospective analysis of 93 liver allograft recipients recaiving ganciclovir (5 mg/kg infused over 1 hour every 12 hours) and oral cydosporine (at therapeutic doses), there was no evidence of an effect on cydosporine whole blood concentrations. Carcinoganasis, Mutag.nes!s: Ganciclovir was carcinogenic in the mouse at oral doses of 20 and 1000 mg/lcg/day (approximataiy 0.lx and 1.4x, respectivaiy, the mean drug exposure in humans following the recommended intravenous dose of 5 mg/kg, based on area under the plasma concentration curve tONTRAINDICAflONS: CYrtJENE-r( and CVTtJENE are COntTathCatOd in patients with hypersensthvfty [AUC] comparisons). At the dose of 1000 mg/kg/day there was a significant increase in the incidence of to gancid,ir or acycIiir tumors of the preputial gland in males, forestomach (nonglandular mucosa) in males and females, and reproductive tissues (aries, uterus, mammary glan ditoral gland and vagina) and liver in females. At the WARNINGS: Hto: CYTOVEJlEN and CY1DVENE should nef be admkulsteted If the absolute p. dose of 20 mg/kg/day, a slightly increased incidence of tumors was noted in the preputia and harderian tv_I count Is less than 500 ceII$/IIL tile platelet count Is less than 25.000 ceIML. Granulocyto- glands in males, forestomach in males and females, and liver in females. No carcinogenic effect was penia fneutropenia), anemia and thrombocytopenia have been observed in patients treated with observed in mice administered gancickwir at 1 mg/lcg/day (estimated as 0.Olx the human dose based on CYT0VENEn and CYTIENE. The frequency and sevetity of these events vary wkiely in different patnt AUC comparison). Escept for Fftstiocytic sarcoma of the livec gancidcwir-induced tumors were generally of populahons (see AIMRSE EVENTS). CYTtNENE-W and CYTtIENE should, therefore, be used with can’ epitheI or vascular origin. Nthough the preputial and ditoral glands, forestornach and harderian glands of tion in patlents with preistin9 cytopemas or with a history of cytoperuc reactions to other dwgs, chemi- mice do not have human counterparts, gancidir should be considered a POtentol carcinogen in humans. cais or irradiabon. Granulocytopenia usually occurs during the first or second week of treatment but may Gancickwir increased mutations in mouse mphorna cells and DNA damage in human lymphocytes in vitro occur at any time during treatment. Cell counts usually begin to recD,er within 3 to 7 days of discontinu- at concentrations between 50 to 500 and 250 to 2000 pg/mL, respectively. In the mouse micronucleus ifl9 dru9. Cotony-stimulating factors have been shown to increase neutrophil and white blood cell counts assay gancidawir was dastogenic at doses of 150 and 500 mg/kg (IV) (2.8 to lOx human exposure based in pahents recwving CYENEn sotabon for treatment of CMV retinitis. Irnpairrrsefst of F&liIity: Anim on AUC) but not 50 mg/kg (exposure apprcwimately comparable to the human based on AUC). Ganciclovir data inthcate that administrabon of gancicira,ir causes inhibition of spermatogenesis and subsequent infer- was not mutagenic in the Ames Salmonefia assay at concentrations of 500 to 5000 pg/mL. tility. These effects were reversible at tower doses and irreversible at higher doses see Caivinogeriesis, Mutageriesis and Intpaimleflt of Fertility in PRECAUTiONS section). Although data tn humans have not Innpalrrnent of F.rt!IIty: Ganciclovir caused decreased mating behavior, decreased fertility, and an been Obtanied regarding this effect, it is coaskiered probable that gancidovir at the recommended doses increased incidence of embryolethality in female mice following intravenous doses of 90 mg/kg/thy causes temporary or permanent inhibitkrn of spermatogenesis. Anim data atso inotcate that suppresn (approicesately 1.7x the mean drug exposure in humans following the dose of 5 mg/kg, based on AUC of fertility in femes may occur. Teratogenesis: Because of the mutagenic and teratogenic POtenti of gao- comparisons). Gancidotnr caused decreased fertility in male mice and hypospermatogenesis in mice and cidovir, women of childbearing pOtentot should be advised to use effective contraceptkw during treat- dogs following daily oral or intravenous administration of doses ranging from 0.2 to 10 mg/kg. Systemic ment. Similarly, men should be advised to practse barner contraception durhig and for at least 90 days drug exposure (AUC) at the lowest dose showing tosicity in each spectes ranged from 0.03 to 0.lx the following treatment with CYT1dENE-W or CYTOVENE (see Fegnancy: Category C). AUC of the recommended human intravenous dose PRECAUTIONS: GaI: In dinat studtes with CYTciThE-/, the maximum sirte dose administered Phwgnancy:Category C: Ganciclovir has been shown to be embryotoxic in rabbits and mice following was 6 mg/kg by intravenous infusien over 1 houc Larger doses have resufted in increased tOXtY. ft is intravenous administration and teratogenic in rabbits. Fetal resorptions were present in at least 85% of likely that more rapid infudons would atso restit in increased tOXiety (see /ERDOSN3E). Mministratlon rabbits and mice administered 60 mg/kg/day and 108 mg/kg/day (2x the human exposure based on AUC of CYTtIENE’PI sotubon should be accompanied by adequate Itydradon. Initially reconstituted solutions comparisons), respectively. Effects observed in rabbits induded: fetal growth retardation, embryolethality of CYTtNENE-IV have a high pH (pH 11). Despite further dilution in intrasenous fluids, phlebitis and/cs’ teratogeniafty and/or maternal tOXioty. TeratOgenic changes induded deft palate, anophthalmia/microph- pare may occur at the site of intravenous infusion. Care must be taken to infuse solutions containing thalmia, a#{216}aSbCorgans (kidney and pancreas), hydrocephaly and brachygnathia. In mica effects deserved CYTOVENE-lV only into veins with adequate blood flow to permit rapid dilution and distribution (see were maternal/fetal toxicity and embryolethality. Daily intravenous doses of 90 mg/kg administered to DOSNE AND ADMINISTRATION in complete product information). Since gancick,ir is wanted by the female mice prior to mating, during gestation, and du#{241}nglactation caused hypoptasia of the testes and kidneys, normal clearance depends on adequate renal function. IF RENAL FUNCTION IS IMPAIRED, seminal vesicles in the month-old male offspring, as well as pathologic changes in the nonglandular region DOSAGE ADJUSTMENTS ARE REQUIRED FOR CYTOVENE-lV AND SHOULD BE CONSIDERED FOR of the stomach (see Carcinogenesis, Mutagernesis). The drug exposure in mice as estimated by the AUC CYTt/ENE CAPSULES. Such adjustments should be based on measured or estimated creatinine dearance was apprdomately 1.7x the human AUC. Ganciclovir may be teratogeiac or embryotoxic at dose levels values (see DOSN3E AND ADMINISTRATION in complete product information). recommended for human use. There are no adequate and well-controlled studies in pregnant women. hIh%lnhfIatl l Patients: All patients should be informed that the maior tOXiotieS of gancicliir are granu- CYTOVENE-IV or CYTOVENE should be used during pregnancy only if the potential benefits justify the locytopenio (neutmpenio), anena and thrombocytopenia and that dose modifications may be required, potentof risk to the fetus. indudIn discontinuation. The importance of dose monitoring of blood counts while on therapy should be Foobmote:M dose comparisons presented in the Carcinogenesis, Mutagenesis, Impairment of Fertility emphasIzed. Pahents should be informed that gancicIir has been associated with elevations in serum and Pregnancy subsections are based on the human AUC following administration of a single 5 mg/kg creatinine Pahents should be instructed to take CY’TWENE capsules with food to maximize bioavailability. intravenous Infusion of tYflh/ENE-n as used duftng the maintenance phase of treatment Compared with Patients should be advised that gancickwir has caused decreased sperm production in animals and may the single 5 mg/kg intravenous infusion, human exposure is doubled during the intravenous induction cause infertility in humans. Woman of childbearing POtent should be advised that gancidoeir causes phase (5 mg/kg bid) and approximately halved during maintenance treatment with CYTOVENE capsules birth defects in animals and should not be used during pregnancy Women of childbearing potential (1000 mg tel). The cross-species dose comparisons should be divided by 2 for intravenous induction should be advised to use effective contraception during treatment with CY’TWENE-lV or CYTOVENE. treatment with CYTOVENEV and multiphed by 2 for CYTOVENE capsuias. Similarly, men should be advised to practhe bamer contraception during and for at least 90 days following NIVthW Mos: It is not known whether gancickwir is excreted in human milk. However, marty drugs are treatment with CYTOVENE’Fi or CYTOVENE. Patients should be advised that ganddir causes tumors in excreted in human milk an because carcmogenic and teratogenic effects occurred in animals treated with animals. Although there is no information from human studies, ganciclcs,ir should be considered a poten- ganciclovic the possibility of serious adverse reactions from ganciclovir in nursing infants is considered tot carcinogen. ,411HIV+ Pataints: These pahents may be recetving zkics,udine (Retrir). Patnts should likely (see Pregnancy: Category C). Mothers should be instructed to discontinue nursing if they are receiv- be counsaled that treathient with both gancickleir and zatiudine simultaneously may not be tolerated by ing CY1WENE-IV or CYTIYJENE. The minimum interval before nursing can safely be resumed after the last some patients and may result in severe granulocytopenia (neutropenia). Patients with ADS may be receiv- dose of CYTOVENE-IV or CYTtNENE is unknown. ing danosine (\#{241}des).Patwnts should be counsaied that concomitant treatment wWi both gandckatr and datanosine can cause thdanosine serum concentrations to be sl9nificantly increased. HI14 Patients with CMV Retirnttis: Gancidcs#{241}ris not a cure for CMV retinitis, and ImmunOcompromised pahents may continue to experience progresaion of retinitis dudag or followmg treatment. Patients should be advised to have ophthalmologic follow-up examinations at a mInimum of every 4 to 6 weeks while being treated with CiTOVENE-n or CYTOVENE. Some patients will require more frequent follow-up. Transp’ant Rnts: Transplant recipients should be counseled regarding the hiqh frequency of Impaired renal function in The spectrum of adverse events reported in 120 immunocomprornised pediatric dinical trial parudpants transplant recipients who received CYT@IENE-IV solution in controlled clinical trials, particularly in with serious CMV infections receiving CYTOVENE-lV solution were similar to those reported in adults. patients receiving concomitant administration of nephrotoxic agents such as cyclosporine and ampho- Granulocytopenia (17%) and thtornbocytopenia (10%) were the most common adverse events reported. terion B. Although the spedfic mechanism of this tOXioty, wiach in most cases was reversibI has not Sixteen pediatric patients (8 months to 15 years of age) with life- or sight-threatening CMV infections were been determined, the higher rate of renal impairment in patients receng Cu1’OVENE-/ solution corn- evaluated in an open-label, CYTOVENE4V solution, pharmacokinetics study. Adverse events reported for pared with those who received placebo in the same trials may indicate that CYTOVENE-P/ ptayed a signifi- more than 1 pediatric patient were as follows: hypokalemia (4/16, 25%), abnormal kidney function (3/16, cant role. 19%), sepsis (3/16, 19%), thrombocytopenia (3/16, 19%), leukopenia (2/16, 13%), coagulation disorder LabavatI%y bsthig: Due to the frequency of neutropenia. anemia and thrombocytopenia in pahents receiv’ (2/16, 13%), hypertension (2/16, 13%), pneumonia (2/16, 13%) and immune system disorder (2/16, 13%). ing CYTWENE-IV and CYTOVENE (see AOVERSE EVENTS), it is recommended that complete blood counts There has been very limited dinical wperience using CYIWENE-IV for the treatment of CMV retinitis in and platelet counts be performed frequently especially in pahents in whom gancIcs,ir or other nudeoside patients under the age of 12 years. Two pediatric patients (ages 9 and 5 yearn) showed improvement or sta- analogues have previously resufted in leukopenia or in whom neuttophil counts are less than 1000 cefls/pL blbzation of retinitis for 23 and 9 months, respectively. These pediatric patients received induction treatment at the beginning of treatment. Increased serum creatinine iwls have been observed in trials evaluating with 2.5 mg/kg tat followed by maintenance therapy with 6 to 6.5 mg/kg once per day, 5 to 7 days per both CYTWENE-P/ and CYTOVENE. Patnts should have serum creatinine or creatinine clearance values week. When retinitis progressed dunng once-dady maintenance therapy, both pediatric patients were treated monitored carefully to allow for dosage adjustments In renally impaired patients (see DOSAGE AND with the 5 mg/kg bid regimen. Two other pediatric patients (ages 2.5 and 4 years) who recenied similar ADMINISTRATION in complete product information). induction regimens showed orfy partial or no response to treatment. Another pediatric patient, a 6-year-old 1vg hntactixs: ianosine: At an oral dose of 1000 mg of CYTOVENE every 8 hours and didanosine, with T-ceIl dysfunction, showed stabilization of retinitis for 3 months while receiving continuous infusions 200 mg esery 12 hours, the steady’state didanosine AUC increased flu ± 114% (range: 10% to 493%) of CYTtNENE-IV at doses of 2 to 5 mg/kg/24 hours. Continuous Infusion treatment was discontinued due when didanosine was admiiastered either 2 hours prior to or concurrent with adminIstration of CYIWENE to granulocytopenia. Eleven of the 72 patients in the placebo-controlled trial in bone marrow transplant (n=12 pahents, 23 observations). A decrease in steady-state gancicIir AUC of 21 a 17% (range: -44% redpnts were pediatric patients, ranging in age from 3 to 10 years (5 treated with CY1WENE-F/ and to 5%) was observed when didanoside wes administered 2 hours prior to administration of CY1WENE, 6 wIth placebo). Five of the pediatric patients treated with CnTtNENE-fl/ received 5 mg/kg intravenously bid but ganciclovir AUC was not affected by the presence of didanosine when the two drugs were adminis- for up to 7 days; 4 patients went on to recelve 5 mg/kg qd up to day 100 posttransplant. Results were teed simultaneously (n=12). There were no significant changes in renal clearance for edher drug. When similar to those observed in adult transpiant recipients treated with CYTOVENE-F.f. Two of the 6 placebo- the standard intravenous gancidir induction dose (5 mg/kg infused csier 1 hour every 12 hours) was treated pediatric patients developed CMV pneumonia vs none of the 5 pahents treated with CYT()JENE-F/. coadministered with didanosine at a dose of 200 mg orally every 12 hours, the steady’state dklanosine The spectrum of adverse events in the pediatric group was similar to that observed in the adult patients. AUC0. increased 70 ± 40% (range: 3% to 121%, n=11) and C,.. increased 49 a 48% (range: -28% to CYTOVENE capsules have not been studmd in pediatric pahents under age 13. 125%. In a separate study, when the standard intravenous ganciclovir maintenance dose (5 mg/kg u_ hi Patients with Renal hnsahnnt CYTOVENE-n and CYTOVENE should be used with caution in infused over 1 hour every 24 hours) was coadministered with didanosine at a dose of 200 mg orally every patients with impalred renal function because the half-life and plasma/serum concentrations of gancilovir 12 hours, didanosine AUC increased 50 a 26% (range: 22% to 110%, n=11) and C,,.. increased 36 ± will be increased due to reduced renal clearance (see DOSAGE AND ADMINISTRATION and ADVERSE 36% (range: ‘27% to 94%) over the first dkianosine dosing interval. Didanoslne piasma concentrations EVENTS: Renal Taity). Hemodofysis has been shown to reduce plasma levels of gancidovir by approxi- (AUCI224) were unchanged during the dosing intervals when ganciclovir was not coadministered. mately 50%. Ganciclovir pharmacokinetics were not affected by didanosine. In neither study were there significant changes in the renal dearance of eIther drug. Zwudkw: At an oral dose of 1000 mg of CYIWENE every we hn Elderly Patiits: The pharmacokinetic profiles of CYTOVENEV and CYTOVENE in elderly patients 8 hours, mean steady-state gancicIir AUC decreased 17 a 25% (range: -52% to 23%) in the presence have not been established Since elderly individuals frequently have a reduced glomerular filtration rate, particular attention should be paid to assessing renal function before and during administration of of zidovudine, 100 mg every 4 hours (n=12). Steady-state zidovudine AUC0.4 increased 19 a 27% (range: -11% to 74%) in the presence of ganciclovir. Since both zidovudine and gancidcsiir have the poten- CYFOVENE-lV or CYTOVENE (see DOSN3E AND ADMINISTRATION in complete product information). tial to cause neutropenia and anemia, some patients may not tolerate concomitant therapy with these ADVERSE EVENTS: Adverse events that occurred during clinical trials of CYTOVENE-lV solution and drugs at full dosage. Thvbenedd: At an oral dose of 1000 mg of CYT()JENE every 8 hours (n=10), ganci- CYTOVENE capsules are summanzed below, according to the participating study subject population. CYTOVENPIV (ganctdovir sodium for injection) and CYTOVBIP (ganciclovir capsules) CY1DVENE5-IV(ganciclovir sodium for in(ection) and CYTOVENP (gancidovir capsules) sIe_ withAt?S:Three controlled, randomized, phase 3 trials comparing CYFOVENE-W and CYTOVENE The folkng table shows the frequency of elevated serum creatiolne values in these controlled dh*al ths: capsules for maintenance treatment of CMV retinitis have been completert Dunng these trials, CYTOVENE -_____ w or CYTtNENE capsules were prematurely discontinued in 9% of subjects because of adverse events. In ______Controlled )IaIs - bns Reciplenis a placebo-controlled, randomized, phase 3 trial of CYTOVENE capsules for prevention of CMV disease in cVT0vENE-lv CYTOVENE______Capsules AIDS, treatment was prematurely discontinued because of adverse events, new or worsening intercurrent illness, or laboratory abnormalities in 195% of subcts treated with CYRPJENE capsules and 16% of Heart AILOQrSII Bone Marrow N)OQraIt Bone Marrow MIOQraIt Liver Allograft subjects recaiving placebo. Laboratory data and adverse events reported during the conduct of these ______1CM1496 _____1CM1570 _____1CM1689 Study040 controlled trials are summarized below. Maximum Laboratory Data: Serum CVTOVENE-IV Placebo CYTOVENE-IV COntrOl CY0VENE’IV Placebo CYTOVENE Placebo Creatinine Capsules Selected Laboratory Abnormalities In IlaIs for lteahnent ol CMV Retinitis Levels )s=76) )n=73) )n=20) )n40) )n=37) )n=35) )iwlSO) )n=154) and PreventionolCMV Disease ______Serum CMV Retinitis Treatment* CMV Disease Prevention’ Creatinine Treatment CYNE CYTOVENE 16% 10% CYTOVENE-fl/’ 2.5m/dL 18% 4% 20% 0% 0% 0% sules Capsules rnacebo’ 3mg/day 5mg/kg/day 3000mg/day Serum Subjects, number 320 175 478 234 Creatinine 1.5-<2.5 Neutropenia: mntdl 58% 69% 50% 35% 43% 44% 39% 42% <500ANC/pL 18% 25% 10% 6% 500-<749 17% 14% 16% 7% in 3 out of 4 trials, patients receMng either CYTC)IENE-F/solution or CYTOVENEcapsules had elevated ______750 - < 1000 ______19% ______26% ______22% ______16% serum creatlnlne levels when compared to those recelving placebo. Most patients in these stuches also Anemia: recereed cydospotine. The mechanism of impairment of renal funCtIOn is not known. However. careful Hemoglobin: monltorhn#{231}of renal function dunng therapy with CYTOVENE-fl/ solution or CYTWENE capsules is essen- <6.5g/dL 2% 5% 1% <1% bat especiafly for those patients receMng concomitant agents that may cause nephrotoXicnty. 6.5 - <8.0 10% 16% 5% 3% 6*al: Other adverse events that were thought to be ‘PmbaLY’ or“Possibly’ related to CYTCNENE-F/ ______8.0 - <9.5 ______25% ______26% ______15% ______16% solution or CYTOVENE capsules in controlled clinical studies in either subjects with AIDS or transplant Maximum Serum Creatinine: reapients are listed below. These events all occurred in at least 3 subcts. Body as a Wfr,ie: abdomen 2.5mg/dL 1% 2% 1% 2% enlarged, asthenla. chest pain, edema. headache, tojection site inflammation, malalse, pain; Digest/lw ______1.5-<2.5 ______12% ______14% ______19% ______11% Syste’n: abnormal liver funCtion test, aphthous stomatilis, constipation, dyspepsia, eructatlon; Henic and * Pooled data from Treatment StucheS, 1CM 1653, Study M 1774 and Study A\l 034 melLymphaticdreamsSystem:anxlety,pancytopenia;confureon, depression,Respkatorydiazlness,System: coughdry mouth,increaseInsomniadyspnea;seizures,Ner.uissornnolencSystem: abnor-think- Mean time on therapy = 91 days, induding allowed reroduction treatment periods ing abnormal, trernor Skin and Appendes: alopeda, dry skin; Soeabl Senses: abnormai utsion, taste t Mean time on therapy = 103 days, indudlng allowed reesduction treatment periods tinnitus vitreous clisorcier; *tabois and Mibitional tNscs’ders:creatinine increased, SOOT IData from Prevention Study, KM 1654 . Mean time on ganciclovir = 269 days Increased, SGPT increase weight loss; Cardewascular Syetern: hypertension, ptflebitis, vasodilatation;

I Mean time on placebo = 240 days UWQ8flItaJ SYstem: creatinine dearance decrease kidner failure, kidneY function abnormai, urinarv fre- quency; Musculoskeletal System: arthralgia. leg cramps, myalgia myasthenia. The following adverse (See discussion of dinical trials under INDICATIONS AND USAGE in complete product information.) reportesi in patients receiving gancicicreir may be potentially fatal: gastrointestinal perforation, mul-

Adberse Events: The following table shows selected adverse events reported in 5% or more of the subjects tiple Ot9Wl failur pancreatitis and sepsis. in three controlled dinical trials during treatment with either CYTOVENE-F/solution (5 mg/kg/day) or AdVSIS8 EVntS Reported During Postmarketlng Experience with CYTOVF.NE#{149}IVand CYTOVENE CYTOVENE capsules (3000 mg/day), and in one controlled clinical trial in which CYIWENE capsules Cqostil.s: The following events have been identified during post-approval use of the drug. Because they (3000 mg/day) were compared to placebo for the prevention of CMV disease & niPCWted voluntarily from a population of unknown siz estImates of frequency cannot be made. Selected Adveree Events Reported In 5% at Subjects In Three Randomized Phase 3 Studies for fldUOfl due to either the seriousness, fresiuencY of reporting, the

______CMV? anilCYTOVBin One PhaseCapsulesfor3 RandOmIzedPreventionto CY1I3VBIE-IVofStudyCMVSolutionComparingDiseasefor Mak*enanceCytovene______lapsuIesbalmentto Placelnoni encepinaiopattiy,ntreaction, cholestasisarthritis,Can5alxtothoiveCOflfleCtIOflcongenitalbronchospasm,dermatitis,oranomaly,a combinationcardIacextrapyramidaldry arrest,eyes,of thesedysesthesiacardiacreactionfactors:conductionaclaidysphasia,acidosispalsyabnOrmaidy,alinrUichallucmations,elevatedreaction.cataracts,triglyceridehemOlytiCanaphylacticcholefithia-levels,anne-

Maintenance Treatment mle. hemolytic uremic syndron* hepatic falIur hepatitis, typercaicemla hyPOnatrernla inappropriate Studies Prevention Study serum ADH, infertility intestinat ulceration, lntracranlai hypertension. irrltaillty. toss of memory, loss of Body System Mverse Event Capsus F/ Capsules Piacebo sense of smell, myelopathy, oculomotor nerve paralysis, penpheral ischemia, pulmonary fibrosis, renal (n=326) (n=179) (n=478) (n=234) tubular disorder, rhabdomyolysis, Stevens-Johnson syndron* strok testicular ttypotrophy, Torsades do Pointes, vasculitis, ventricular taChyCardia. Body as a Whole Fever 38% 48% 35% 33% Infection 9% 13% 8% 4% OVERDOS: CYIOV9E-W: Overdosage with CY1WENE-IV has been reported in 17 patients (13 adults and 4 children under 2 years of age). Five patients experienced no adverse events foHng overdosage at Chills 7% 10% 7% 4% the following doses: 7 doses of 11 mg/kg over a 3-clay period (adult) single dose of 3500 mg (adult) Sepsis 4% 15% 3% 2% single dose of 500 mg (72.5 mg/kg) followed by 48 hours of peritcxieai dialysis (4-month-old), singl Digestive System Diarrhea 41% 44% 48% 42% dose of approximately 60 mg/kg followed by exchange transfusion (18-month-old) 2 doses Anoneth 15% 14% 19% 16% Vomiting 13% 13% 14% 11% ______CMVof500 cOlitIsmg insteadafter receivingof 31 mg each#{176}of 2 consecutivein 1 adultdays.with HeAIDSestpeti-and Hemic and Lymphatic Leukopenia 29% 41% 17% 9% enced worsening GI symptoms and acute renal fallure that required short-term thalvsis. Pancytopenia System Anemia 19% 25% 9% 7% developed and persisted until his death from a malignancy several months later. Other adverse events ______Thrombocytopenia ______6% 6% ______3% 1% reported following overdosage induded: persistent bone marrow suppression (1 adult with neutropenia and thrombocytopenia after a single dose of 6000 mg). reversible neutropenia or granulocytopenia Nervous System Neuropathy 8% 9% 21% 15% (4 adults, overdoses ranging from 8 mg/kg daily for 4 days to a single dose of 25 mg/kg), hepatitis Other Sweating 11% 12% 14% 12% (1 adult recaiving 10 mg/kg daily, and one 2 kg Infant after a single 40 mg dose), renal toxicity (1 adult 9% ______Pruritus ______6% 5% ______10% with transient worsetting of hernaturia after a single 500 mg dos and 1 adult with elevated creatinine Catheter Related’ Total Catheter Events 6% 22% (5.2 mg/dL) after a single 5000 to 7000 mg dose), and snizure (1 adult with known senzure disorder after Catheter Infection 4% 9% days of 9 mg/kg). In addition, 1 adult received OA mL (iostead of 01 mL) CYTCNENE-fl/ solution by Catheter Sepsis 1% 8% intravitreal injection, and experienced temporary loss of vision and central retinal artery ocdusion sec- *Some of these events also appear under other cody systems. increased intraocular pressure related tothe incted fluidvolume CYTOtENE Capsules: There ______aret no reports of werdosage with CYTOVENE capsules. Doses as high as 6000 mg/day, given Thefollowing events were frequently deserved in dinical trials but occurred with equal or greater frequen- as 1000 m 6 times daily or as 2000 mg ti did not result in overt tovicity other than transient neu- cv in placebo-treated su*ts: abdominal pan, nausea, flatulenc pneumonia. paresthesia, rash. Rethnd DailY d055 offlOth 6000 mg have not been studled. Since gancidceitr is dialyzable, dialysis Ltachment: Retinal detachment has been observed in subjects with CMV retinitis both before and after be useful in reductng serum concentrations. Adequate hydration shouldbe maintained. The use of initiation of therapy with ganciclovir. Its relationship to therapy with ganciclovir is unknown. Retinal 9l’tth taCt0(’55houldbeconsidered. detachment occurred in 11% of patlents treated with CYTCNENE-(V Solution and in 8% of patients treated HOW SIJPPLIB): C’YlWENE-F/ (ganciclovw sodium for lejection) is supphed to10 mL sterile vlals, each with CYTOVENE capsules. Patients withCMVretinitis should han frequent ophthalmologic evaluateans to containing gancidcwir sodium equivalent to 500 mg ofgancicknii in cartons of25 (NDC0004-6940-03). monitor the status of thair retinitis and to detect any other retinal pathology. vials at temperatures below 40’C (104’9. hnsplant Recipients: There have been three controlled dinical thals of CYTtdENE-F/ solution and one YtNENE (gancidovir capsules) 250 mg are two-piece size No. 1, opaque green hard g&atin cap- controlled clinical trial of CY1WENE capsules for the prevention of CMV disease in transplant recipients. wins CYTOVENE capsules are supplned as follows: Bottles of 180 capsules (NDC 0004-0269-48). Laboratory data and adverse events reported during these trials are summarized below. Labceatory Data: The following table shows the frequency of granulocytopenia (neutropenia) and thrombocytopenia CYTOVENE (gancidovir capsules) 500 mg are two-pieced. size No. 0 elongated. opaque yellow/opaque observed: green bard gelatin capsules. CYTOVENE capsules are supplied as follows: Bottles of 180 capsules (NDC 0004-0278-48). Controlled 1tIaIs-1hans Redpie,ds Store between 5#{176}and 25’C (41’ and 77#{176}F). CYTOVENE-F/ CYTOVENECapsules Heart Aflograft’ Bone Marrow Allograft’ Liver PJlograW CYIWENE-P/ CYffNENE-P/ Control CYTCF/ENE Piacebo Capsules (n=76) (n=73) (n=57) (n-_55) (n=150) (n=154) Neutropenia CYTOVENE-lV for intravenous Infusion manufactured by Parke-Davis, Division of Warner-Lambert Minimum ANC Company, Morris Plalns, NJ 07950 and CYTOVENE Capsules for oral administration manufactured by <500/pL 4% 3% 12% 6% 3% 1% Syntax Puerto Rico, Inc., Humacao, Puerto Rico 00791 for: Minimum ANC 500-1000/pL 3% 8% 29% 17% 3% 2% TOTALANC 1000/pL 7% 11% 41% 23% 6% 3% Thrombocytopenia Pharmaceuticals Ptelet count <25I00/pL 3% 1% 32% 28% 0% 3% Platelet count Roche Laboratories Inc. 25L100-50,000/pL 5% 3% 25% 37% 5% 3% FOTALPiatelet 340 Kingsland Street 5000/pL 8% 4% 57% 65% 5% 6% Nutley, New Jersey 07110-1199 * Study 1CM 1496. Mean duration Ot treatment = 28 days

, Study KM 1570 and KM 1689. Mean duration of treatment = 45 days S Study GANO4O.Mean duration of gancidovir treatment = 82 days (See discussion of dinical trials under INDICATIONS AND USN3E in complete product information.) CY198A Revised: December 1997 is an official educational program of The American Society of Nephrology

‘ailable for nsultation 4 hours a day. Every day.

hen it comes to getting Each UpToDate CD-ROM disk Editor-in-Chief recommendations on patient includes the equivalent of 25,000 pages Burton I). Rose, MD, Harvard Mcdicul School care and treatment, most physicians of essential, up-to-date information, Bone Disease consult a colleague. arranged in an easy-to-access, L. Darryl Quarks Hillel N. Rosen, MD Now you can consult with dozens of convenient way. You receive a new disk Michael Rosenblatt, MI), Harvard Medical School leading experts in your specialty with every four months, which completely Cystic Diseases UpToDate- a revolutionary CD-ROM replaces the old one. William M. Bennett, Mt) University ofOregon Health Sciences Center program that is available to you 24 Diabetic Nephropathy hours a day, every day. Eli A. Friedman, MD, SUNY Health Science Center at Brooklyn

UpToDate answers your clinical Dialysis questions and provides current William L. Henrich, MD, Medical College of Ohio Thomas A. Golper, MD, University ofArkansasfor Medical Sciences information on important new trials, studies and treatment protocols. The Drugs and Drug Interactions D. Craig Brater, MD, University oflndiana School result is that you will make confident of Medicine decisions more quickly and have Fluid and Electrolytes more time for your patients. Burton D. Rose, MD, Harvard Medical School Glomerular Diseases Get updated clinical information Gerald B. Appel. MD Columbia University College ofPhysicians and Surgeons and treatment recommendations Hypertension Unlike medical texts that can be several Norman M. Kaplan, MD, Unirersity ofTexas Southwestern Medical years out of date, or MedLineTM School searches that only provide abstracts, Mineral Metabolism Zalman S. Agus, MD, University ofPennsylvania School of Medicine UpToDate is specifically organized to I,. the only software program of its Pediatric Nephrology answer your clinical questions and kind.” -JAMA Patrick Niaudet, MD, H/pita) Necker, Paris provide recommendations for therapy. Renal Pathology UpToDate is painstakingly UpToDat?, Inc. Helmut C. Rennke, MD, Hars’ard Medical School

researched, written, edited, and 34 Washington Street, Suite 320 Renal Transplantation updated every four months by an Wellesley, MA 02181-1903 USA Mohamed H. Sayegh. MI), Harvard Medical School Charles B. Carpenter. MD, Harvard Medical School internationally recognized expert Toll Free (US & Canada) William M. Bennett, MI), University ()fOrego?1 Health Sciences faculty, who review over 1 30 medical (800) 998-6374 Center journals and texts every month, for the Phone: (781) 237-4788 most important and most relevant Fax: (781 ) 239-0391 studies. E-mail: [email protected]

ZENAPAX#{174}(Daclizumab), S Binds with high affinity to the Tac subunit which is expressed the first humanized IL-2R- on activated but not resting lymphocytes. specific monoclonal antibody, #{149}A unique, bioengineered monoclonal antibody therapy, prevents acute renal allograft 9O%humangGseunces and 10% murine sequences,

rejection as part of an . , , . . . . a . . Inhibits IL-2-mediated activation and proliferation of T cells, immunosuppressive regimen. a critical pathway in the cellular immune response involved in allograft rejection.

WARNING: Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe ZENAPAX#{174}(Daclizumab). The physician responsible for ZENAPAX administration should have complete information requisite for the follow-up of the patient. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources.

Patients on immunosuppressive therapy are at increased risk for developing lymphoproliferative disorders and opportunistic infections and should be monitored accordingly. ZENAPAX is contraindicated in patients with known hypersensitivity to Daclizumab or to any components of this product. Anaphylactoid reactions have not been observed following ZENAPAX administration, but can occur following the administration of proteins. Please see brief summary of product information for ZENAPAXand for CellCept#{174}(mycophenolate mofetil), which include contraindications, warnings, precautions and adverse events, on back pages of this advertisement.

#{176}Data from two randomized, double-blind, multicenter trialS that compared a dose of 1.0 mg/kg of ZENAPAX with placebo when each was administered as part of an immunosuppressive regimen with triple therapy (cyclosporine+ corticosteroids+ AZA) or double therapy (cyclosponne+ corticosteroids).

Copyright © 1998 by Roche Laboratories Inc. Al) rights reserved. ZENAPAX #{149}Significantly reduces acute renal allograft rejection episodes when added to triple increases efficacy and double immunosuppressive protocols.* without an #{149}Associated with signfficantly better paflent survival at 1 year in the double-therapy regimen. increase in serious No significant difference in paflent survival when added to a triple-therapy regimen. side effects. . A retrospective analysis of the combined endpoint of patient survival, graft survival and acute rejection in triple- and double-therapy regimens at 1 year suggests a better outcome for patients receiving ZENAPAX as part of their immunosuppressive regimen. S No increases in lymphomas or overall incidence of infectious episodes were observed. S The most frequently reported adverse events were Gl disorders (eg, consflpaon, nausea, diarrhea, vomiting), which were reported with equal frequency in the ZENAPAX group (67% [226/336]) and placebo group (68% [199/293]). The overall incidence of infectious episodes was not higher in patients treated with ZENAPAX compared with patients receiving placebo. However, cellulitis and wound infections occurred in 8.4% (24/286) of patients treated with ZENAPAX and 4.1 % (11/268) receiving placebo. #{149}Well tolerated with CellCept (mycophenolate mofetil), cyclospone and corticosteroids.

Dadllzumab !ib Immunosuppression wi/i a human touch. Cate

for Infect/al

Before prescribing, please see complete product information, a summary of which follows: ZENAPAX(Daclizumab) Geriatric Use: Clinical studies of ZENAPAX did not include sufficient numbers of subjects WARNING: age 65 and older to determine whether they respond differently from younger subjects. Only physicians experIenced in Immunosuppressive therapy and management of Caution must be used in giving immunosuppressive drugs to elderly patients. organ transplant patients should prescribe ZENAPAX (Dacllzumab). The physician ADVERSEREACTIONS:The safety of ZENAPAX was determined in four clinical studies, responsible for ZENAPAX administration should have complete information three of which were randomized controlled clinical trials, in 629 patients receiving renal requisite for the follow-up of the patient. Patients receiving the drug should be allografts of whom 336 received ZENAPAX and 293 received placebo. All patients received managed in facilities equipped and staffed with adequate laboratory and supportive concomitant cyclosporine and corticosteroids. medical resources. ZENAPAXdidnot appear to alter the pattern, frequency or severity of known major toxici- INDICATION AND USAGE: ZENAPAX is indicated for the prophylaxis of acute organ rejec- ties associated with the use of immunosuppressive drugs. tion in patients receiving renal transplants. It is used as part of an immunosuppressive Adverse events were reported by 95% of the patients in the placebo-treated group and regimen that includes cyclosporine and corticosteroids. 96% of the patients in the ZENAPAX-treated group. The proportion of patients prematurely CONTRAINDICATION: ZENAPAXis contraindicated in patients with known hypersensitivity withdrawn from the combined studies because of adverse events was 8.5% in the place- to Daclizumab or to any Components of this product. bo-treated group and 8.6% in the ZENAPAX-treated group. WARNINGS: See Boxed WARNING. ZENAPAXdid not increase the number of serious adverse events observed compared with placebo. The most frequently reported adverse events were gastrointestinal disorders, ZENAPAX should be administered under qualified medical supervision. Patients should be which were reported with equal frequency in ZENAPAX- (67%) and placebo-treated (68%) informed of the potential benefits of therapy and the risks associated with administration patient groups. of immunosuppressive therapy. The incidence and types of adverse events were similar in both placebo-treated and ZENAPAX- While the incidence of lymphoproliferative disorders and opportunistic infections, in the treated patients. The following adverse events occurred in 5% of ZENAPAX-treated limited clinical trial experience, was no higher in ZENAPAX-treated patients compared with patients. These events included: Gastrointestinal System: constipation, nausea, diarrhea, placebo-treated patients, patients on immunosuppressive therapy are at increased risk for vomiting, abdominal pain, pyrosis, dyspepsia, abdominal distention, epigastric pain not developing lymphoproliferative disorders and opportunistic infections and should be mon- food-related; Metabolic and Nutritional: edema extremities, edema; Central and Peripheral itored accordingly. Nervous System: tremor, headache, dizziness; Urinary System: oliguria, dysuria, renal Anaphylactoid reactions following the administration of ZENAPAX have not been observed tubular necrosis; Body as a Whole - General: post-traumatic pain, chest pain, fever, pain, but can occur following the administration of proteins. Medications for the treatment of fatigue; Autonomic Nervous System: hypertension, hypotension, aggravated hypertension; severe hypersensitivity reactions should, therefore, be available for immediate use. Respiratory System: dyspnea, pulmonary edema, coughing; Skin and Appendages: impaired wound healing without infection, acne; Psychiatric: insomnia; Musculoskeletal PRECAUTIONS: General: It is not known whether ZENAPAX use will have a long-term effect on the ability of the immune system to respond to antigens first encountered during System: musculoskeletal pain, back pain; Heart Rate and Rhythm: tachycardia; Vascular Extracardiac: thrombosis; Platelet, Bleeding and Clotting Disorders: bleeding; Hemic and ZENAPAX-induced immunosuppression. Lymphatic: lymphocele. Re-administration of ZENAPAX after an initial course of therapy has not been studied in The following adverse events occurred in <5% and 2% Of ZENAPAX-treated patients. humans. The potential risks of such re-administration, specifically those associated with These included: Gastrointestinal System: flatulence, gastritis, hemorrhoids; Metabolic and immunosuppression and/or the occurrence of anaphylaxis/anaphylactoid reactions, are Nutritional: fluid overload, diabetes mellitus, dehydration; Urinary System: renal damage, not known. hydronephrosis, urinary tract bleeding, urinary tract disorder, renal insufficiency; Body as Immunogenicity: Low titers of anti-idiotype antibodies to Daclizumab were detected in the a Whole - General: shivering, generalized weakness; Central and Peripheral Nervous ZENAPAX-treated patients with an overall incidence of 8.4%. No antibodies that affected System: urinary retention, leg cramps, prickly sensation; Respiratory System: atelectasis, efficacy, safety, serum Daclizumab levels or any other clinically relevant parameter exam- congestion, pharyngitis, rhinitis, hypoxia, rales, abnormal breath sounds, pleural effusion; ned were detected. Skin and Appendages: pruritus, hirsutism, rash, night sweats, increased sweating; Drug Interactions: The following medications have been administered in clinical trials with Psychiatric: depression, anxiety; Musculoskeletal System: arthralgia, myalgia; Vision: ZENAPAX with no incremental increase in adverse reactions: cyclosporine, mycophenolate vision blurred; Application Site: application site reaction. mofetil, ganciclovir, acyclovir, azathioprine, and corticosteroids. very limited experience Incidence of Malignancies: One year after treatment, the incidence of malignancies was exists with the use of ZENAPAX concomitantly with tacrolimus, muromonab-CD3, antithy- 2.7% in the placebo group compared with 1.5% in the ZENAPAXgroup. Addition of mocyte globulin, and antilymphocyte globulin. ZENAPAX did not increase the number of post-transplant lymphomas, which occurred with In renal allograft recipients treated with ZENAPAX and mycophenolate mofetil, no pharma- a frequency of <1 % in both placebo-treated and ZENAPAX-treated groups. cokinetic interaction between Daclizumab and mycophenolic acid, the active metabolite of Hyperglycemia: No differences in abnormal hematologic or chemical laboratory test mycophenolate mofetil, was observed. results were seen between placebo-treated and ZENAPAX-treated groups with the excep- Carcinogenesis, Mutagenesis and Impairment of Fertility: Long-term studies to evaluate tion of fasting blood glucose. Fasting blood glucose was measured in a small number of the carcinogenic potential of ZENAPAX have not been performed. ZENAPAX was not geno- placebo- and ZENAPAX-treated patients. A total of 16% (10 of 64 patients) of placebo- toxic in the Ames or the V79 chromosomal aberration assays, with or without metabolic treated and 32% (28 of 88 patients) of ZENAPAX-treated patients had high fasting blood activation. The effect of ZENAPAX on fertility is not known, because animal reproduction glucose values. Most of these high values occurred either on the first day post-transplant studies have not been conducted with ZENAPAX (see WARNINGS and ADVERSE REAC- when patients received high doses of corticosteroids or in patients with dtabetes. TIONS). Incidence of Infectious Episodes: The overall incidence of infectious episodes, including Pregnancy: Pregnancy Category C: Animal reproduction studies have not been conducted viral infections, fungal infections, bacteremia and septicemia, and pneumonia, was not with ZENAPAX. Therefore, it is not known whether ZENAPAX can cause fetal harm when higher in ZENAPAX-treated patients than in placebo-treated patients. The types of infec- administered to pregnant women or can affect reproductive capacity. In general, IgG tions reported were similar in both the ZENAPAX-treated and the placebo-treated groups. molecules are known to cross the placental barrier. ZENAPAX should not be used in preg- Cytomegalovirus infection was reported in 16% of the patients in the placebo group and nant women unless the potential benefit justifies the potential risk 10 the fetus. Women of 13% of the patients in the ZENAPAX group. One exception was cellulitis and wound infec- childbearing potential should use effective contraception before beginning ZENAPAX ther- tions, which occurred in 4.1% of placebo-treated and 8.4% of ZENAPAX-treated patients. apy, during therapy, and for 4 months after completion of ZENAPAX therapy. At 1 year post-transplant, 7 placebo patients and only 1 ZENAPAX-treated patient had died of an infection. Nursing Mothers: It is not known whether ZENAPAX is excreted in human milk. Because many drugs are excreted in human milk, including human antibodies, and because of the OVERDOSAGE:There have not been any reports of overdoses with ZENAPAX. A maximum potential for adverse reactions, a decision should be made to discontinue nursing or to tolerated dose has not been determined in patients. A dose of 1.5 mg/kg has been admin- discontinue the drug, taking into account the importance of the drug to the mother. istered to bone marrow transplant recipients without any associated adverse events. Federal (USA) law prohibits dispensing without a prescription. Pediatric Use: No adequate and well-controlled studies have been completed in pediatric CAUTION: patients. The preliminary results of an ongoing safety and pharmacokinetic study (N=25) In pediatric patients (median age: 12 years of age, range: 11 months to 17 years of age; 11 months to 5 years = 7 patients; 6 years to 12 years = 6 patients; 13 years to 17 years = 12 patients) treated with ZENAPAX in addition to standard immunosuppressive agents including mycophenolate mofetil, cyclosporine, tacrolimus, azathioprtne, and cortico- Pharmaceuticals steroids indicate that the most frequently reported adverse events were hypertension (48%), post-operative (post-traumatic) pain (44%), diarrhea (36%), and vomiting (32%). The reported rates of hypertension and dehydration were higher for pediatric patients than for adult patients. It is not known whether the immune response to vaccines, infection, Roche Laboratories Inc. and other antigenic stimuli administered or encountered during ZENAPAX therapy is 340 Kingsland Street impaired or whether such response will remain impaired after ZENAPAX therapy. Nutley, New Jersey 07110-1199 The preliminary pharmacokinetic results from this ongoing study in pediatric patients mdi- cate Daclizumab serum levels (N=6) appear to be somewhat lower in pediatric renal trans- plant patients than in adult transplant patients administered the same dosing regimen. However, Daclizumab levels in these pediatric patients were sufficient to saturate the Tac subunit of the IL-2 receptor on lymphocytes as measured by flow cytometry (N=24). The Issued: December 1997 Tac subunit of the IL-2 receptor was saturated immediately after the first dose of 1.0 mg/kg of Daclizumab and remained saturated for at least the first 3 months post-trans- plant. Saturation of the Tac subunit of the IL-2 receptor was similar to that observed in adult patients receiving the same dose regimen. Printed in U.S.A. 17-090-072-003-078 (mycophenolate mofetil capsules (mycophenolate mofetil capsules CellCept (mycophenolate mofetil tablets CellCepr (mycophenolate mofetil tablets Before prescribing, please see complete product information, a in the AUCof MPA by cholestyramine,cautionshould beused in the tion assay. Mycophenolate mofetil had no effect on fertility of male summary of which follows: concomitant administration of CelICept with dnas that interfere with ratsat oral doses up to 20 mg/k/day. This dose represents 0.1 times enterohepaticrecirculationbecauseof the potentialto reducethe effi- the recommended dinical dose in renal transplant patients and 0.07 CIIC mycophenolate mofetil tablets)capsules) cacy of CelICept (see PRECAUTIONS: Drug Interactions). times the recommended dinical dose in cardiac transplant patients SI, Inlorniatlon hirPatIesls: Patients should be informed of the need for when corrected for BSA. In a female fertility and reproduction study WARNING:Increased susceptibility to infection and the possi- repeated appropriate laboratory tests whitetheyare receheng CeIlCept conducted In rats, oral doses of4.5 mgflg/day caused malformations ble development of lymphoma may result from lmmunosup- Patients should be given complete dosage instructions and informed (principally of the head and eyes) in the first generation offspring in presslon. Only physicians experienced in immunosuppressive of the increased risk of lymphoproliferativediseaseand certain other the absence of maternal toxicity.This dose was 0.02 times the rec- malignancies. Women of childbearingpotentialshould be instructed ommended clinical dose in renal transplant patients and 0.01 times therapy and management of renal or cardiac transplant ofthe potential risks during pregnancy, and that they shoulduseeffec- the recommended dinical dose in cardiac transplant patients when receMug drug patients should use CelICept. Patients the by contraceptionbefore beginningCellCepttherapy, during therapy corrected for BSk No effects on fertlifty or reproductive parameters should be managed In facilities equipped and staffed with and for 6 weeksafter CeIlCepthas been stopped (see WARNINGS and were evident in the dams or in the subsequent generation. adequate laboratory and supportive medical resources. The PRECAUTIONS:Pregnancyt. Category C. In teratology studies in rats and rabbits,fetal physician responsible br maintenance therapy should have Laboratory T.sCompIete blood counts should be performed week- resorplions and malformations occurred in rats at 6 mplcg/day and in complete InformatIon requisite for the follow-up of the patient. ly during the first month, twice monthly for the second and third rabbits at 90 mIkg/day, in the absence of maternaltoxicity.These iev- months oftreatment, then monthly through the first year (see WARN- eta are equivalent to 0.03 to 0.92 times the recommendeddielcal dose CONTRAINOICATIONS: Allergic reactions to Cellcept have been INGS,ADVERSEREACTIONS,and DOSAGE AND ADMINISTRATION). in renal transplant patients and 0.02 to 0.61 times the recommended din- observed; therefore, CeIlCept is contraindicated in patients with a Drug Intaractions: Drug interaction studies with mycophenolate icaldose in cardw; transplant patients on a BSA basis. In a femalefertill- hypersensitivity to mycophenolatemofetil, mycophenolicadd or any mofetil have been conducted with acyclovir, antacids,cholestyramine, ty and reproduction study conducted in rats, oral doses of 4.5 rngflcg/day component ofthe drug product. cyclosporine, ganoclovir, oral contraceptives, and thmethoprim/sul- caused malformations (principally of the head and eyes) in the first gen- WARNINGS(See boxed WARNING): Patients receiving immunosup- famethoxazole. Drug interaction studies have notbeen conducted with eration offspring ie the absence of maternal toalcity. This dose was 0.02 pressive regimens invoMng combinabons of drugs, induding CellCepL other drugs that may be commonly administered to renal or cardiac times the recommended dinical dose in renaltransplant patientsand as partof an immunosuppressn,e regimen are at increed risk of devel- transplant patients. CellCept has not been administeredconcomitant- 0.01times the recommended dinical dose in cardi transplant patients oping lymphomasand other malignancies,particularly of the skin. The ly with azathioprine. A.cLQyjr: Coadministration of mycophenolate when corrected for BSA. There are no adequate and well-controfled risk appears to be related to the intensityand duration of immunosup- mofetil (1 g) and acyclovir (800 mg) to twelve healthy volunteers studies in pregnant women. Celkept should not be used in pregnant pression rather than to the use of any specific agent. Oversuppression resulted in no significant change in MPA AUC and C,,.. However, women unless the potential benefit lustifles the potential risk to the of the immune system can also increasesusceptibilityto infection.As MPAGand acyclovirplasmaAUCs were increased10.6% and 21.9%, fetus. Effective contraception must be used before beginning CeilCept usualfor patients with increased risk for skincancer,exposureto sun- respectively. Because MPAGplasma concentrations are increased in therapy, during therapy and for 6 weeks after CeilCept has been stopped light and UV light should be limited by wearing protective dothing and the presenceof renal Impairment, as are acyclovir concentrations, the (seeWARNINGS, PRECAU11ONS: Infonnation flWPa. usin#{231}a sunscreen with a high protection factor. CelICept has been potential exists for the two drugs to compete for tubular secretion, Mi Atm.v Studies in rats treated with mwphenolate mofetil admtnistered in combination with the following agents in clinicalhi- further increasing the concentrations of both drugs. Antacc with have shown mycophenolic acid to be excretedin milk. ft is not known als: antithymocyte globulin (ATGAM), 0KT3 (Orthoclone OKT 3), MagnesiumandftJuminum HImxides:Absorption ofa single dose of whether this drug Is excreted in human milk. Because many drugs are cyclosporine (Sandimmune, Neoral), and corticosteroids. The effi- mycophenolatemofetil 2 g) was decreased when administered to ten excreted In human milk and because ofthe potential for serious adverse cacy and safety of the use of CeIlcept in combination with other rheumatoid arthritis pat ents also taking Maalox TC(10mL qid). The reactions in nursing Infants from mydophenolate motetil, a decision immunosuppressive agents have not been determined. Lympho- Cmax and AUC.24for MPAwere 33% and 17% lower,respectively,than should be made whether to discontinuenursing or to discontinue the proliferative diseaseor lymphoma developed in approximately 1% of when mycophenolate mofetll was administered alone under fasting dru ,takl lntoaccounttheimportanceofthedrugtothemother. patients receMng CelICept(2 g or 3 g) with other immunosuppressive conditions. CefiCept may beadministered to patients who arealsotak- -Safetyand effectiveness in nedlatric natients have not agents in controlled clinical trials of renal and cardiac transplant ing antacidscontainingmagnesium and aluminum hydroxides;how- beeneStabhshed.Verylirhited phamlacoionetic data ar#{252}vallabiein pedi- patents (see ADVERSE REACTIONS). Adverse effects on fetal devel- ever, it is recommended that CelICept and the antacid not be adminis- atric patients(seeCLINICALPHARMACOLOGY:Phamzacoionedes). opment (including malformations) occurred when pregnant rats and tered simultaneously. Chos,iamine:FoIlowing single-dose adminis- ADVERSE REACTiONS:The principal adverse reactions associated rabbits were dosed during organogenesis. These responses occurred tration of 1.5 g mycophenolate mofetil to twelve healthy volunteers with the administrationof CelICeptinclude diarrhea, leukopenia,sep- at doses lower than those associated with maternal toxicity. and at pretreatedwith4gtidofcholestyraminefor4days,MPAAUC sis and vomiting, and there is evidence of a higherfrequency of car- dosesbelowthe recommendedclinicaldosefor renalor cardiacbans- decreased approximately 40%. This decreaseis consistent with inter- fain types of infections. The incidence of adverse events for CeIlCept plantation.There are no adequateand well-controlledstudies in preg- ruption of enterohepaticrecirculation which may be due to bindingof was determined in three randomized, comparative, double-blind trials rant women. However,as CeIlCept has been shown to have terato- recirculating MPAG with choiestyramine in the intestine. CellCept is in prevention of rejection in renal transplant patients, and in one ran- genic effects in animals, it may cause fetal harm when administered not recommended to be given with cholestyramine or other agents domtred, comparative, double-blind trial in cardiac transplant to a pregnantwoman. Therefore, CeIlCeptshouldnot be used in preg- that may interfere with enterohepatic recirculation. Cydospoilne: patients. Safety data are summarized below for all renal transplant nant women unless the potentialbenefit justifies the potential risk to Cydosporine (Sandlmmune) pharmacokinetics (at doses of 275 to patients in the double-blindpreventionstudies; approximately 53% of the fetus. Women of childbearing potential should have a negative 415mg/day)were unaffected bysingleand muttipiedosesof 1.5g bid these patientshave been treatedfor more than 1 year. Adverse events serum or urine pregnancytest with a sensitivity ofatleast 50 mlu/mL of mycophenolatemofetil in ten stable renal transplant patients. The that were reported In 1O% of patients in either CeIKept treatment within 1 week prior to beginning therapy. It is recommended that mean (±SD)AUC.,2and C,, of dyclosporine after 14days of multi- group are presented belowfor the two aCtive-COntrOlled studies corn- CelICepttherapyshould not be initiatedbythe physicianuntil a report pie doses of mycophenolatemofetil were 3290 (±822) ng’h/mL and bined (USA and Europe/Canada/Australia)arid for the one European of a negativepregnancytest has been obtained. Effectivecontracep- 753 (±161) ng/mL, respectively,comparedto 3245 (±1088) ng.h/mL placebo-controlled study. Becauseof the lower overall reporting of tion must be used before beginning CelICept therapy, during therapy, and 700 (±246) ng/mL respectively,one week before administration events in the Europeanplacebo-controlledstudy,these data were not and for 6 weeks followinq discontinuationof therapy, even where of mycophenolatemofetil. The effect of cydosporine on mycopheno- comlaned with the other two active-controlled prevention trials, but therehas beena historyof infertility,unlessdue to hysterectomy.Two late mofetil pharmacokineticscould not be evaluated in this study; are instead presented separately. reliable forms of contraception must be used simultaneously unless however, plasma concentrations of MPA were similar to that for Adverse Events In Controlled Studies in Prevention of Renal abstinence is the chosen method. If pregnancy does occur during healthy volunteers. &andoloidr: Followingsingle-doseadministration Allograft Refection treatment, the physicianand patient should discussthe desirabilityof to twelve stablerenaltransplant patients,no pharmacokineticinterac- continuing the pregnancy (see PRECAUTIONS: Pregnancy and tion was observedbetween mycophenolate mofetil (1.5 g) and IV gan- USA Study Combined with Europe/Canada/Austraila Shady Information for Patients). In controlledstudiesfor preventionof renal ciclovir(5 mglkg). Mean (±SD) ganciclovirAUC and C,,. (n=1O) were CellCept CeilCept Azathioprine or cardiac reiection, stmdar rates of fatat infedbon/eepsis (<2%) 54.3 (a 19.0) pg.h/mL and 11.5 (±1 .8) pg/mL, respectIvely, after 2gMay 3 occurred in patients receiving CellCept (2 g or 3 g) (see ADVERSE coadministration of the two drugs, compared to 51.0 (±17.0) REACTIONS). Severe neutropenia [absolute neutrophtl count (MC) pg.h/mL and 10.6 (±2.0)pg/mL respectively, after administrationof rt I’ I- <0.5 x 1O’/pL] developed in up to 2.0% of renal transplant patients IV ganciclovir alone. The mean (±50) AUCand C,,. of MPA (n=12 Body as a Whole and up to 2.8% of cardiac transplant patients receiving CellCept (see after coadministrationwere 80.9 (±21.6)pg.h/mL and 27,8 (±13.9 Paln 33.0% 31.2% 322% ADVERSE REACTIONS). Patients receiving CelICept should be moni- pg/mL respectively, compared to valuesof 80.3 (±16.4)pg.h/mL and Abdominal pain 24.7 27.6 23.0 tored for neutropenia (see PRECAUT1ONS:Laborato,y Tests). The 30.9 (a 11.2) pg/mL respectively,after administrationof mycopheno- Fever 21.4 23.3 23.3 development of neutropenia may be related to CellCept itself, con- latemofetilalone. BecauseMPAGplasmaconcentrations are increased Headache 21.1 16.1 21.2 comitant medications, viral infections, or some combination of these in the presenceof renalimpairment, as areganciclovir concentrations, Infection 18.2 20.9 19.9 causes. If neutropenia develops (ANC <1.3 x 10’/pL), dosing with thepotential exists for the two drugs to compete for tubular secretion Sepsis 17.6 19.7 15.6 CellCeptshould be interruptedor the dose reduced,appropriatediag- and thus further increasesin concentrations of bothdrugs may occur. Asthenla 13.7 16.1 19.9 nostic tests performed, and the patient manaqed appropriately (see Oral Contraceptives: Following single-dose administrationto fifteen Chest pain 13.4 13.3 14.7 DOSAGEAND ADMINISTRATION).Neutropenta has been observed healthy women, no pharmacokinetic interaction was observed Backpain 11.6 12.1 14.1 most frequently in the period from 31 to 180 days posttransplant in between mycophenolate mofetil (1 g) and two tablets of Ortho- Hem and Lymohatic patients treated for preventionof renal and cardiac rejection. Patients Novum 7/717 (1 mg norethindroneINETI and 35 pg estradiol ethinyl receiving CeilCept should be Instructed to report immediately any evi- Anemia 25.6 25.8 23.6 IEEI). This single-dose study suggests the lack of a gross pharmaco- Leukopenla 23.2 34.5 24.8 dence of infection,unexpectedbruising, bleedingor any other mani- kineticinteraction,but cannotexcludethe possibilityof changesInthe festation of bone marrow depression. Thrombocytopenla 10.1 8.2 13.2 pharmacokinetics of the oral contraceptive under long-term dosing Hypochromicanemia 7.4 11.5 9.2 PRECAUTIONS: General: Gastrointestinal hemorrhage has been conditionswith CellCept,which might adverselyaffect the efficacy of in Leukocytosis 7.1 10.9 7.4 observed approximately 3% of renal transplant patients and in m ‘ =‘--“=‘- llimethoorinvuffamethoxazole:FoIlowlno sin- 2.8% of cardiac transplant patients treated with CellCept 3 g daily. gle-dose administration of mycophenolate mofetil (1.5 g) to twelve urogenital Gastrointestinal perforations have rarely been observed. Most healthy male volunteers on day 8 of a 10 day course of Bactrim OS Urinarytract infection 37.2 37.0 33.7 patients receivmn#{231}CelICept were also receiving other drugs known to (trimethoprim 160 mg/sulfamethoxazole 800 mg) administered bid, Hematuria 14.0 12.1 11.3 be associated with these complications. Patients with active peptic no effect on the bioavailabul’tty of MPA was observed. The mean (±SD) Kidney tubularnecrosis 6.3 10.0 5.8 ulcer disease were excluded from enrollment in studies with AUCand C,,, of MPA after concomitant administration were 75.2 Cardiovascular mycophenolate mofetil. Because CelICept has been associated with an (a 19.8) pg.h/mL and 34.0 (±6.6) pg/mL respectively, compared to Hypertension 32.4 28.2 32.2 increased incidence of digestive system adverse events, including 79.2 (±27.9)and 34.2 (±10.7), respectively, after administration of infrequent cases of gastrointestinal tract ulceration, hemorrhage, and Metabolic and Nutritional mycophenoiate mofetil alone. Otderlnteiactions:The measured value Peripheral edema 28.6 27.0 28.2 perforation, CelICept should be administered with caution in patients for renal clearance of MPAG inthcates removal occurs by renaltubu- with active serious digestive system disease. Subjects with severe lar secretion as well as glomerular filtration. Consistent with this, Hypercholesteremia 12.8 8.5 11.3 chronic renal impairment (GFR <25 mLlmin/1.73 m) who have coadministration of probenecid,a known inhibitor of tubular secre- received single doses of CeIlCept showed higher plasma MPA and mhosPhatemia 1 tion, with mycophenolatemofetil in monkeys results in a three-fold Hypokalemia 10.1 10.0 8.3 MPAGALJC5 relative to subjects with lesser degrees of renal impair- increase in plasma MPAGAUC anda two-fold increase in plasma MPA ment or normal healthyvolunteers. No dataare availableon the safe- Hyperlialemia 8.9 10.3 16.9 AUC.Thus, other drugs known to undergorenaltubular secretion may Hyperglycemia 8.6 12.4 15.0 ty of long-term exposureto these levels of MPAG. Doses of CelICept compete with MPAG and thereby raise plasma concentrations of greater than 1 g administeredtwice a day to renaltransplant patients MPAGor the other drug under9oing tubular secretion. Drugs that alter D$flve should be avoided and they should be carefully observed (see the gastrointestinalflora may tnteract with mycophenolate mofetil by Diarrhea 31.0 36.1 20.9 CLINICAL PHARMACOLOGY: Pharmacokinetics and DOSAGE AND disrupting enterohepatic recarculation. Interference of MPAG hydroly- Constipation 22.9 18.5 22.4 ADMINISTRATION). No data are available for cardiac transplant sis may lead to lessMPA availablefor absorption. Nausea 19.9 23.6 24.5 patientswith severe chronic renal impairment. CeIlCeptmay be used Caicnasls, Mutag.nes Impalmwnt of F.dllIty In a 104- Dyspepsia 17.6 13.6 13.8 for cardiactransplantpatientswith severechronic renalimpairment if week oral carclnogenicttystudy in mice, mycophenolate mofetil in Vomiting 12.5 13.6 9.2 the potential benefits outweigh the potential risks. In patients with daily doses up to 180 mgilg was not tumongenic. The highest dose Nausea and vomiting 10.4 9.7 10.7 delayed renal graft function posttransplant,mean MPA AUC.,2 was tested was 0.5 times the recommendeddinical dose (2 g/day)in renal Oralmoniliasis 10.1 12.1 11.3 comparable, but MPAGAuC.,2was two- to three-fold higher,com- transplant patients and 0.3 times the recommended clinical dose Respiratory pared to that seen in posttransplant patients without delayed renal (3 g/day) in cardiac transplant patients when corrected for differences Infection 22.0 23.9 19.6 graft function. In the three controlled studies of preventionof renal in body surface area (BSA). In a 104-week oral carcinogenicity study Dyspnea 15.5 17.3 16.6 reiection, there were 298 of 1483 patients (20%) with delayed graft in rats, mycophenolate mofetil in daily doses upto 15 mg/lg was not Cough increased 15.5 13.3 15.0 function. Althou9h patients with delayed graft function have a higher tumorigenic. The highest dose was 0.08 times the recommendeddin- Pharyngitis 9.5 11.2 8.0 incidence of certatn adverse events (anemia, thrombocytopenia, ical dose in renal transplant patients and 0.05 times the recommend- SIdn and Appendages hyperkalemia) than patients without delayed graft function, these ed clinical dose in cardiac transplant patients when corrected for events were not morefrequent in patients recewing CellCeptthan a- Acne 10.1 9.7 6.4 BSA. While these animal doses were lower than those given to Rash 7.7 6.4 10.4 thioprine or placebo. No dose adiustment is recommended for these patients, they were maximal in those species and were considered patients;however, they should be carefully observed (see CLINICAL adequateto evaluatethe potentialfor human risk (see WARNINGS). Nervous System PHARMACOLOGY:Pharmacokineticsand DOSAGE AND ADMINIS- Mycophenolate mofetil was not genotoxic, with or without metabolic Tremor 11.0 11.8 12.3 TRATION). It is recommendedthat CeIlCeptnot be administeredcon- activation, in several assays: the bacterial mutation assay, the yeast Insomnia 8.9 11.8 10.4 comitantly with azathioprmne because such concomitant administra- mitotic gene conversion assay, the mouse micronudeus aberration Dizziness 5.7 11.2 11.0 hon has not been studiedclinically.In view of the significantreduction assay,or the Chinesehamster ovary cell (CHO) chromosomalaberra- (continued) (mycophenolate mofetil capsules (mycophenolate mofetil capsules Ce I ep (mycophenolate(mycophenolatemofetilmofetilcapsulestablets e ept’ (mycophenolate mofetil tablets Ce ept (mycophenolate mofetil tablets Adverse Events In the Controlled Study In PreventIon of Renal Adverse Events in the Controlled Study In PreventIon of Cardiac Opportunistic Infections In Prevention of Cardiac Rejection Trial Aliograft Rejection (continued) Allograft Rejection (continued) CellCept Azathloprine Europe Study CeliCept Azathioprine 1.5 to1g/day CeliCept CelICept Placebo 1 .5 tog/day Herpes simplex 20.8% 14.5% Nervous System Body as a Whole CMV Tremor 24.2 23.9 viremia/syndrome 12.1 10.0 Sepsis 21.8% 17.5% 13.9% Insomnia 40.8 37.7 tissue invasive disease 11.4 8.7 Infection 12.7 15.6 13.3 Dizziness 28.7 27.7 CMV infection 2.8 2.8 Abdominal pain 12.1 11.9 11.4 Anxiety 28.4 23.9 CMV urine 2.4 2.8 Hemic and Lymphatic Paresthesia 20.8 18.0 CMV nasal secretions 0.3 0.0 Leukopenia 11.5 16.3 4.2 Hypertonia 15.6 14.5 CMV saliva 0.3 0.0 Urogenital Depression 15.6 12.5 Herpes zoster 10.7 5.9 Urinary tract infection 45.5 44.4 37.3 Agitation 13.1 12.8 Herpeszoster cutaneousdisease 10.0 5.5 Urinary tract disorder 6.7 10.6 4.2 Somnolence 11.1 10.4 Herpes zoster visceral disease 0.7 0.3 Cardiovascular Confusion 13.5 7.6 Nervousness 11.4 9.0 Candida 18.7 17.6 Hypertension 17.6 16.9 19.3 Musculoskeletal System mucocutaneous 18.0 17.3 urinary tract infection 0.7 1.0 Leg Cramps 16.6 15.6 fungemia/disseminateddisease 0.7 0.3 Diarrhea 16.4 18.8 13.9 Myasthensa 12.5 9.7 Resoiratory invasivetissue disease 0.0 0.3 Myalgia 12.5 9.3 Cryptococcosis 0.7 0.3 Infection 15.8 13.1 9.0 Soecta Senses Aspergillus/Mucor 2.1 2.1 Bronchitis 8.5 11.9 8.4 Amblyopia 14.9 6.6 Asper9illus pulmonary or 0.7 1.4 Pneumonia 3.6 10.6 10.8 Endocrine System 12.1 12.8 sinus invasive In the randomized, double-blind, comparative trial in cardiac trans- The above data demonstrate that in three controlled trials for pre- Aspergillusdisseminatedor 0.3 1.0 plant recipients, approximately 65% of patients have been treated for vention of renal rejection, patients receiving 2 g/day of CelICept had metastatic more than 1 year.Adverse events reported in 10% of patients in the Aspergillus cutaneous 0.7 0.0 group treated with CelICepI are provided below. an overall better safety profile than did patients receiving 3 g/day of CellCept. Sepsis, which was generally CMV viremia, was slightly Aspergillussputum 0.3 0.3 Adverse Events In the Controlled Study In Prevention of Cardiac more common in those renal patients treated with CellCept, with an Pneumocystis carinii 0.0 1.7 Listeriosis 0.0 0.7 Allograft Rejection incidence of 18 to 22%, compared to 16% in patients receiving aza- CeilCept Azathioprlne thioprine and 14% in patients receiving placebo. In the controlled In controlled studies for prevention of renal or cardiac rejection, sim- 3 g/day 1.5 cardiac transplant study, there was no difference in the incidence of ilar rates of fatal infection/sepsis (<2%) occurred in patients receiving ffie289) sepsis (18.7%) between patients treated with CellCept and control CellCept (2 9or 3 g) (see WARNINGS). In cardiac transplant patients, Body as a Whole patients. In the digestive system, diarrhea was increased in renal the overall incidence of opportunistic infections was approximately Pain 75.8% 74.7% and cardiac patients receiving CeIlCept, with an incidence of up to 10% higher in patients treated with CellCeptthan in those receiving azathioprine, but this difference was not associated with excess mor- Abdominal pain 33.9 33.2 36%, compared to 21% for patients receiving azathioprine and Fever 47.4 46.4 14% for patients receiving placebo in the renal transplant studies. tality due to infection/sepsis among patients treated with CelICept. The Headache 54.3 51.9 In the controlled cardiac transplant study, an incidence of diarrhea following adverse events, not mentioned In any of the tables above, Infection 25.6 19.4 up to 45.3% In the patients treated with CeIlCeptwas reported com- were reported with 3% Incidencein both renal and cardiac transplant Sepsis 18.7 18.7 pared to 34.3% for patients receiving azathioprine. The types of patients treated with CeIlCept, in combination with cyclosporine and Asthenia 43.3 36.3 adverse events in the cardiac transplant patients studied in the mul- corticosteroids: Bovas a Whole:abdomen enlarged, chills occurring with fever, cyst, face edema, flu syndrome, hemorrhage, peMc pain, Chest pain 26.3 26.0 ticenter controlled trial were qualitatively similar to those observed Back pain 34.6 28.4 in renal transplant patients. The incidence of malignancies among malaise; Uroqenitai: dysuria, impotence, urinary frequency; jjg Accidental injury 19.0 14.9 the 1483 patients treated in controlled trials for the prevention of xsgcangina pectoris, atrial fibrillation, palpitation, peripheral vas- cular disorder, postural hypotension; MetuboIa and Nutritionai: alka- Chills 11.4 11.4 renal allograft reiection who were followed for 1 year was similar line phosphatase increased, dehydration, hypervolemia, hypocalce- Hemic and Lvmohatic to the incidence reported in the literature for renal allograft recipi- ents. Lymphoproliferative disease or lymphoma developed in mia, hypoglycemia, hypoproteinemia; DJ,gs.b: anorexia, esophagi- Anemia 42.9 43.9 approximately 1% of patients receiving CelICept (2 g or 3 q) with tis, gastritis, gastroententis, gingivitis, gum hyperplasia, infection, Leukopenia 30.4 39.1 other immunosuppressive agents in controlled clinical trials of liver function tests abnormal, rectal disorder; Respiratory.- lung Thrombocytopenla 23.5 27.0 renal and cardiac transplant patients (see WARNINGS). The follow- edema; Skin andAppendages:fungal dermatitis, pruritus, skin benign Hypochromic anemia 24.6 23.5 ing table summarizes the incidence of malignancies observed in the neoplasm, skin hypertrophy, skin ulcer, sweating; Endocrine: diabetes Leukocytosis 40.5 35.6 controlled renal and cardiac trials. mellitus; Musculoskeietal: arthralgia, ioint disorder; Special Senses: Ecchymosis 16.6 8.0 conjunctivitis. The following adverse events, not mentioned in any of Urogenital Malignancies Observed In Renal and Cardiac ltansplant Trials the tables above were reported with 3% incidence in renal transplant patients only treated with CeIlCept, in combination with other Urinary tract infection 13.1 11.8 8Udale Kidney function abnormal 21.8 26.3 ___ immunosuppressiveagents: Body as a Whole:accidental injury, her- cuIIct cuilcipi Placahe Azathkapdns CuilCept*zathic#{216}ee Oliguria 14.2 12.8 nia; !‘Iemic and Lymphatic: ecchymosls, polycythemia; Urogenital: 2geiay 3May lle2mglk#{216}syor3#{216}ay ISle Cardiovascular albuminuria, hydronephrosis, pain, pyelonephritis, urinary tract disor- lOOtoISOnagMay 3mMcWday der; Cardiovascular.’ cardiovasculardisorder, hypotension, tachycar- Hypertension 77.5 72.3 t. St Hypotension 32.5 36.0 dia, thrombosis, vasodilatation; Metabolic and Nutritional: acidosis, Cardiovasculardisorder 25.6 24.2 LymPhOma/ 0.6% 1.0% 0.0% 0.3% 0.7% 2,1% creatinine increased, gamma glutamyl transpeptidase increased, mphoproftt- hypercalcemia, hyperiipemia, hyperuricemia, lactic dehydrogenase Tacttycardia 20.1 18.0 eretive su increased,SGOT increased,SGPT increased,weight 9am; Qjg,afLy,: Arrhythmia 19.0 18.7 Bradycardia 17.3 17.3 Non-melanoma 4.0 1.6 0.0 2.4 4.2 2.8 flatulence, gastrointestinal hemorrhage, gastrointestinal moniliasis, hepatitis, ileus, mouth ulceration; Respiratory: asthma, lung disorder, Pericardial effusion 15.9 13.5 skin carcinoma pleural effusion, rhinitis, sinusitis; SkinandApoendages:alopecia, hir- Heartfailure 11.8 8.7 Othermalignancy0.8 1.4 1.8 1.8 2.1 2.1 sutism, rash, skin disorder- fjy,p.j: anxiety, depression, hypertonia, Metabolic and Nutritional Up to 2.0% of patients receiving CelICept 3 g daily for prevention of paresthesia, somnolence; Endocrine: parathyroid disorder’ Muazido Peripheral edema 64.0 53.3 renal rejection developed severe neutropenia [absolute neutrophil &af[-Ieg cramps, myalgia, myasthenia; Special Senses: amblyopia, Hypercholesteremia 41.2 38.4 count (ANC) <0.5 x 10’/pLl. Up to 2.8% of cardiac transplant cataract (not specified). The following adverse events, not mentioned Edema 26.6 25.6 patients receiving CelICept 3 g daily developed severe neutropenia in any of the tables above, were reported with 3% incidence in car- Hypokalemia 31.8 25.6 (see WARNINGS, PRECAUTIONS: Laboratory Tests and DOSAGE diac transplant patients only treated with CeIlCept, in combination with Hyperkalemia 14.5 19.7 AND ADMINISTRATION). The following tables show the incidence other immunosuppressive agents: Body as a Whole: neck pain, cel- Hyperglycemia 46.7 52.6 of opportunistic infections that occurred in the renal and cardiac lulitis; Hemic and Lymphatic: prothrombin increased, thromboplastin Creatinine increased 39.4 36.0 transplant populations in the controlled prevention trials: decreased, petechia; Urogenital: nocturia, kidney failure, urine abnor- BUN increased 34.6 32.5 mality, hematuria, urinary incontinence, prostatic disorder, urinary Lactic dehydrogenase Opportunistic Infections In Prevention of Renal Reiectlon Trials retention; Cardiovascular ventricular extrasystole, congestive heart increased 23.2 17.0 USA Study Combined wIth Eumpe/Canada/Austraiia Study failure, supraventricular tachycardia, ventricular tachycardia, atrial Bilirubinemia 18.0 21.8 flutter, pulmonary hypertension, heart arrest, venous pressure Hypervolemia 16.6 22.8 CeliCept CellCept Azathloprine increased,syncope,supraventricularextrasystoles,extrasystoles,pal- Generalizededema 18.0 20.1 2glday 3g/day lto2mg/kg/dayor br, vasospasm;MetabodeandNutritionai’hypoxia, hypophosphatemia, Hyperuricemia 16.3 17.6 100 to 150 mg/day gout, abnormal healing, alkalosis, weight loss, hypochloremia,thirst, SGOT increased 17.3 15.6 t-=t ftts3m Oisz1 respiratory acidosis; Qjg.,afjy.: gastrointestinal disorder, melena, liver Hypomagnesemia 18.3 12.8 Herpes simplex 16.7% 20.0% 19.0% damage, dysphagia, iaundice,stomatitis;Respi,atory.atelectasis, hic- Acidosis 14.2 16.6 cup, pneumothorax, sputum increased, respiratory disorder, epis- Weightgain 15.6 15.2 CMV taxis, apnea, voice alteration, pain, hemoptysis, neoplasm; fiigo,,od SGPT Increased 15.6 12.5 viremia/syndrome 13.4 12.4 13.8 Appendages: hemorrhage, skin carcinoma; /jjy,gj: emotional labili- Hyponatremia 11.4 11.8 tissue invasivedisease 8.3 11.5 6.1 ty, neuropathy, convulsion, hallucinations, thinking abnormal, vertigo; Hyperilpemia 10.7 9.3 Herpes zoster 6.0 7.6 5.8 Endocrine: Cushing’s syndrome, hypothyroidism; Special Senses:ear Candida pain, deafness, ear disorder, tinnitus, abnormal vision, lacrimation Diarrhea 45.3 34.3 disorder, eye hemorrhage. Constipation 41.2 37.7 fungemia/disseminated 0.6 0.6 0.3 Postmarkating ExperIence:Qjg,s,t/y,: colitis (sometimes caused by Nausea 54.0 54.3 tissue invasive disease 0.6 0.6 0.3 cytomegalovirus), pancreatitis; Resistance Mechanism Disorders: Dyspepsia 18.7 19.4 Aspergillus/Mucor 0.3 0.9 0.3 Serious life-threatening infections such as meningitis and infectious Vomiting 33.9 28.4 endocarditis have been reported occasionally and there is evidence Nausea and vomiting 11.1 7.6 invasive disease of a higher frequency of certain types of senous infections such as Oral moniliasis 11.4 11.8 Pneumocystis carinii 0.3 0.0 1.2 tuberculosis and atypical mycobacterial infection. Flatulence 13.8 15.6 Europe Study CAUTION:Federal (USA) law prohibits dispensing without a pre- Respiratory scription. CeliCept CeilCept Placebo Infection 37.0 35.3 Manufactured by Syntex Puerto Rico, Inc., Humacao, Puerto Rico Dyspnea 36.7 36.3 00791 for: Cough increased 31.1 25.6 Pharyngitis 18.3 13.5 Herpes simplex 15.2% 12.5% 6.0% Lung disorder 30.1 29.1 CMV Sinusitis 26.0 19.0 viremia/syndrome 15.2 15.0 13:3 Pharmaceuticals Rhinitis 19.0 15.6 tissue invasive disease 3.6 7.5 Pleural effusion 17.0 13.8 Asthma 11.1 11.4 Herpes zoster 6.7 6.9 2.4 Pneumonia 10.7 10.4 Candida Roche Laboratories Inc. Skin and Appendages fungemia/disseminated 0.0 0.6 0.0 340 Kingsland Street Acne 12.1 9.3 tissue invasive disease 0.0 0.6 0.0 Nutley. New Jersey 07110-1199 Rash 22.1 18.0 Skindisorder 12.5 8.7 Pneumocystis carinli 0.0 0.0 2.4 February 1998 (continued) Reduce the Pressure of Hypertension

, Effective as monotherapy’

, Effective in combination with other antihypertensive agents1’2

Well Tolerated

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

V 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. TERI4ZOSIN HCI Call: 1MN ex. for moreinformation. Re uce t e Pressure

References: Pleaseseeadlacentpagefor briefsummaryof prescribinginformation. 1. HYTRINpackageinsert, Abboff Laboratories. 2. Luther RR,GlassmanNH, JordanDC,Sperzal WD. Efficoqr of terazosin as an antihypertensive agent. Am iMed. 1986;80(suppl 5B):73-76. El Abbott Laboratories Inc.

North Chicago, IL 60064

©1997,Abboit Laboratories Inc. December Printed in U.S.A. BRIEFSUMMARY Drug Interactions: tn controlled trials, terazosin has been added terazosin, as monotherapy or in combination with other antihy- CONSULTPACKAGEINSERTFOR FULL PRESCRIBING to diuretics, and several beta-adrenergic blockers; no unex- pertensive agents, at doses ranging from to 40 mg. INFORMATiON pected interactions were observed. Terazosin ha.s also been used Adverse experiences in these trials where the prevalence rate HYTRIN#{174}(terazosin hydrochloridel Capsules in patients on a variety of concomitant therapies: while these in the lerazosin group was at least 5c, 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 INDICATiONSAND USAGE:HYTRIN is indicated for the treat- observed. Terazosin has been used concomitantly in at least prevalence rate for the placebo group, or where the reaction is of ment of hypertension. Ii can be used alone or in combination 50 patients on the following drugs or drug classes: I) anal- with other antihypertensive agents such as diuretics or beta- particular interest are (TERAZOSIN In=859I - PLACEBO gesic/anti-inflammatory (e.g., acetaminophen, aspirin, codeine, adrenergic blocking agents. ln=506D: asthenia (I l.3% - 4.3%), back pain (2.4’F - 1.2%), ibuprofen, indomethacin); 2) antibiotics (e.g., erythromycin, headache (16.2% - 15.8%), palpitations (4.3% - 1.2%), postural in CONTRAINDICAT1ONS:HYTRIN capsules are contraindicated trimethoprim and sulfamethoxazole); 3) anticholinergic/sympa- hypotension (t.3’/c - 0.4%). lachycardia (1.9% - 1.2%), nausea patients known to be hypersensitive to terazosin hydrochloride. thomimetics (e.g., phenylephrine hydrochloride, phenyl- (4.4% - 1.4%), edema (0.9% - 0.6%), peripheral edema (5.5% WARNINGS: Syncope and “First-dose” Effect: HYTRIN propanolamine hydrochloride, psuedoephedrine hydrochloride): 2.4%), weight gain (0.5’k - 0.2%). pain-extremities (3.5% - capsules, like other alpha.adrenergic blocking agents, can 4) antigout (e.g., allopunnol): 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%), turai hypotension, and syncope in association with the first hydrochlorothiazide, methyclothiazide, propranolol); 7) corti- paresthesia (2.9% - I .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%l, 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). l.4%(, blurred vision 11.6% - 0.0%), and impotence (1.2% - then restarted. Syncope has also been reported with other Use with Other Drugs: tn a study (n=24) where terazosin and 1.4%). Asthenia includes weakness, tiredness, lassitude. and aipha-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. AUC.24 increased 11% 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 com- postural hypotensive effect, although occasionally the synco. sled increases in Cma. (25%) and Cm,, (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 tachycardia 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 terazosin plus captopril (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: Both 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- mendatlons in the Dosage and Administration section and vascular System: arrhythmia. vasodilation: Digestive System: zosin was devoid of mutagenic potential when evaluated in rico additional antihypertensive agents should be added with constipation. diarrhea. dry mouth, dyspepsia. flatulence, vomit- and in vitro (the Ames test, in s’is’o cytogenetics, the dominant caution. The patient should be cautioned to avoid situations, ing: Metabolic/Nutritional Disorders: gout: Musculoskeletal lethal test in mice, in s’is’o Chinese hamster chromosome aberra- such as driving or hazardous tasks, where injury could System: arthralgia, arthritis, joint disorder. myalgia: Nervous tion test and V79 forward mutation assay). result should syncope occur during initiation of therapy. System: anxiety, insomnia: Respiratory Ss’stem: bronchitis, cold Terazosin, administered in the feed to rats at doses of 8, 40, In early investigational studies. where increasing single doses symptoms. epistaxis. flu symptoms, increased cough. pharyngi- and 250 mg/kg/day (70, 350, and 2100 mgfM/day). for two up to 7.5 mg were given at 3 day intervals. 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- cia! Senses: abnormal vision, conjunctivitis. tinnitus: 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 lerazosin at doses of reported in postmenopausal women, urinary tract infection. mended human dose of 20 mg (12 mgIM2). 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 adnsinis- dose: in addition, severe orthostatic hypotension (blood pressure patients may develop allergic reactions, including anaphylaxis, 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. Thete have 32 mg/kg/day (I 10 mg/M2: 9 times the maximum recommended tachycardia, 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 carcinogenicity In three placebo-controlled BPH studies, the incidence of pos- sity but sometimes were serious enough to interrupt treatment. assay, of increased total tumor incidence in either species. and lural hypotension in the terazosin treated patients was 5.1%, The adverse reactions that were most 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 event. Numerous other diverse pharmaceuti- In multiple dose clinical trials involving nearly 2000 hyper- 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 In=8591 - 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. (1.3% - 1.0%), palpitations (1.4% - 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 0.0%), nausea (0.8% - 0.0%), peripheral edema (0.6% - 0.0%), recumbent position and treated supportively as necessary. female rats were administered oral doses of 8, 30 and There is evidence that the orthostatic effect of terazosin 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) 0.0%). and blurred vision (0.6% - 0.0% 1. the events is greatest during the initial seven days of treat- and five of 19 male rats given 120 mg/kg (960 mgfM2: 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) lerazosin 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 terazosin 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 DOSAGEAND ADMINISTRATiON:If HYTRIN administration is prostate and BPH cause many of the same symptoms. These two rats exposed to 8 mg/kg/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 the dose interval rule out the presence of carcinoma of the prostate. ommended human dose) for three months but not after one year (l2 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 to mended human dose). This lesion has also been seen with Mini- orthostatic effect of terazosin (see Warnings), other symptoms of its administration: pressa, another (marketed) selective-alpha-l blocking agent. lowered blood pressure, such as dizziness. lightheadedness and Initial Dose: I mg at bedtime is the starting dose for all palpitations, were more common and occurred in some 28% of Pregnanc,v: 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, zosm 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 at 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 resorptions 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 to 5 mg administered once a day: fetal resorptions, decreased fetal weight and an increased num- Information Jr Patients (see Patient Package Insert): Patients however, some patients may benefit from doses as high as tier of supernumerary ribs were observed in offspring of rabbits should be made aware of the possibility of syncopal and orthosta- 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 dosed with 60 times the maximum recommended human dose. These findings (in both species) were most likely secondary to ther blood pressure effect and doses over 40 mg have not been 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 studies in pregnant women and the safety of lerazosin in preg- dosing interval to be sure control is maintained throughout the is resumed. They should be cautioned to avoid situations where interval. It may also be helpful to measure blood pressure injury could result should syncope occur during initiation of tera- 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 tial risk to the mother and fetus. responses are similar, and to evaluate symptoms such as dizzi- down when symptoms of lowered blood pressure occur, although ness or palpitations which can result from excessive hypotensive Nonteratogenic effects: In a peri- and post-natal development these symptoms are not always orthostatic, and to be careful when response. If response is substantially diminished at 24 hours an rising from a sitting or lying position. If dizziness, lightheaded- study in rats. significantly more pups died in the group dosed with 120 mg/kg/day (> 75 times the maximum recommended increased dose or use of a twice daily regimen can be consid- ness, or palpitations are bothersome they should be reported to the ered. If terazosin administration is discontinued for several human dose) than in the control group during the three-week physician, so that dose adjustment can be considered. days or longer, therapy should be reinstituted using the mi. postpartum period. 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 to a nursing woman. HYTRIN is administered concomitantly with other antihyper- result of treatment with HYTRIN and other similar medications. tensive agents. especially the calcium channel blocker vera- Patients should know that this reaction to H’s’TRIN is extremely Pediatric Use: Safety and effectiveness in children have not pamil, to avoid the possibility of developing significant rare, but that if it is not brought to immediate attention, it medical been determined. hypotension. When using HYTRIN and other antihypertensive can lead to permanent erectile dysfunction (impotence). ADVERSE REACTIONS agents concomitantly, dosage reduction and retitration of either L,aborators Tests: Small but statistically significant decreases in Hypertension: The prevalence of adverse reactions has been agent may be necessary (see Precautions). hematocrit, hemoglobin, white blood cells, total protein and ascertained from clinical trials conducted primarily in the Ref. 03-4655-R3-Revised: October, 1996-HYP albumin were observed in controlled clinical trials. These latin- 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 a ABBOTTLABORATORIES 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. 3Otfi Innua(!7v1eeting andExposition

Wovember 2-5, 1997 #{149}SanYtntonio, Texas

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El i Presidential Address, R. Luke I Belding H. Scribner r::i I 5 Young Investigator Award and Address: The Role of Award, K. No/ph; Introduced by Z. Twardowski I Protein and Personal Interactions in the Growth of State-of-the-Art Lecture: Carcinogenesis and the an Investigator, B. Margolis; Introduced by Kidney, C. Walker (2 Tapes) R.. Wiggins I Homer W. Smith Award and Address: r::i 2 Technology Update: Hemodialysis, S. Schwab; A Journey from Basic Science to Bartter’s J_ Bosch; R. Ward (2 Tapes) Syndrome, S. Hebert; Introduced by T Andreoli r:i Literature Update: Hypertension, N. Kaplan; (1 Tape) S. Textor; R. Toto (2 Tapes) r::i 16 Improving Hemodialysis: The Financial Impact, r::i IGA Nephropathy and Henoch Sch#{246}enlein Purpura: W. Owen; A. Besarab; C. Charytan; J. Roberts; An Update, W. Couser; R. Falk; J. Grande; R. Hogg J. Wish (2 Tapes) (2 Tapes) r:i i Organ Transplantation: Complications Seen in the r::i Cancer Related Acute Renal Failure, K. Badr; Intensive Care Unit, W. Bennett; A. de Mattos; C. Flombaum; J. Lindberg; R. Rieselbach; R. Zager T. Gonwa; A. Olyaei; S. Tomlanovich (2 Tapes) (2 Tapes) :: i 8 Literature Update: Kidney Stones, F. Coe; .1. Asplin; r: 6 John P. Peters Award, R. Schrier; Introduced by S. Bartosh; .1. Lindberg; S. Scheinman (2 Tapes) T. Ben I Symposium: Living Unrelated Donor r::i 19 Basic Science for Clinical Nephrologists:

Transplantation Progress and Potential, Fibrogenesis - The Biology and Pathogenesis of R. Luke; R. Wiggins; P. Terasaki; J. Childress; Glomerular and Interstitial Fibrosis, E. Neilson; J. Curtis (2 Tapes) W. Border; N. Noble; F. Zivadeh (2 Tapes) r::i Hemodialysis Catheters: Hate Living with Them; r:i 20 The Nephrology Quiz, R. Glassock; W. Henrich; Can’t Live without Them, G. Beathard; T. Depner; R. Narins; B. Rose (2 Tapes) C. Kirkland; S. Trerotola (2 Tapes) t:i 2 1 The Disruptive Dialysis Patient: Management t:i 8 The Role of the Renal Transplant Biopsy in Clinical Strategies, J. Lazurus; J. Bower; J. Ojeda; C. Price Management, R. Colvin; P. Randhawa; R. Sible)’; (2 Tapes) K. Solez; W. Williams (2 Tapes) r:i . 22 Management of Advancing Non-Diabetic Renal r:i Pregnancy and the Kidney: An Update, P. August; Failure, R. Schrier; J. Breyer; A. Chapman, W. Mitch S. Hou; P. Jungers; M. Lindheimer (2 Tapes) (2 Tapes) r::i 10 Gastrointestinal Disorders: Associated Fluid- ::i 23 The Renal Biopsy: Interpretation and Clinical Electrolyte and Acid Base Derangements, D. BatIle; Application, A. Fogo; C. Alpers; A. Cohen; V. D ‘Agati; F. Dumler; J. Herrin (2 Tapes) J. Jennette; S. Korbet; H. Rennke (2 Tapes) r:i 1 Calcium Channel Blockers: Their Role in r::i 24 State-of-the-Art Lecture: Hepatitis C Virus and the Cardiovascular and Renal Medicine, R. Gifford; Nephrologist, W. Suki; B. Pereira (1 Tape) G. Bakris; J. Cohn; D. Siscovick (2 Tapes) r::i i 2 HIV Nephropathy: Aspects of Management, P. Klotman; G. Appel; G. Burns; M. Klotman; T. Rao; J. Winston (2 Tapes) r::i 13 Technology Update: Peritoneal Dialysis, K. Nolph; qqr P. Blake; J. Burkart; 1 Golper; C. Thompson (2 Tapes) r::i 14 Acid-Base Disorders & Hypernatremia: “Where #{231}Foq1J#{231}QScELWTI0WSd:45((D Molecular Biology Meets Clinical Medicine”, M. Halperin; S. Gluck; 0. Moe (2 Tapes) oqclYEqFOVvt 30th Ytnnua(I7t4eeting andExposition J’fovem6er 2-5, 1997 #{149}SanYintonlo, ‘Texas

Presidential Address, R. Luke I i:i i 5 Young Investigator Award and Belding H. Scribner Award, Address: The Role of Protein and K. Noiph; Introduced by Personal Interactions in the Growth z. Twardowski I State-of-the-Art of an Investigator, B. Margolis, Lecture: Carcinogenesis and the Introduced by R. Wiggins I Homer Kidney, C. Walker ($37.50) w. Smith Award and Address: A r:i 6 John P. Peters Award, R. Schrier; Journey from Basic Science to Introduced by T. Berl I Symposium: Bartter’s Syndrome, S. Hebert; Living Unrelated Donor Introduced by T. Andreoli ($37.50)

Transplantation - Progress and i::i 24 State-of-the-Art Lecture: Potential, R. Luke; R. Wiggins; P. Hepatitis C Virus and the

. Terasaki; J. Childress; J. Curtis Nephrologist, W. Suki; B. Pereira ($37.50) ($24.95)

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Criteria: (1) Applicants must be active ASN members who have submitted an NIH grant proposal in the field of nephrology that was favor- ably reviewed and close to the funding range, but did not receive support; (2) Applicants shall not have other substantial research funding for the specific unfunded proposal or other projects; (3) Applicants shall have a full-time academic appointment at the time the award is initiated. drip drip d

Introducing SIMULECT#{174} (basiliximab) - Now Two Doses Complete Antibody Induclion New SIMULECT, when used as part of an immunosuppressive regimen that includes Neoral#{174}* (cyclosporine for microemulsion) + corticosteroids, lowers acute rejection and maintains 1-year graft survival-with just two 20-mg doses.t Chimerization maintains high affinity for the IL-2 receptor, with low immunogenicity (0.4% anti-idiotype; I out of 246 patients) - and offers a simple, 2-dose treatment course.t Well tolerated compared to placebo,t SIMULECT provides antibody induction that is effective, convenient, and simple. SIMULECT#{174} (basilixi ma b)

Antibody induction simply delivered 12-15 years of age (n=4), median age 9.5 years] were treated with Simulect#{174}via intra- Simulect#{174} venous bolus injection in addition to standard immunosuppressive agents including (basiliximab) cyclosporine, corticosteroids, azathioprine, and mycophenolate mofetil. Preliminary For Injection results indicate that 16.7% (2/12) of patients had experienced an acute rejection episode Rxonly by 3 months post-transplantation. The most frequently reported adverse events were fever and urinary tract infections (41 .7% each). Overall, the adverse event profile was consis- BRIEF SUMMARY: Please see package insert for full prescribing information. tent with general clinical experience in the pediatric renal transplantation population and with the profile in the controlled adult renal transplantation studies. The available pharma- WARNING cokinetic data in children and adolescents are described in CLINICAL PHARMACOLOGY Only physicians experienced In Immunosuppression therapy and management and DOSAGEAND ADMINISTRATION in the fullprescribing information. of organ transplantation patients should prescribe Simulect (basillximab). The It is not known whether the immune response to vaccines, infection, and other antigenic physician responsible for Slmulect#{174}administration should have complete Informa- stimuli administered or encountered during Simulect#{174}therapy is impaired or whether tion requisite for the follow-up of the patient. Patients receiving the drug should such response will remain impaired after Simulect#{174}therapy. be managed In facilities equipped and staffed with adequate laboratory and supportive medical resources. Geriatric Use Controlled clinical studies of Simulect#{174}have included a small number of patients 65 years INDICATiONSAND USAGE and older (Simulect#{174}15: placebo 19). From the available data comparing Simulect#{174}-and Simulect (basiliximab) is indicated for the prophylaxis of acute organ rejection in placebo-treated patients, the adverse event profile in patients 65 years of age is not dif- patients receiving renal transplantation when used as part of an immunosuppressive ferent from patients <65 years of age and no age-related dosing adjustment is required. regimen that includes cyclosporine and corticosteroids. Caution must be used in giving immunosuppressive drugs to elderly patients.

CONTRAIHOICATIONS ADVERSE REACTiONS Simulect (basiliximab) is contraindicated in patients with known hypersensitivity to The incidence of adverse events for Simulect#{174}(basiliximab) was determined in two ran- basiliximab or any other component of the formulation. See composition of Simulect#{174} domized comparative double-blind trials for the prevention of renal allograft rejection. A under DESCRIPTION in the fullprescribing information. total of 721 patients received renal allografts, of which 363 received Simulect#{174}and 358 received placebo. All patients received concomitant cyclosporine for microemulsion and WARNINGS: Sii Boxed WARNING. corticosteroids. General Simulect#{174}(basiliximab) should be administered under qualified medical supervision. Simulect#{174}did not appear to add to the background of adverse events seen in organ Patients should be informed of the potential benefits of therapy and the risks associated transplantation patients as a consequence of their underlying disease and the concurrent with administration of immunosuppressive therapy. Anaphylactoid reactions following administration of immunosuppressants and other medications. Adverse events were the administration of Simulect#{174}have not been observed but can occur following the reported by 99% of the patients in the placebo-treated group and 99% of the patients administration of proteins. Medications for the treatment of severe hypersensitivity reac- in the Simulect#{174}-treatedgroup. Simulect#{174}did not increase the incidence of serious tions should be available for immediate use. adverse events observed compared with placebo. The most frequently reported adverse events were gastrointestinal disorders, reported in 75% of Simulect#{174}-treatedpatients While neither the incidence of lymphoproliferative disorders nor opportunistic infections and 73% of placebo-treated patients. was higher in Simulect#{174}-treatedpatients than in placebo-treated patients, patients on immunosuppressive therapy are at increased risk for developing these complications The incidence and types of adverse events were similar in Simulect#{174}-treatedand and should be monitored accordingly. placebo-treated patients. The following adverse events occurred in 1O% of Simulect#{174}- treated patients: Gastrointestinal System: constipation, nausea, diarrhea, abdominal PRECAUTIONS pain, vomiting, dyspepsia, moniliasis: Metabolic and Nutritional: hyperkalemia, hypo- General kalemia, hyperglycemia, hyperuricemia, hypophosphatemia, hypocalcemia, weight It is not known whether Simulect#{174}(basiliximab) use will have a long-term effect on the increase, hypercholesterolemia, acidosis: Central and Peripheral Nervous System: ability of the immune system to respond to antigens first encountered during Simulect#{174}- headache, tremor, dizziness: Urinary System: dysuria, increased non-protein nitrogen, induced immunosuppression. urinary tract infection: Body as a Whole-General: pain, peripheral edema, edema, fever, Re-administration of Simulect#{174}after an initial course of therapy has not been studied in viral infection, leg edema, asthenia: Cardiovascular Disorders-General: hypertension: humans. The potential risks of such re-administration, specifically those associated with Respiratory System: dyspnea, upper respiratory tract infection, coughing, rhinitis, immunosuppression and/or the occurrence of anaphylaxis/ anaphylactoid reactions, are pharyngitis: Skin andAppendages: surgical wound complications, acne: Psychiatric: not known. insomnia: Musculoskeletal System: leg pain, back pain: Red Blood Cell: anemia. Immunogenlcity The following adverse events, not mentioned above, were reported with an incidence Of renal transplantation patients treated with Simulect#{174}(basiliximab) and tested for anti- of 3% and <10% in patients treated with Simulect#{174}in the two controlled clinical trials: idiotype antibodies, 1/246 developed an anti-idiotype antibody response, with no delete- Body as a Whole: accidental trauma, chest pain, increased drug level, face edema, rious clinical effect upon the patient. In the us Study, the incidence of human anti-murine fatigue, infection, malaise, generalized edema, rigors, sepsis: Cardiovascular: angina antibody (HAMA) in renal transplantation patients treated with Simulect#{174}was 2/138 in pectoris, cardiac failure, chest pain, abnormal heart sounds, aggravated hypertension, patients not exposed to muromonab-cD3 and 4/34 in patients who subsequently received hypotension: Nervous System: hypoesthesia, neuropathy, paraesthesia: Endocrine: muromonab-C03. The available clinical data on the use of muromonab-c03 in patients increased glucocorticoids: Gastrointestinal: enlarged abdomen, flatulence, gastrointesti- previously treated with Simulect#{174}suggest that subsequent use of muromonab-cD3 or nal disorder, gastroenteritis, GI hemorrhage, gum hyperplasia, melena, esophagitis, other murine anti-lymphocytic antibody preparations is not precluded. ulcerative stomatitis: HeartRate andRhythm:arrhythmia, atrial fibrillation, tachycardia: Metabolic andNutritional: dehydration, diabetes mellitus, fluid overload, hypercalcemia, Drug Interactions hyperlipemia, hypoglycemia, hypoproteinemia, hypomagnesemia: Musculoskeletal: No formal drug-drug interaction studies have been conducted. The following medications arthralgia, arthropathy, bone fracture, cramps, hernia, myalgia: Nervous System: paraes- have been administered in clinical trials with Simulect#{174}(basiliximab) with no incremental thesia, hypoesthesia: Platelet and Bleeding: hematoma, hemorrhage, purpura, throm- increase in adverse reactions: ATG/ALG, azathioprine, corticosteroids, cyclosporine, bocytopenia, thrombosis: Psychiatric: agitation, anxiety, depression: Red Blood Cell: mycophenolate mofetil, and muromonab-cD3. polycythemia: Reproductive Disorders, Male: impotence, genital edema; Respiratory: Carcinogenesis, Mutagenesis and Impairment of Fertility bronchitis, bronchospasm, abnormal chest sounds, pneumonia, pulmonary disorder, No mutagenic potential of Simulect#{174}was observed in the in vitro assays with Salmonella pulmonary edema, sinusitis; Skin andAppendages: cyst, herpes simplex, herpes zoster, (Ames) and V79 Chinese hamster cells. No long-term or fertility studies in laboratory ani- hypertrichosis, pruritus, rash, skin disorder, skin ulceration; Urinary: albuminuria, blad- mals have been performed to evaluate the potential of Simulect#{174}to produce carcino- der disorder, hematuria, frequent micturition, oliguria, abnormal renal function, renal genicity or fertility impairment, respectively. tubular necrosis, surgery, ureteral disorder, urinary retention; VascularDisorders: vas- cular disorder; Vision Disorders: cataract, conjunctivitis, abnormal vision. Pregnancy Category B There are no adequate and well-controlled studies in pregnant women. No maternal tox- Incidence ofMallgnancies:The overall incidence of malignancies among all patients in icity, embryotoxicity, or teratogenicity was observed in cynomolgus monkeys 100 days the two 12-month controlled trials was not significantly different between the Simulect#{174} post coitum following dosing with basiliximab during the organogenesis period: blood and placebo treatment groups. Overall, lymphoma/lymphoproliferative disease occurred levels in pregnant monkeys were 13-fold higher than those seen in human patients. in 1 patient (0.3%) in the Simulect#{174}group compared with 2 patients (0.6%) in the Immunotoxicology studies have not been performed in the offspring. Because IgG mole- placebo group. Other malignancies were reported among 5 patients (1 .4%) in the cules are known to cross the placental barrier, because lL-2 receptor may play an impor- Simulect#{174}group compared with 7 patients (1 .9%) in patients treated with placebo. tant role in development of the immune system, and because animal reproduction studies Incidence oflnfectious Episodes: Cytomegalovirus infection was reported in 14% of are not always predictive of human response, Simulect#{174}should only be used in pregnant Simulect#{174}-treated patients and 1 8% of placebo-treated patients. The rates of infections, women when the potential benefit justifies the potential risk to the fetus. Women serious infections, and infectious organisms were similar in the Simulect#{174}and placebo of childbearing potential should use effective contraception before beginning Simulect#{174} treatment groups. therapy, during therapy, and for 2 months after completion of Simulect#{174}therapy. Store Iyophilized Simulect#{174}under refrigerated conditions (2#{176}Cto 8#{176}C;36#{176}Fto 46#{176}F). Nursing Mothers Do not use beyond the expiration date stamped on the vial. It is not known whether Simulect#{174}is excreted in human milk. Because many drugs including human antibodies are excreted in human milk, and because of the potential for Distributed by: adverse reactions, a decision should be made to discontinue nursing or to discontinue Novartis Pharmaceuticals Corporation the drug, taking into account the importance of the drug to the mother. East Hanover, New Jersey 07936 Pediatric Use US License No. 1244 No adequate and well-controlled studies have been completed in pediatric patients. In an ongoing safety and pharmacokinetic study, pediatric patients [2-1 1 years of age (n=8), MAY1998 P30154901 TRANSPLANTBRIEFSUMMARY Patients should be advised that during treatment with cyctosponne, vaccination may be less effectiveand the useof live attenuatedvaccines should be avoided. Patients should be given careful dosage instructions. Neoral#{176}Orat Solution(cyclosporineoral solution for microemuision) NEORAL#{174} Soft Gelatin Capsules should be diluted, preferably with orange or apple juice that isat room temperature. The combination of Neora Oral 5olution (cydosporine oral solution for microemuision) with mOb can be unpalatable. (cyclosporine capsules for microemulsion) Patients should be advised to take NeoratOon a consistent schedule with regard to time of clayand relation to meals. Grapefruit and grapefruit juice affect metabolism, increasrng blood concentration of cyciosponine, thus should be avoided. NEORAL#{174}Oral Solution Laboratory Toets In all patients treated with cydosporine, renal and liver functions should be assessed repeatedly by measurement of serum creatinine, BUN, serum bilirubin, and liver enzymes. Serum lipids, magnesium, and potassium (cyclosporine oral solution for microemulsion) should also be monitored. Cycfosporine blood concentrations should be routinely monitored. CutIon: Federallaw prohibits dispensing without prescription. Drug Isleroctlens: All of the individualdrugs cited below are well substantiatedto Interact with cyclosporine. In addition, concomitant non-steroidalanti-inflammatory drugs, particularly in the setting of dehydration. may potentiate renal The following i a briet summary for transptanton see tuft prescribing information for compte product iformation on dysfunction. Drugs that may potetitlate renal dysfunction include antibiotics (geeteamtcin, tobramycin, vancotnycin, trimethoprim with tfie other inthcahons for rheamatod arthritis and psoriasis. as wetf as ontrndations, Warnings and Adverse Reactions sutfannethonazole), antineoplastics (melphalan), antifungats lamphotericin B, ketoconazole), anti-inflammatory drugs w_ Only physiciansexperienced in managementof systemicimmunosuppressivetherapyfor the indicated (azapropazon, dicfotenac, naprosen, sutindac). gastrointestinal agents (cimetidine, ranitidine), immunosuppresslves disease should prescribe Neorul#{174}.At doses used in solid organ transplantation, only physiciansexperienced in immunosuppressive therapy and management of organ transplant recipients should prescribe Neoral#{176}.Patienta Itacrolimus). receivingthe drug shouldbe managed in facilities equipped and staffed with adequate laboratory and supportive Lvgs 7hotAp.dO. ceou.ofraIl.os- cyclosporine is extensively metabokzed. cyctosporine concentrations may medical resources. The physician responsiblefor maintenancetherapy should havecomplete information requisite beinfluenced by drugs that affect microsomal enzymes, particularly cytochrome P450 lIt-k Substances that inhibitthis for the follow-up of the patient. enzyme could decrease metabolism and incrosse cyctosponne concentrations. 5ubstances that are Inducers of cytochrome P-450 activity could increase metabolism and decrease cyclosporine concentrations. Monitoring of ciivulahngcyclosporine NeoraPa,a systemic immunosuppressant, may increase thesusceptibilityto infection and the development of concentrations and appropriate Neoral dosage adlustment are essential when these drugs are usedconcomitantly. neoplao In kidney, liver. and heart transplant patients Neorat may be administered with other immunosuppressive agents. Increased susceptibility to infection and the possibledevelopmentof lymphomuand other neoplasms may Drugs that toscossu cyclosporine concentrations Indade caldum channel blockers (diltiazem, nicardipine, verapamit), result from the increase in the degree of immunosuppression in transplant patients. antifungats (ftuconazole, itraconazole, ketoconazole), antibiotics (ctarithromycin, erythromycln), glucocorticoids (methytprednisolonel, other drugs (allopunnol, brOmOcriptine, danazol, metoclopramide). The HN profuse ishibitors (e.g., isdvnavir,neIflnavi ritonavir, and saquinavir) are known to inhibit cytochronw P-4 lIt-A Neora soft Gelatincapsuho (cyclosporine capsules for microemutsion)and Neoraf* Oral 5olution (cyclospodne and increasethe concentrationsof drugs metabolized by the cytochrome P-450 system. The interaction between HIV oral sokibon for micrnemulsion) have increased bioavailability in comparison to sandimmune Soft Gelatin Capsules protease inhibitors and cyclosporine hasnot been Studied. Gare should be exercised when these drugs are administered (cyclosporine capsules, U5P) and 5andimmune#{174}Oral 5olution (cyclosporineoral solution, U5P). Neoraf and concomitantly. 5undimmune are not bioequivalentand cannot be used interchangeably without physician supervision. For a given Grapefruit and grapefruit juice affect metabolism, increasing blend concentrations of cyclosporine.thus should be avoided. trough concentration,cyclosporineesposurewill be greater with NeoralS than with 5andimmune. If a patient who is receiving exceptionally high doses of sandimmane#{174}is convertedto NeoralO,particular caution should be exercised. Drugs that dte2 cyclosponne concentrations inclede antibiOtics (nafcillin, rifampinl, anticonvulsants (carbamazeplne, Cyclosporine blood concentrations shouldbe monitoredin transplantand rheumatoidarthritis patients taking Neora phenobarbutal, phenytoin), other drugs (OctreOtide, ticlopidme). to avoidtoxicity due to high concentrations. Dose adjustments should be mede in transplant patients to minimize Rifabutin is known to increase the metabolism of other drags metabolized by the cytochrome P-450 system. The possible organ rejectiondue to low concentrations.Comparisonof blondconcentrationsin the publishedliterature interaction between rifabutin and cyclosponne has not been studied. Care should be eseicised when these two drugs with blood concentrations obtained using current assays must he done with detailedknowledgeof the assaymethods are administered concomitantly. employed. OffiorOrwg IrderactioeL#{149}Reduced clearance of prednisolone,digooln,and tovastatinhas been observed when these drugs are administered with cyclosponne. In addition, a decrease In the apparent volume of distributionof digosin has been MUICATIOUM AIS EASE: NeoraP io inthcated for the prophytaxis of organ rejection in kidney,finer,and heati aRegeneic reported after cydosponne administration. 5evere digitalis tosicity has been seen Within days of starting cyclosporine in transptants. NeoraP has been med in combination with azathioprirte and corticosteroeis. several patients tatting digosin. tyclospohne should not be used with potassium-sparing diuretics became hypertialemie SSUITRAUIOISATIOU$: Neoraw is contraindicated in patients with a hypersensitivity to cycfosponne or to any of the can occur. ingredients of the formulation. During treatment with cyclosporine,vaccinationmay be lesseffective. The use oflive vaccines should be avoided. wA (See Boxed WARNINGS): cyclosporine,the active ingredient of Neural, can cause nephrotosicity and Myosdis has occurred with concomitant tovastatin, frequent gingival hyperplasia with nifedipine, and convulsions with hepatotonicity. The risk increaseswith increasingdoses of cyclosporine.Renaldysfunctionincludingstructuralkidney high dose methytprednisolone. damage ria potential consequence of Neoraf and therefore renal function must be monitoredduringtherapy.Cats should Carclnogonesta, Mutagenesls, and ImpaIrment of FertIlIty: carcinogenicity studies were carried out in male and be taken in eels, cyclospottes with nsphrotozk druga. (5.. PREC.4LIT1ONS) female rats and mict In the 78-week mouse study, evidence of a statistically significant trend was found for lymphocytic Patients receiving Neora require frequent monitoringof serum creatinine.Elaerfy patients should be monitored with lymphoman in females, and the incidence of hepatoceflalar carcinomas in mid-dose males significantly exceeded the particular care, since decreases in renalfunction also occurwith age. If patients are not properlymonitoredand doses control value. In the 24-month rat study, pancreatic islet cell adenomas significantly esceeded the control rate in the tow are not properfyadjusted, cyclosporinetherapy can be associated with the occurrence of structural kidney damage and dose level Doses used in the mouse and rat studies were 0.01 to 0.16 times the clinical matotenance dose (6 mgtg). persistent renal dysfunction. The hepatocetlular carcinomasand pancreaticislet cell adenomas were not dose related. Published reports indicate that An increase in serum creatinine and BUN may occur during NeoraP therapy and reflect a redaction in the glomerular co-treatment of hairless truce with (N irradiation and cyclosporine or other immunosuppressiveagentsshorten the time filtration rate. Impaired renal function at any time requires close monitoring, and frequent dosage adjustment may be to skin tumor formationcomparedto IN irradiahon alone. indicated. The frequency and severity of serum creatinine elevationsIncrease with dose and duration of cyclosponne cydosporine was not mutagenic in appropriate test syotetno. lycIosporine has not been found to be mutagenic/genotoxlc therapy. These elevations are likely to become more pronounced without dose reduction or discontinuation. in the Ames Test, the V79-HGPRT Test, the micronucleustest in mice and Chinese hamsters, the chromosome-aberration knees. Neorul Is not hlosqelvelsat to seedImmune, cosneersiesfrom Neoral to Rendlmmues using a 1:1mIle tests in chinese hamsterhone-marrow,the mouse dominant lethalassay,and the DNA-repairtest in sperm from treated (mglh#{216}ay)lusT risuft hi lower cyclospodu. blood ceece*stlons. Conversion from Nseml#{149}10 $sadhnmuusS should mice. A recent study analyzing sister chromatid eschange (SCE) inductionby cyctosporine using human lymphocytes be muds wIth Increased monitoring to avoId the poleetlal of usdordoelog. in vitro gave indication of a positiveeffect(i.e., inductionof 5CE), at high concentrationsIn this system. ft is not unusual for serum creatinine and BUN levels to be elevated during cycfosporine therapy. These elevations in No #{241}npavmentin tertitity was demonstrated in studies in male and female rats. renaltransplant patients do not necessarity indicaterejection, and each Patient must be tiNy evaluated before dosage An increased Incidence of malignancy is a recognized complication of immunoseppression in recipientsof organ adjustment is initiated. transplants. The most common forms of neoplasmsare son-Hodgldn lymphoma and carcinomas of the skin. The risk Bused on the historical5andimmune experiencewith oral solution, nephrotoxicityassociatedwith cyclosporinehad of malignancies in cyctosporise recipients ishigher than in the normal, heafthy population but Sunder to that in patients been noted in 25% of cases of renaltransplantation,38% of casesof cardiactransplantation,and 37% of casesof liver receiving other immunosuppressivetherapies. Reductionor discontinuanceof immunosuppreaoionmay cause the transplantation.Mild nephrotoxicitywas generally noted 2-3 months after renal transplant and consisted of an arrest in lesions to regress. the fall of the pre-operasive elevations of BUN and creatinineat a range of 35-45 mg/it) and 2.0-2.5 mg/dl respectively. Progaaacy Pfsposaq category c. cyctosporine wan not terutogenic in appropriate test systems. Only at dose levels These elevations were often responsiveto cyctosporine dosage reduction. toxic to dams, were adverse effects seen in reproduction Studies in rats. Cydosporine has been shown to be embryo- and More oveR nephrotoxicity was seen early after transplantation and was tharacterized by a rapelty rising BUNand creatinine. fetotosic in rats and rabbits following oral administrahon at maternally toxic doses. Fetal toxicity was noted in rats at 5ince these events ure similar to renal rejection episodes, core must be taken to differentiate between them. This form of 0.8 and rabbits at 5.4times the transplant doses in humans of 6.0 mg/kg, where dose corrections are based on body nephrotosicity is usually responsive to cyclosporine dosage reduction. surface area. lydosponine wan embryo- and fetotoxic as kshcated by kicruesed pm- and postnatal mortality and reduced fetal weight together with related skeletal retardation. Although specific diugnostic criteria which reliably differentiate renal graft rejection from drug tosicity have not been found,a number of parameters have been significantlyassociated with one or the other. It shountbe noted however. that There are no adequateand well-controlledstudies in pregnant women. Neoraf* should be used during pregnancy only if up to 20% of patientsmay havesimultaneousnephrotosicityand rejection. the potentialbenefitjustifies the potentialnsk to the fetus. A form of a cyciosporine-associated rtephroputhy is characterized by serial deterioration in mint function and morpholagic The following data represent the reported outcomes of 116 pregnancies in women receiving cyclosponine duringpregnancy changes in the kidneys. From 5%-15% of transplantredpientSwho havereceivedcyclospodnewOl tail to show a reduction 90% of whom were transplant patients, and most of whom receivedcyciosporine throughout the entire geStahOnalperiod. iv rising sersm creahnine despite a decrease or discontinuation of cyciosporkie therapy Renal biopsies from these patients The only consistentpatterns of abnormality were prematurebirth(gestations)period of 28 to 36 weeks) and low birth will demonstrate one or several ofthe following alterations: tubular vacuolizasion, tubular microcalcifications, peritubular weight for gestational age. Sbtteen fetal tosses occurred. Most of the pregnancies (85 of 100) were complicated by die- capillary congestion, arteriolopathy, and a striped form of interstitial fibrosis with tabular atrophy. Though none of these orders: induding, pre-eclampsia. eclampu premature labor, abruptio placentae, ohgoftydramnios, RhincompatibIlity morphologic changes is entirely specific, a diagnosis of cyclosporine-associated structural nephrotosicity requires and fetoplacentaldysfunction.Pry-term dehvery occurred In 47%. seven malfOrmatiOns were reported in 5 viable infants evidenceof thesefindings. and in 2 cases of fetal loss. Twenty-eight percentof the infantswere small for gestational age. Neonatal complications occurred in 27%. Therefore, the risks and benefitsof using Neorat* during pregnancy should be carefullyweighed. When consideringshe development of cyclosporine-associated nephropathy, it is noteworthy that several authors have reported an associationbetween the appearance of interstitialfibrosis and higher cumulativedoses or persistently high NamIng Mothers: Since cyclosporineis excretedin human milk, breast-feedingshould be avoided. arcolating trough ievelnof cyclosporine. This is particularly true during the first 6 post-transplant months when the PediatrIc Uso: Afthoughno adequate and well-controlled studieshave been completed is children, transplant recipients dosage tends to be highest and when, in katney recipients, the organ appears to be most vulnerable to the tosic effects us young us one year of age have received Neoral with no unusual adverse effects. of cycfosporine. Among other contnbuting factors to the development of interstitialfibrosis in these patients are prolonged AIVR ACTlOU$The principal adverse reactions of cyctosporinetherapy are renal dysfunction, tremor, hirsutism, perfusion time, warm ischemia time, as wet as episodes of acute tosicity,and acute and chronic rejection. The reversibility hypertension. and gum hyperplasa of interstitial fibrosis and its correlation to renal function have not yet been determined. Reversibilityof arteriotopathy has been reported after stopping cyclosponne or lowering the dosage. Hypertension, which is usuallymild to moderate,may occuris approxunately 50% of patients following renal transplants- tion and in most cardiac transplant Patients. Impaired renal function at any time requiresclose monitoring,and frequent dosage adjustment may be indicated. Glomerular capillary thrombosis has been found in patientstreated with cyclosponne and may progressto graft failure. In the event of severe and unremitting resection, when rescue therapy with pulse steroids and monoctonalantibodies fail The pathologicchanges resembledthose seen in the hemolytic-uremicsyndrome and includedthrombosis ofthe renal to reverse the rejection episode. it may be preferable to switch to aftemativeimmunosuppressivetherapy rather than microvasculature,with platelet-fibrinthrombi Occludingglomerular capillaries and afferent arterioles, microangiopathic increase the Neoraw dose to excessivetovets. hemolytic anemia, thrombocytopenla. and decreased renal function. similar findings havebeen observed when other Occasionally patients have developed a syndrome ofthrombocytopenia and microangiopathichemotyticanemia which immunosuppressives have been employed post-transplantation. Ffypomagnesemia has been reported in some. bet not all, may result in graft failure. The vauculopathy can occur in the absenceof rejectionand is accompanied by avid platelet patients exhibiting convulsions while on cyclosporine therapy. Although magnesium-depletion studies in normalsebects consumption within the graft as demonstrated by Indium 1 11 labeled plateletstudies.Neitherthe pathogenesis nor the suggest that bypomagnesemia isassociated with neurologic disorders, multiple factors, deluding hypertension. high dose management nfthis syndrome is clear.Thoughresolutionhas occurred after reductionor discontinuationof cyclosporine methylprednisotone, bypocholesterotem and nephrotoslcity associated with high plasma concentrations of cyclospodne and 1) administration of streptokinase and hepann or 2) plasmapheresis, this appears to depend upon early detection appear to be relatedto the neurologicalmanifestationsof cyclosporine toxicity. with Indium 111 labeledplatelet scans. (SeeAOVERSE REACTIONS) In controlledstudies,the nature, seventy,and incidence ofthe adverseeventsthat were observed in 493 transplanted 5ignificant hyperltalemia Isometimes associated with hyperchloremic metabolic acetosis) and hyperuncemia have been patientstreated with Neoral were comparable with those observed in 208 transplanted patientswho received seen occasionally in individual patients. Sundimmune in these same studies when the dosage ofthe two drugs was adjusted to achievethe same cyclospodne Hepatotoxicity associated with cyclosponne use had been noted in 4% of cases of renal transplantation, 7%of cases of blood trough concentrations. cardiac transplantation,and 4% of cases ofliver transplantation. Thiswas usually noted during the first month of therapy The following reactions occurred in 2% or less of Sandlmmunes-treated patients: allergic reactions, anen* anorexia. when high doses of cyctosponne were used and consistedof elevationsof hepatic enzymes and bilirubin. The chemistry confusion, conjunctivitis,edema. fever, brittle fmgernads, gastritis, hearing toss, hiccup hyPerglycen* muscle pain elevations usually decreased with a reductionin dosage. peptic ulcer, thrombocytopenia, tinnitus. The following reactions occurred rarely: anxiety, chest pain, constipation, As in patients receiving other immunosuppressants, those patients receiving cyclosporine are at increased risk for depression, hair breaking, hematuna. joint pain, lethargy, mouth sores, myocardial infarction, night sweats, pancreatitis. development of fymphomasand other malignancies,particularly those ofthe skin. The increased risk appears relatedto pruritus, swallowing difficulty, tingling, upper GI bleeding, visual disturbance, weakness, weight toss. the intensity and duration of immunosuppressiun rather than to the use of specific agents. Because of the danger of Increased susceptibility to infection andthe possibledevelopmentof lymphoma and other neoplasmsmay resultfrom oversuppresoion of the immune system resulting in increased risk of infection or malignancy,a treatment regimen the degree of immunosuppression. containing multiple immunosuppressants should be used with caution. Please see the current padiage insert for completeinformationregardingadversereactions. There have been reports of convulsions in adolf and Pediatricpatients receiving cyclosponne, particularly in combination with high dose methylprednisolone. N.oml#{176}sell Golallo Capsules (cycloeporlne capsules lot mlcro.molaloo) tare should be taken in usingcyclosporinewith nephrotosicdrugs. (See PRECAUTIONS) 25 mg: Oval, blue-gray imprinted in red, leeorar over 25 mg. Packages of 30 unit-dose blisters (NBC 0078-0246-15). Oblong, blue-gray imprintedin red, NEORAL over 100 mg.’ Packages of 30 anit-dose blisters PRECAUTiONS:NpvtaseIon: cyclosporine is the active ingredientof Neoraf. Hypertension is a common side effect of lsng: cyclosporinetherapy which may persist. (See ADVERSE REACTIONS) Mild or moderate hypertensionis encountered (NBC 0078-0248-15). more frequentlythan severe hypertension and the incidence decreases ever time. In recipientsof kidney, liver,and heart Stesi and Olapenso: In the original unit-dosecontainerat controlledroom temperature68-7rF (2o-25c). allografts treated with cyctosporine, untihypertensive therapy may be required.However, since cyclosporine may cause NoomI’ Oral SolutIon (cyclosporlns oral solutIon for mlcroomulslon): A clear, yellow liquid supplied In 50 mL bottles hypertcatemia, potassium-sparing diureticsshouto not be used. While cuiciem antagonists can be effective agents in containing 100 mg/mI (NDC 0078-0274-22). treating cyclosporine-associated hypertension, they can interfere with cyctosporine metabolism.(See Drug Interactions) 5*0,0 aud Olapeoso:In the originalcontainer at controlled room temperature 68#{176}-77#{176}F(20-25C). Do not store in the VaccinsUon: During treatment with cyclospurine, vaccination may be less effective; and the use oflive attenuated vaccines refrigerator.Onceopened,the contentsmust heused withifi two months. At temperatures below 68F (20C) the solution should be avoided. may gal; itght flocculation or the formationof a hghtSedimentmay alsooccur.Thereis no impact on product performance hdornsotioefor Patisets: Patloets should ho advised that soy change of cycloeporlne fermulatlon should ho made or dosing using the syringe provided. Allowto warm to room temperature 77#{176}F(25C) to reverse these changes. cautiously and only under physicIan suporvlslus because It may tousle In the need for a change In dosage. Patients should be informedofthe necessityof repeatedlaboratorytests while they are receiving cyctosporine. Patients NovurtloPharmaceuticalscorporation. EastHanover,New Jersey 07936 should be advised of the potentialrisks during pregnancy and informed of the increased risk of neoplasia.Patientsshould also be informedof the risk of hypertensionand renal dysfunction. REV: NOVEMBER1997 P30771904 NEO-8065 TRANSPLANT BRIEF sUMMARY 7MotJnfluen1ia1Jouma1 #{252}iFie1d bnsplantatioff OjjflcialJournal ofthe Transplantatkm Society

Editor: James Neuberger (England), AnthonyP. Monaco (&4), PeterJ. Morris (ngI;, David H. Sachs ((A4), Manlkkam Suthanthiran (tA4), and KathiynJ. Wood nghnd)

Pubi twice monthly, this 4 EAsY W To ORDER frequentlydted sdentific journal CAlL1-800-638-6423 - Outs#{224}detheU.S.: 410-528-8555 features comprehensive coverage London: 171-543-4848 Hong Koog 852-2610-2339 ofthe important advinces in traits- Tokyo: 03-5689-5400 plantaiion surgeiy #{163} Fx 410-528-8596 Expert researchers and din!- E-Ma [email protected] clans contribute formal papers and MAILorder form today to: Williwts&Willdns briefabstracts in every pertinent P.O. Box 23291 Baltimore, MD 21203-9990 sal13 You’ll get current insights r 1 on... I Yes, my subscription to

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CARNffOR (Levocamitine) Pediatric use QIRB1LOR#{174} Brief Summary of Prescribing Information See Dosage and administration. (Please see package Insert for full prescribing information) Adverse reactions CARNITOR (Levocamftine) Oral Solution and Tablets. Indications and usage Iv - TABLETS #{149}ORAL SOLUTION Various mild gastrointestinal complaints have been reported during CARNIIOR#{176}(Lecamfone) l#{228}bletsand Or Sokation are kidkated in the long-term administration of oral L - or D,L-camitine; these include the treatment of primary systenc carnifine deficbency. In the reported transient nausea and vomiting, abdominal cramps, and diarrhea Mild CUnicat Findings Associated cases, the clinical presentation consisted of recurrent episodes of Reye- myasthenia has been described only in uremic patients receMng DL- like encephatopathy, hypoketotic hypogiycemio, and/or cardkxiipathy camfone. Gastrcntestinef adverse reactions with CARNflDR (Levo- with Camitine Deficiency: ASSOaated symptoms Wnduded hypotonla, muscle weakness and fl- camitine) Oral Solution dissolved in liquids might be avoided by a slow Utin to thrive. A dagnoxis of primary carnftine deficncy reqUires that consumption of the solution or by a greater dilution. Decreasing the . cardiomyopathy serum, red cell and/or tissue camitine levels be low and that the patient dosage often diminishes or eliminates drug-related patient body odor or gastrointestinal symptoms when present. Tolerance should be mon- does not have a primary defect wt fatty acki or organk add OddatiOn . muscle weakness itored very closely during the first week of administration, and after any (see Pharmacology). In some patients, particularly those pre- dosage increases. . lethargy senting wfth cardkxThvpathy, carnfone suppiernentation rapdy alleviet- ed signs and symptoms. Treatment should wsclude, in addition to cami- Seizures have been reported to occur in patients with or without pro- . poor muscle tone tine, supportive and other therapy as tdicated by the condition of the existing seizure activity receiving either oral or intravenous levocamitine. patient. CARNIIOR (Levocamitine) Tablets and Orwi Sokation are afao In patients with pre-existing seizure activity, an increase in seizure . seizures indicated for acute and chrorac babrent of patients wfoi an bom error frequency and/or seventy has been reported.

of metabolism that SUftS in a secondary carnitine deficiency. . low levels of activity CARNffOR (Levocamitine) Injection. Transient nausea and vomiting have been observed. Less frequent CARNfl’OR (Levocarnitine) Injection is indicated for the acute and . developmental delay adverse reactions are body odor, nausea, and gastritis. An incidence chronic treatment of patients with an inborn error of metabolism that for these reactions is difficult to estimate due to the confounding . slow growth reSUltS in secondary camitine deficiency. effects of the underlying pathology.

Contraindications Seizures have been reported to occur in patients with or without pro- ConditionsAssociated None known. existing seizure actMty receiving either oral or intravenous (evocar- with Increased Risk for nitine. In patients with pre-existing seizure activity, an increase in seizure frequency and/or severity has been reported. Developing Camitine Warnings None. Deficiency: Ax oni.

Precautions . fatty acid oxidation References General 1. Bobmer E Rynding A, Solberg HE: Camitine levels in human defects CARNIIOR (Leocamtine) Ornd Solution j for oral#{241}ntemnduse oni. serum in health and disease. Clin Chim Acts 57: 55-61, 1974.

. mitochondrial myopathy 2. Brooks H, Goldberg L, Holland R et al.: Carnitine-induced Not for parenterai use. effects on cardiac and peripheral hemodynamics. J Clin Pharmacol 17: 561-578, 1977. . dialysis Gastroicitestin reactions may result from too rapid consumption of car- 3. Christiansen A, Bremer J: Active transport of butyrobetaine . premature birth nitine. CARNflOR#{174}(Levocarnitine) Oral Sslution may be consumed and carnitine into isolated liver cells. Biochem Biophys Acts alone, ordiesoWed i dnnks or otherIkuk1 foods to reduce taste fatigue. 448: 562-577, 1977. . administration of ft should be consumed stonily and doses should be spaced everdy 4. Lindstedt S, Lindstedt G: Distribution and excretion of carnitine 14C02 in the rat. Acts Chim Scand 15: 701-702, 1961. carnitine- free TPN throughout the day to mnsdmize toicrance. 5. Rebouche CJ, Engel AG: Camitine metabolism and deficiency syndromes. Mayo Ciin Proc 58: 533-540, 1983. . treatment for HIV- Carcinogenesis, mutagenesis, impairment of fertility 6. Rebouche CJ, Paulson DJ: Carnitine metabolism and function especially administration Mutagenicity tests performed ii Saksxrsela pt*mi*in, Sacdnaiorsves in humans. Ann Rev Nutr 6: 41-68, 1986. cefek1e, and Sctasacchaicvnes pcrite ‘tdicate that CARNflOR of zidovudine (AZI) (Lecamibne) ts n mutagenic. Long-term animai studies have not been 7 Scriver CR, Beaudet AL Sty WS, Valle D: The Metabolic Basis conducted to evaluate the caidnogercity of the compouid. of Inherited Disease. McGraw-Hill, New York, 1989. . administration 8. Schaub J, Van Hoof F, Vis HL: Inborn Errors of Metabolism. Raven Press, New York, 1991. of valproic acid Pregnancy Pregnancy Category B. 9. Marzo A, Arrigoni Martelli E, Mancinelli A, Cardace G, . administration of Corbelletta C, Bassani E, Solbiati M: Protein binding of L-car- Reproductive studies have been performed in rats and rabbits at nitine family components. Eur J Drug Met Pharmacokin, pivalate derivatives doses up to 3.8 times the human dose on the basis of surface area Special Issue III: 364-368, 1992. and have revealed no evidence of impaired fertility or harm to the . 10. Rebouche C: Quantitative estimation of absorption and degra- administration fetus due to CARNITOR#{174}. There are, however, no adequate and well dation of a carnitine supplment by human adults. Metabolism: of emetine controfled studies in pregnant women. Because animef reproduchan 1305-1310, 1991. studies are not always predictive of human response, thie drug should . administration of be used during pregnancy only if clearly needed. sodium benzoate Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into sigma-tau account the importance of the drug to the mother. PHARMACEUTICALS, INC.

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Mail completed form and $35 payment to: American Society of Nephrology 1200 19th Street, NW, Suite 300 Washington, DC 20036-2422 ( ImL ANTIZOL M] AMERiCAN SOC1ETY (fomepizole) Injection ot: NEPOROLOGY Brief Summary ASN Basic SciericeIlSN ForeftOntSConference Sterile Presented by: The American Society o1NephrOIO.Y (ASN) and Caution: Must be diluted prior to use. The Internationa! Society ofNephrOI0Y (ISN) CUNICAL PHARMACOLOGY: Mechanism of Action: Antizol (fomepizole) is a competitive inhibitor of alcohol dehydrogenase Alcohol dehydrogenase catalyzes the oxidation of ethanol to October 28-31, 1998 #{149}Skytop Lodge #{149}Skytop,PA acetaldehyde. Alcohol dehydrogenase also catalyzes the initial steps in the metabolism of ethyl- ene glycol (the main component of antifreeze and coolants) and methanol to their tosic metabo- lites ion Channe1oPat1 HereditarY DysfuflCtiOfl of ion Channels INDICARONSAND USAGE. Antizol is indicated as an antidote for ethylene gtycol (antifreeze) poi- soning, or for use in suspected ethylene glycol ingestion. Specific topics will Include: CONTRAINDICAT1OHS: Antizol should not be administered to patients with a documented seri- ous hypersensitivity reaction to Antizol or other pyrazoles. S MechafliS of Ion Channel DysfunctiOfl Relating Structure to PRECAUTIONS: General: Anlizol should not be given undiluted or by bolus injection. Venous rn- Function tation and phlebosclerosis were noted in two of sit normal volunteers given bolus injections (over #{149}Delective Ion Channel Molecular Complexes and AccessorY 5 minutes) of Antizol at a concentration of 25 mg/mL. Minor allergic reactions (mild rash, Subunit Dysfunction eosinophilia) have been reported in a few patients receiving Antizol (see ADVERSEREACTIONS). #{149}Disorders Involving Abnormal lon Channel ssembly Trafficking Therefore, patients should be monitored for signs of allergic reactions. and Targeting Laboratory Tests: In addition to specific antidote treatment with Antizol, patients intosicated with #{149}Role of ion Channel Defects in Disorders with Complex or ethylene glycol must be managed ton metabolic acidosis, acute renal failure, adult respiratory dis- tress syndrome. and hypocalcemia. Fluid therapy and sodium bicarbonate administration are Multisystem pathophysiologY potential supportive therapies. In addition, potassium and calcium supplementation and oxygen #{149}Therapeutic Strategies in the lon ChannelOPathies administration are usually necessary. Hemodiatysis is necessary in the anunic patient, or in patients wfh severe metabolic acidosis or azotemia (see DOSAGE AND ADMINISTRATION). Conference Chairs: Treatment success should be assessed by frequent measurements of blood gases, pH, elec- Alfred George.midethut UniversitY William GuggmnO.J0hi Hopkins Uiiiversii\ trolytes, BUN, creatinine, and urinalysis, in addition to other laboratory tests as indicated by mdi- Steven Hebeff.Vafldeilt Univeisit’ Bruce Stanton, Dartmouth Medical School vmdual patient conditions. Ethylene glycol plasma and unne concentrations and presence of un- nary oxalate crystals should also be monitoredfrequentlythroughout treatment to assess tttesta- tus of ethylene glycol and metabolite clearance. Since acidosis and electrolyte imbalances can For more information regarding course registration and/or application for affect the cardiovascular system, electrocardiography should be performed. In the comatose course young investigator travel grants. please contact Neely Nichols at the patient, eleclroencephalography may also be required. In addition, hepatic enzymes and white MN at 202-8574 190 or E-mail nee_nmchoIS&#{174}c0m blood cell counts should be monitored during treatment, as transient increases in serum transam- inase levels and eosinophilia have been noted with repealed Antizol dosing. The ASN Basic Science/ISN ForefrofltS Conference at!! conclude

Drug Interactions: Oral doses of Antizol )10-20 mg/kg), via alcohol dehydrogenase inhibition, sig- ASN’S 1998 Renal Week - the premier week in nephrology nificantly reduced the rate of elimination of ethanol (by approximately 40%) given to healthy vol- unteers in moderate doses. Similarly, ethanol decreased the rate of elimination of Antizol (by approximately 50%) by the same mechanism. Reciprocal interactions may occur with concomi- tant use of Antizol and drugs that increase or inhibit the cytochrome P45(J system (e.g., phe- nytomn,canbamazepmne,cimetidine, ketoconlazole), though this has not been studied. Carcinogermesms, Mutagenesis. and Impairment of Fertility:There have been no long-term studies performed in animals to evaluate carcinogenic potential. There was a positive Ames test result in the Esctmenctiia colitester strain WP2uwA and the Salmonella tyjm?,imuriumtesterstrainTA1O2in the absence of 59 mis. In rats, fomepizole (110 mg/kg) administered orally for 40 to 42 days resulted in decreased testicular mass (approximately 8% reduction). This dose is approximately 0 6 times the human maximum daily exposure based on surface area (mg/m). This reduction was similar for rats treated with either ethanol cx fomepizole alone. When fomepizole was given Put Your Fin er on the in combination with ethanol, the decrease in testicular mass was significantly greater (approxi- mately 30% reduction) compared to those rats treated exclusively with fomepiZole or ethanol. Pregnancy Pregnancy Category C: Animal reproductionstudies have not been conducted with Best nd Health fomepizole. It is also not known whether Antizol can cause fetal harm when administered to preg- nant women or can affect reproduction capacity. Antizol should be given to pregnant women only if clearly needed. Science Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, Caution should be exercised when Antizol is administered to a Resou ble... nursing woman. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Geriatric Use: This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. ADVERSE REACTIONS: The most frequent adverse events reported in the 76 patients and 63 normal volunteers who received Antizol were headache (12%), nausea (11%), and dizziness (7%). I Ity Other adverse events reported in approximately 6% or fewer of those receiving Antizol are listed below Nervous: Seizure, vertigo, lightheadedness. nystagmus, feeling of drunkenness, strange feeling, slurred speech, decreased environmental awareness. Digestive: Vomiting. diarrhea, anorexia, heartburn. Bodyas a Whole:Abdominal patn, fever, somnolence, lumbalgia, hangover. Special Senses Bad/metallic taste, abnormal smell, blurred vision, visual problems. Cardiovascular Bradycardia, tachycardia, hypotenston,injection site reaction, phlebosclerosis. Ic Hemmc./Lyrnphatmc:Lymphangitis, eosinophilia, anemia. Skin/Aendages: Rash. Respiratory: from .. Hiccups, pharyngitis. DOSAGE AND ADMINISTRATiON: A loading dose of 15 mg/kg should be administered, followed by doses of 10 mg/kg every 12 hours for 4 doses, then 15 mg/1g every 12 hours thereafter until ethylene glycol levels have been reduced below 20 mg/dL. All doses should be administered as a slow intravenous infusion over 30 minutes. Save $ monthly specials and Dosage with Renal Dialysis: Antizol is dialyzable and the frequency of dosing should be Preferred incentives! increased to every 4 hours during hemodialysis. HOWSIJPPUED:Antizol is supplied as a sterile, preservative-free solution for intravenous use as: NDC 621 61 -003-34 1 g/mL, 1.5 mL vial in packages of four vials. Store at controlled room tom- PUT YOUR IT perature, 2O to 25CC )6& to 77F) see USP]. Caution: Federal law prohibits dispensing without prescription. Ant 1 3 Rev. 12/97 #{248}nline . #{149}OIPHANU C 1998, Orphan Medical, Inc. .. a i D I C A I p www.wwiIkins.com

WW01980 1 I DUCINGATACAN ANEWSIGNOF H IN BPREDUCTION

Once -A-Day

CANDESARTANCLEXETL #{174} A new angiotensin II receptor blocker

I (ARBIwith power @ every dose

ANEIJV bloodNew once-dailypressure (BP)ATACANDat the 16-mghas significantstarting dose.powerAndtoa reducedosage

increase to 32 mg leads to an even greater reduction in OF HIN #{149}ATACAND delivers effective BP reduction when compared

BP to(at amlodipinedoses of 10atmgtheenalapril,starting 8dosesmg ATACAND).2’3and to enalapril Exhibits a long-lasting effect @ the AT1receptor site for 24-hour control

. ATACAND gets @ the site where angiotensin II causes vasoconstriction.

. ATACAND stays @ the site, where its antihypertensive effect is not overcome by angiotensin II.

Prescribenew ATACANDtablets-and Get the Power! Once-A-Day

CANDFSARTAN CHFXFTH BRIEF SUMMARY contraceptives in healthy volunteers. Because candesartan is not metab- Before prescribing, please see full Prescribing Information for ATACAND. olized by the cytochrome P450 system and has no effects on P450 enzymes, interactions with drugs that inhibit, or are metabolized by, USE IN PREGNANCY those enzymes would not be expected. PI-egnancy: Pregnancy When used In pregnancy during the second and thIrd trlmesters, Categories C (first trimester) and 0 (second and third trimesters). See drugsthat act dIrectly on the renln-angiotensln system can cause WARNINGS, Fetal’NeonatalMorbmdmtyandMortality. Nursing Mothers: It Injury and even death to the developIng fetus. When pregnancy is is not known whether candesartan is excreted in human milk, but detected, ATACAND should be discontinued as soon as possible. 5ee candesartan has been shown to be present in rat milk. Because of the WARNINGS,Fetal/NeonatalMorbidityand Mortality. potential for adverse effects on the nursing infant, a decision should be made whetherto discontinue nursing or discontinuethe drug, taking into ATACAND (candesartan cilexetil) was effective in reducing blood pres- account the importance of the drag to the mother. Pediatric Use: Safety GETTHE sure regardless of race, although the effect wassomewhatlessin blacks and effectiveness in pediatric patients have not been established. (usually a low-renin population). Geriatric lisa: Of the total number of subjects in clinical studies of ATACANEP(candesartan cilexetil), 21% were 65 and over, while 3% were CONTRAINDICATIONS: ATACAND is contraindicated in patients who 75 and over. No overall differences in safety or effectiveness were are hypersenstive to any component of this product. observed between these subjects and younger subiects, and other WARNINGS: FetaIflieonataI Morbidity and Mortality: Drugs that act reported clinical experience has not identified differences in responses p between the elderly and younger patients, but greater sensitivity of some if directly on the renin-angiotensin system can cause fetal and neonatal morbidity and deathwhen administeredto pregnantwomen. Several older individuals cannot be ruled out. In a placebo-controlled trial of about200 elderly hypertensive patients (ages 65 to 87 years), adminis- dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. When pregnancy tration of candesartan cilexetil was well tolerated and lowered blood . pressure by about 12/6 mmHg more than placebo. Powerful BP reduction is detected, ATACAND should be discontinued as soon as possible. The use of drags that act directly on the renin-angiotensin system during (u the starting dose ADVERSE REACTiONS: ATACAND has been evaluated for safety in the second and third trimesters of pregnancy has been associated with more than 3600 patients/subiects, including more than 3200 patients fetal and neonatal iniury, including hypotension, neonatal skull treated for hypertension. About 600 of these patients were studied for at hypoplasia, anuria, reversible or irreversible renal failure, and death. least 6 months and about 200 for more than at least 1 year. In general, . First line for Oligohydramnios has also been reported, presumably resuting from treatment with ATACAND was well tolerated. The overall incidence of decreased fetal renal function; oligohydramnios in this setting has been adverseeventsreportedwithATACANDwassimilarto placebo.Therate hypertensive patients associatedwith fetal limb contractures, craniofacial deformation, and of withdrawals due to adverse events in all trials in patients (7510 total) hypoplastic lung development. Prematurity, intrauterine growth retarda- was 3.3% (i.e., 108 of 3260) of patients treated with candesartan cilexetil bun, and patent ductus arteriosus have also been reported, although d is as monotherapy and 3.5% (i.e., 39 of 1106) of patients treated with not clear whether these occurrences were due to exposure to the drag. . Convenient once-daily placebo. In placebo-controlled trials, discontinuation of therapy due to Theseadverseeffectsdo not appearto have resulted from intrauterine clinical adverse events occurred in 2.4% (i.e., 57 of 2350) of patients drag exposure that has been limited to the first trimester. Mothers whose treatedwith ATACANDand 3.4% (i.e., 35 of 1027) of patientstreated with dosing for 24-hour embryos andfetusesare exposed to an angiotensin II receptor antago- placebo. The most common reasons for discontinuation oftherapy with nist only during the first trimester should be so informed. Nonetheless, ATACAND were headache (0.6%) and dizziness (0.3%). The adverse when patients become pregnant, physicians should have the patient BP reduction experiences that occurred in placebo-controlled clinical trials in at least discontinue the use of ATACANDas soonas possible.Rarely(probably 1% of patients treated with ATACAND and at a higher incidence in less often than once in every thousand pregnancies), no alternative to a candesartan cilexetil (n=2350) than placebo (n=1027) patients included drag acting on the renin-angiotensin system will be found. In these rare . Usual starting dose: back pain (3% vs. 2%), dizziness (4% vs. 3%), upper respiratory tract cases,the mothersshouldbe apprisedof the potentialhazardsto their infection (6% VS. 4%(, pharyngitis (2% vs. 1%), and rhinitis (2% vs. fetuses, and serial ultrasound examinations should be performed to 1%). The following adverse experiences occurred in placebo-controlled 16 mg once daily assessthe intra-amnioticenvironmentIf oligohydramniosis observed, clinical trials at a more than 1% rate but at about the same or greater mci- ATACAND should be discontinued unless ft is considered Ife saving for dence in patients receiving placebo compared to candesartan cilexetil: the mother.Contractionstresstesting(CST),a nonstresstest(NST), or fatigue, peripheral edema, chest pain, headache, bronchitis, coughing, biophysical profiling (BPP) may be appropriate, depending upon the sinusitis, nausea, abdominal pain, diarrhea, vomiting, arthralgia, albu- week of pregnancy. Patients and physicians shouldbe aware, however, minuna. Other potentially important adverse events that have been that oligohydramnios may not appear until after the fetus has sustained reported,whether or not attributed to treatment, with an incidenceof irreversible iniury. Infants with histories of in utem exposure to an 0.5% or greaterfrom the more than 3200 patientsworldwide treated with angiotensin II receptor antagonist should be closely observed for ATACANDare listed below. It cannot be determined whetherthese events hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention were causally related to ATACAND. Body as a Whole: asthenia, fever shouldbedirected toward support of blood pressure and renal perfusion. Central and Peripheral Nervous System: paraesthesia, vertigo; Exchange transfusion or dialysis may be required as means of reversing Gastrointestinal Syslem Olsorder: dyspepsia,gastroenteritis;Heart hypotension and/or substituting for disordered renal function. There is Rat. and Rhythm Disorders: tachycardia, palpitation; Metabolic and no clinical experience with the use of ATACANDin pregnant women. Oral Nutritional Disorders: creatmne phosphokinase increased, hyper- doses 1O-mg candesartancilexetil/lg/dayadministered to pregnant rats glycemia, hypertriglyceridemi hyperuricemia; Musculoskaletal during late gestation and continued through lactation were associated System Disorders: mygla; PlataleL’ti.edingClottlng Disordeis: with reduced survival and an increased incidence of hydronephrosis in epistaxis; Psychiatric Disorders: anxiety, depression, somnolence; I the offspring. The 10-mg/kg/day dose in rats is approximately 2.8 times Respiratory System Disorders: dyspnea; Skin and Appendages the maximumrecommendeddailyhumandose(MRHD) of 32 mg on a Disorders: rash, sweating increased; Urinary System Olsorders: hema- mg/m’ basis (comparison assumes human body weight of 50 kg). turia. Other reported events seen less frequently included angina Candesartan cilexetil given to pregnant rabbits at an oral dose of 3 pectoris, myocardial infarction, and angioedema. Adverse events mg/kg/day (approximately 1.7 times the MRHD on a mg/m basis) occurred at aboutthe same rates in men and women, older and younger caused matemal toxicity (decreased body weight and death) but. in patients, and blackand nonblackpatients. LabOraIOIy Test Findings: In 1WE1ti1 Once-A-Day surviving dams, had noadverseeffects on fetal survival, fetal weight or controlled clinical trials, clinically important changes in standard labora- on extemal, visceral, or skeletal development.No maternaltoxicityor tory parameters were rarely associated with the administration of adverse effects on fetal development were observed when oral doses up ATACAND. Creatinine, Blood Urea Nitrogen: Minor increases in blood ataeanu to 1000-mg candesartan cilexetit4g/day (approximately 138 times the ureanitrogen(BUN) and serumcreatininewere observedinfrequently. MRHD on a mg/m’ basis) were administeredto pregnant mice. Hyperuricemia: Hyperuricemia was rarely found (19 or 0.6% of 3260 Hypotanslonln Voluma-andSalt-DepletedPatlents:ln patients with an patients treated with candesartan cilexetil and 5 or 0.5% of 1 i06 patients CANDESARTAN CLEXETIL activated renin-angiotensin system, such as volume- and/or salt- treatedwith placebo). Hemoglobin and Hematocrit: Small decreasesin depletedpatients (e.g.,thosebeingtreatedwith diuretics),symptomatic hemoglobin and hematocrit (mean decreases of approximately 0.2 hypotension may occur. These conditions should be corrected prior to grams/dL and 0.5 volume percent, respectively) were observed in patients Please see adjacent brief summary of Prescribing Information. administration of ATACAND,or the treatment should start under close treated with ATACAND alone but were rarely of clinical importance. medical supervision. If hypotension occurs, the patients should be Anemia, leukopenia, and thrombocytopenia were associated with with- placed in the supine position and, f necessary, given an intravenous infu- drawal ofone patienteach from clinicaltrials. Potassium:A small increase sion of normal saline. A transient hypotensive response is not a (mean increase of 0.1 mEg/I..) was observed in patients treated with contraindication to further treatment which usually can be continued ATACANDalone but was rarely of clinical importance. One patient from a without difficulty once the blood pressure has stabilized. congestive heart failure trial was withdrawn for hyperkulemia (serum potassium = 7.5 mEg/I.). This patient was also receiving spironolactone. PRECAUTiONS: General: Impaired RenalFunction: As a conse- quenceof inhibitingthe renin-angiotensin-aldosteronesystem,changes Liver Function Tests: Elevationsof liverenzymesand/orserumbilirubin In renal function may be anticipated in susceptible individuals treated wereobservedinfrequently.Five patients assignedto candesartancilexetil in clinicaltrials were withdrawn becauseof abnormal liver chemistries. All with ATACAND. In patients whose renal function may depend upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with hadelevatedtransaminases.Two hadmildlyelevatedtotal bilirubin,but severe congestive heart failure), treatment with angiotensmnconverting one of these patients was diagnosed with HepatitisA. . Reif M, While WN, Fagan TC, et al. Effects of References: 1 enzyme Inhibitors andangiotensinreceptorantagonistshas been associ- candesartan cilexetil in patients with systemic hypertension. Am J ated with oliguria and/or progressive azotemia and (rarely) with acute Distributed by: Cardiol. In press. 2. Farsang C, Kawecka-Jaszcz K, Langan J, et al. renal failure and/or death. Similar results may be anticipated in patients Antihypertensive effects and tolerability of candesartan cilexetil, ASTItA treatedwithATACAND.InstudiesofACEinhibitorsin patientswith unilat- AsfroPha,,oc.uhcds amlodipine, and their combination. AmdHypertens. 1997;1O:80A. eral or bilateral renal artery stenosis, increases in serum creatinine or Wayne. PA 19087, USA. Abstract H13. 3. Franke H. Antihypertensive effects of candesartan blood urea nitrogen (BUN) have been reported. There has been no long- cilexetil, enalapril and placebo. J Hum Hypertens.1997:1 1(suppl 2): term use of ATACAND in patients with unilateral or bilateral renal artery Packaged by: stenosis, but similar results may be expected. InformatIon for Patients: Merck & Co., INc., West Point, PA 19486, USA. 561 -S62. Pregnancy: Femalepatientsofchildbearingageshouldbetoldaboutthe ASTRAt consequencesof second-andthird-trimesterexposuretodrugsthatact Astro PharmoceuticaIs on therenin-angiotensinsystem,andtheyshouldalsobetoldthatthese consequences do not appear to have resulted from intrauterine drag Manufactured under the license ‘ Manufactured under the license exposure that has been limited to the first trimester. These patients from Takeda Chemicallndustries, Ltd., from Takeda chemicel Industries, Ltd. shouldbe askedto reportpregnanciesto their physiciansas soonas by: Astra AB, 5-151 85 SOdert#{227}lje,Sweden. possible. Drug InteractIons: No significant drag interactions have been © 1998 Astra Pharmaceuticals, L.P. reported in studies of candesartan cilexetilgiven with other drugs such as July1998 Printed in USA All rights reserved. 158411 8/98 glyburide, nfedipine, digoxin, warfarin, hydrochlorothiazide, and oral ATAO1 Chromagen Forte Liquid-Iron Gelcaps

I Contains 151 mg of elemental I Reduces the need for and risks iron-the most elemental iron assodateci with IV iron5 available in an oral hematinic today #{149}e1ivers 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

Recommend the most ( wyprescrthedoraI CHROMAGEN

formulated to meet the needsofthose whoneed

The strength of liquid iron in a soft gelcap

Menus see fuR prescribing mformation odaset to Ibis ad. #{149}Bon a nationwide survey ofnephrologists. Dole on file, Savage Laboratories. hd on MS National PrescnpfiseAudit, September 1997. © 1998Savagebiboratories ‘Epogen(epoelin afIa)ts a registeredtrademark ofAmgen kic 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. S DOSAGE AND ADMINISTRATION 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 CHRcMAGEN#{174} I?cIg.TI 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. 3Brise, 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. 4New 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. N3reenberg, SM., Tucker, A. E., Mathues, H and J.D.: “Iron Absorption and DISCUSSION: The amount of elemental iron and the absorption of the iron components of commercial iron preparations vary widely. It is further Metabolism, I. Interrelationship ofAscorbic Acid and Vitamin E’ J. Nutrition 63:19-31, 1957. 7Moore, CV. and Dubach, A. “Observations on the established that certain “accessory components” may be included to enhance absorption and utilization of iron. Chromagen#{174}Forte Capsules Absorption of Iron from Foods Tagged with Radioiron” Trans. Assoc. Amer. Physic. 64:245, 1951 . ‘Steinkamp, R. Dubach, A. and Moore, CV.: are formulated to provide the essential factors for a complete, versatile hematinic. “Studies in Iron Transportation and Metabolism’Arch. Int. Med. 95:181, 1955. “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. inMaxur, 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 af.: “The Anemia of Scurvy’ Amer. J. Med. 42:220- with 20% for ferrous sulfate (heptahydrate) and 13% for ferrous glu- 227, 1967. 2McEvoy, 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. ‘3Franken 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- 1 994; 1 7:1 59-62. i4Braftstrom L, lsraelsson 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 femc compounds. 1990; 81 : 2004-6. ‘5Kang S. Wong PWK, Norusis M. “Homocysteinemia PROMOTES MOVEMENT OF PLASMA IRON: Ascorbic acid also plays due to folate deficiency” Metabolism 1987; 36: 458-62. ‘6Allen 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 Orations. 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 1985. “Underlying disorder associated with severe early-onset preeclamp- action,69 and some evidence that it may have a direct effect upon erythro- sia Am. J. Obstet. Gynecol. 173: 1042-1048. ‘8Mills 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 RP, 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 1 436-1 441 . #{176}LandgrenF, lsraelsson 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. 2Mayer EL, Jacobsen DW, Robinson K. 1 996. “Homocysteine and the gastrointestinal tract. It does not precipitate proteins or have the astrin- Coronary Atherosclerosis.” J. Am. CoIl. Cardiol. 27: 517-27. 22Berenbaum, gency of more ionizable forms of iron, and does not interfere with MC. et al.: Blood, 15:540, 1960. 23Drug 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, Chroma9en#{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 al, 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 alfa-focus on iron supplementation. risk of neural tube defects in the developing fetus.12 Folic acid has also ANNA Journal. 1 993; 20:678-681 . 4. Wingard AL, Parker AA, Ismail N. et been shown to reduce circulating homocysteine levels in the blood,13 4 al. Efficacy of oral iron therapy in patients receiving recombinant human Folate as 5-methyltetrahydrofolate and B2 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 Laboratories. Elevated homocysteine plasma levels are associated with increased risk of preeclampsia, neural tube defects, myocardial infarction and artherosclerosis,12 TOXICITY: Ferrous fumarate was found to be the least toxic of three pop- ular oral iron salts, with an oral LDsoof 630 mg/kg. In the same report, the LOso of ferrous gluconate was reported to be 320 mg/kg and ferrous sul- fate 230 mg/kg.’ 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. tn Manufactured for: CONTRAINDICATIONS SAVAGE LABORATORIES#{174} Hemochromatosis and hemosiderosis are contraindications to iron therapy. a division ofAltana Inc. Folic acid is contraindicated in patients with pernicious anemia (see PRE- MELVILLE, NEWYORK 11747 , CAUTIONS). WARNING by: AR Scherer Corporation, St. Petersburg, Florida 33702 Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6. Keep this product out of reach of children. In case of accidental overdose, call a doctor or poison control center 1F7O262C immediately. ©1997 SAVAGE LABORATORIES#{174} R9197 Satellite Symposia on the Internet at the Hypertension Dialysis Clinical Nephrology Site (www.hdcn.com)

Visit this website to see and hear this symposium and others in their entirety including transcripts,

slides and audio. Includes hyperlinks to reference articles, guidelines, and related issues. Shaping the Future of Peritoneal Dialysis Held in conjunction with the 18th Annual CAPD Conference in Nashville, TN, February 1998

“A Brief History of Peritoneal Dialysis” “Peritoneal Dialysis in the Year 2000” Dimitrios Oreopoulos, M.D. Karl D. Nolph, M.D. University of Toronto, Toronto, Ontario, Canada University of Missouri-Columbia, Columbia, Missouri

An overview of PD’s history, tracing the Opportunities for PD into the future, including its use in critical milestones. “Healthy initiation ofdialysis;” the favorable economics of PD; the growing role ofnew PD solutions including “PD,Miidity and Mortality: amino-acid solutions for better management of nutrition, An International Perspective” and osmotic agents such as Icodextrin which allow for Peter G. Blake, M.B. improved ultrafiltration. London Health Sciences Centre, London, Ontario, Canada The positive results of the Canadian Organ Replacement Registry, and interpretation of early USRDS data. Points to favorable trends in outcomes and survival rates in latest Supported by an educational grant from cohort periods. Baxter Healthcare Corporation.

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