`
`
`
`
`
`
`ALVOGEN, Exh. 1024, p. 0001
`
`
`
`
`
`
`
`

`

`
`
`2000}
`
`EDITION.
`
`
`
`
`
`PHYSICIANS
`Pee
`oie
`
`
`
`
`
`
`Senior Vice President, Directory Services: Paul Walsh
`
`;
`
`Director of Product Management: Mark A. Friedman
`Associate Product Manager:Bill Shaughnessy
`Senior Business Manager: Mark S.Ritchin
`Financial Analyst: Wayne M. Soitis
`Director of Sales: Dikran N. Barsamian
`National Sales Manager, Pharmaceutical Sales: Anthony Sorce
`National Account Manager: Don Bruccoleri
`Senior Account Manager: Frank Karkowsky
`Account Managers:
`Marion’Gray, RPh
`Lawrence C. Keary
`Jeffrey F. Pfoht
`Suzanne E. Yarrow, RN
`Electronic Sales Account Manager: Stephen M. Silverberg
`National Sales Manager, Medical EconomicsTrade Sales: Bill Gaffney
`Director of Direct Marketing: Michael Bennett
`List and Production Manager: Lorraine M. Loening
`Senior Marketing Analyst: Dina A. Maeder
`
`:
`
`Director, New Business Development and
`Professional Support Services: Mukesh Mehta, RPh
`Manager, Drug Information Services: Thomas Fleming, RPh
`Drug Information. Specialist: Maria Deutsch, MS, RPh, CDE
`Editor, Directory Services: David W. Sifton
`Senior Associate Editor: Lori Murray
`Director of Production: Carrie Williams
`Managerof Production: Kimberly H. Vivas
`Senior Production Coordinator: Amy B. Brooks
`Production Coordinators: Gianna Caradonna, Maria Volpati
`Data Manager: Jeffrey D. Schaefer
`Senior Format Editor: Gregory J. Westley
`Index Editors: Johanna M. Mazur, Robert N. Woerner
`Art Associate: Joan K. Akerlind
`Senior Digital Imaging Coordinator: Shawn W. Cahill
`Digital Imaging Coordinator: Frank J. McElroy,
`III
`Electronic Publishing Designer: Livio Udina
`Fulfillment Manager:, Stephanie DeNardi
`
`
`
`Ba Copyright©2000 and published by Medical Economics Company,Inc. at Montvale, NJ 07645-1742. All rights reserved. None ofthe contentofthis publication may
`be reproduced,storedin a retrieval system,resold, redistributed, or transmitted in any form or:by‘any means(electronic, mechanical, photocopying, recording, or
`otherwise) without the prior written permission of the publisher. PHYSICIANS' DESK REFERENCE®, PDR®, PDRFor Ophthalmology®, Pocket PDR®, and The PDR® Family
`Guide to Prescription Drugs® are registered trademarks used herein underlicense. PDR For Nonprescription Drugs and Dietary Supplements™, PDR Companion Guide™,
`PDR? for Herbal Medicines™, PDR® Medical Dictionary™, PDR® Nurse's’ Drug Handbook™, PDR® Nurse's Dictionary™, The PDR® Family Guide Encyclopedia of Medical
`Care™, The PDR® Family Guide to Natural Medicines and Healing Therapies™, The PDR® Family Guide to Common Ailments™, The PDR® Family Guide to Over-the-
`Counter Drugs™, and PDR® Electronic Library™ are trademarks used herein under license.
`
`Officers of Medical Economics Company: President and Chief Executive Officer: Curtis B. Allen; Vice President, New Media: L. Suzanne BeDell; Vice President, Corporate Human
`Resources: Pamela M. Bilash; Vice President and Chief Information Officer: Steven M. Bressler; Chief Financial Officer: ChristopherCaridi; Vice President and Controller: Barry
`Gray; Vice President, New Business Planning: Linda G. Hope; Vice President, Business Integration: David A.Pitler; Vice President, Finance: Donna Santarpia; Senior Vice President,
`Directory Services: Paul Walsh; Senior Vice President, Operations: John R. Ware; Senior Vice President, internet Strategies: Raymond Zoeller
`
`® Printed on recycled paper
`
`ISBN: 1-56363-330-2
`
`ALVOGEN, Exh. 1024, p. 0002
`
`ALVOGEN, Exh. 1024, p. 0002
`
`

`

`AND CYTOVENE-IV INCLUDES GRANULOCYTOPENIA,
`
`powder or the constituted suspension. If such contact oc-
`appropriately (see WARNINGS, ADVERSE REACTIONS,
`(see
`PLANT RECIPIENTS
`USAGE).
`curs, wash thoroughly with soap and water; rinse eyes with
`and PRECAUTIONS:Laboratory Tests).
`water.
`BECAUSE CYTOVENE CAPSULES ARE ASSOCIATED
`HANDLING AND DISPOSAL: Mycophenolate mofetil has
`WITH A RISK OF MORE RAPID RATE OF CMV RETINITIS
`1 Tap the closed bottle several times to loosen the powder.
`demonstrated teratogenic effects in rats and rabbits.
`PROGRESSION, THEY SHOULD BE USED AS MAINTE-
`2. Measure 94 mL of water in a graduated cylinder.
`CellCept tablets should not be crushed and CellCept cap-
`NANCE TREATMENT ONLY IN THOSE PATIENTS FOR
`3, Add approximately half the total amount ofwaterfor con-
`sules should not be openedor crushed. Avoid inhalation or
`WHOMTHIS RISK !S BALANCED BY THE BENEFIT AS-
`stitution to the bottle and shake the closed bottle well for
`direct contact with skin or mucous membranesof the pow-
`SOCIATED WITH AVOIDING DAILY INTRAVENOUSIN-
`about 1 minute.
`der contained in CellCept capsules and CellCept Oral Sus-
`FUSIONS.
`4,Add the remainder of water and shaketheclosed bottle
`pension (before or after constitution). If such contact occurs,
`well for about 1 minute.
`
`wash thoroughly with soap and water;rinse eyes with plain
`DESCRIPTION
`water. Should a spill occur wipe up using paper towels wet-
`5. Remove the child-resistant cap and push bottle adapter
`into neck of bottle.
`Ganciclovir is a synthetic guanine derivative active against
`ted with water to remove spilled powder or suspension,
`cytomegalovirus (CMV), CYTOVENE-IV and CYTOVENE
`6. Close bottle with child-resistant cap tightly. This will as-
`Caution should be exercised in the handling and prepara-
`are the brand namesfor ganciclovir sodium for injection and
`sure the proper seatingofthe bottle adapteriinthe bottle
`tion of solutions of CellCept Intravenous. Avoid skin contact
`and child-resistant status of the cap.
`ganciclovir capsules, respectively.
`of the solution. If such contact occurs, wash thoroughly with
`CYTOVENE-IV is available as sterile lyophilized powder in
`Dispense with patient instruction sheet and oral dispensers.
`soap and water; rinse eyes with plain water.
`strength of 500 mg per vial for intravenous administration
`Itis recommendedto write the date of expiration ofthe con-
`HOW SUPPLIED
`only. Each vial of CYTOVENE-IV contains the equivalent of
`stituted suspension on thebottle label. (The shelf-life of the
`500 mg ganciclovir as the sodium salt (46 mg sodium). Re-
`CellCept (mycophenolate mofetil capsules)
`constituted suspension is 60 days.)
`constitution with 10 mL of Sterile Water for Injection, USP,
`250 mg
`After constitution the oral suspension contains 200 mg/mL
`yields a solution with pH 11 and a ganciclovir concentration
`Blue-brown, two-piece hard gelatin capsules, printed in
`nycophenolate mofetil. Store constituted suspension at
`of approximately 50 mg/mL. Further dilution in an appro-
`black with “CellCept 250” on the blue cap and “Roche” on
`25°C (77°F); excursions permitted to 15° to 30°C (59° to
`priate intravenous solution must be performed before infu-
`the brown body. Supplied in the following presentations:
`sion (see DOSAGE AND ADMINISTRATION).
`86°F). Storage in a refrigerator at 2° to 8°C (86° to 46°F)is
`NDC Number
`Size
`acceptable. Discard any unused portion 60-days after con-
`CYTOVENE is available as 250 mg and 500 mgcapsules.
`NDC 0004-0259-01
`Bottle of 100
`stitution,
`Each capsule contains 250 mgor 500 mgganciclovir,respec-
`NDC 0004-0259-43
`Bottle of 500
`CellCept intravenous: CellCept Intravenous isan alterna-
`tively, and inactive ingredients croscarmellose sodium, mag-
`Storage: Store at 25°C (77°F); excursions permitted to 15°
`tive dosage form to CellCept capsules, tablets and oral sus-
`nesium stearate and povidone. Bothhard gelatin shells con-
`to 30°C (59°to 86°F).
`pension recommended for patients unable to take oral
`sist of gelatin, titanium ssa yellow iron oxide and
`CallCept (mycophenolate mofetil tablets)
`FD&C Blue No.2.
`CeliCept. CellCept Intravenous should be administered
`500 mg-
`within 24 hours following transplantation. CellCept Intra-
`Ganciclovir is a white to off-white crystalline powder with a
`‘Lavender-colored, caplet-shaped,film-coated tablets printed
`venous can be administered for up to 14 days; patients
`molecular formula of CgH,;N;04'and a molecular weight of
`should be switched to oral CellCept as soon as they can tol-
`in black with “CellCept 500” on one side and “Roche”on the
`255.23, The chemical namefor ganciclovir is 9-[[2-hydroxy-
`erate oral medication.
`~
`other. Supplied in the following presentations:
`1-(hydroxymethyl)ethoxy]methyl]guanine. Ganciclovir is a
`NDC Number
`Size
`CellCept Intravenous must be reconstituted and diluted to a
`polar hydrophilic compound with a solubility of 2.6 mg/mL
`NDC 0004-0260-01
`Bottle of 100
`concentration of 6 mg/mL using 5% Dextrose Injection USP.
`in water at 25°C and an n-octanol/waterpartition coefficient
`NDC 0004-0260-43
`Bottle of 500
`CellCept Intravenous is incompatible with other intrave-
`of 0.022. The pK,s for ganciclovir are 2.2 and 9.4.
`Storage and Dispensing. Information: Storeat 25°C
`Ganciclovir, when formulated as monosodium salt in the IV
`nous infusion solutions. Following reconstitution, CellCept
`' (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
`Intravenous must be administered by slow intravenous in-
`dosage form,is a white to off-white lyophilized powder with
`Dispensein light-resistant containers, such as the manufac-
`fusion over a period of NO LESS THAN 2 HOURS byeither
`a molecular formula of CgH,,.N;NaO,, and a molecular
`turer’s original containers.
`peripheral or central vein.
`weight of 277.22, The chemical name for ganciclovir sodium
`CellCept Oral Suspension (mycophenolate mofetil for oral
`CAUTION:. CELLCEPT INTRAVENOUS SOLUTION
`is 9-[[2-hydroxy-1-(hydroxymethyl) ethoxy]methyllguanine,
`suspension)
`SHOULD NEVER BE ADMINISTERED BY RAPID OR
`monosodium salt. The lyophilized powder has an aqueous
`BOLUS INTRAVENOUS INJECTION.
`Supplied as a white to off-white powderblend for constitu-
`solubility of greater than 50 mg/mL at 25°C. At physiologi-
`tion to a white to off-white mixed-fruit flavor suspension.
`Preparation of Infusion Solution (6 mg/mL):
`cal pH, ganciclovir sodium exists as the un-ionized form
`Supplied in the following presentation:
`Caution should be exercised in the handling and prepara-
`with a solubility of approximately 6 mg/mL at 37°C.
`NDC Number
`Size
`tion of solutions of CellCept Intravenous. Avoid skin contact
`All doses in this insert are specified in terms of ganciclovir,
`NDC 0004-0261-29
`225 mL bottle with bottle adapter
`ofthe solution. If such contact occurs, wash thoroughly with
`VIROLOGY
`and 2 oral dispensers
`soap and water; rinse eyes with plain water (see WARN-
`Mechanism ofAction: Ganciclovir is an acyclic nucleoside
`Storage: Store dry powder at 25°C (77°F); excursions per-
`INGS, PRECAUTIONS, ADVERSE REACTIONS, and
`mitted to 15° to 30°C (59° to 86°F). Store constituted sus-
`HANDLING AND DISPOSAL).
`analogue of 2'-deoxyguanosine that inhibits replication of
`herpes viruses. Ganciclovir has been shown to be active
`pension at 25°C (77°F); excursions permitted to 15° to 30°C
`CellCept Intravenous does not contain an antibacterial pre-
`against cytomegalovirus (CMV) and herpes simplex virus
`(59° to 86°F) for up to 60 days. Storage in a refrigerator at 2°
`servative; therefore, reconstitution and dilution of the prod-
`(HSV) in human clinical studies,
`to 8°C (36° to 46°F) is acceptable. Do not freeze,
`uct must be performed under aseptic conditions.
`To achieve anti-CMV activity, ganciclovir is phosphorylated
`CellCept intravenous (mycophenolate mofetil hydrochto-
`CellCept Intravenous infusion solution must'be prepared in
`tide for injection)=-
`first to the monophosphate form by a CMV-encoded (UL97
`two steps; the first step is a reconstitution step with 5%
`Supplied in a 20 mL,sterile vial containing the equivalent
`gene) protein kinase homologue, then to the di- and triphos-
`Dextrose Injection, USP and the second step is a dilution
`of 500 mg mycophenolate mofetil as the hydrochloride salt
`phate forms bycellular kinases. Ganciclovir triphosphate
`step with 5% Dextrose Injection, USP. A detailed description
`in cartonsof 4 vials:
`concentrations may be 100-fold greater in CMV-infected
`of the preparation is given below:
`NDC‘Number *
`than in uninfected cells, indicating preferential phosphory-
`*
`Step 1
`NDC 0004-0298-09
`p
`lation in infected cells. Ganciclovir triphosphate, once
`a, Two (2) vials of CellCept Intravenous are used for pre-
`Storage:
`formed, persists for days in the CMV-infectedcell. Ganciclo-
`paring each 1 g dose, whereas three (3) vials are
`Store powder and reconstituted/infusionsaintions at 25°C
`vir triphosphate is believed to inhibit viral DNA synthesis
`needed for each 1.5 ¢ dose. Reconstitute the contents of
`(77°F); excursions permitted to 15° to 30°C (59° to 86°F).
`by (1) competitive inhibition of viral DNA polymerases; and
`each vial byinjecting 14 mL of 5% Dextrose Injection,
`USP.
`CAUTION: Federal (USA) law prohibits dispensing with-
`(2) incorporation into viral DNA, resulting in eventual ter-
`out a prescription.
`mination of viral DNA elongation,
`b. Gently shake the vial to dissolve the drug. _'
`CellCept capsules and tablets manufactured by: Syntex
`Antiviral Activity: The median concentration ofganciclovir
`c. Inspect the resulting slightly yellow solution for partic-
`Puerto Rico, Inc., Humacao, Puerto Rico 00791
`that inhibitsCMV replication (IC,;,) in vitro (laboratory
`ulate matter and discoloration priorto furtherdilution.
`CellCept Intravenous manufactured by: Parkedale Pharma-
`strains or clinical isolates) has ranged from 0.02 to 3.48 pe/
`Discard the vial ifparticulate matteror.siiscolbnationis
`observed.
`mL. Ganciclovir inhibits mammalian cell proliferation
`ceuticals, Inc., 870 Parkdale Road, Rocheater, Michigan
`48307
`Step 2
`(CIC;,) in vitro at higher concentrations ranging from 30 to
`for:
`725 pg/mL. Bone marrow-derived colony-formingcells are
`a. To prepare a 1 g dose,furtherdilute the contents of the
`Roche Pharmaceuticals
`more sensitive (CIC5, 0.028 to 0.7 pg/mL). The relationship
`two reconstituted vials (approx. 2 X 15 mL) into 140
`Roche Laboratories Inc.
`of in vitro sensitivity of CMV to ganciclovir and clinicalre-
`mL of 5% Dextrose Injection: USP. To prepare a 1.5 g
`340 Kingsland Street
`sponse has not been established.
`dose, further dilute the contentsof the three reconsti-
`Nutley, Naw Jersey 07110-1199
`Clinical Antiviral Effect of CYTOVENE-IV and CYTOVENE
`tuted vials (approx. 3 X 15 mL) into 210 mL of 5% Dex-
`Revised: September 1998
`trose Injection USP. Thefinal concentration of both so-
`Capsules: CYTOVENE-IV: In a study of CYTOVENE-IV
`Shown in Product Identification Guide, page 334
`lutions is 6:mg mycophenolate mofetil per mL.
`treatmentof life- or sight-threatening CMV disease in im-
`b. Inspect the infusion solution for particulate matter or
`munocompromised patients, 121 of 314 patients had CMV
`discoloration. Discard the infusion solution if particu-
`cultured within 7 days prior to treatment and sequential
`late matter or discoloration is observed.
`posttreatment viral cultures of urine, blood, throat and/or
`
`Ifthe infusion solution is not prepared immediately-prior to
`semen, As judged by conversion to culture negativity, or a
`administration, the commencementof administration of the
`greater than 100-fold decrease in in vitro CMV titer, at least
`infusion solution should be within 4 hours from reconstitu-
`
`83% of patients had a virologic response with a median re-
`tion and dilution ofthe drug product. Keep solutions at 25°C
`sponse time of 7 to 15 days.
`
`(IF); excursions permitted to 15° to 30°C (59° to 86°F).
`Antiviral activity of CYTOVENE-IV was demonstrated in
`CellCept Intravenous should not be mixed or. administered
`two randomized studies for the prevention of CMV disease
`
`eoncurrently via the same infusion catheter with ‘other in-
`in transplant recipients (see table below).
`travenous drugs or infusion admixtures.
`[See first table at top of next page]
`
`Dosage Adjustments:
`In renal transplantpatients with se-
`CYTOVENECapsules: In trials comparing CYTOVENE-IV
`
`vere chronic renal impairment (GFR <25 mL/min/1.73m")
`with CYTOVENE capsules for the maintenance treatment
`
`outside of the immediate posttransplant period, doses of
`CellCept greater than 1 g administered twice'a day should
`
`
`
`
`
`
`
`
`
`CYTOVENE®-IV
`(ganciclovir sodium forinjection)
`FOR INTRAVENOUS INFUSION ONLY
`CYTOVENE®
`(ganciclovir capsules)
`FOR ORAL ADMINISTRATION
`
`R
`
`The following text is complete prescribing information
`based onofficial labeling in effect June 1999.
`
`WARNING: THE CLINICAL TOXICITY OF CYTOVENE |
`
`Continued on next page
`Consult 2000 PDR® supplements and future editions for revisions
`" ALVOGEN, Exh. 1024, p. 0003
`
`ALVOGEN, Exh. 1024, p. 0003
`
`

`

`2624/ROCHE LABORATORIES
`PHYSICIANS’ DESK REFERENC#
`Patients With Positive CMV Cultures
`
`Heart Allograft* (n=147) Bone Marrow Allograft (n=72)
`
`
` Time CYTOVENE-IV+ Placebo CYTOVENE-IV¢ Placebo
`
`
`
`
`
`
`
`
`
`of CMV retinitis in patients with AIDS,serial urine cultures
`and other available cultures (semen, biopsy specimens,
`blood and others) showed that a small proportionof patients
`remained culture-positive during maintenance therapy with
`no statistically significant differences in CMV isolation
`rates between treatment groups.
`A study of CYTOVENE capsules (1000 mg q8h) for preven-
`tion of CMV disease in individuals with advanced HIV in-
`fection (ICM 1654) evaluated antiviral activity as measured
`by CMV isolation in culture; most cultures were from urine.
`At baseline, 40% (176/436) and 44% (92/210) of ganciclovir
`and placebo recipients, respectively, had positive cultures
`(urine or blood), After 2 months.on treatment, 10% vs 44% of
`ganciclovir vs placebo recipients had positive cultures.
`Viral Resistance: The current working definition of CMV
`resistance to ganciclovir in in vitro assays'is IC, >3.0
`pe/mL (12.0 pM), CMV resistance to ganciclovir has been
`observed in individuals with AIDS and CMV retinitis who
`have never received ganciclovir therapy. Viral resistance
`has also been observed in patients receiving prolonged
`treatment for CMV retinitis with CYTOVENE-IV. In a con-
`trolled study of oral ganciclovir for prevention of AIDS-
`associated CMV disease, 364 individuals had one or more
`cultures performed after at least 90 days of ganciclovir
`treatment. Of these, 113 had at least one positive culture.
`Thelast available isolate from each subject was tested for
`reduced sensitivity, and 2 of40 were foundto beresistant to
`ganciclovir. These resistant isolates were associated with
`subsequent treatmentfailure for retinitis.
`The possibility of viral resistance should be considered in
`patients who show poorclinical response or experience per-
`sistent viral excretion during therapy. The principal mech-
`anism of resistance to ganciclovir in CMVis the decreased
`ability to form the active triphosphate moiety; resistant vi-
`ruses have been described that contain mutations in the
`UL97 gene of CMV that controls phosphorylation of ganci-
`clovir. Mutations in the viral DNA polymerase have also
`been reported to confer viral resistance to ganciclovir.
`CLINICAL PHARMACOLOGY
`
`BECAUSE THE MAJOR ELIMINATION PATHWAY FOR GAN-
`CICLOVIR IS RENAL, DOSAGE REDUCTIONS ACCORDING
`TO CREATININE CLEARANCE ARE REQUIRED FOR CY-
`TOVENE-IV AND SHOULD BE CONSIDERED FOR CY-
`TOVENE CAPSULES. FOR DOSING INSTRUCTIONSIN PA-
`TIENTS WITH RENAL IMPAIRMENT, REFER TO DOSAGE
`
`Absorption: The absolute bioavailability of oral ganciclo-
`vir under fasting conditions was approximately 5% (n=6)
`and following food was 6% to 9% (n=32). When ganciclovir
`was administeredorally with food at a total daily dosage of
`3 g/day (500 mg qh, 6 times daily and 1000 mgtid), the
`steady-state absorption as measured by area under the
`serum concentration vs time curve (AUC)over 24 hours and
`maximum serum concentrations (C,,,,) were similar follow-
`ing both regimens with an AUCy_., of 15.9 + 4.2 (mean +
`SD) and 15.4 + 4.3 pg-hr/mL and C,,,, of 1.02 + 0.24 and
`1.18 + 0.36 pg/mL, respectively (n=16).
`At the end of a 1-hour intravenous infusion of 5 mg/kg gan-
`ciclovir, total AUC ranged between 22.1 + 3.2 (n=16) and
`26.8 + 6.1 pg-hr/mL (n=16)and C,,,, ranged between 8.27 +
`1.02 (n=16) and 9.0 + 1.4 pg/mL (n=16).
`Food Effects; When CYTOVENE capsules were given with
`a meal containing 602 calories and 46.5% fat at a dosage of
`1000 mg every 8 hours to 20 HIV-positive subjects, the
`steady-state AUC increased by 22 + 22% (range: -6% to
`68%) and there was a significant prolongation of time to
`peak serum concentrations (T,,,..,) from 1.8 + 0.8 to 3.0 + 0.6
`hours and a higher C,,,.. (0.85 + 0.25 vs 0.96 + 0.27 pg/mL)
`
`Distribution: The steady-state volume of distribution of
`ganciclovir after intravenous administration was 0.74 +
`0.15 L/kg (n=98). For CYTOVENEcapsules, no correlation
`was observed between AUC andreciprocal weight (range: 55
`to 128 kg); oral dosing according to weight is not required.
`Cerebrospinal fluid concentrations obtained 0.25 to 5.67
`hours postdose in 3 patients whoreceived 2.5 mg/kgganci-
`clovir intravenously q$h or q12h ranged from 0.31 to 0.68
`pe/mL representing 24% to 70% of the respective plasma
`concentrations. Binding to plasma proteins was 1% to 2%
`over ganciclovir concentrations of 0.5 and 51 pg/mL.
`Metabolism: Following oral administration of a single
`1000 mg dose of “C-labeled ganciclovir, 86 + 3% of the ad-
`ministered dose was recovered in the feces and 5 + 1% was
`recovered in the urine (n=4). No metabolite accounted for
`more than 1% to 2% of the radioactivity recovered in urine
`
`Elimination: When administered intravenously, ganciclo-
`vir exhibits linear pharmacokinetics over the range of 1.6 to
`
`
`
`
`
`
`
`
`5/64 (8%)
`1/67 (2%)
`Pretreatment
`1/67 (16%)
`2/75 (3%)
`Week 2
`
`28/66 (43%)
`3/66 (5%)
`Week 4
`
`
`* CMV seropositive or receiving graft from seropositive donor
`1 5 mg/kg bid for 14 days followed by 6 mg/kg qd for 5 days/week for 14 days
`
`+5 mg/kg bid for 7 days followed by 5 mg/kg ad until day 100 posttransplant
`
`
`
`Estimated
`Clearance
`
`Creatinine
`(mL/min)
`
`Clearance
`Mean + SD
`
`(mL/min)
`
`46414
`128 + 63
`
`
`
`25-49
`57 +8
`44404
`
`
`
`10.7 + 5.7
`30 + 13
`
`
`
`37/37 (100%)
`2/31
`(6%)
`0/24
`(0%)
`
`35/35 (100%)
`19/28 (68%)
`16/20 (80%)
`
`Population Characteristics in Studies ICM 1653, ICM 1774 and AVI 034
`
`
`ICM 1653
`(n=121)
`
`38
`24-62
`
`116 (96%)
`
`3 (3%)
`
`11 (9%)
`
`98 (81%)
`
`9.5
`» 0-141
`
`ICM 1774
`(n=225)
`
`37
`22-56
`
`292 (99%)
`
`5 (2%)
`
`9 (4%)
`
`186 (83%)
`
`7.0
`0-80
`
`107.9 (43.0)
`
`97.6 (42.5)
`
`Median age (years)
`Range
`
`Sex
`
`Asian
`
`Ethnicity
`
`Median CD,' Count
`Range
`Mean (SD)
`Observation Time (days)
`
`AVI 084
`(n=159)
`
`39
`23-62
`
`148 (93%)
`
`7 (4%)
`
`3 (2%)
`
`140 (88%)
`
`10.0
`0-320
`
`80.9 (47.0)
`
`
`
`
`Incidence of CMV Disease at 6 Months (Kaplan-Meier Estimates)
`
`CMV Disease at 6 months
`
`
`
`Relative Risk (95% Cl)
`
`
`
`0.22 (0.10, 0.51)
`CMV Disease,” N (%)
`
`
`CMV syndromet
`
`
`CMV hepatitis
`
`
`
`CMV GIdisease
`
` CMV lungdisease
`
`
`0 (0.0%)
`
`4 (2.6%)
`
`* One or more CMV endpoints
`{ CMV syndrome: CMV viremia and unexplained fever, accompanied by malaise and/or neutropenia.
`
`was 3.5 + 0.9 hours (n=98).following IV administration and
`4.8 + 0.9 hours (n=39) following oral administration.
`Special Populations: Renal Impairment: The pharmacoki-
`netics
`following
`intravenous
`administration
`of
`CYTOVENE-IV solution were evaluated in 10 immunocom-
`promised patients with renal impairment who received
`doses ranging from 1.25 to 5.0 mg/kg.
`f
`‘i
`[See second table above]
`:
`The pharmacokinetics of ganciclovir following oral adminis-
`tration of CYTOVENE capsules were evaluated in:44 pa-
`tients, who were either solid organ transplant recipients or
`HIV positive, Apparent oral clearance of ganciclovir de-
`creased and AUC).24, increased with diminishing renal
`function (as expressed by creatinine clearance). Based on
`these observations, it is necessary to modify the dosage of
`ganciclovir in patients with renal impairment (see DOS-
`AGE AND ADMINISTRATION),
`:
`Hemodialysis reduces plasma concentrations of ganciclovir
`by about 50% after both intravenous and oral administra-
`tion.
`j
`Race/Ethnicity and Gender: The effects of race/ethnicity
`and gender were studied in subjects receiving a dose regi-
`men of 1000 mg every 8 hours. Although the numbers of
`
`Ganciclovir phrmacokinetics were also studied in 10 pediat-
`Tic patients, aged 9 months to 12 years. The pharmacoki-
`netic characteristics of ganciclovir were the sameaftersin-
`gle and multiple (q12h) intravenous doses (5 mg/kg). The
`steady-state volume of distribution was 0.64 + 0.22 Lg,
`Cosy Was 7.9 + 3.9 ng/mL, systemic clearance was 4.7 = 22
`mL/min/kg, and t, was 2.4 = 0.7 hours, The pharmacoki-
`netics of intravenous ganciclovir in pediatric patients are
`similar to those observed in adults.
`Elderly: .No studies have been conducted in adults older
`than 65 years of age.
`INDICATIONS AND USAGE
`CYTOVENE-IV is indicated for the treatment of CMV reti-
`nitis in immunocompromised patients, includingpatients
`with acquired immunodeficiency syndrome
`(AIDS).
`CYTOVENE-IV is also indicated for the prevention of CMV
`disease in transplantrecipients at risk for CMV disease(see
`CLINICAL TRIALS).
`’
`CYTOVENE capsules are indicated for the prevention of
`CMV diseasein solid organ transplantrecipients andin in-
`dividuals with advanced HIV infection at risk for develop-
`ing CMV disease. CYTOVENE capsulesare also indicated
`as an alternative to the intravenous formulation for main-
`
` RUDE
`ODRBEREREHEBSRPRSERITRRETS
`
`ALVOGEN, Exh. 1024, p. 0004
`
`

`

` was significantly lower
`
`Figuro 2ICM 1774
`
`‘Timetrom Sturtof MsintonanceTherapy(Oxy)
`(CM 1774: Timeto Progreaston of CAV Retinitis
`AYI034: Timeto Progresaion of CMY Retinitis
`
`Agen2 -Avie
`
`
`
`
`12 months
`
`18 months
`
`8% (897)
`14% (225)
`
`20% (27)
`
`fsatation of these conditions. The diagnosis of CMV ret-
`both at day 100 and day 180 posttransplant. Although the
`ais may be supported by culture of CMV from urine,
`differences in hematologic toxicities werenot statistically
`significant, the incidence of neutropenia washigher in the
`Shed, throat or other sites, but a negative CMV culture
`he vot rule out CMV retinitis.
`group treated with CYTOVENE-IV (refer to table in AD-
`VERSE EVENTS).
`Sudies With CYTOVENE-IV:
`In a retrospective, non-ran-
`ICM 1570: A second, randomized, unblinded study evalu-
`boired, single-center analysis of 41 patients with AIDS
`ci (MYretinitis diagnosed by ophthalmologic examina-
`ated 40 allogeneic bone marrow transplant recipients at
`risk for CMV disease.’ Patients underwent bronchoscopy
`Sebetween August 1983 and April 1988, treatment with
`and bronchoalveolar lavage (BAL) on day 35 posttransplant.
`‘WIOVENE-IV solution resulted in a significant delay in
`tz (median) timetofirst retinitis progression compared
`Patients with histologic, immunologic or virologic evidence
`of CMV infection in the lung were then randomized to ob-
`‘sutreated controls [105 (71) days from diagnosis vs 35
`servation or treatment with CYTOVENE-IV solution (5
`days from diagnosis]. Patients in this series received
`mg/kg bid for 14 days followed by5 mg/ke qd 5 days/week
`Soction treatment of CYTOVENE-IV 4 meyke bid for 14 to
`until ‘day 120). Four of 20 (20%) patients treated with
`‘dws followed by maintenance treatment with either 5
`CYTOVENE-IV and 14 of 20 (70%) control patients devel-
`-sgkg once daily, 7 days per week or 6 mg/kg once daily, 5
`oped interstitial pneumonia. The incidence of CMV disease
`is per week (see DOSAGE AND ADMINISTRATION).
`in the group treated with
`‘Estontrolled, randomized study conducted between Feb-
`CYTOVENE-IV, consistent with the results observed in
`ICM 1689.
`ratty 1989 and December1990," immediate treatment with
`(I0VENE-IV was compared to delayed treatment in 42
`CYTOVENE Capsules: GANO40: CYTOVENE capsules were
`stint: with AIDSand-peripheral CMV retinitis: 35 of 42:
`evaluatedin a randomized, double-blind, placebo-controlled
`wizats (19 in the immediate-treatment group and» 22 in
`study of 304 orthotopicliver transplant recipients whowere
`‘tedelayed-treatment group) were included in the analysis
`CMV seropositive or recipients of an organ from a seropos-
`‘dime to retinitis progression: Based on:masked assess- :
`itive donor. Administration of CYTOVENE capsules {1000
`set of fundus photographs, the mean (95% CI] and me-
`mg three times daily) or matching placebo commenced as
`fn (95% CI] times to progression ofretinitis were 66 days
`soon as patients were able to take medication by mouth, but
`no later than 10 days following transplantation, and contin-
`Ed) and 50 days (40, 84), respectively, in the immediate-
`twiment group:compared to 19 days [11,27] and 13.5 days
`ued through 14 weeks after transplantation. Dosing was ad-
`5 18], respectively, in the delayed-treatment group:
`justed for patients with an estimated creatinine clearance
`<50 ml/min. The incidence of CMV disease at 6 months is
`Sudies Comparing CVTOVENE Capsules to CYTOVENE-IV:
`Ss third table on previous page]
`summarized in the table below.
`.
`Tif 1683; In this randomized, open-label, parallel group
`(See fourth table on previous pagel
`cal, conducted between March 1991 and November-1992,
`CYTOVENE capsules significantly reduced the 6-month in-
`sims with AIDS and newly diagnosed CMV retinitis re-
`cidence of CMV disease in patientsat increased risk of CMV
`ssid a $-week induction course of CYTOVENE-IV solu-
`disease, including seronegative recipients of organs from se-
`ix, mg/kg bid for 14 days followed by 5 mg/kg once daily
`Topositive donors (15% [3/21] with CYTOVENE capsules vs
`| &|edditional week.* Following the 21-day intravenous in-
`44% [11/25] with placebo), andpatients receiving antilym-
`sth course, patients with stable CMV retinitis were ran-
`phocyte antibodies (5% [2/44] with CYTOVENE capsules ve
`izined to receive 20 weeks of maintenance treatment with
`33% [12/37] with placebo). The incidence ofHSV infection at
`sie CYTOVENE-IV solution, 5 mg/kg once daily, or
`6 months was 4% (5/150) in ganciclovir vs 24% (86/154) in
`(WIOVENE capsules, 500 mg6times daily (3000 mg/day).
`placebo recipients (relative risk:013; 95% CI: 0.05, 0.32).
`Te study showed that the mean [95% Cl] and median [95%
`CONTRAINDICATIONS
`(] time: to progression of CMY retinitis, as assessed by
`CYTOVENE-IV and CYTOVENE are contraindicated in pa-
`cuted reading of fundus photographs, were 57 days [44,
`tients with hypersensitivity to ganciclovir or acyclovir.
`Wand 29 days [28, 43], respectively, for patients on oral
`WARNINGS
`Sry compared to 62 days [50, 73] and 49 days [29, 61],
`sxcively, for patients on intravenous therapy. The differ-
`Hematolagic: CYTOVENE-IV and CYTOVENE should not
`(ex: (55%Cl] in the mean time to progression between the
`be administered if the absolute neutrophil count is less
`than 500 cells/pL or the platelet count is less than 25,000
`ciland intravenous therapies (oral - IV)-was -5 days [-22,
`‘ES Figure 1 for comparison of the proportion of pa-
`cells/pl. Granulocytopenia (neutropenia), anemia and
`| = remaining free of progression over time.
`thrombocytopenia have been observed in patients treated
`Tl 1774: In this three-arm,randomized, open-label, par-
`with CYTOVENE-IVand CYTOVENE.The frequency and
`grouptrial, conducted between June 1991 and August
`severity of these events vary widely in different patient
`{Si patients with AIDS and stable CMV retinitis follow-
`populations (see ADVERSE EVENTS).
`tm imm 4 weeks to 4: months ‘of treatment with
`CYTOVENE-IV and CYTOVENE should, therefore, be used
`M0VENE-IVsolution were randomized to receive main-
`with caution in patients with pre-existing cytopenias or
`‘eme treatment with CYTOVENE-IV solution; 5 mg/kg
`with a history of cytopenic reactions to other drugs, chemi-
`sx daily, CYTOVENE. capsules, 500 meg 6 times daily, or
`cals or irradiation. Granulocytopenia usually occurs during
`GIOVENE capsules, 1000 mg tid for 20 weeks. The study
`the first or second week of treatment but may occur at any
`deved that the mean [95% CI] and median [95% Cl] times
`time during treatment. Cell counts usually begin to.recover
`apmeression of CMV retinitis, as assessed by masked
`within 3 to 7 days of discontinuing drug. Colony-stimulating
`sing offundus photographs, were 54 days [48, 60] and 42
`factors have been shown to increase neutrophil and white
`ty: (31, 54], respectively, for patients on oral therapy com-
`blood cell counts in patients receiving CYTOVENE-IV solu-
`tion for treatment of CMV retinitis.
`za to 66 days (56, 76] and 54 days [41, 69], respectively,
`irutients on intravenous therapy. Thedifference [95% cv
`Impairment of Fertility: Animal-data indicate that admin-
`+ meantime to progression between the oral and intra-
`istration of ganciclovir causes inhibition ofspermatogenesis
`montherapies (oral - IV) was -12 days[-24, 0]. See Figure
`and subsequent infertility. These effects werereversible at
`.
`3. Prevention of CMVDisease In TransplantRecipients :
`ii comparison of the proportion of patients atl
`lower doses andirreversible at higher doses (see PRECAU-
`CYTOVENE-IV:. CYTOVENE-IV was evaluated in three
`Sealprogression over time.
`TIONS: Carcinogenesis, Mutagenesis and Impairment of
`57 034: I