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

`

`
`
`2000 .
`
`EDITION.
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`PHYSICIANS
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`
`
`powder or the constituted suspension. If such contact oc-
`curs, wash thoroughly with soap and water; rinse eyes with
`water.
`1. Tap the closed bottle several times to loosen the powder.
`2. Measure 94 mL of water in a graduated cylinder.
`_
`3. Add approximately half the total amount ofwater for con-
`stitution to the bottle and shake the closed bottle well for
`about 1 minute.
`4. Add the remainder of water and shake the closed bottle
`well for about 1 minute.
`5. Remove the childresistant cap and push bottle adapter
`into neck of bottle
`6. Close bottle with child-resistant cap tightly This will as-
`sure the proper seating of the bottle adapter'1n the bottle
`and child-resistant status of the cap.
`Dispense with patient instruction sheet and oral dispensers.
`It is recommended to write the date of expiration of the con-
`stituted suspension on the bottle label. (The shelf-life of the
`constituted suspension is 60 days.)
`Alter constitution the oral suspension contains 200 mg/mL
`nycophenolate mofetil. Store constituted suspension at
`25°C (77°F); excursions permitted to 15° to 30°C (59° to
`86°F). Storage in a refrigerator at 2° to 8°C (36° to 46°F) is
`acceptable. Discard any unused portion 60 days after con-
`stitution.
`CellCept Intravenous: CellCept Intravenous is an alterna-
`tive dosage form to CellCept capsules, tablets and oral sus-
`pension recommended for patients unable to take oral
`CellCept. CellCept Intravenous should be administered
`within 24 hours following transplantation. CellCept Intra-
`venous can be administered for up to 14 days; patients
`should be switched to oral CellCept as soon as they can tol-
`erate oral medication.
`'
`CellCept Intravenous must be reconstituted and diluted to a
`concentration of 6 mg/mL using 5% Dextrose Injection USP.
`CellCept Intravenous is incompatible with other intrave-
`nous infusion solutions. Following reconstitution, 'CellCept
`Intravenous must be administered by slow intravenous in-
`fusion over a period of N0 LESS THAN 2 HOURS by either
`peripheral or central vein.
`CAUTION; CELLCEPT INTRAVENOUS SOLUTION
`SHOULD NEVER BE ADMINISTERED BY RAPID 0R
`BOLUS INTRAVENOUS INJECTION.
`Preparation of Infusion Solution (6 mg] mL):
`Caution should be exercised in the handling and prepara-
`tionofeolmions of CellCept Intravenous. Avoid skin contact
`ofthe solution. If such contact occurs, wash thoroughly with
`soap and water; rinse eyes with plain water (see WARN-
`INGS, PRECAUTIONS, ADVERSE REACTIONS, and
`HANDLING AND DISPOSAL).
`CellCept Intravenous does not contain an antibacterial pre-
`servative; therefore, reconstitution and dilution of the prod-
`uct must be performed under aseptic conditions.
`Cel!Cept Intravenous infusion solution must-be prepared in
`{on steps: the first step is a reconstitution step with 5%
`Dextrose Injection, USP and the second step is a dilution
`nepwith 5% Dextrose Injection, USP. A detailed description
`of the preparation is given below:
`‘
`Step 1
`a. The (2) vials of CellCept Intravenous are used for pro-
`paring each 1 g dose, whereas three (3) vials are
`needed for each 1.5 g dose. Reconstitute the contents of
`each vial layinjecting 14 mL of 5% Dextrose Injection,
`USP.
`‘
`.
`b. Gently shake the vial to dissolve the drug.
`c. Inspect the resulting slightly yellow solution for partic-
`ulate matter and discoloration prior to further dilution.
`observed.
`Discard the vial 1fparticulate matter ordiscolorationis
`Step 2
`a. To prepare a 1 g dose, further dilute the contents of the
`two reconstituted vials (approx. 2 X 15 mL) into 140
`mL of 5% Dextrose Injection; USP. To prepare a 1.5 g
`dose, fin'ther dilute the contents of the three reconsti-
`tuted vials (approx. 3 X 15 mL) into 210 mL of 5% Dex-
`trose Injection USE The final concentration of both so;
`lutions is 62mg mycophenolate mofetil per mL.
`b. Inspect the infusion solution for particulate matter or
`discoloration Discard the infusion solution if particu-
`late matter or discoloration is observed.
`Ifthe infusion solution is not prepared immediately-prior to
`
`administration, the commencement of administration of the
`infusion solution should be within 4 hours from reconstitu-
`
`tion and dilution ofthe drug product. Keep solutions at 25°C
`(77°F); excursions permitted to 15° to 30°C (59° to 86°F).
`
`CellCept Intravenous should not be mixed ore administered
`concurrently via the same infusion catheter with-other in-
`
`travenous drugs or infusion admixtures.
`
`flange Adjustments:
`In renal transplant patients with aa-
`
`rarc chronic renal impairment (GFR <25 mIJminlL'l'sz)
`outside of the immediate posttransplent period, doses of
`
`CellCept greater than 1 g administered twicea day should
`
`
`
`
`
`
`
`appropriately (see WARNINGS, ADVERSE REACTIONS,
`and PRECAUTIONS: Laboratory Tbsts).
`HANDLING AND DISPOSAL: Mycophenolate mofetil has
`demonstrated teratogenic efl‘ects in rats and rabbits.
`CellCept tablets should not be crushed and CellCept cap-
`sules should not be opened or crushed. Avoid inhalation or
`direct contact with skin or mucous membranes of the pow-
`der contained in CellCept capsules and CellCept Oral Sus-
`pension (before or afier constitution). If such contact occurs,
`wash thoroughly with soap and water; rinse eyes with plain
`water. Should a spill occur wipe up using paper towels wet-
`ted with water to remove spilled powder or suspension.
`Caution should be exercised in the handling and prepara-
`tion of solutions of CellCept Intravenous. Avoid skin contact
`of the solution. If such contact occurs, wash thoroughly with
`soap and water; rinse eyes with plain water.
`HOW SUPPLIED
`CellCept (mycophenolate mofetil capsules)
`250 mg
`Blue-brown, two-piece hard gelatin capsules, printed in
`black with “CellCept 250” on the blue cap and “Roche" on
`the brown body. Supplied in the following presentations:
`NDC Number
`Si_ze
`NDC 0004-0259-01
`Bottle of 100
`NDC 0004-0259-43
`Bottle of. 500
`Storage: Store at 25°C (77°F); excursions permitted to 15°
`to 30°C (59°.to 86°F).
`CellCept (mycophenolate mofetil tablets)
`500 mg ,
`Lavender-colored, caplet-shaped, film-coated tablets printed
`in black with “CellCept 500” on one side and “Roche" on the
`other. Supplied in the following presentations:
`NDC Number
`Sic
`NDC 0004-0260-01
`Bottle of 100
`NDC 0004-0260-43
`Bottle of 500
`Storage and Dispensing Information: Store at 25°C
`‘ (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
`Dispense in light-resistant containers, such as the manufac-
`turer’s original containers.
`CellCept Oral Suspension lmycophenolate mofetil for oral
`suspension)
`Supplied as a white to ofl-white powder blend for constitu-
`tion to a white to off-white mixed-fruit flavor suspension.
`Supplied in the following presentation:
`NDC Number
`%
`NDC 0004-0261-29
`225 mL bottle with bottle adapter
`and 2 oral dispensers
`Storage: Store dry powder at 25°C (77°F); excursions per-
`mitted to 15° to 30°C (59° to 86°F). Store constituted sus-
`pension at 25°C (77°F); excursions permitted to 15° to 30°C
`(59" to SB‘F) for up to 60 days. Storage in a refi-Igeratorat 2°
`to 8°C [36° to 46°F) is acceptable Do not Eugene
`CellCept Intravenous (mycophenolate mofetil hydrochlo-
`ride for injection)
`"
`Supplied1n a 20 mL, sterile vial containing the equivalent
`of 500 mg mycophenolate mofetil as the hydrochloride salt
`in cartons of 4 vials:
`NDC Number "
`NDC 0004-0298-09
`'
`Storage:
`Store powder and reconstituted/infusion solutions at 25°C
`(77°F); excursions permitted to 15° to 30°C (59" to 86°F).
`CAUTION: Federal (USA) law prohibits dispensing with-
`out 3 prescription.
`CellCept capsules and tablets manufactured by: Syntex
`Puerto Rico, Inc, Humacao, Puerto Rico 00791
`CellCept Intravenous manufactured by: Parkedale Pharma-
`ceuticals, Inc, 870 Parkdale Road, Rochester, Michigan
`48307
`for:
`Roche Pharmaceuticals
`Roche Laboratories Inc.
`340 Kingsland Street
`Nutley, New Jersey 07110-1199
`Revised: September 1998
`Shown in Product Identification Guide, page 334
`
`‘
`
`CYTOVENE®-IV
`(ganciclovir sodium for injection)
`FOR INTRAVENOUS INFUSION ONLY
`CYTOVENE®
`(ganciclovir capsules)
`FOR ORAL ADMINISTRATION
`
`E
`
`The following text is complete prescribing information
`based on oflicial labeling in efl‘ect June 1999.
`
`WARNING: THE CLINICAL TOXICITY OF CYTOVENE I
`AND CYTOVENE-IV INCLUDES GRANULOCYTOPENIA,
`
`
`
`(s,ee
`PLANT RECIPIENTS
`USAGE).
`BECAUSE CYTOVENE CAPSULES ARE ASSOCIATED
`WITH A RISK OF MORE RAPID RATE OF CMV RETINITIS
`PROGRESSION, THEY SHOULD BE USED AS MAINTE-
`NANCE TREATMENT ONLV IN THOSE PATIENTS FOR
`WHOM THIS RISK IS BALANCED BY THE BENEFIT AS-
`SOCIATED WITH AVOIDING DAILY INTRAVENOUS IN-
`FUSIONS.
`
`DESCRIPTION
`Ganciclovir is a synthetic guanine derivative active against
`cytomegalovirus (CMV). CYTOVENE-IV and CYTOVENE
`are the brand names for ganciclovir sodium for injection and
`ganciclovir capsules, respectively
`CYTOVENE-IV is available as sterile lyophilized powder in
`strength of 500 mg per vial for intravenous administration
`only. Each vial “CYTOVENE—IV contains the equivalent of
`500 mg ganciclovir as the sodium salt (46 mg sodium). Re-
`constitution with 10 mL of Sterile Water for Injection, USP,
`yields a solution with pH 11 and a ganciclovir concentration
`of approximately 50 mgy‘mI. Further dilution in on appro-
`priate intravenous solution must be performed before infu-
`sion (see DOSAGE AND ADMINISTRATION).
`CYTOVENE'rs available as 250 mg and 500 mg capsules.
`Each capsule contains 250 mg or 500 mg ganciclovir,respec-
`tively, and inactive ingredients croscarmellose sodium, mag-
`nesium stearate and povidone. Both‘ hard gelatin shells con-
`FD&C Blue No.2.
`sist of gelatin, titanium dioxide, yellow iron oxide and
`Ganciclovir'1s a white to oE—white crystalline powder with a
`molecular formula of 09H13N‘504'and a molecular weight of
`255.23. The chemical name for ganciclovir is 9-[[2-hydroxy~
`1.-(hydroxyrnethyl)ethoxylmethyl]guanine. Ganciclovir is a
`polar hydroch compound with a solubility of 2.6 mg/mL
`in water at 25°C and an n-octanol/water partition coeficient
`of 0.022. The pKus for ganciclovir are 2.2 and 9.4.
`Ganciclovir, when formulated as monosodium salt in the IV
`dosage form, is a white to ofl-white lyophilized powder with
`a molecular formula of CgH12N5N304, and a molecular
`weight of 277.22. The chemical name for ganciclovir sodium
`is 9-1[2-hydroxy-1-(hydroxymethy1) ethoxy]methyl]guanine,
`monosodium salt. The lyophilized powder has an aqueous
`solubility of greater than 50 mymL at 25°C. At physiolog-
`cal pH, ganciclovir sodium exists as the un-ionized form
`with a solubility of approximately 6 mg/mL at 37°C.
`All doses in this insert are specified in terms of ganciclovir.
`VIROLOGY
`Mechanism ofacrim- Ganciclovir is an acyclic oucleoside
`analogue of 2’-deoxyguanoeine that inhibits replication of
`herpes viruses. Ganciclovir has been shown to be active
`against cytomegalovirus (CMV) and herpes simplex virus
`(HSV) in human clinical studies.
`Tb achieve anti-CMV activity, ganciclovir is phosphorylated
`first to the monophosphate form by a CMV-encoded (UL97
`gone) protein kinase homologue. then to the di- and triphos-
`pbate forms by cellular kinaaes. Ganciclovir triphosphote
`concentrations may be lilo-fold greater in CMV-infected
`than in uninfected cells, indicating preferential phosphor-y-
`lotion in infected cells. Ganciclovir triphosphate, once
`formed, persists for days in the CMV-infected cell. Ganciclo-
`vir triphosphate is believed to inhibit viral DNA synthesis
`by [1) competitive inhibition of viral DNA polymerases; and
`(2) incorporation into viral DNA. resulting in eventual ter-
`mination of viral DNA elongation.
`Antiolmlfirciciry: The median concentration ofganciclovir
`that inhibits CMV replication (1050) in vitro (laboratory
`strains or clinical isolates) has ranged from 0.02 to 3.43 pgf
`ml... Ganciclovir inhibits mammalian cell proliferation
`(CICm) in vitro at higher concentrations ranging fi'om 30 to
`725 ugmL. Bone marrow-derived colony-forming cells are
`more sensitive (CICSO 0.028 to 0.7 pg/mL). The relationship
`of in vitro sensitivity of CMV to ganciclovir and clinical re-
`sponse has not been established.
`Clinical Antiviral Effect of CYTOVENE-IV and CYTOVENE
`Capsules: CYTOVENE-IV. In a study of CYTOVENE-IV
`treatment of life- or sight-threatening CMV disease in im-
`munocompromised patients, 121 of 314 patients had CMV
`cultured within 7 days prior to treatment and sequential
`posttreatment viral cultures of urine, blood, throat and/or
`semen. As judged by conversion to culture negativity, or a
`greater than 100-fold decrease in in vitro CMV titer, at least
`83% of patients had a virologic response with a median re-
`sponse time of 7 to 15 days.
`Antiviral activity of CYTOVENE-IV was demonstrated in
`two randomized studies for the prevention of CMV disease
`in transplant recipients (see table below).
`[See first table at top of next page]
`CYTOVENE Capsules: In trials compan'ng CYTOVENE-IV
`with CYTOVENE capsules for the maintenance treatment
`
`Continued on next page
`Consult 2000 PDFIo supplements and future editions for revisions
`
`‘ ALVOGEN, Exh. 1024, p. 0003
`
`ALVOGEN, Exh. 1024, p. 0003
`
`

`

`2624/ROCHE LABORATORIES
`PHYSICIANS’ DESK REFERENCEI
`
`
`Patients With Positive CMV Cultures
`Heart Allegraft* (n=147)
`Bone Marrow Allografi (n=72)
`
`
`Time
`CYTOVENE-NT
`Placebo
`CYTOVENE-IV:
`Placebo
`
`35/35 (100%)
`37/37 (100%)
`5/64 (8%)
`1/67 (2%)
`Pretreatment
`Week 2
`2/75 (3%)
`11/67 (16%)
`2/31
`(6%)
`19/28 (68%)
`
`Week 4
`3/66 (5%)
`28/66 (43%)
`0/24
`(0%)
`16/20 (80%)
`* CMV seropositive or receiving graft from seropositive donor
`1‘ 5 mgikg bid for 14 divs followed by G mgfkg qd for 5 days'weelr for 14 days
`3' 5 mykg bid for 7 days followed by 5 mgflrg qd until day 100 potttramplant
`
` Estimated
`Clearance
`
`Creatinine
`(mL/min)
`(hours)
`
`Clearance
`Mean 1 SD
`Mean 1- SD
`
`(mL/min)
`
`
`Population Characteristics in Studies ICM 1653, ICM 1774 and AVI 034
`
`of CMV retinitis in patients with AIDS, serial urine cultures
`and other available cultures (semen. biopsy specimens,
`blood and others) showed that a small proportion ofpa'oients
`remained culture-positive during maintenance therapy with
`no statistically signifith 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 monthson 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 assaysis I05), >3.0
`pgirnL (12.0 11M}. 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.
`The last available isolate from each subject was tested for
`reduced sensitivity, and 2 of40 were found to be resistant to
`ganciclovir. These resistant isolates were associated with
`subsequent treatment failure for retinitis.
`The possibility of viral resistance should be considered in
`patients who show poor clinical response or experience per-
`sistent viral excretion during therapy The principal mech—
`anism of resistance to ganciclmlir in CMV, is the decreased
`ability to form the active triphospbate moiety: resistant vi-
`ruses have been described that contain mutations in the
`ULST gene of CMV that controls phosphorylation of ganci-
`ciovir. 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 ls RENAL, DOSAGE FIEDUCTIONS ACCORDING
`TO CREATININE CLEARANCE ARE REQUIRED FOR CY-
`TOVENE-IV AND SHOULD BE CONSIDERED FOR CV-
`TOVENE CAPSULES. FOR DOSING INSTRUCTIONS IN 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 administered orally with food at a total daily dosage of
`3 g/day (500 mg q3h, 6 times daily and 1000 mg tid), the
`steady-state absorption as measured by area under the
`serum concentration vs time curve (AUC) over 24 hours and
`maximum serum concentrations (Cum) were similar follow-
`ing both regimens with an AUCo_24 of 15.9 a 4.2 (mean 1
`SD) and 15.4 i 4.3 ug-hr/mL and cm of 1.02 t 0.24 and
`1.18 I 0.36 ug/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 1' 3.2 (n=16) and
`26.8 1' 6.1 ug-hr/mL (n=16) and CW ranged between 8.27 1'
`1.02 (n=16) and 9.0 1' 1.4 ug/mL (n=16).
`Food Efi’ects: 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 t 22% (range: -6% to
`68%) and there was a significant prolongation of lime to
`peakserumooncentrations (mel from 1.8 1- 0.8 to 3.0 : 0.6
`hours and a higher Cm, (0.85 : 0.25 vs 0.96 t 0.27 ugiml.)
`
`Distribution: The steady-state volume of distribution of
`ganciclovir after intravenous administration was 0.74 1-
`0.15 L/kg (n=98). For CYTOVENE capsules, no correlation
`was observed betweenAUC and reciprocal weight (range: 55
`to 128 kg); oral dosing according to weight is not required.
`Cerebrospinal fluid concentrations obtained 0.25 to 5.67
`hours postdoae in 3‘patients who received 2.5 mgflcg‘ganci-
`clovir intravenously ash or qlfih ranged from 0.31 to 0.68
`uyml. 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 ug/mL.
`Metabolism: Following oral administration of a single
`1000 mg dose of 1“IE-labeled ganciclovir. 86 i 3% of the ad-
`ministered dose was recovered in the feces and 5 t 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
`
`
`
`
`
`Median age (years)
`Range
`
`Sex
`
`Asian
`
`Ethnicity
`
`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
`
`222 (99%)
`
`5 (2%)
`
`9 (4%)
`
`186 (83%)
`
`7.0
`0—80
`
`
`
`AVI 034
`(n=159)
`
`39
`23—62
`
`14s (93%)
`
`7 (4%)
`
`3 (2%)
`
`140 (88%)
`
`10.0
`0—320
`
`
`
`Median CD4 Count
`Range
`Mean (SD)
`Observation Time (days)
`107.9 (43.0)
`97.6 (42.5)
`80.9 (47.0)
`
`Incidence of CMV Disease at 6 Months (Kaplan-Meier Estimates)
`
`CMV Disease at 6 months
`
`
`Relative Risk (95% Cl)
`
`
`
`
`CMV Disease,* N (%)
`
`CMV syndrome‘l'
`
`
`
`0.22 (0.10, 0.51)
`
`
`CMV hepatitis
`
`
` CMV GI disease
`
`
`
` CMV lung disease
`0 (0.0%)
`
`
`* One or more CMV endpoints
`T CMV syndrome: CMV viremia and unexplained fever, accompanied by malaise and/or neutropcoia.
`
`was 3.5 1- 0.9 hours (n=98);following IV administration and
`4.8 1- 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 nag/kg.
`'
`‘
`[See second table above]
`3
`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 ganoiclovir de-
`creased and AUCMM, 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.
`’
`Race/Ethnicity and Gender: The efi‘ects of racaethnicity
`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-
`ric patients, aged 9 months to 12 years. The pharmacoki-
`netic characteristics of ganciclovir were the same afier sin-
`gle and multiple (q12h) intravenous doses (5 mg/kg). The
`steady-state volume of distribution was 0.64 i 0.22 Mg,
`Cm was 7.9 t 3.9 pgimL. systemic clearance was 4.? : 22
`niIJniinJ'kg, and t», was 2.4 : 0.? hours. The pharmatnifl"
`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, including patients
`with acquired immunodeficiency syndrome
`(AIDS).
`CYTOVENE-IV is also indicated for the prevention of CMV
`disease in transplant recipients at risk for CMV disease (see
`CLINICAL TRIALS).
`‘
`CYTOVENE capsules are indicated for the prevention of
`CMV disease in solid organ transplant recipients and in in-
`dividuals with advanced HIV infection at risk for develop
`ing CMV disease. CYTOVENE capsules are also indicated
`as an alternative to the intravenous formulation for main-
`
`
`
` 'rrwarrant-E
`EE‘Eigag‘EEEESEE
`
`ALVOGEN, Exh. 1024, p. 0004
`
`

`

`imitation of these conditions. The diagnosis ofCMV ret-
`hit-s may be supported by culture of CMV from urine,
`lief throat or other sites, but a negative CMV culture
`Jinan rule out CMV retinitis.
`ands; With CYTOVENE-III:
`In a retrospective, non-ran-
`.L‘mrcd. single—center analysis of 41 patients With AIDS
`nlClIV retinitis diagnosed by ophthalmologic examina-
`2between August 1983 and April 1988, treatment with
`'FHBVENEN solution resulted in a significant delay in
`a: (median) time to first retinitis progression compared
`untreated controls [105 (71) days from diagnosis vs 35
`aldays from diagnosis]. Patients in this series received
`fiction treatment ofCWOVEN'EJV 5 mgr‘ltg bid for 141.0
`:fliays followed by maintenance treatment with either 5
`apropos daily, 7 days per week or 6 mgflcg once daily, 5
`.hgs per week. (see DOSAGE AND ADlIflL'lSTRATIDN).
`Ihecoutrolled, randomized study conducted between Feb-
`mry 1939 and December 1990,1 immediate treatment with
`Eiffll'Eh'E-IV was compared to delayed treatmentIn 42
`mowileIDS andperrpheml CMV retinitis; 35 ofJ12.
`pinata (13 in the immediate-treatment group and 22 in
`'irddayed-treatment group) were includedIn the analysis
`Elliot to retinitis progression; Based onsmasked assess- =
`z: of iuadus photographs; the mean {95% CI] and me-
`te. use CI} times to progression of retinitis were 66 days
`Iii-ti and 50 days {40. 3‘1}. respectively, in the immediate-
`nameat group-compared to 19 days [11, 27] and 13.5 days
`3.18], respectively, in the delayed-treatment group;
`m Comparing CYTOVENE Capsules to CYTOVENE-IV:
`Seabird table on previous page]
`H 1656‘: In this randomized, open-label, parallel group
`alouducted between March 1991 and November 1992,
`madame and newly diagnosed CMV retinitis rev
`are-é [13-week induction course of C'I‘I‘OVEN‘E-IV solu-
`.:'o,5mg'kg bid for 111 days followed by 5 mgikg once daily
`isladditional weal-1.2 Following the 21—day intravenous in—
`mice course, patients with stable CMV retinitis were ran—
`'mitcdto receive 20 weeks of maintenance treatment with
`use C‘I‘IOVEN'E-IV solution. 5 mgfltg once daily, or
`HYGIENE capsules, 500 mg 6- times daily (3000 mg/day).
`he only :howed that the mean [95% CI] and median [95%
`film to progression of CMV retinitis, as assessed by
`:ehdrasding of'fimdua photographs, were 5'? days [44.
`Iii, and 29 days [28, 43], respectively, for patients on oral
`Improimpored to 62, days [50. 73] and J19 days [29. 61].
`v " 'ely, for patients on intravenous therapy. The difl'er-
`£9052- Cl] in the mean time to progression between the
`salad intraienous therapies (oral - IV) was -5 days {-22.
`dies figure 1 for comparison of the-proportion of pa-
`12:: remaining free of progression over time.
`till 1774: In dds three-arm;randomized; open-label, par-
`élaoup trial, conducted between June 1991 and August
`Diagnostics with AIDS and stable CMV retinitis follow-
`1; iron 4 weeks to 4: months iof treatment with
`ITI‘Dl'Eh'E-le solution were randomized to receive main-
`znn treatment with CYTOVENE-IV solution; 5 mg/kg
`malady, CITOVENE capsules. 500 mg 5 times daily. or
`BIWENE capsules, 1000 mg bid for 20 weeks. The study
`ind that the mean [95% CH and median [95% Cl] times
`adaptation of CMV retinitis, as assessed by masked
`afingoifilndusphotographs, were 54 days [48. 601 and 42
`trail! 54] respectively. for patients on oral therapy com-
`and to 66 days [55 T6] and 5J1 days [4-1, 69], respectively.
`bulimia an intravenous therapy. The difl‘erenoe [95% CH
`its meantime to progression between the oral and intra-
`mdcrpa (oral IV)was-12 days [-24, 0]. See Figure
`:hoomparison of the proportion of patients remaining
`hdymgrcssion over time.
`81034: In this randomized, open-label, parallel group
`included between June 1991. and February 1993, pa-
`J'xtt with AIDS and- newly diagnosed (81%,) or previously
`“all15%) CMV retinitis who had tolerated 10 to 21 days
`inflation treatment with CYTOVENE—IV. 5 mykg twice
`ismmzdomized to native 20 weeks of maintenance
`mtwith either CYTOVENE capsales, 500 mg 6
`mink,- or CYTGVENEJV solution, 5 mgfligldays The
`Inlhi‘bCli and median [95% 01'] times to progression of
`mm as assessed by masked reading of fondue
`tombs, were 51 days [44. 57'] auddd days [31, J15]. rev
`wildflor patients on. oral therapy compared to 62 days
`Elli ml 60 dm (J12. 33l,- respectively, for patients on
`.. m therapy. The difference [95% CI] in thegmean
`in: progression between the oral andzintravenous ther-
`piod - IV] was -11 days {-24, 1|. See Eigure 3 for com-
`..
`ofthe proportion of patients remaining free of pro-
`..1 over time.
`harbour of other CMV retinitis outcomes between oral
`'
`filmmulations (development of bilateral retinitis, pro-
`u into Zone 1, and deterioration of visual acuity), .
`addefinifive, showed no marked difl'erences between
`will groups in these studies:. Because of low event
`
`J
`
`mmmumww)
`
`120
`
`130
`
`00
`
`W
`
`Hurtf- ICM 1774
`
`ICII lfldszwPrWMNVMm.
`
`
`
`mavmw
`
`AVIW:TImtoProgrudmoICIIV/Ws
`
`
`
`2. Prevention of- CMV Disease in Subjects With AIDS
`ICM 1654: In a double-blind study conducted between No-
`vember 1992 and July- 1994, 725 subjects with AlDS, who
`were CMV seropositive and/or culture positive, were ran-
`domized to receive CY'IUVENE {2981035.1000 mg, every 8_
`hours, or placebo.“ The study population had a median age
`of 38 years (range. 21 to 69); were 99% male; were 82% CauJ
`casian, 10% Hispanic, 7% African-American and 1% Asian;
`and had a median CD4 count of 2.1 (range; _0 to 100). The
`mean observation time was 351 days (range: 5 to 621). As
`shown'In the following table, significantly more placebo re-
`cipients developed CMV disease.
`.
`.
`
`Incidence of CMV Disease at 6,12 and 18 Months
`After Enrollment (Kaplan--Meier Estimates)
`
`Incidence (Number Still At Risk)
`CMVDisaase
`-
`
`
`
`
`:11%<190)
`26% (92)
`12 months
`14% (225‘)
`
`
`39% (9) -,
`18 months
`' "
`20% (27)
`
`3. Prevention of CMV Disease In ‘I'ransplant5flecipie'nts '-
`.
`CYTOVENE-IV: CYTOVENE-IV was evaluated in three
`randomized, controlled trials of prevention of CMV disease
`in organ transplant recipients.
`ICM 1493;1n a. randomized, double-blind placebo-con-
`trolled stndy of 149 heart transplant recipients‘ at risk for
`CMV infection (CMV seropositive or a seronegative recipi-
`ent ofan organ from a CMV seropositn've donor), there was a
`statistically significant reduction in the overall incidence of
`CMV disease inpatients treated with CYTOVENE-IV. Im-
`mediately posttransplant, patients received: CYTOVENE-IV
`solution 5 mg/kg bid for 14 days followed‘by 6 mg/kg qd for
`5 days/week for an additional 14 days. Twelve of the 76
`(16%)-patients treated with CYTOVENE-IV vs 31 of the 73
`(43%) placebo-treated patientsdeveloped CMV disease dur-
`ing the 120-day posttransplant observatibn period. No sig-
`nificant difi‘erenoes1n hematologic toxicities were seen be-
`EVENTS).
`tween the two treatment groups(refer to table inADVERSE
`ICM 1389: In a randomized double-blind. placebo-con-
`trolled atudy of 72 bone marrow transplant recipients;s with
`asymptomatic CMV infection (CMV positive culture of
`urine; throat 'or blood) there was a statistically significant
`reduction in the incidence of CMV disease in patients
`treated with :CYTOVENE-IV following successful hemato-
`
`
`
`both 'at day '100 and day 130 postnansphnt. Although the
`did‘ercnccs in hematologic toidc'rties were. not statistically
`significant, the'incidenee ofneutropenia was higher in the
`group treated with CYTO'VENE-IV (refer to table in ADv
`VERSE Mil-“13).
`ICM 15m- A second, randomized unblindcd study evalu-
`ated 40 allogeneic bone marrow transplant recipients at
`1151: for CMV disease. Patients