GANCICLOVIR

GANCICLOVIR- ganciclovir capsule
Ranbaxy Pharmaceuticals Inc.

WARNING

THE CLINICAL TOXICITY OF GANCICLOVIR INCLUDES GRANULOCYTOPENIA, ANEMIA AND THROMBOCYTOPENIA. IN ANIMAL STUDIES GANCICLOVIR WAS CARCINOGENIC, TERATOGENIC AND CAUSED ASPERMATOGENESIS.

GANCICLOVIR CAPSULES ARE INDICATED ONLY FOR PREVENTION OF CMV DISEASE IN PATIENTS WITH ADVANCED HIV INFECTION AT RISK FOR CMV DISEASE, FOR MAINTENANCE TREATMENT OF CMV RETINITIS IN IMMUNOCOMPROMISED PATIENTS, AND FOR PREVENTION OF CMV DISEASE IN SOLID ORGAN TRANSPLANT RECIPIENTS (see INDICATIONS AND USAGE).

BECAUSE GANCICLOVIR CAPSULES ARE ASSOCIATED WITH A RISK OF MORE RAPID RATE OF CMV RETINITIS PROGRESSION, THEY SHOULD BE USED AS MAINTENANCE TREATMENT ONLY IN THOSE PATIENTS FOR WHOM THIS RISK IS BALANCED BY THE BENEFIT ASSOCIATED WITH AVOIDING DAILY INTRAVENOUS INFUSIONS.

DESCRIPTION

Ganciclovir is a synthetic guanine derivative active against cytomegalovirus (CMV).

Ganciclovir is available as 250 mg and 500 mg capsules. Each capsule contains 250 mg or 500 mg ganciclovir, USP respectively, and inactive ingredients croscarmellose sodium, FD&C blue #2, gelatin, iron oxide black, iron oxide yellow, lecithin, magnesium stearate, microcrystalline cellulose, povidone, shellac, simethicone, and titanium dioxide.

Ganciclovir is a white to off-white crystalline powder with a molecular formula of C9 H13 N5 04 and a molecular weight of 255.23. The chemical name for ganciclovir is 9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]guanine. Ganciclovir is a polar hydrophilic compound with a solubility of 2.6 mg/mL in water at 25° C and an n-octanol/water partition coefficient of 0.022. The pKa s for ganciclovir are 2.2 and 9.4. The molecular structure of ganciclovir is:

structure

All doses in this insert are specified in terms of ganciclovir.

VIROLOGY

Mechanism of Action: Ganciclovir is an acyclic nucleoside analogue of 2′-deoxyguanosine 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.

To achieve anti-CMV activity, ganciclovir is phosphorylated first to the monophosphate form by a CMV-encoded (UL97 gene) protein kinase homologue, then to the di- and triphosphate forms by cellular kinases. Ganciclovir triphosphate concentrations may be 100-fold greater in CMV-infected than in uninfected cells, indicating preferential phosphorylation in infected cells. Ganciclovir triphosphate, once formed, persists for days in the CMV-infected cell. Ganciclovir 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 termination of viral DNA elongation.

Antiviral Activity: The median concentration of ganciclovir that inhibits CMV replication (IC50 ) in vitro (laboratory strains or clinical isolates) has ranged from 0.02 to 3.48 mcg/mL. Ganciclovir inhibits mammalian cell proliferation (CIC50 ) in vitro at higher concentrations ranging from 30 to 725 mcg/mL. Bone marrow-derived colony-forming cells are more sensitive (CIC50 0.028 to 0.7 mcg/mL). The relationship of in vitro sensitivity of CMV to ganciclovir and clinical response has not been established.

Clinical Antiviral Effect of Ganciclovir Capsules: In trials comparing ganciclovir IV with ganciclovir capsules for the maintenance treatment 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 of patients remained culture-positive during maintenance therapy with no statistically significant differences in CMV isolation rates between treatment groups.

A study of ganciclovir capsules (1000 mg q8h) for prevention of CMV disease in individuals with advanced HIV infection (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 IC50 > 3 mcg/mL (12 µM). CMV resistance to ganciclovir has been observed in individuals with AIDS and CMV retinitis who have never received ganciclovir therapy. In a controlled 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 of 40 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 persistent viral excretion during therapy. The principal mechanism of resistance to ganciclovir in CMV is the decreased ability to form the active triphosphate moiety; resistant viruses have been described that contain mutations in the UL97 gene of CMV that controls phosphorylation of ganciclovir. Mutations in the viral DNA polymerase have also been reported to confer viral resistance to ganciclovir.

CLINICAL PHARMACOLOGY

Pharmacokinetics

BECAUSE THE MAJOR ELIMINATION PATHWAY FOR GANCICLOVIR IS RENAL, DOSAGE REDUCTIONS ACCORDING TO CREATININE CLEARANCE SHOULD BE CONSIDERED FOR GANCICLOVIR CAPSULES. FOR DOSING INSTRUCTIONS IN PATIENTS WITH RENAL IMPAIRMENT, REFER TO DOSAGE AND ADMINISTRATION.

Absorption: The absolute bioavailability of oral ganciclovir 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 (Cmax ) were similar following both regimens with an AUC0-24 of 15.9 ± 4.2 (mean ± SD) and 15.4 ± 4.3 mcg•hr/mL and Cmax of 1.02 ± 0.24 and 1.18 ± 0.36 mcg/mL, respectively (n = 16).

Food Effects: When ganciclovir 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 (Tmax ) from 1.8 ± 0.8 to 3 ± 0.6 hours and a higher Cmax (0.85 ± 0.25 vs 0.96 ± 0.27 mcg/mL) (n = 20).

Distribution: For ganciclovir capsules, no correlation was observed between AUC and reciprocal weight (range: 55 to 128 kg); oral dosing according to weight is not required. Binding to plasma proteins was 1% to 2% over ganciclovir concentrations of 0.5 and 51 mcg/mL.

Metabolism: Following oral administration of a single 1000 mg dose of 14 C-labeled ganciclovir, 86 ± 3% of the administered 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 or feces.

Elimination: When administered orally, it exhibits linear kinetics up to a total daily dose of 4 g/day. Renal excretion of unchanged drug by glomerular filtration and active tubular secretion is the major route of elimination of ganciclovir. After oral administration of ganciclovir, steady-state is achieved within 24 hours. Renal clearance following oral administration was 3.1 ± 1.2 mL/min/kg (n = 22). Half-life was 4.8 ± 0.9 hours (n = 39) following oral administration.

Special Populations: The pharmacokinetics of ganciclovir following oral administration of ganciclovir capsules were evaluated in 44 patients, who were either solid organ transplant recipients or HIV positive. Apparent oral clearance of ganciclovir decreased and AUC0-24 h 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 DOSAGE AND ADMINISTRATION).

Hemodialysis reduces plasma concentrations of ganciclovir by about 50% after oral administration.

Race/Ethnicity and Gender: The effects of race/ethnicity and gender were studied in subjects receiving a dose regimen of 1000 mg every 8 hours. Although the numbers of blacks (16%) and Hispanics (20%) were small, there appeared to be a trend towards a lower steady-state Cmax and AUC0-8 in these subpopulations as compared to Caucasians. No definitive conclusions regarding gender differences could be made because of the small number of females (12%); however, no differences between males and females were observed.

Elderly: No studies have been conducted in adults older than 65 years of age.

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