GANCICLOVIR: Package Insert and Label Information

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.

INDICATIONS AND USAGE

Ganciclovir capsules are indicated for the prevention of CMV disease in solid organ transplant recipients and in individuals with advanced HIV infection at risk for developing CMV disease. Ganciclovir capsules are also indicated as an alternative to the intravenous formulation for maintenance treatment of CMV retinitis in immunocompromised patients, including patients with AIDS, in whom retinitis is stable following appropriate induction therapy and for whom the risk of more rapid progression is balanced by the benefit associated with avoiding daily IV infusions (see CLINICAL TRIALS).

SAFETY AND EFFICACY OF GANCICLOVIR HAVE NOT BEEN ESTABLISHED FOR CONGENITAL OR NEONATAL CMV DISEASE; NOT FOR THE TREATMENT OF ESTABLISHED CMV DISEASE OTHER THAN RETINITIS; NOR FOR USE IN NON-IMMUNOCOMPROMISED INDIVIDUALS. THE SAFETY AND EFFICACY OF GANCICLOVIR CAPSULES HAVE NOT BEEN ESTABLISHED FOR TREATING ANY MANIFESTATION OF CMV DISEASE OTHER THAN MAINTENANCE TREATMENT OF CMV RETINITIS.

CLINICAL TRIALS

1. Treatment of CMV Retinitis

The diagnosis of CMV retinitis should be made by indirect ophthalmoscopy. Other conditions in the differential diagnosis of CMV retinitis include candidiasis, toxoplasmosis, histoplasmosis, retinal scars and cotton wool spots, any of which may produce a retinal appearance similar to CMV. For this reason it is essential that the diagnosis of CMV be established by an ophthalmologist familiar with the retinal presentation of these conditions. The diagnosis of CMV retinitis may be supported by culture of CMV from urine, blood, throat or other sites, but a negative CMV culture does not rule out CMV retinitis.

Studies Comparing Ganciclovir-Capsules to Ganciclovir-IV:

Population Characteristics in Studies ICM 1653, ICM 1774 and AVI 034

ICM 1653 (n = 121)ICM 1774 (n = 225)AVI 034 (n = 159)
Median age (years) Range383739
24 to 6222 to 5623 to 62
SexMales116 (96%)222 (99%)148 (93%)
Female5 (4%)3 (1%)10 (6%)
EthnicityAsian3 (3%)5 (2%)7 (4%)
Black11 (9%)9 (4%)3 (2%)
Caucasian98 (81%)186 (83%)140 (88%)
Other9 (7%)25 (11%)8 (5%)
Median CD4 Count Range9.5710
0 to 1410 to 800 to 320
Mean (SD) Observation Time (days)107.9 (43)97.6 (42.5)80.9 (47)

ICM 1653: In this randomized, open-label, parallel group trial, conducted between March 1991 and November 1992, patients with AIDS and newly diagnosed CMV retinitis received a 3-week induction course of ganciclovir- IV solution, 5 mg/kg bid for 14 days followed by 5 mg/kg once daily for 1 additional week.1 Following the 21-day intravenous induction course, patients with stable CMV retinitis were randomized to receive 20 weeks of maintenance treatment with either ganciclovir-IV solution, 5 mg/kg once daily, or ganciclovir capsules, 500 mg 6 times daily (3000 mg/day). The study showed that the mean [95% CI] and median [95% CI] times to progression of CMV retinitis, as assessed by masked reading of fundus photographs, were 57 days [44, 70] and 29 days [28, 43], respectively, for patients on oral therapy compared to 62 days [50, 73] and 49 days [29, 61], respectively, for patients on intravenous therapy. The difference [95% CI] in the mean time to progression between the oral and intravenous therapies (oral — IV) was -5 days [-22, 12]. See Figure 1 for comparison of the proportion of patients remaining free of progression over time.

ICM 1774: In this three-arm, randomized, open-label, parallel group trial, conducted between June 1991 and August 1993, patients with AIDS and stable CMV retinitis following from 4 weeks to 4 months of treatment with ganciclovir-IV solution were randomized to receive maintenance treatment with ganciclovir-IV solution, 5 mg/kg once daily, ganciclovir capsules, 500 mg 6 times daily, or ganciclovir capsules, 1000 mg tid for 20 weeks. The study showed that the mean [95% CI] and median [95% CI] times to progression of CMV retinitis, as assessed by masked reading of fundus photographs, were 54 days [48, 60] and 42 days [31, 54], respectively, for patients on oral therapy compared to 66 days [56, 76] and 54 days [41, 69], respectively, for patients on intravenous therapy. The difference [95% CI] in the mean time to progression between the oral and intravenous therapies (oral — IV) was -12 days [-24, 0]. See Figure 2 for comparison of the proportion of patients remaining free of progression over time.

AVI 034: In this randomized, open-label, parallel group trial, conducted between June 1991 and February 1993, patients with AIDS and newly diagnosed (81%) or previously treated (19%) CMV retinitis who had tolerated 10 to 21 days of induction treatment with ganciclovir-IV, 5 mg/kg twice daily, were randomized to receive 20 weeks of maintenance treatment with either ganciclovir capsules, 500 mg 6 times daily or ganciclovir-IV solution, 5 mg/kg/day.2 The mean [95% CI] and median [95% CI] times to progression of CMV retinitis, as assessed by masked reading of fundus photographs, were 51 days [44, 57] and 41 days [31, 45], respectively, for patients on oral therapy compared to 62 days [52, 72] and 60 days [42, 83], respectively, for patients on intravenous therapy. The difference [95% CI] in the mean time to progression between the oral and intravenous therapies (oral — IV) was -11 days [-24, 1]. See Figure 3 for comparison of the proportion of patients remaining free of progression over time.

Comparison of other CMV retinitis outcomes between oral and IV formulations (development of bilateral retinitis, progression into Zone 1, and deterioration of visual acuity), while not definitive, showed no marked differences between treatment groups in these studies. Because of low event rates among these endpoints, these studies are underpowered to rule out significant differences in these endpoints.

Figure 1 — ICM 1653

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Figure 2 — ICM 1774

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Figure 3 — AVI 034

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2. Prevention of CMV Disease in Subjects With AIDS

ICM 1654: In a double-blind study conducted between November 1992 and July 1994, 725 subjects with AIDS, who were CMV seropositive and/or culture positive, were randomized to receive ganciclovir capsules, 1000 mg, every 8 hours, or placebo.3 The study population had a median age of 38 years (range: 21 to 69); were 99% male; were 82% Caucasian, 10% Hispanic, 7% African-American and 1% Asian; and had a median CD4 count of 21 (range: 0 to 100). The mean observation time was 351 days (range: 5 to 621). As shown in the following table, significantly more placebo recipients developed CMV disease.

Incidence of CMV Disease at 6, 12 and 18 Months After Enrollment (Kaplan-Meier Estimates)

Incidence (Number Still at Risk)
CMV Disease
GanciclovirPlacebo
6 months8% (397)11% (190)
12 months14% (225)26% (92)
18 months20% (27)39% (9)

3. Prevention of CMV Disease in Transplant Recipients

GAN040: Ganciclovir capsules were evaluated in a randomized, double-blind, placebo-controlled study of 304 orthotopic liver transplant recipients who were CMV seropositive or recipients of an organ from a seropositive donor. Administration of ganciclovir capsules (1000 mg three times daily) or matching placebo commenced as soon as patients were able to take medication by mouth, but no later than 10 days following transplantation, and continued through 14 weeks after transplantation. Dosing was adjusted for patients with an estimated creatinine clearance < 50 mL/min. The incidence of CMV disease at 6 months is summarized in the table below:

Incidence of CMV Disease at 6 Months (Kaplan-Meier Estimates)

CMV Disease at 6 months
Ganciclovir (n = 150)Placebo (n = 154)Relative Risk (95% Cl)
CMV Disease,* N (%)7 (4.8%)29 (18.9%)0.22 (0.10, 0.51)
CMV syndrome# 6 (4.1%)19 (12.4%)
CMV hepatitis1 (0.7%)9 (5.9%)
CMV GI disease0 (0%)3 (2%)
CMV lung disease0 (0%)4 (2.6%)

* One or more CMV endpoints

# CMV syndrome: CMV viremia and unexplained fever, accompanied by malaise and/or neutropenia.

Ganciclovir capsules significantly reduced the 6-month incidence of CMV disease in patients at increased risk of CMV disease, including seronegative recipients of organs from seropositive donors (15% [3/21] with ganciclovir capsules vs 44% [11/25] with placebo), and patients receiving antilymphocyte antibodies (5% [2/44] with ganciclovir capsules vs 33% [12/37] with placebo). The incidence of HSV infection at 6 months was 4% (5/150) in ganciclovir vs 24% (36/154) in placebo recipients (relative risk: 0.13; 95% CI: 0.05, 0.32).

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