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 14C-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 AUC0-24h 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.

General

Since ganciclovir is excreted by the kidneys, normal clearance depends on adequate renal function. IF RENAL FUNCTION IS IMPAIRED, DOSAGE ADJUSTMENTS SHOULD BE CONSIDERED FOR GANCICLOVIR CAPSULES. Such adjustments should be based on measured or estimated creatinine clearance values (see DOSAGE AND ADMINISTRATION).

Information for Patients

All patients should be informed that the major toxicities of ganciclovir are granulocytopenia (neutropenia), anemia and thrombocytopenia and that dose modifications may be required, including discontinuation. The importance of close monitoring of blood counts while on therapy should be emphasized. Patients should be informed that ganciclovir has been associated with elevations in serum creatinine.

Patients should be instructed to take ganciclovir capsules with food to maximize bioavailability.

Patients should be advised that ganciclovir has caused decreased sperm production in animals and may cause infertility in humans. Women of childbearing potential should be advised that ganciclovir causes birth defects in animals and should not be used during pregnancy. Women of childbearing potential should be advised to use effective contraception during treatment with ganciclovir. Similarly, men should be advised to practice barrier contraception during and for at least 90 days following treatment with ganciclovir.

Patients should be advised that ganciclovir causes tumors in animals. Although there is no information from human studies, ganciclovir should be considered a potential carcinogen.

All HIV+ Patients: These patients may be receiving zidovudine (Retrovir®*). Patients should be counseled that treatment with both ganciclovir and zidovudine simultaneously may not be tolerated by some patients and may result in severe granulocytopenia (neutropenia). Patients with AIDS may be receiving didanosine (Videx®#). Patients should be counseled that concomitant treatment with both ganciclovir and didanosine can cause didanosine serum concentrations to be significantly increased.

HIV+ Patients With CMV Retinitis: Ganciclovir is not a cure for CMV retinitis, and immunocompromised patients may continue to experience progression of retinitis during or following treatment. Patients should be advised to have ophthalmologic follow-up examinations at a minimum of every 4 to 6 weeks while being treated with ganciclovir. Some patients will require more frequent follow-up.

Laboratory Testing

Due to the frequency of neutropenia, anemia and thrombocytopenia in patients receiving ganciclovir (see ADVERSE EVENTS), it is recommended that complete blood counts and platelet counts be performed frequently, especially in patients in whom ganciclovir or other nucleoside analogues have previously resulted in leukopenia, or in whom neutrophil counts are less than 1000 cells/µL at the beginning of treatment. Increased serum creatinine levels have been observed in trials evaluating ganciclovir. Patients should have serum creatinine or creatinine clearance values monitored carefully to allow for dosage adjustments in renally impaired patients (see DOSAGE AND ADMINISTRATION).

Drug Interactions

Didanosine: At an oral dose of 1000 mg of ganciclovir every 8 hours and didanosine, 200 mg every 12 hours, the steady-state didanosine AUC0-12 increased 111 ± 114% (range: 10% to 493%) when didanosine was administered either 2 hours prior to or concurrent with administration of ganciclovir (n = 12 patients, 23 observations). A decrease in steady-state ganciclovir AUC of 21 ± 17% (range: -44% to 5%) was observed when didanosine was administered 2 hours prior to administration of ganciclovir, but ganciclovir AUC was not affected by the presence of didanosine when the two drugs were administered simultaneously (n = 12). There were no significant changes in renal clearance for either drug.

Zidovudine: At an oral dose of 1000 mg of ganciclovir every 8 hours, mean steady-state ganciclovir AUC0-8 decreased 17 ± 25% (range: -52% to 23%) in the presence of zidovudine, 100 mg every 4 hours (n = 12). Steady-state zidovudine AUC0-4 increased 19 ± 27% (range: -11% to 74%) in the presence of ganciclovir.

Since both zidovudine and ganciclovir have the potential to cause neutropenia and anemia, some patients may not tolerate concomitant therapy with these drugs at full dosage.

Probenecid: At an oral dose of 1000 mg of ganciclovir every 8 hours (n = 10), ganciclovir AUC0-8 increased 53 ± 91% (range: -14% to 299%) in the presence of probenecid, 500 mg every 6 hours. Renal clearance of ganciclovir decreased 22 ± 20% (range: -54% to -4%), which is consistent with an interaction involving competition for renal tubular secretion.

Imipenem-cilastatin: Generalized seizures have been reported in patients who received ganciclovir and imipenem-cilastatin. These drugs should not be used concomitantly unless the potential benefits outweigh the risks.

Other Medications: It is possible that drugs that inhibit replication of rapidly dividing cell populations such as bone marrow, spermatogonia and germinal layers of skin and gastrointestinal mucosa may have additive toxicity when administered concomitantly with ganciclovir. Therefore, drugs such as dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin, amphotericin B, trimethoprim/sulfamethoxazole combinations or other nucleoside analogues, should be considered for concomitant use with ganciclovir only if the potential benefits are judged to outweigh the risks.

No formal drug interaction studies of ganciclovir and drugs commonly used in transplant recipients have been conducted.

Carcinogenesis, MutagenesisT

Ganciclovir was carcinogenic in the mouse at oral doses of 20 and 1000 mg/kg/day (approximately 0.1x and 1.4x, respectively, the mean drug exposure in humans following the recommended intravenous dose of 5 mg/kg, based on area under the plasma concentration curve [AUC] comparisons). At the dose of 1000 mg/kg/day there was a significant increase in the incidence of tumors of the preputial gland in males, forestomach (nonglandular mucosa) in males and females, and reproductive tissues (ovaries, uterus, mammary gland, clitoral gland and vagina) and liver in females. At the dose of 20 mg/kg/day, a slightly increased incidence of tumors was noted in the preputial and harderian glands in males, forestomach in males and females, and liver in females. No carcinogenic effect was observed in mice administered ganciclovir at 1 mg/kg/day (estimated as 0.01x the human dose based on AUC comparison). Except for histiocytic sarcoma of the liver, ganciclovir- induced tumors were generally of epithelial or vascular origin. Although the preputial and clitoral glands, forestomach and harderian glands of mice do not have human counterparts, ganciclovir should be considered a potential carcinogen in humans.

Ganciclovir increased mutations in mouse lymphoma cells and DNA damage in human lymphocytes in vitro at concentrations between 50 to 500 and 250 to 2000 mcg/mL, respectively. Ganciclovir was not mutagenic in the Ames Salmonella assay at concentrations of 500 to 5000 mcg/mL.

Impairment of FertilityT

Ganciclovir caused decreased fertility in male mice and hypospermatogenesis in mice and dogs following daily administration of doses ranging from 0.2 to 10 mg/kg.

Pregnancy: Teratogenic Effects: Pregnancy Category CT

Ganciclovir has been shown to be embryotoxic in rabbits, mice and teratogenic in rabbits. Fetal resorptions were present in at least 85% of rabbits and mice administered 60 mg/kg/day and 108 mg/kg/day (2 x the human exposure based on AUC comparisons), respectively.

Effects observed in rabbits included: fetal growth retardation, embryolethality, teratogenicity and/or maternal toxicity. Teratogenic changes included cleft palate, anophthalmia/microphthalmia, aplastic organs (kidney and pancreas), hydrocephaly and brachygnathia. In mice, effects observed were maternal/fetal toxicity and embryolethality.

Ganciclovir may be teratogenic or embryotoxic at dose levels recommended for human use. There are no adequate and well-controlled studies in pregnant women. Ganciclovir should be used during pregnancy only if the potential benefits justify the potential risk to the fetus.

TFootnote: Compared with the single 5 mg/kg intravenous infusion, human exposure is doubled during the intravenous induction phase (5 mg/kg bid) and approximately halved during maintenance treatment with ganciclovir capsules (1000 mg tid). The cross-species dosage treatment should be multiplied by 2 for ganciclovir capsules.

Nursing Mothers

It is not known whether ganciclovir is excreted in human milk. However, many drugs are excreted in human milk and, because carcinogenic and teratogenic effects occurred in animals treated with ganciclovir, the possibility of serious adverse reactions from ganciclovir in nursing infants is considered likely (see Pregnancy: Teratogenic Effects: Pregnancy Category C). Mothers should be instructed to discontinue nursing if they are receiving ganciclovir. The minimum interval before nursing can safely be resumed after the last dose of ganciclovir is unknown.

Pediatric Use

SAFETY AND EFFICACY OF GANCICLOVIR IN PEDIATRIC PATIENTS HAVE NOT BEEN ESTABLISHED. THE USE OF GANCICLOVIR IN THE PEDIATRIC POPULATION WARRANTS EXTREME CAUTION DUE TO THE PROBABILITY OF LONG-TERM CARCINOGENICITY AND REPRODUCTIVE TOXICITY. ADMINISTRATION TO PEDIATRIC PATIENTS SHOULD BE UNDERTAKEN ONLY AFTER CAREFUL EVALUATION AND ONLY IF THE POTENTIAL BENEFITS OF TREATMENT OUTWEIGH THE RISKS.

Ganciclovir capsules have not been studied in pediatric patients under age 13.

Geriatric Use

The pharmacokinetic profiles of ganciclovir in elderly patients 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 ganciclovir (see DOSAGE AND ADMINISTRATION).

Clinical studies of ganciclovir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Ganciclovir 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. In addition, renal function should be monitored and dosage adjustments should be made accordingly (see Use in Patients With Renal Impairmentand DOSAGE AND ADMINISTRATION)

Use in Patients With Renal Impairment

Ganciclovir should be used with caution in patients with impaired renal function because the half-life and plasma/serum concentrations of ganciclovir will be increased due to reduced renal clearance (see DOSAGE AND ADMINISTRATION and ADVERSE EVENTS: Renal Toxicity).

Hemodialysis has been shown to reduce plasma levels of ganciclovir by approximately 50%.

Subjects With AIDS

Three controlled, randomized, phase 3 trials comparing ganciclovir-IV and ganciclovir capsules for maintenance treatment of CMV retinitis have been completed. During these trials, ganciclovir-IV or ganciclovir capsules were prematurely discontinued in 9% of subjects because of adverse events. In a placebo-controlled, randomized, phase 3 trial of ganciclovir capsules for prevention of CMV disease in AIDS, treatment was prematurely discontinued because of adverse events, new or worsening intercurrent illness, or laboratory abnormalities in 19.5% of subjects treated with ganciclovir capsules and 16% of subjects receiving placebo. Laboratory data and adverse events reported during the conduct of these controlled trials are summarized below.

Laboratory Data:

Selected Laboratory Abnormalities in Trials for Treatment of CMV Retinitis and Prevention of CMV Disease

Adverse events: The following table shows selected adverse events reported in 5% or more of the subjects in three controlled clinical trials during treatment with ganciclovir capsules (3000 mg/day) and in one controlled clinical trial in which ganciclovir capsules (3000 mg/day) were compared to placebo for the prevention of CMV disease.

The following events were frequently observed in clinical trials but occurred with equal or greater frequency in placebo-treated subjects: abdominal pain, nausea, flatulence, pneumonia, paresthesia, rash.

Retinal Detachment: Retinal detachment has been observed in subjects with CMV retinitis both before and after initiation of therapy with ganciclovir. Its relationship to therapy with ganciclovir is unknown. Retinal detachment occurred in 8% of patients treated with ganciclovir capsules. Patients with CMV retinitis should have frequent ophthalmologic evaluations to monitor the status of their retinitis and to detect any other retinal pathology.

Transplant Recipients

There has been one controlled clinical trial of ganciclovir capsules for the prevention of CMV disease in transplant recipients. Laboratory data and adverse events reported during these trials are summarized below.

Laboratory Data: The following table shows the frequency of granulocytopenia (neutropenia) and thrombocytopenia observed:

The following table shows the frequency of elevated serum creatinine values in these controlled clinical trials:

In 3 out of 4 trials, patients receiving either ganciclovir-IV solution or ganciclovir capsules had elevated serum creatinine levels when compared to those receiving placebo. Most patients in these studies also received cyclosporine. The mechanism of impairment of renal function is not known. However, careful monitoring of renal function during therapy with ganciclovir capsules is essential, especially for those patients receiving concomitant agents that may cause nephrotoxicity.

General

Other adverse events that were thought to be “probably” or “possibly” related to ganciclovir capsules in controlled clinical studies in either subjects with AIDS or transplant recipients are listed below. These events all occurred in at least 3 subjects.

Body as a Whole: abdomen enlarged, asthenia, chest pain, edema, headache, injection site inflammation, malaise, pain

Digestive System: abnormal liver function test, aphthous stomatitis, constipation, dyspepsia, eructation

Hemic and Lymphatic System: pancytopenia

Respiratory System: cough increased, dyspnea

Nervous System: abnormal dreams, anxiety, confusion, depression, dizziness, dry mouth, insomnia, seizures, somnolence, thinking abnormal, tremor

Skin and Appendages: alopecia, dry skin

Special Senses: abnormal vision, taste perversion, tinnitus, vitreous disorder

Metabolic and Nutritional Disorders: creatinine increased, SGOT increased, SGPT increased, weight loss

Cardiovascular System: hypertension, phlebitis, vasodilatation

Urogenital System: creatinine clearance decreased, kidney failure, kidney function abnormal, urinary frequency

Musculoskeletal System: arthralgia, leg cramps, myalgia, myasthenia

The following adverse events reported in patients receiving ganciclovir may be potentially fatal: gastrointestinal perforation, multiple organ failure, pancreatitis and sepsis.

Adverse Events Reported During Postmarketing Experience With Ganciclovir Capsules

The following events have been identified during postapproval use of the drug. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either the seriousness, frequency of reporting, the apparent causal connection or a combination of these factors:

acidosis, allergic reaction, anaphylactic reaction, arthritis, bronchospasm, cardiac arrest, cardiac conduction abnormality, cataracts, cholelithiasis, cholestasis, congenital anomaly, dry eyes, dysesthesia, dysphasia, elevated triglyceride levels, encephalopathy, exfoliative dermatitis, extrapyramidal reaction, facial palsy, hallucinations, hemolytic anemia, hemolytic uremic syndrome, hepatic failure, hepatitis, hypercalcemia, hyponatremia, inappropriate serum ADH, infertility, intestinal ulceration, intracranial hypertension, irritability, loss of memory, loss of sense of smell, myelopathy, oculomotor nerve paralysis, peripheral ischemia, pulmonary fibrosis, renal tubular disorder, rhabdomyolysis, Stevens-Johnson syndrome, stroke, testicular hypotrophy, Torsades de Pointes, vasculitis, ventricular tachycardia