Induction Dosage: The recommended initial dosage of ganciclovir for patients with normal renal function is 5 mg/kg (given intravenously at a constant rate over one hour) every 12 hours for 14 to 21 days.

Maintenance Dosage: Following induction treatment, the recommended maintenance dosage of ganciclovir is 5 mg/kg (given intravenously at a constant rate over one hour) once daily for 7 days per week, or 6 mg/kg once daily for 5 days per week.

Induction Dosage: The recommended initial dosage of ganciclovir for patients with normal renal function is 5 mg/kg (given intravenously at a constant rate over one hour) every 12 hours for 7 to 14 days.

Maintenance Dosage: Following induction, the recommended maintenance dosage of ganciclovir is 5 mg/kg (given intravenously at a constant rate over one hour) once daily for 7 days per week, or 6 mg/kg once daily for 5 days per week until 100 to 120 days post-transplantation.

Patients Undergoing Hemodialysis

Induction dosing for ganciclovir in patients undergoing hemodialysis should not exceed 1.25 mg/kg 3 times per week; and maintenance dosing should not exceed 0.625 mg/kg 3 times per week following each hemodialysis session. Ganciclovir should be given shortly after completion of the hemodialysis session, since hemodialysis has been shown to reduce plasma levels by approximately 50% [see Clinical Pharmacology (12.3)].

Adverse Reactions in Patients with CMV Retinitis

Three controlled, randomized, phase 3 trials comparing ganciclovir for injection and ganciclovir capsules for maintenance treatment of CMV retinitis have been completed. During these trials, ganciclovir for injection or ganciclovir capsules were prematurely discontinued in 9% of subjects because of adverse reactions. Selected adverse reactions and laboratory abnormalities reported during the conduct of these controlled trials are summarized in Table 2 and Table 3, respectively [see Clinical Studies (14.1)].

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 for injection is unknown. Retinal detachment occurred in 11% of patients treated with ganciclovir for injection and in 8% of patients treated with ganciclovir capsules.

Adverse Reactions in Transplant Recipients

 There have been three controlled clinical trials of ganciclovir for the prevention of CMV disease in transplant recipients. Selected laboratory abnormalities are summarized in Table 4 and Table 5 below. Table 4 shows the frequency of neutropenia and thrombocytopenia and Table 5 shows the frequency of elevated serum creatinine values observed in these trials [see Clinical Studies (14.2)].

Other Adverse Reactions in Clinical Trials in Patients with CMV Retinitis and in Transplant Recipients

Adverse drug reactions with ganciclovir for injection or ganciclovir capsules in controlled clinical studies in either subjects with AIDS or transplant recipients are listed below [see Clinical Studies (14)]. All these events occurred in at least 3 subjects.

Blood and lymphatic disorders: pancytopenia, bone marrow failure

Cardiac disorders: arrhythmia

Ear and labyrinth disorders: tinnitus, ear pain, deafness

Eye disorders: visual impairment, vitreous disorders, eye pain, conjunctivitis, macular edema

Gastrointestinal disorders: nausea, abdominal pain, dyspepsia, flatulence, constipation, mouth ulceration, dysphagia, abdominal distention, pancreatitis, gastrointestinal perforation, eructation, dry mouth

General disorders and administration site conditions: fatigue, injection site inflammation, edema, pain, malaise, asthenia, chest pain, multiple organ failure

Immune system disorders: hypersensitivity

Infections and infestations: candida infections including oral candidiasis, upper respiratory infection, influenza, urinary tract infection, cellulitis

Investigations: blood alkaline phosphatase increased, hepatic function abnormal, aspartate aminotransferase increased, alanine aminotransferase increased, creatinine clearance decreased

Metabolism and nutrition disorders: weight decreased

Musculoskeletal and connective tissue disorders: back pain, myalgia, arthralgia, muscle spasms, leg cramps, myasthenia

Nervous system disorders: headache, insomnia, dizziness, paresthesia, hypoesthesia, seizure, somnolence, dysgeusia (taste disturbance), tremor

Psychiatric disorders: depression, confusional state, anxiety, agitation, psychotic disorder, thinking abnormal, abnormal dreams

Renal and urinary disorders: kidney failure, renal function abnormal, urinary frequency, hematuria

Respiratory, thoracic and mediastinal disorders: cough, dyspnea

Skin and subcutaneous tissues disorders: dermatitis, alopecia, dry skin, urticaria, rash

Vascular disorders: hypotension, hypertension, phlebitis, vasodilation

Risk Summary

In animal studies, ganciclovir caused maternal and fetal toxicity and embryo-fetal mortality in pregnant mice and rabbits as well as teratogenicity in rabbits at exposures two times the exposure at the recommended human dose (RHD) [see Data]. Although placental transfer of ganciclovir has been shown to occur based on ex vivo experiments with human placenta and in at least one case report in a pregnant woman, no adequate human data are available to establish whether ganciclovir poses a risk to pregnancy outcomes. The background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Data

Risk Summary

No data are available regarding the presence of ganciclovir in human milk, the effects on the breastfed infant, or the effects on milk production. When ganciclovir was administered to lactating rats, ganciclovir was present in milk [see Data]. Advise nursing mothers that breastfeeding is not recommended during treatment with ganciclovir because of the potential for serious adverse reactions in nursing infants [see Warnings and Precautions (5.1, 5.3, 5.4, 5.5), Nonclinical Toxicology (13.1)]. Furthermore, the Centers for Disease Control and Prevention recommends that HIV-infected mothers not breastfeed their infants to avoid potential postnatal transmission of HIV.

Data

Pregnancy Testing

Females of reproductive potential should undergo pregnancy testing before initiation of treatment with ganciclovir [see Dosage and Administration (2.2), Use in Specific Populations (8.1)].

Contraception

Infertility

Ganciclovir at the recommended doses may cause temporary or permanent female and male infertility [see Warnings and Precautions (5.3), Nonclinical Toxicology (13.1)].

Data

Absorption

At the end of a one hour intravenous infusion of 5 mg/kg ganciclovir, total AUC ranged between 22.1 ± 3.2 (n = 16) and 26.8 ± 6.1 mcg·hr/mL (n = 16) and Cmax ranged between 8.27 ± 1.02 (n = 16) and 9.0 ± 1.4 mcg/mL (n = 16).

Distribution

The steady-state volume of distribution of ganciclovir after intravenous administration was 0.74 ± 0.15 L/kg (n = 98). Ganciclovir diffuses across the placenta. Cerebrospinal fluid concentrations obtained 0.25 to 5.67 hours post-dose in 3 patients who received 2.5 mg/kg ganciclovir intravenously every 8 hours or every 12 hours ranged from 0.31 to 0.68 mcg/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 mcg/mL.

Elimination

When administered intravenously, ganciclovir exhibits linear pharmacokinetics over the range of 1.6 to 5.0 mg/kg. Renal excretion of unchanged drug by glomerular filtration and active tubular secretion is the major route of elimination of ganciclovir.  In patients with normal renal function, 91.3 ± 5.0% (n = 4) of intravenously administered ganciclovir was recovered unmetabolized in the urine.  Systemic clearance of intravenously administered ganciclovir was 3.52 ± 0.80 mL/min/kg (n = 98) while renal clearance was 3.20 ± 0.80 mL/min/kg (n = 47), accounting for 91 ± 11% of the systemic clearance (n = 47). Half-life was 3.5 ± 0.9 hours (n = 98) following intravenous administration.

Specific Populations

Drug Interaction Studies

Table 8 and Table 9 provide a listing of established drug interaction studies with ganciclovir. Table 8 provides the effects of coadministered drug on ganciclovir plasma pharmacokinetic parameters, whereas Table 9 provides the effects of ganciclovir on plasma pharmacokinetic parameters of coadministered drug.

Mechanism of Action

Ganciclovir is a synthetic analogue of 2'-deoxyguanosine, which inhibits replication of human CMV in cell culture and in vivo. In CMV-infected cells, ganciclovir is initially phosphorylated to ganciclovir monophosphate by the viral protein kinase, pUL97. Further phosphorylation occurs by cellular kinases to produce ganciclovir triphosphate, which is then slowly metabolized intracellularly. As the phosphorylation is largely dependent on the viral kinase, phosphorylation of ganciclovir occurs preferentially in virus-infected cells. The virustatic activity of ganciclovir is due to inhibition of the viral DNA polymerase, pUL54, by ganciclovir triphosphate.

Antiviral Activity

The quantitative relationship between the cell culture susceptibility of human herpes viruses to antivirals and clinical response to antiviral therapy has not been established, and virus sensitivity testing has not been standardized. Sensitivity test results, expressed as the concentration of drug required to inhibit the growth of virus in cell culture by 50% (EC50), vary greatly depending upon a number of factors including the assay used. Thus the median concentration of ganciclovir that inhibits CMV replication (EC50 value) in cell culture (laboratory strains or clinical isolates) has ranged from 0.08 to 13.6 µM (0.02 to 3.48 mcg/mL). Ganciclovir inhibits mammalian cell proliferation (CC50 value) in cell culture at higher concentrations ranging from 118 to 2840 µM (30 to 725 mcg/mL). Bone marrow-derived colony-forming cells are more sensitive [CC50 value = 0.1 to 2.7 µM (0.028 to 0.7 mcg/mL)]. The relationship between the antiviral activity in cell culture and clinical response has not been established.

Viral Resistance

Cell Culture: CMV isolates with reduced susceptibility to ganciclovir have been selected in cell culture. Growth of CMV strains in the presence of ganciclovir resulted in the selection of amino acid substitutions in the viral protein kinase pUL97 and the viral DNA polymerase pUL54.

Cross-resistance

Cross-resistance has been reported for amino acid substitutions selected in cell culture by ganciclovir, cidofovir or foscarnet. In general, amino acid substitutions in pUL54 conferring cross-resistance to ganciclovir and cidofovir are located within the exonuclease domains and region V of the viral DNA polymerase. Whereas, amino acid substitutions conferring cross-resistance to foscarnet are diverse, but concentrate at and between regions II (codons 696-742) and III (codons 805-845). The amino acid substitutions that resulted in reduced susceptibility to ganciclovir and either cidofovir and/or foscarnet are summarized in Table 11.

Carcinogenesis, Mutagenesis

Ganciclovir was carcinogenic in mice at the same mean drug exposure in humans as at the RHD (5 mg/kg). At the dose of 1000 mg/kg/day (1.4 times the exposure at the RHD), 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 (0.1 times the exposure at the RHD), 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 (exposure estimated as 0.01 times the RHD). 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 µg/mL, respectively. In the mouse micronucleus assay, ganciclovir was clastogenic at doses of 150 and 500 mg/kg (2.8 to 10 times the exposure at the RHD) but not at doses of 50 mg/kg (exposure approximately comparable to the RHD). Ganciclovir was not mutagenic in the Ames Salmonella assay at concentrations of 500 to 5000 µg/mL.

Impairment of Fertility

Ganciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of embryolethality in female mice following doses of 90 mg/kg/day (exposures approximately 1.7 times the RHD). Ganciclovir caused decreased fertility in male mice and hypospermatogenesis in mice and dogs following daily oral or intravenous administration of doses ranging from 0.2 to 10 mg/kg. Systemic drug exposure (AUC) at the lowest dose showing toxicity in each species ranged from 0.03 to 0.1 times the exposure at the RHD.

Trial 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 for injection solution, 5 mg/kg twice daily for 14 days followed by 5 mg/kg once daily for one additional week. Following the 21-day intravenous induction course, patients with stable CMV retinitis were randomized to receive 20 weeks of maintenance treatment with either ganciclovir for injection 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.

Trial 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 for injection solution were randomized to receive maintenance treatment with ganciclovir for injection solution, 5 mg/kg once daily, ganciclovir capsules, 500 mg 6 times daily, or ganciclovir capsules, 1000 mg three times daily 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.

Trial 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 for injection, 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 for injection solution, 5 mg/kg/day. 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 Trial ICM 1653: Time to Progression of CMV Retinitis

Figure 2 Trial ICM 1774: Time to Progression of CMV Retinitis

Figure 3 Trial AVI 034: Time to Progression of Retinitis

Trial ICM 1496: In a randomized, double-blind, placebo-controlled study of 149 heart transplant recipients at risk for CMV infection (CMV seropositive or a seronegative recipient of an organ from a CMV seropositive donor), there was a reduction in the overall incidence of CMV disease in patients treated with ganciclovir. Immediately post-transplant, patients  received  ganciclovir for injection  solution  5 mg/kg  twice  daily  for  14  days  followed  by  6  mg/kg  once  daily  for 5 days/week for an additional 14 days. Twelve of the 76 (16%) patients treated with ganciclovir vs. 31 of the 73 (43%) placebo-treated patients developed CMV disease during the 120-day post-transplant observation period. No significant differences in hematologic toxicities were seen between the two treatment groups [see Adverse Reactions (6.1)].

Trial ICM 1689: In a randomized, double-blind, placebo-controlled study of 72 bone marrow transplant recipients with asymptomatic CMV infection (CMV positive culture of urine, throat or blood) there was a reduction in the incidence of CMV disease in patients treated with ganciclovir following successful hematopoietic engraftment. Patients with virologic evidence of CMV infection received ganciclovir for injection solution 5 mg/kg twice daily for 7 days followed by 5 mg/kg once daily through day 100 post-transplant. One of the 37 (3%) patients treated with ganciclovir vs. 15 of the 35 (43%) placebo-treated patients developed CMV disease during the study. At 6 months post-transplant, there continued to be a reduction in the incidence of CMV disease in patients treated with ganciclovir. Six of 37 (16%) patients treated with ganciclovir vs. 15 of the 35 (43%) placebo-treated patients developed disease through 6 months post- transplant. The overall rate of survival was higher in the group treated with ganciclovir, both at day 100 and day 180 post-transplant. Although the differences in hematologic toxicities were not statistically significant, the incidence of neutropenia was higher in the group treated with ganciclovir [see Adverse Reactions (6.1)].

Trial ICM 1570: This was a randomized, unblinded study that evaluated 40 allogeneic bone marrow transplant recipients at risk for CMV disease. Patients underwent bronchoscopy and bronchoalveolar lavage (BAL) on day 35 post-transplant. Patients with histologic, immunologic or virologic evidence of CMV infection in the lung were then randomized to observation or treatment with ganciclovir for injection solution (5 mg/kg twice daily for 14 days followed by 5 mg/kg once daily 5 days/week until day 120). Four of 20 (20%) patients treated with ganciclovir and 14 of 20 (70%) control patients developed interstitial pneumonia. The incidence of CMV disease was lower in the group treated with ganciclovir, consistent with the results observed in ICM 1689.