: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 of CYTOVENE-IV contains the equivalent of 500 mg ganciclovir as the sodium salt (46 mg sodium). Reconstitution with 10 mL of Sterile Water for Injection, USP, yields a solution with pH 11 and a ganciclovir concentration of approximately 50 mg/mL. Further dilution in an appropriate intravenous solution must be performed before infusion (see DOSAGE AND ADMINISTRATION).

CYTOVENE is available as 250 mg and 500 mg capsules. Each capsule contains 250 mg or 500 mg ganciclovir, respectively, and inactive ingredients croscarmellose sodium, magnesium stearate and povidone. Both hard gelatin shells consist of gelatin, titanium dioxide, yellow iron oxide and FD&C Blue No. 2.

Ganciclovir is a white to off-white crystalline powder with a molecular formula of C₉H₁₃N₅0₄ 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 pK_as for ganciclovir are 2.2 and 9.4.

Ganciclovir, when formulated as monosodium salt in the IV dosage form, is a white to off-white lyophilized powder with a molecular formula of C₉H₁₂N₅Na0₄, and a molecular weight of 277.22. The chemical name for ganciclovir sodium is 9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]guanine, monosodium salt. The lyophilized powder has an aqueous solubility of greater than 50 mg/mL at 25°C. At physiological pH, ganciclovir sodium exists as the un-ionized form with a solubility of approximately 6 mg/mL at 37°C.

The chemical structures of ganciclovir sodium and ganciclovir are:

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 µg/mL. Ganciclovir inhibits mammalian cell proliferation (CIC₅₀) in vitro at higher concentrations ranging from 30 to 725 µg/mL. Bone marrow-derived colony-forming cells are more sensitive (CIC₅₀ 0.028 to 0.7 µg/mL). The relationship of in vitro sensitivity of CMV to ganciclovir and clinical response 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 immunocompromised 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 response 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).

Patients with Positive CMV Cultures
	Heart Allograft* (n=147)		Bone Marrow Allograft (n=72)
Time	CYTOVENE-IV#	Placebo	CYTOVENE-IV##	Placebo
Pretreatment Week 2 Week 4	1/67   (2%) 2/75   (3%) 3/66   (5%)	5/64   (8%) 11/67 (16%) 28/66 (43%)	37/37   (100%)   2/31       (6%)   0/24        (0%)	35/35  (100%) 19/28    (68%) 16/20    (80%)

*  CMV seropositive or receiving graft from seropositive donor
^#  5 mg/kg bid for 14 days followed by 6 mg/kg qd for 5 days/week for 14 days
^## 5 mg/kg bid for 7 days followed by 5 mg/kg qd until day 100 post-transplant

CYTOVENE Capsules: In trials comparing CYTOVENE-IV with CYTOVENE 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 CYTOVENE 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 >3.0 µg/mL (12.0 µM). 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 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.