Cytovene (Ganciclovir Sodium)

CYTOVENE® Capsules CYTOVENE® Injection

Roche

Ganciclovir

Ganciclovir Sodium

Antiviral

Action And Clinical Pharmacology: Ganciclovir is a synthetic nucleoside analog of guanine which inhibits the replication of herpes viruses both in vitro and in vivo.

Intracellular ganciclovir is phosphorylated to ganciclovir monophosphate by a cellular deoxyguanosine kinase. Further phosphorylation occurs by several cellular kinases to produce ganciclovir triphosphate. It has been shown in vitro that the levels of ganciclovir triphosphate are as much as 100-fold greater in CMV-infected cells than noninfected cells. Thus, there is a preferential phosphorylation of ganciclovir in virus-infected cells. In virus-infected cells, ganciclovir triphosphate is metabolized slowly, with 60 to 70% remaining intracellularly 18 hours after removal of ganciclovir from the extracellular fluid. The antiviral activity of ganciclovir is the result of inhibition of viral DNA synthesis by 2 modes: (1) ganciclovir triphosphate competitively inhibits dGTP incorporation into DNA by DNA polymerase and (2) incorporation of ganciclovir triphosphate into viral DNA causes subsequent termination or very limited viral DNA elongation.

Ganciclovir inhibits mammalian cell proliferation in vitro at concentrations from 10 to 60 µg/mL, with bone marrow colony forming cells being most sensitive (IC50 of 10 µg/mL).

Pharmacokinetics: The pharmacokinetics of i.v. ganciclovir have been evaluated in immunocompromised patients with serious CMV disease. In patients with normal renal function, the plasma half-life was 2.9±1.3 hours. Dose independent kinetics were demonstrated over the range of 1.6 to 5.0 mg/kg. Renal excretion through both glomerular filtration and active tubular secretion is the major route of elimination of ganciclovir (see Precautions, Patients with Renal Impairment). At the end of a 1 hour i.v. infusion of 5 mg/kg ganciclovir, total AUC ranged between 22.1±3.2 (n=16) and 26.8±6.1 µg.h/mL (n=16) and Cmax ranged between 8.27±1.02 (n=16) and 9.0±1.4 µg/mL (n=16).

The absolute bioavailability of ganciclovir following oral administration of ganciclovir capsules 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 dose of 3 g/day (500 mg q3h, 6 times daily and 1 000 mg t.i.d.), 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 µg.h/mL and Cmax of 1.02±0.24 and 1.18±0.36 µg/mL, respectively (n=16).

Food Effects: When ganciclovir capsules were given with a meal containing 602 calories and 46.5% fat at a dose of 1 000 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±0.6 hours and a higher Cmax (0.85±0.25 vs 0.96±0.27 µg/mL) (n=20).

Indications And Clinical Uses: I.V.: For the treatment of CMV retinitis in immunocompromised patients, including patients with acquired immunodeficiency syndrome (AIDS), iatrogenic suppression secondary to organ transplantation or those administered chemotherapy for neoplasia. Ganciclovir i.v. solution is also indicated for the prevention of CMV disease in transplant recipients at risk for CMV disease.

Oral: For the prevention of CMV disease in solid organ transplant recipients at risk of developing CMV disease.

For the maintenance treatment of CMV retinitis in immunocompromised patients, including patients with AIDS, where the retinitis is stable following at least 3 weeks of therapy with ganciclovir i.v. Oral ganciclovir provides an alternative to continued i.v. therapy following satisfactory induction treatment in patients who have been diagnosed with CMV retinitis, and for whom the risk of more rapid progression is balanced by the benefit associated with avoiding daily i.v. infusions.

Diagnosis of CMV Retinitis: The diagnosis of CMV retinitis is primarily an ophthalmologic one and 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 aided by culture of CMV from urine, blood, throat, or other sites, but a negative CMV culture does not rule out CMV retinitis.

Contra-Indications: In pregnant women and in patients who are hypersensitive to ganciclovir or to acyclovir.

Manufacturers’ Warnings In Clinical States: The clinical toxicity of ganciclovir includes leukopenia and thrombocytopenia. In animal and in vitro studies ganciclovir caused aspermatogenesis, mutagenicity, teratogenicity and carcinogenicity; therefore it should be considered a potential teratogen and carcinogen in humans. Ganciclovir is indicated for use only in immunocompromised patients, where the potential benefit outweighs the risks stated herein. The safety and efficacy of ganciclovir have not been evaluated for congenital or neonatal CMV disease, nor for treatment of CMV infection in nonimmunocompromised individuals.

Hematologic: Ganciclovir should not be administered if the absolute neutrophil count is less than 0.5´10cells/L or the platelet count is less than 25´10cells/L. Granulocytopenia (neutropenia) and thrombocytopenia have been observed in patients treated with ganciclovir. The frequency and severity of these events vary widely in different patient populations (see Adverse Effects). Ganciclovir should therefore, be used with caution in patients with pre-existing cytopenias, or with a history of cytopenic reactions to other drugs, chemicals, or irradiation.

Neutropenia: Neutropenia typically occurs during the first or second week of induction therapy and prior to administration of a total cumulative dose of 200 mg/kg of ganciclovir i.v. but may occur at any time during treatment. Evidence of recovery of cell counts usually occurs within 3 to 7 days after discontinuing the drug. Colony stimulating factors have been shown to increase neutrophil and white blood cell counts in patients receiving ganciclovir i.v. solution for treatment of CMV retinitis.

Thrombocytopenia: Thrombocytopenia (platelet count of less than 50´10L) was observed in patients treated with ganciclovir. Immunodeficient patients without AIDS were more likely to develop lowered platelet counts than those with AIDS. Patients with initial platelet counts less than 100´10L were also at increased risk of this toxicity of ganciclovir.

Pregnancy and Reproduction: Animal data indicate that administration of ganciclovir caused inhibition of spermatogenesis and infertility, which were reversible at lower doses and irreversible at higher doses. Although clinical data have not yet been obtained regarding this effect, it is considered likely that i.v. ganciclovir in the recommended doses will result in temporary or permanent male infertility. Animal data also indicate that permanent suppression of fertility in women may occur.

Mutagenic tests of ganciclovir have indicated the potential for altering the chromosomes, therefore male and female patients should be advised to practise barrier contraception during treatment with ganciclovir, and males for an additional 90 days following treatment.

Female mice exhibited decreased fertility, decreased mating behavior, and increased embryolethality after daily i.v. doses of 90 mg/kg.

In male mice, fertility was decreased after daily i.v. doses of ³2 mg/kg and daily oral doses of ³10 mg/kg. These effects were reversible after daily i.v. doses of 2 mg/kg and daily oral doses of 10 mg/kg, but were irreversible or incompletely reversible after daily i.v. doses of 10 mg/kg and daily oral doses of 100 or 1 000 mg/kg. Ganciclovir has also caused hypospermatogenesis in rats after daily oral doses of ³100 mg/kg and in dogs after daily i.v. and oral doses of ³0.4 mg/kg and 0.2 mg/kg, respectively.

Ganciclovir caused maternal/fetal toxicity and embryolethality in mice, at daily doses of 108 mg/kg (see also Lactation).

Ganciclovir caused fetal growth retardation, embryolethality, teratogenicity, and/or maternal toxicity in mice at daily doses of 20 or 60 mg/kg. Teratogenic changes seen included cleft palate, an/microphthalmia, aplastic organs (kidney and pancreas), hydrocephaly, and brachygnathia.

Lactation : It is not known if ganciclovir is excreted in human milk. Since many drugs are, 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. Ganciclovir should not be given to breast-feeding mothers. The minimum interval before nursing can safely be resumed after the last dose of ganciclovir is unknown.

Daily i.v. doses of 90 mg/kg ganciclovir administered to female mice prior to mating and during gestation and lactation caused hypoplasia of the testes and seminal vesicles in the month-old offspring, as well as pathologic changes in the nonglandular region of the stomach.

Precautions: General: In clinical studies with ganciclovir i.v., the maximum single dose studied has been 6 mg/kg infused i.v. over 1 hour. It is likely that larger doses, or more rapid infusions, could result in increased toxicity. Administration of ganciclovir i.v. solution should be accompanied by adequate hydration.

Solutions of ganciclovir have a high pH (approximately 11) and may cause phlebitis and/or pain at the site of i.v. infusion. Therefore, care must be taken to infuse ganciclovir solutions only into veins with adequate blood flow to afford rapid dilution and distribution.

Information for the Patient: 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 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 practise 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.

Patients with AIDS and 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 followup examinations at a minimum of every 4 to 6 weeks while being treated with ganciclovir. Some patients will require more frequent followup. Patients with AIDS may be receiving zidovudine (ZDV; AZT); 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 (ddI); patients should be counseled that concomitant treatment with both ganciclovir and didanosine can cause didanosine levels to be significantly increased.

Transplant Recipients: Transplant recipients should be counseled regarding the high frequency of impaired renal function in transplant recipients who received ganciclovir i.v. solution in controlled clinical trials, particularly in patients receiving concomitant administration of nephrotoxic agents such as cyclosporine and amphotericin B. Although the specific mechanism of this toxicity, which in most cases was reversible, has not been determined, the higher rate of renal impairment in patients receiving i.v. administered ganciclovir compared with those who received placebo in the same trials may indicate that ganciclovir played a significant role.

Drug Interactions: Probenecid: At a dose of 1 000 mg of ganciclovir oral every 8 hours, ganciclovir serum concentrations increased 45% in the presence of probenecid, 500 mg every 6 hours. Renal clearance of ganciclovir decreased 22%, which is consistent with an interaction involving competition for renal tubular secretion.

Zidovudine: At a dose of 1 000 mg of ganciclovir oral every 8 hours, there was a trend for decreased ganciclovir AUC in the presence of zidovudine, 100 mg every 4 hours (18%), but the decrease was not statistically significant. There was a statistically significant increase in AUC for zidovudine (15%) in the presence of ganciclovir.

Since both zidovudine and ganciclovir have the potential to cause neutropenia and anemia, many patients will not tolerate combination therapy with these two drugs at full dosage strength.
Didanosine: At a dose of 1 000 mg of ganciclovir oral every 8 hours, the steady-state AUC0-12 for didanosine, 200 mg every 12 hours, increased approximately 80% when didanosine was administered 2 hours prior to or concurrently with administration of ganciclovir capsules. Decreased steady-state AUC (23%) was observed for ganciclovir oral in the presence of didanosine when the drug was administered 2 hours prior to administration of ganciclovir capsules, but AUC was not affected by the presence of didanosine when the two drugs were administered simultaneously. There were no significant changes in renal clearance for either drug.

When the standard ganciclovir i.v. induction dose (5 mg/kg infused over 1 hour every 12 hours) was coadministered with didanosine at a dose of 200 mg orally every 12 hours, the steady-state didanosine AUC0-12 increased 70±40% (range, 3 to 121%, n=11) and Cmax increased 49±48% (range, -28 to 125%). In a separate study, when the standard i.v. ganciclovir maintenance dose (5 mg/kg infused over 1 hour every 24 hours) was coadministered with didanosine at a dose of 200 mg orally every 12 hours, didanosine AUC0-12 increased 50±26% (range, 22 to 110%, n=11) and Cmax increased 36±36% (range, -27 to 94%) over the first didanosine dosing interval. Didanosine plasma concentrations (AUC12-24) were unchanged during the dosing intervals when ganciclovir was not coadministered. Ganciclovir pharmacokinetics were not affected by didanosine. In neither study were there significant changes in the renal clearance of either drug.

Didanosine has been associated with pancreatitis. In 3 controlled trials, pancreatitis was reported in 2% of patients taking didanosine and ganciclovir. The rates of pancreatitis were similar in the ganciclovir i.v. solution and capsule groups.

Other than laboratory abnormalities, concomitant treatment with zidovudine, didanosine, or zalcitabine did not appear to affect the type or frequency of reported adverse events, with the exception of moderately increased rate of diarrhea. Among patients taking ganciclovir, the diarrhea rates were 51% and 49% respectively with didanosine versus 39% and 35% respectively, without didanosine.

Imipenem-Cilastatin: Generalized seizures have been reported in patients who received ganciclovir i.v. solution and in patients who received 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 analogs, 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 i.v. and drugs commonly used in transplant recipients have been conducted. Allograft recipients treated with ganciclovir i.v. in 3 controlled clinical studies also received a variety of concomitant medications, including amphotericin B, azathioprine, cyclosporine, muromonab-CD3 (OKT3), and/or prednisone. Increases in serum creatinine were observed in patients treated with ganciclovir plus either cyclosporine or amphotericin B, drugs with known potential for nephrotoxicity (see Adverse Effects). In a retrospective analysis of 93 liver allograft recipients receiving ganciclovir (5 mg/kg infused over 1 hour every 12 hours) and oral cyclosporine (at therapeutic doses), there was no evidence of an effect on cyclosporine whole blood concentrations.

Laboratory Testing: Due to the frequency of neutropenia, anemia or thrombocytopenia observed in patients receiving ganciclovir (see Adverse Effects), it is recommended that complete blood counts and platelet counts be performed frequently, especially in patients in whom ganciclovir or other nucleoside analogs have previously resulted in cytopenia, or in whom pretreatment neutrophil counts are less than 1´10L. Because dosing may be modified in patients with renal impairment and because of the incidence of increased serum creatinine levels that have been observed in transplant recipients treated with ganciclovir, patients should have serum creatinine or creatinine clearance monitored carefully (see also sections on renal adverse events under Adverse Effects and Dosage, Patient Monitoring).

Mutagenesis/Carcinogenesis: Ganciclovir caused point mutations and chromosomal damage in mammalian cells in vitro and in vivo, but did not cause point mutations in bacterial or yeast cells, dominant lethality in mice, or morphologically transformed cells in vitro.

In a study conducted over 18 months, ganciclovir was carcinogenic in the mouse after oral doses of 20 and 1 000 mg/kg/day. The principally affected tissues at the dose of 1 000 mg/kg/day were the preputial gland in males, forestomach (nonglandular mucosa) in males and females, and reproductive tissues and liver in females. At dose of 20 mg/kg/day, slightly increased tumor incidences occurred in the preputial and harderian glands in males, forestomach in males and females, and liver in females. All ganciclovir-induced tumors were of epithelial or vascular origin except for histiocytic sarcoma of the liver. No carcinogenic effect occurred at 1 mg/kg/day. The preputial and clitoral glands, forestomach and harderian glands of mice have no human counterpart. Ganciclovir should be considered a potential carcinogen in humans.

Children: Safety and efficacy of ganciclovir in children have not been established. The use of ganciclovir in children warrants extreme caution due to the probability of long-term carcinogenicity and reproductive toxicity. Administration to children should be undertaken only after careful evaluation and only if the potential benefits of treatment outweigh these considerable risks.

There has been very limited clinical experience using ganciclovir for the treatment of CMV retinitis in patients under the age of 12 years.

Renal Considerations: Administration of ganciclovir i.v. should be accompanied by adequate hydration, since ganciclovir is excreted by the kidneys and normal clearance depends upon adequate renal function. If renal function is impaired, dosage adjustments are recommended. Such adjustments should be based on creatinine clearance (see Dosage).

It is possible that probenecid, as well as other drugs which inhibit renal tubular secretion or resorption, may reduce renal clearance of ganciclovir and could increase its plasma half-life.

Patients with Renal Impairment: Ganciclovir should be used with caution in patients with impaired renal function. Both the plasma half-life of ganciclovir as well as peak plasma levels are increased in patients with elevated serum creatinine levels. In a small number of patients who were undergoing dialysis, ganciclovir plasma levels were reduced by approximately 50% following dialysis (see Dosage).

Geriatrics: No studies on the efficacy or safety of ganciclovir specifically in elderly patients have been conducted. Since elderly individuals may have reduced renal function, ganciclovir should be administered to the elderly patients with care and with special consideration of their renal status (see Dosage).

Adverse Reactions: Adverse events that occurred during clinical trials of ganciclovir are summarized below, according to the participating study subject population.

Subjects with AIDS: Three controlled, randomized, phase 3 trials comparing ganciclovir i.v. and ganciclovir oral for maintenance treatment of CMV retinitis have been completed. During these trials, ganciclovir was prematurely discontinued because of adverse events, new or worsening intercurrent illnesses, or laboratory abnormalities in 9% of the subjects.

Overall, patients treated with ganciclovir i.v. solution experienced lower minimum ANCs and hemoglobin levels, consistent with more neutropenia and anemia, compared with those who received ganciclovir oral (P=0.024 for neutropenia; P=0.027 for anemia).

Retinal Detachment: Retinal detachment has been observed in subjects with CMV retinitis both before and after initiation of therapy with ganciclovir. The relationship of retinal detachment to therapy with ganciclovir is unknown. Retinal detachment occurred in 11% of patients treated with ganciclovir i.v. solution and 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 have been 3 controlled clinical trials of ganciclovir i.v. and 1 controlled clinical trial of ganciclovir oral for the prevention of CMV disease in transplant recipients. Laboratory data and adverse events reported during these trials are summarized below.

In 3 out of 4 trials, patients receiving ganciclovir 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 is essential, especially for those patients receiving concomitant agents that may cause nephrotoxicity.

Adverse Reactions: CNS: In 2 placebo-controlled trials in transplant recipients, headache (17% vs 11%, respectively) and confusion (6% vs 1%, respectively) were noted to occur more frequently in patients treated with ganciclovir i.v. than in placebo-treated patients.

Other: In the same 2 studies, sepsis was observed more frequently in the patients treated with ganciclovir i.v. than in the placebo-treated patients (6% vs 2%, respectively).

Additional Adverse Reactions: General: Adverse events that were thought to be “probably” or “possibly” related to orally administered or i.v. administered ganciclovir in clinical studies in either subjects with AIDS or transplant recipients are listed below. These events all occurred with a frequency of less than 1%.

Body as a Whole: abdomen enlarged, abscess, ascites, back pain, cellulitis, chest pain, chills, chills and fever, drug level increased (ganciclovir), edema, face edema, injection site abscess, injection site edema, injection site hemorrhage, injection site phlebitis, laboratory test abnormality, malaise, photosensitivity reaction, neck pain, neck rigidity.

Digestive: aphthous stomatitis, constipation, dysphagia, eructation, esophagitis, fecal incontinence, gastritis, gastrointestinal moniliasis, gastrointestinal perforation, gingivitis, hemorrhage, hepatitis, jaundice, liver tenderness, melena, mouth ulceration, peptic ulcer, tongue disorder.

Hemic and Lymphatic: eosinophilia, hypochromic anemia, leukocytosis, lymphoma, marrow depression, pancytopenia, splenomegaly.

Respiratory: cough increased, dyspnea, pharyngitis.

Nervous System: abnormal dreams, abnormal gait, agitation, amnesia, anxiety, aphasia, ataxia, coma, confusion, convulsion, depression, dizziness, dry mouth, emotional lability, encephalopathy, euphoria, hyperkinesia, hypertonia, hypesthesia, insomnia, libido decreased, manic reaction, myoclonus, nervousness, psychosis, seizures, somnolence, speech disorder, thinking abnormal, tremor, trismus, vertigo.

Skin and Appendages: acne, alopecia, dry skin, fixed eruption, herpes simplex, maculopapular rash, skin discoloration, sweating, urticaria, vesiculobullous rash.

Special Senses: abnormal vision, amblyopia, blindness, conjunctivitis, deafness, ear disorder, ear pain, eye pain, glaucoma, retinitis, photophobia, taste perversion, tinnitus, vitreous disorder.

Metabolic and Nutritional Disorders: alkaline phosphatase increased, creatinine increased, creatine phosphokinase increased, healing abnormal, hyperglycemia, hypokalemia, lactic dehydrogenase increased, pancreatitis, peripheral edema, AST increased, ALT increased.

Cardiovascular: arrhythmia, deep thrombophlebitis, hypertension, hypotension, migraine, palpitation, vasodilatation.

Urogenital: breast pain, creatinine clearance decreased, hematuria, impotence, increased blood urea nitrogen (BUN), kidney failure, kidney function abnormal, polyuria, urinary frequency, urinary tract infection.

Laboratory Abnormalities: decreased blood sugar.

Musculoskeletal: arthralgia, bone pain, cyst, leg cramps, myalgia, myasthenia.

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

Adverse Events Reported in Postmarket Surveillance of Ganciclovir: The following are adverse events reported since the marketing introduction of ganciclovir, and which are not listed under adverse reactions above. 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, 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, ischemia, loss of memory, loss of sense of smell, myelopathy, peripheral oculomotor nerve paralysis, pulmonary fibrosi, renal tubular disorder, rhabdomyolysis, Stevens-Johnson syndrome, stroke, testicular hypotrophy, torsades de pointes, vasculitis, ventricular tachycardia.

Symptoms And Treatment Of Overdose: Symptoms: I.V.: Overdosage with ganciclovir i.v. has been reported in both adults and children below 2 years of age. In 2 cases of overdosage in adults, no adverse events were reported after patients received either one dose of 3 500 mg or 7 doses of 11 mg/kg over a 3 day period. Similarly, the following overdoses in pediatric patients did not result in adverse events: a single dose of 500 mg (72.5 mg/kg) followed by 48 hours of peritoneal dialysis (4-month-old), single dose of approximately 60 mg/kg followed by exchange transfusion (18-month-old), 2 doses of 500 mg instead of 31 mg (21-month-old).

Irreversible pancytopenia developed in 1 adult with AIDS and CMV colitis after receiving 3 000 mg of ganciclovir i.v. on each of 2 consecutive days. He experienced worsening gastrointestinal symptoms and acute renal failure which required short-term dialysis. Pancytopenia developed and persisted until his death from a malignancy several months later. Other adverse events reported following overdosage included: persistent bone marrrow suppression (1 adult with neutropenia and thrombocytopenia after a single dose of 6 000 mg), reversible neutropenia or granulocytopenia (4 adults, overdosages ranging from 8 mg/kg daily for 4 days to a single dose of 25 mg/kg, hepatitis (1 adult receiving 10 mg/kg daily, and one 2 kg infant after a single 40 mg dose), renal toxicity (1 adult with transient worsening of hematuria after a single 500 mg dose, and 1 adult with elevated creatinine [5.2 mg/dL] after a single 5 000 to 7 000 mg dose), and seizure (1 adult with known seizure disorder after 3 days of 9 mg/kg). In addition, 1 adult received 0.4 mL (instead of 0.1 mL) ganciclovir i.v. by intravitreal injection, and experienced temporary loss of vision and central retinal artery occlusion secondary to increased intraocular pressure related to the injected fluid volume.

Oral: There have been no reports of overdosage with orally administered ganciclovir. Doses as high as 6 000 mg/day, given either as 1 000 mg 6 times daily or as 2 000 mg t.i.d., did not result in overt toxicity other than transient neutropenia. Daily doses of more than 6 000 mg have not been studied.

Treatment: Since ganciclovir is dialyzable, dialysis may be useful in reducing serum concentrations. Adequate hydration should be maintained. The use of hematopoietic growth factors should be considered.

Dosage And Administration: Caution: Do not administer ganciclovir i.v. by rapid or bolus i.v. Injection. The toxicity of ganciclovir may be increased as a result of excessive plasma levels.

Caution: I.M. or s.c. injection may result in severe tissue irritation due to the high pH (approximately 11) of ganciclovir i.v. solutions.

The recommended dose for ganciclovir i.v. and ganciclovir oral should not be exceeded. The recommended Infusion rate for ganciclovir i.v. should not be exceeded.

Because of individual patient variations in the clinical response of CMV disease and the sensitivity to the myelosuppressive effects of ganciclovir, the treatment of each patient with ganciclovir should be individualized on a case by case basis. Changes in dose should be based on regular clinical evaluations as well as on regular hematologic monitoring.

Treatment of CMV Retinitis: Induction Treatment: The recommended dose for patients with normal renal function is 5 mg/kg every 12 hours for 14 to 21 days, given as a constant i.v. infusion over 1 hour. Ganciclovir capsules should not be used for induction treatment.

Maintenance Treatment: I.V.: Following the induction treatment, the recommended dose is 5 mg/kg given as an i.v. infusion over 1 hour once/day for 7 days each week, or 6 mg/kg once/day for 5 days each week.

Oral: For patients with stable CMV retinitis following at least 3 weeks of treatment with ganciclovir i.v., the recommended maintenance dose is 1 000 mg t.i.d. with food. Alternatively, the dosing regimen of 500 mg 6 times daily with food, during waking hours, may be used.

For patients who experience progression of CMV retinitis while receiving maintenance treatment with either formulation of ganciclovir, reinduction treatment using the twice daily regimen of ganciclovir i.v. is recommended.

The safety and efficacy of ganciclovir oral have not been established for treating any manifestation of CMV disease other than maintenance treatment of CMV retinitis.

Prevention of CMV Disease in Transplant Recipients: I.V.: The recommended initial dose for patients with normal renal function is 5 mg/kg (given i.v. at a constant rate over 1 hour) every 12 hours for 7 to 14 days, followed by either 5 mg/kg once/day if on a 7-day weekly regimen, or 6 mg/kg once/day if on a 5-day weekly regimen.

Oral: The recommended prophylactic dose in patients with normal renal function is 1 000 mg t.i.d. (3 000 mg/day) with food.

The duration of treatment with ganciclovir in transplant recipients is dependent upon the duration and degree of immunosuppression. In controlled clinical trials in bone marrow allograft recipients, treatment with ganciclovir i.v. was continued until day 100 to 120 post-transplantation. CMV disease occurred in several patients who discontinued treatment with ganciclovir i.v. prematurely. In heart allograft recipients, the onset of newly diagnosed CMV disease occurred after treatment with ganciclovir i.v. was stopped at day 28 post-transplant, suggesting that continued dosing may be necessary to prevent late occurrence of CMV disease in this patient population.

In a controlled clinical trial of liver allograft recipients, treatment with ganciclovir oral was continued through Week 14 post-transplantation.

Patient Monitoring: Due to the frequency of granulocytopenia, anemia and thrombocytopenia in patients receiving ganciclovir (see Adverse Effects), it is recommended that complete blood counts and platelet counts be performed frequently, especially in patients in whom ganciclovir or other nucleoside analogs have previously resulted in cytopenia, or in whom neutrophil counts are less than 1 000 cells/µL at the beginning of treatment. Patients should have serum creatinine or creatinine clearance values followed carefully to allow for dosage adjustments in renally impaired patients.

Reduction of Dose: Dosage reductions in renally impaired patients are recommended for ganciclovir i.v. and should be considered for ganciclovir oral (see Renal Impairment). Dosage reductions should also be considered for patients with neutropenia, anemia and/or thrombocytopenia. Ganciclovir should not be administered in patients with severe neutropenia (ANC less than 500/µL) or severe thrombocytopenia (platelets less than 25 000/µL).

Dosing for patients undergoing hemodialysis should not exceed 1.25 mg/kg 3 times/week, following each hemodialysis session. Ganciclovir i.v. should be given shortly after completion of the hemodialysis session, since hemodialysis has been shown to reduce plasma levels by approximately 50%.

I.V. Administration: Infusion concentrations greater than 10 mg/mL are not recommended. Do not administer ganciclovir by rapid or bolus i.v. injection. It should be given by constant i.v. infusion over 1 hour.

Reconstitution of Sterile Lyophilized Powder: Reconstitute by injecting sterile water for injection into the vial.

Do not use bacteriostatic water for injection containing parabens, since these are incompatible with ganciclovir sterile powder and may cause precipitation.

The reconstituted solution should be inspected for particulate matter or discoloration prior to proceeding with admixture preparation.

Admixture Preparation: The reconstituted solution is further diluted in one of the solutions listed below for i.v. infusion.

Solutions for I.V. infusion: normal saline, dextrose 5% in water, Ringer’s injection, lactated Ringer’s injection.

Stability and Storage: Sterile Powder: Store at room temperature (15 to 30°C), avoid excessive heat above 40°C. The reconstituted solution in the vial may be stored at room temperature up to 12 hours and should not be refrigerated.

Ganciclovir, when reconstituted with sterile water for injection, further diluted with 0.9% sodium chloride injection, and stored refrigerated at 5°C in polyvinyl chloride (PVC) bags, remain physically and chemically stable for 14 days. However, because ganciclovir is reconstituted with nonbacteriostatic sterile water, it is recommended that the infusion solution be used with 24 hours of dilution to reduce the risk of bacterial contamination. The reconstituted and further diluted solutions should be stored under refrigeration. Freezing is not recommended.

Handling and Disposal: Caution should be exercised in the handling and preparation of ganciclovir solution. Avoid ingestion, inhalation or direct contact with the skin and mucous membranes. Ganciclovir should be considered a potential teratogen and carcinogen in humans. Ganciclovir solutions are alkaline (pH approximately 11). The use of latex gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If the solution contacts the skin or mucous membranes, wash thoroughly with soap and water; rinse eyes for at least 15 minutes with plain water. Ganciclovir capsules should not be opened or crushed.

Several guidelines for the handling and disposal of hazardous pharmaceuticals (including cytotoxic drugs) are available (e.g., CSHP, 1991). Disposal of ganciclovir should follow provincial, municipal, and local hospital guidelines or requirements.

Availability And Storage: Capsules: Each opaque, green, hard gelatin capsule, printed in blue with ROCHE logo and CY250 on cap with 2 blue lines partially encircling the capsule body, contains: ganciclovir 250 mg. Nonmedicinal ingredients: croscarmellose sodium, gelatin, indigotine, iron oxide, magnesium stearate, povidone and titanium dioxide. Bottles of 84. Store at controlled room temperature (15 to 30°C).

Sterile Powder: Each 10 mL clear, glass vial of sterile, lyophilized powder contains: ganciclovir sodium equivalent to ganciclovir 500 mg.

CYTOVENE® Capsules CYTOVENE® Injection Roche GanciclovirGanciclovir Sodium Antiviral

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