Ganciclovir can cause significant bone marrow suppression. Anemia (2% to 26%), neutropenia (3% to 29%), pancytopenia, leukopenia (29% to 41%), thrombocytopenia (3% to 57%), and bone marrow failure all can occur. In addition, hemolytic anemia, agranulocytosis, and granulocytopenia have been noted during postmarketing reports.[32676] Related symptoms can include unusual bleeding or bruising. Both granulocytopenia and thrombocytopenia are usually reversible and respond to a dose reduction. Use of the drug is not recommended in patients with neutropenia defined as an absolute neutrophil count (ANC) less than 500 cells/mm³, anemia with hemoglobin less than 8 g/dL, or thrombocytopenia with a platelet count less than 25,000 cells/mm³. In neonates, ganciclovir therapy has been resumed when ANC is 750 cells/mm³ or more; then after treatment re-initiation, the dose reduced to one-half if subsequent ANC is less than 500/mm³, and therapy discontinued if neutropenia persisted while on the reduced dose.[32656] The incidence of hematologic reactions may be higher in bone marrow transplant patients and less in other transplant patients. The hematologic toxicity usually develops within the early weeks of therapy and is generally dose-related and reversible, but occasionally it can be prolonged or irreversible. Blood counts usually begin to recover within 3 to 7 days of discontinuing the drug. Colony-stimulating factors have been shown to increase neutrophil counts in patients receiving ganciclovir.[32676]

The most common gastrointestinal adverse effects of systemic ganciclovir include abdominal pain, anorexia (14% to 15%), diarrhea (41% to 44%), nausea, vomiting (13%), dysgeusia, and flatulence. Other GI-related adverse events include aphthous stomatitis, constipation, dyspepsia, eructation, GI perforation, pancreatitis, weight loss, and xerostomia (dry mouth). Intestinal ulceration was noted during postmarketing surveillance.[32676]

Adverse CNS effects are fairly common during systemic ganciclovir therapy and include abnormal dreams, anxiety, confusion, depression, dizziness, headache, insomnia, drowsiness and fatigue, dysphagia, hypoesthesia, abnormal thinking, paresthesias, peripheral neuropathy (8% to 9%), tremor, or more serious reactions such as seizures.[32676] Very few cases of ganciclovir-induced seizures have been reported.[23647] Other adverse events noted during postmarketing surveillance include dysesthesia, dysphasia, aphasia, encephalopathy, extrapyramidal reaction, facial palsies or cranial nerve palsies, hallucinations, increased intracranial pressure, irritability, loss of memory and memory impairment, oculomotor nerve paralysis, and stroke.[32676] Some CNS adverse effects have been caused by opportunistic infection rather than by the drug.

Systemic ganciclovir is moderately nephrotoxic. Mild to moderate increases in serum creatinine have been reported during therapy. In general, this adverse reaction occurs during the first week of therapy and is reversible. If renal function worsens during therapy, the ganciclovir dosage should be reduced since ganciclovir is extensively eliminated unchanged via glomerular filtration. Patients receiving ganciclovir following transplantation seem to have a higher incidence of nephrotoxicity as compared to patients treated for CMV retinitis. Between 12% to 58% of patients may experience serum creatinine concentrations of 1.5 to 2.4 mg/dL; serum creatinine concentrations of 2.5 mg/dL or more may be seen in up to 20% of patients. Renal failure (unspecified), decreased creatinine clearance, abnormal renal function, hematuria, increased urinary frequency, and urinary retention have also been reported with ganciclovir therapy. Hemolytic-uremic syndrome and renal tubular disorder were noted in postmarketing reports.[32676]

Dermatologic and allergic adverse effects reported during ganciclovir therapy include alopecia, hyperhidrosis (11% to 12%), pruritus (5% to 6%), dermatitis, rash (unspecified), urticaria, and xerosis (dry skin). Phlebitis or injection site reaction (e.g., local inflammation, pain) can occur with IV ganciclovir. Rash, pruritus, or urticaria may indicate hypersensitivity to ganciclovir. Allergic reaction, anaphylactoid reactions, exfoliative dermatitis, and Stevens-Johnson syndrome have been noted in postmarketing reports.[32676]

Ganciclovir is considered a potential carcinogen in humans and may cause a new primary malignancy. Ganciclovir has been associated with clastogenesis during in vitro testing at doses 2.8- to 10-times the normal human dose but not at doses comparable to human exposure. Tumors have developed in mice treated with approximately one-tenth to 1.4 times the human dose. Most tumors were of epithelial or vascular origin, although histiocytic sarcoma of the liver was reported. Tumors appeared in some tissues for which there is no human counterpart.[32676]

Animal and limited human data indicate that ganciclovir may cause temporary or permanent spermatogenesis inhibition and subsequent infertility in males and suppression of fertility in females. Effects on spermatogenesis were reversible at lower doses and irreversible at higher doses. In addition, ganciclovir causes teratogenesis in animals and should not be used during pregnancy. Advise women of childbearing potential about the necessity of using effective contraception during treatment. Females should use effective contraception during and for at least 30 days after treatment with ganciclovir. Males must practice barrier contraception during and for at least 90 days after treatment with ganciclovir.[28463] [32676]

Infection (9% to 13%), sepsis (4% to 15%), catheter-related infection (4% to 9%), and catheter-related sepsis (1% to 8%) were reported during ganciclovir clinical trials. Other, less frequently reported infections included cellulitis, influenza, upper respiratory tract infections, urinary tract infections, and candida infections including oral candidiasis.[32676]

General adverse events associated with the use of systemic ganciclovir include fever (38% to 48%), chills (7% to 10%), enlarged abdomen, asthenia, chest pain (unspecified), congenital anomaly, edema, malaise, unspecified pain, testicular hypotrophy/testicular atrophy, and potentially fatal multiple organ failure.[32676]

Elevated hepatic enzymes were reported with the use of systemic ganciclovir. Hepatic failure, cholelithiasis, cholestasis, and hepatitis were noted during postmarketing reports.[32676]

Tinnitus, otalgia, and hearing loss (deafness) were reported with the use of systemic ganciclovir. Loss of the sense of smell (anosmia) was noted during postmarketing reports.[32676]

Increased cough and dyspnea were reported with systemic ganciclovir. Bronchospasm and pulmonary fibrosis were noted during postmarketing reports.[32676]

Arthralgia, muscle cramps, muscle spasms, back pain, myalgia, and myasthenia have been reported with the use of systemic ganciclovir. Other adverse events noted during postmarketing surveillance include arthritis, myelopathy, and rhabdomyolysis.[32676]

Hypertension, hypotension, arrhythmia exacerbation, and peripheral vasodilation were reported with the use of systemic ganciclovir. Other cardiovascular adverse events reported during postmarketing surveillance include cardiac arrest, cardiac conduction abnormalities, peripheral ischemia, torsade de pointes, vasculitis, and ventricular tachycardia.[32676]

Retinal detachment may occur with systemic (8% to 11% of adults) administration of ganciclovir; however, the precise relationship to the drug is not clear. Retinal detachment has occurred in patients with CMV retinitis both before and after initiation of ganciclovir therapy.[32676] Adverse reactions associated with administration of ganciclovir ophthalmic gel include blurred vision (60%), ocular irritation (20%), punctate keratitis (5%), and conjunctival hyperemia (5%).[36875] Other ocular reactions noted with systemic ganciclovir include abnormal vision or visual impairment, ocular pain, conjunctivitis, macular edema, and vitreous disorder. Xerophthalmia and cataracts were noted in postmarketing reports with systemic ganciclovir.[32676]

Metabolic adverse events noted during postmarketing surveillance with ganciclovir include metabolic acidosis, hypertriglyceridemia, hypercalcemia, hyponatremia, and syndrome of inappropriate antidiuretic hormone secretion (SIADH).[32676]

Ganciclovir is contraindicated in patients with a significant ganciclovir hypersensitivity, valganciclovir hypersensitivity, or acyclovir hypersensitivity.[32676] [61771] Although not specifically contraindicated by the manufacturer, ganciclovir ophthalmic gel should be used with extreme caution in these patients as well. Because of similar chemical structures and possible cross-sensitivity, ganciclovir should not be used in patients with famciclovir hypersensitivity, penciclovir hypersensitivity, or valacyclovir hypersensitivity. Alternative agents such as foscarnet or cidofovir may be suitable since they are not structurally related to these antivirals.

Use systemic ganciclovir with caution in patients with bone marrow suppression or to those who are receiving other myelosuppressive chemotherapy or radiation therapy. Severe anemia, leukopenia, neutropenia, pancytopenia, and thrombocytopenia have been reported during ganciclovir therapy. The frequency and severity of these events vary widely in different patient populations. Patients with neutropenia (absolute neutrophil count (ANC) less than 500 cells/mm³), anemia (hemoglobin less than 8 g/dL), or thrombocytopenia (platelet count less than 25,000 cells/mm³) should not receive the drug. Complete blood counts with differential and platelet counts should be performed frequently, especially in patients who have experienced previous drug-induced leukopenia or in patients with a baseline ANC less than 1,000 cells/mm³. The manufacturer notes that ganciclovir should only be used as indicated within the prescribing information; avoid unnecessary use.[32676] [61771]

Ganciclovir toxicity may be increased with rapid administration which results in excessive plasma levels. Do not administer ganciclovir by rapid or bolus IV, instead administer by slow IV infusion at a constant rate over 1 hour. Do not give ganciclovir by subcutaneous administration or intramuscular administration.[32676] [61771]

Adjust systemic ganciclovir dosage in patients with renal impairment because it is primarily eliminated unchanged via renal mechanisms. Avoid dehydration in patients on ganciclovir therapy; maintain renal elimination with adequate hydration and fluid intake. The risk of toxic reactions to ganciclovir is greater in patients with renal impairment, especially renal failure. Although clinical studies did not include sufficient numbers of geriatric patients, dose selection for these patients should be cautious, reflecting the greater frequency of decreased cardiac, hepatic, or renal function, and of concomitant disease or drug therapy.[32676]

Take care to avoid accidental exposure to ganciclovir during preparation, handling or administration, due to the potential mutagenicity and alkaline pH of intravenous ganciclovir. Although human data are not available, the development of neoplastic disease is a potential risk to consider during ganciclovir therapy based on animal carcinogenicity data. The use of protective gowns, gloves and goggles is recommended. Avoid direct contact of ganciclovir solution with skin or mucous membranes. If skin contact occurs, wash thoroughly with soap and water. Following ocular exposure, rinse eyes thoroughly with plain water. Consider handling and disposing of ganciclovir according to guidelines issued for antineoplastic agents. There is no agreement that all the procedures recommended in the guidelines are necessary or appropriate for ganciclovir. The manufacturer notes that ganciclovir should only be used as indicated within the prescribing information; avoid unnecessary use.[32676]

Because of the potential for long-term carcinogenicity and reproductive toxicity, carefully consider the risks and benefits of using systemic ganciclovir therapy in neonates, infants, children, and adolescents. Carcinogenicity and impaired fertility have occurred in animal models at doses similar to those used in humans; the precise risk in human patients is not known. Although specific human data are not available, it is considered probable in humans that ganciclovir at recommended doses may cause temporary or permanent inhibition of spermatogenesis.[32676]

Ganciclovir is associated with reproductive risk. The drug can be teratogenic if taken by the father near the time of conception (male-mediated teratogenicity) or by the mother during pregnancy. Discuss contraception requirements with the patient. Females should use effective contraception during and for at least 30 days after treatment with ganciclovir. Males must use a condom during and for at least 90 days after treatment. Females of reproductive potential should undergo pregnancy testing prior to initiation of ganciclovir. In addition, based on animal and limited human data, ganciclovir may cause temporary or permanent inhibition of spermatogenesis and subsequent infertility. Animal studies also indicate that suppression of fertility in females may occur.[32676]

Antimicrobial resistance to ganciclovir may develop following prolonged treatment and has been reported in ganciclovir naive individuals. The possibility of viral resistance should be considered in patients who show poor clinical response or who experience persistent viral excretion during therapy.[32676]

There are no adequate and well-controlled human studies evaluating use of ganciclovir during pregnancy; however, based on data from animal studies, ganciclovir may be teratogenic or embryotoxic at doses recommended for human use. If considering use of ganciclovir in a pregnant female, consider that most maternal CMV infections are subclinical or may be associated with mononucleosis-like syndrome. However, in immunocompromised patients, CMV infections are often symptomatic and associated with significant morbidity and mortality. Also consider that the risk and severity of congenital CMV infection appear to be higher in infants born to mother with primary CMV infection than in those born to mothers with reactivation of the disease. Of the newborns who are infected with CMV, only 10% are symptomatic at birth and the mortality rate among symptomatic infants is about 10%; however, approximately 50% to 90% of the surviving infants may experience significant problems, including sensorineural hearing loss, mental retardation, and other neurologic defects. It is not known if topically administered ophthalmic ganciclovir could result in significant systemic absorption; therefore, the manufacturer recommends the administration of ophthalmic ganciclovir to pregnant women only if the potential benefit to the mother outweighs the potential risk to the fetus.[32676] [36875] [61771]

It is not known if ganciclovir is excreted into breast milk. Due to the potential for serious adverse reactions in nursing infants, the manufacturer recommends instructing mothers to stop or not to start breast-feeding if they are receiving ganciclovir. Additionally, ganciclovir may be used to treat infections in patients with HIV and the Centers for Disease Control and Prevention (CDC) recommends that in the US, HIV-infected mothers not breast-feed their infants to avoid the risk of postnatal transmission of HIV. It is not known if topically administered ophthalmic ganciclovir could result in sufficient systemic absorption to produce detectable quantities in breast milk; therefore, the manufacturer recommends caution if ophthalmic ganciclovir is administered to breast-feeding women. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested or administered drug, health care providers are encouraged to report the adverse effect to the FDA.[32676] [36875] [46675] 

Contact lenses should be removed prior to administration of ganciclovir ophthalmic gel. Ganciclovir ophthalmic gel contains the preservative benzalkonium chloride, which may be absorbed by soft contact lenses. Patients should not wear contact lenses if they have signs or symptoms of herpetic keratitis or during the course of therapy with ganciclovir ophthalmic gel. Ganciclovir ophthalmic gel is indicated for topical ophthalmic use only.[36875]