GANCICLOVIR SODIUM

General Administration Information
For storage information, see the specific product information within the How Supplied section.
-Perform frequent hematologic monitoring in patients during treatment and do not administer if the absolute neutrophil count (ANC) falls below 500/mm3, hemoglobin is less than 8 g/dL, or the platelet count falls below 25,000/mm3.

Hazardous Drugs Classification
-NIOSH 2016 List: Group 2
-NIOSH (Draft) 2020 List: Table 1
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-INJECTABLE: Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
-ORAL CAPSULES: Use gloves to handle. Cutting, crushing, or otherwise manipulating capsules will increase exposure and require additional protective equipment. Eye/face and respiratory protection may be needed during preparation and administration.
-TOPICAL: Use double chemotherapy gloves and protective gown. Eye/face and respiratory protection may be needed during preparation and administration.

Route-Specific Administration

Injectable Administration
-Use caution when preparing and administering the product to avoid direct contact with skin. If contact occurs, wash the area thoroughly with soap and water. Ganciclovir solution for injection is alkaline and may cause irritation.
-Do NOT administer by rapid infusion or injection; toxicity may be increased.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit; the solution should be colorless. Discard if discoloration or particulate matter is observed.
Intravenous Administration
Reconstitution
-Reconstitute 500 mg vials with 10 mL of Sterile Water for Injection. The resultant solution is 50 mg/mL. Do NOT use Bacteriostatic Water for Injection containing parabens; precipitation may occur.
-Gently swirl vial until a clear reconstituted solution is obtained.
-Storage: Reconstituted vials are stable at room temperature 25 degrees C (77 degrees F) for 12 hours. Do not refrigerate or freeze. Discard any unused portion of the reconstituted solution.

Dilution
-Withdraw appropriate dose of reconstituted 50 mg/mL solution and dilute with a compatible IV infusion solution including 0.9% Sodium Chloride Injection, 5% Dextrose Injection, Ringer's Solution for Injection, or Lactated Ringer's Injection. Infusion concentrations greater than 10 mg/mL are not recommended.
-Storage: Once diluted in an IV solution, use within 24 hours to reduce the risk of bacterial contamination. Refrigerate the diluted infusion solution at 2 to 8 degrees C (36 to 46 degrees F). Do not freeze.

Premixed IV solution
-Dilution is not required.
-Solution does not contain preservatives and is for single use only. Any unused portion must be discarded.

Intermittent IV Infusion
-Infuse slowly over 1 hour via a large peripheral or central vein at a constant rate of administration; accompany with adequate hydration. Take precautions to avoid extravasation.
-A controlled-infusion device is recommended for highly concentrated solutions.

Other Injectable Administration
Intravitreal injection
NOTE: Ganciclovir is not approved by the FDA for administration via intravitreal injection.
-Reconstitute and dilute ganciclovir IV powder in 0.9% NaCl Injection to a concentration of 2 mg/0.04 mL to 2 mg/0.1 mL.
-Inject appropriate dose intravitreally using a tuberculin syringe.



Ophthalmic Administration
-Ganciclovir ophthalmic gel is for topical ophthalmic use only.
-To avoid contamination or the spread of infection, do not use dropper for more than 1 person.
-Do not touch the tip of the dropper to the eye, fingertips, or other surface to prevent contamination.
-Instruct patient on proper instillation of eye gel.
-Wash hands before and after use. Tilt the head back slightly and pull the lower eyelid down with the index finger to form a pouch. Squeeze the prescribed number of drops into the pouch. Close eyes to spread drops.
-Advise patients not to wear contact lenses while using ganciclovir ophthalmic gel.

Ganciclovir use is associated with significant bone marrow suppression and requires careful monitoring. Neutropenia is typically the most common effect and may be more common in pediatric patients than in adults; the severity and incidence can vary widely among patient populations. Neutropenia has been reported in up to 63% of infants receiving ganciclovir for congenital CMV. While still common, the incidence appears to be lower in children than in neonates and infants. One study of children receiving oral ganciclovir reported an incidence of neutropenia (defined as ANC less than 400/mm3) of 22%. Another trial of 9 lung transplant recipients (ages 6 to 18 years), reported no cases of neutropenia (defined as ANC less than 500/mm3) after 12 weeks of intravenous ganciclovir for prophylaxis (5 mg/kg/dose IV every 12 hours for 21 days, then 5 mg/kg/dose IV once daily to complete 12 weeks). A neutropenia incidence of 18% to 25% has been reported in adults. Neutropenia usually develops during the first or second week of therapy but can occur at any time during treatment. Consider a dosage reduction for patients who develop neutropenia during therapy and hold ganciclovir in patients with an ANC less than 500/mm3. Cell counts usually begin to recover within 3 to 7 days of discontinuing the drug. Colony-stimulating factors increased neutrophil and white blood cell counts in adult patients receiving ganciclovir for CMV retinitis. Counsel patients and/or caregivers about the signs and symptoms of infection, which could be a complication of neutropenia, and instruct them to promptly notify their healthcare provider if any develop. In a small study of pediatric patients (n = 16) receiving IV ganciclovir, sepsis was reported in 19% and pneumonia in 13% of patients. Infection (9% to 13%), sepsis (4% to 15%), catheter-related infection (4% to 9%), and catheter-related sepsis (1% to 8%) have also been reported in adult patients receiving systemic ganciclovir. Other, less frequently reported infections include cellulitis, influenza, upper respiratory tract infections, urinary tract infections, and candida infections including oral candidiasis.

In addition to neutropenia, other adverse hematologic effects are relatively common with systemic ganciclovir therapy and warrant careful monitoring. In a small phase II study of 45 neonates with congenital CMV, thrombocytopenia (defined as platelet count of 50,000/mm3 or less) occurred in 38% of patients. In other clinical trials, thrombocytopenia occurred in 10% to 19% of pediatric patients. Coagulopathy and immune system disorder were each reported in 13% of pediatric patients. Anemia (2% to 26%) and leukopenia (29% to 41%) have been reported in adult patients; the incidence in pediatric patients is unknown. Hemolytic anemia, agranulocytosis, and granulocytopenia have been noted in postmarketing reports. Pancytopenia has also been reported. Counsel patients and caregivers to report any signs of increased bleeding (e.g., when brushing teeth) or symptoms of anemia (e.g., lack of energy) to their healthcare provider.

Systemic ganciclovir is moderately nephrotoxic. Mild to moderate increases in serum creatinine have been reported during therapy. In a small study of pediatric patients (n = 16) receiving IV ganciclovir, abnormal renal function was reported in 19% of patients. In a study of 47 infants receiving ganciclovir for congenital CMV, 3 experienced an increase in serum creatinine (SCr) of 0.3 to 0.5 mg/dL; no patients had a SCr more than 2 mg/dL during the study period. In clinical trials, 12% to 58% of adult patients experienced serum creatinine concentrations of 1.5 to 2.4 mg/dL; serum creatinine concentrations of 2.5 mg/dL or more were seen in up to 20% of adult patients. In general, this adverse reaction occurs during the first week of therapy and is reversible. If renal function worsens during therapy, reduce the ganciclovir dosage because ganciclovir is extensively eliminated unchanged via glomerular filtration. Patients receiving ganciclovir after transplantation seem to have a higher incidence of nephrotoxicity as compared to patients treated for CMV retinitis. Renal failure (unspecified), decreased creatinine clearance, 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.

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

In a study of 47 infants treated with IV ganciclovir for congenital CMV, hyperbilirubinemia occurred in 7% of patients; elevated hepatic enzymes occurred in 36% of infants. Related adverse reactions that have been noted in adult patients during either clinical trials or postmarketing use include hepatic failure, cholelithiasis, cholestasis, and hepatitis.

Adverse CNS reactions are relatively common during systemic ganciclovir therapy; probably the most commonly noticed effect in infants and young children is irritability. Other adverse reactions include abnormal dreams, anxiety, confusion, depression, dizziness, fatigue, headache, insomnia, drowsiness, hypoesthesia, dysphagia, abnormal thinking, paresthesias, peripheral neuropathy (8% to 9%, adults), tremor, or more serious reactions such as seizures. Very few cases of ganciclovir-induced seizures have been reported. Other adverse reactions noted during postmarketing surveillance in adult patients include aphasia, dysesthesia, dysphasia, encephalopathy, extrapyramidal reaction, facial palsies/cranial nerve palsies, hallucinations, increased intracranial pressure, loss of memory/memory impairment, oculomotor nerve paralysis, and stroke. Some CNS adverse reactions have been caused by opportunistic infection rather than by the drug.

Ganciclovir is considered a potential carcinogen in humans and may cause a new primary malignancy, although the precise risk in humans has not been defined. In mouse models, ganciclovir was carcinogenic at oral doses of 20 and 1,000 mg/kg/day (approximately 0.1 times and 1.4 times, respectively, the mean exposure to humans after a 5 mg/kg IV dose based on AUC). 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. 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.

Dermatologic and allergic adverse reactions reported during systemic ganciclovir therapy in adults 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., inflammation, pain) can occur with IV ganciclovir; ensure proper IV access prior to administration. 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.

In a small study of pediatric patients (n = 16) receiving IV ganciclovir, hypertension was reported in 13% of patients; hypotension, peripheral vasodilation, and arrhythmia exacerbation have also been reported with the use of systemic ganciclovir. Other cardiovascular adverse reactions reported during postmarketing surveillance include cardiac arrest, cardiac conduction abnormalities, peripheral ischemia, torsade de pointes, vasculitis, and ventricular tachycardia.

In a small study of pediatric patients (n = 16) receiving IV ganciclovir, hypokalemia occurred in 25% of patients. Metabolic adverse reactions noted during postmarketing surveillance with ganciclovir include metabolic acidosis, hypertriglyceridemia, hypercalcemia, hyponatremia, and inappropriate serum ADH (SIADH).

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. Adverse reactions associated with administration of ganciclovir ophthalmic gel include blurred vision (60%), ocular irritation (20%), punctate keratitis (5%), and conjunctival hyperemia (5%). 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.

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. Testicular hypotrophy/testicular atrophy has been reported during postmarketing use. In addition, ganciclovir causes teratogenesis in animals and should not be used during pregnancy. Counsel male patients (if age appropriate) and caregivers about the potential long-term risks of ganciclovir use. In addition, counsel adolescents, both male and female, 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.

General adverse reactions associated with the use of systemic ganciclovir in adult patients include fever (38% to 48%), chills (7% to 10%), enlarged abdomen, asthenia, chest pain (unspecified), edema, malaise, unspecified pain, and potentially fatal multiple organ failure.

Tinnitus, otalgia, hearing loss (deafness), and dysgeusia have been reported with the use of systemic ganciclovir. Loss of the sense of smell (anosmia) has also been noted during postmarketing reports.

Increased cough and dyspnea have been reported with systemic ganciclovir. Bronchospasm and pulmonary fibrosis were noted during postmarketing reports.

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

Ganciclovir is contraindicated in patients with a significant ganciclovir hypersensitivity, valganciclovir hypersensitivity, or acyclovir hypersensitivity. Although not specifically contraindicated in the FDA-approved product labeling, ganciclovir ophthalmic gel should also be used with extreme caution in these patients. Because of similar chemical structures and possible cross-sensitivity, avoid use of ganciclovir 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 those who are receiving 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. Perform complete blood and platelet counts frequently, especially in patients who have experienced previous drug-induced leukopenia or in patients with a baseline ANC less than 1,000/mm3. The FDA-approved product labeling notes that ganciclovir should only be used as indicated within the prescribing information; avoid unnecessary use.

Ganciclovir toxicity may be increased with rapid administration that results in excessive plasma concentrations. Do not administer ganciclovir by rapid or bolus IV; infuse slowly at a constant rate over 1 hour. As the pH of diluted ganciclovir solutions is highly alkaline, do not administer by subcutaneous administration or intramuscular administration. Ensure that the patient is adequately hydrated and only infuse through a vein with adequate blood flow.

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.

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 a new primary malignancy 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. After 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 FDA-approved product labeling notes that ganciclovir should only be used as indicated within the prescribing information; avoid unnecessary use.

Antimicrobial resistance to ganciclovir may develop after prolonged treatment and has been reported in ganciclovir naive individuals. Consider the possibility of viral resistance in patients who show poor clinical response or who experience persistent viral excretion during therapy.

Remove contact lenses prior to administration of ganciclovir ophthalmic gel. Ganciclovir ophthalmic gel contains the preservative benzalkonium chloride, which may be absorbed by soft contact lenses. Advise patients not to 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.

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.

Counsel adolescents, both male and female, about the reproductive risk and contraception requirements during treatment. Prior to initiating treatment, females of reproductive potential should undergo pregnancy testing. Ganciclovir can be teratogenic if taken by the father near the time of conception (male-mediated teratogenicity) or by the mother during pregnancy. Females should use effective contraception during treatment and for at least 30 days after treatment with ganciclovir. Males must practice barrier contraception during and for at least 90 days after treatment. Based on animal and limited human data, ganciclovir may cause temporary or permanent inhibition of spermatogenesis and subsequent infertility in males and suppression of fertility in females. These effects were reversible at lower doses and irreversible at higher doses. Although fertility is not an immediate concern for most pediatric patients, the possible risks should be discussed with the patient (if age appropriate) and the patient's guardian(s).

Description: Ganciclovir is a synthetic, purine nucleoside analog used for the treatment and prevention of cytomegalovirus (CMV) infections. An ophthalmic gel is used for the treatment of herpetic keratitis. In addition, ganciclovir has been shown to be active against other viruses, including herpes simplex, varicella zoster, and human herpesvirus 6 and 8. Ganciclovir is recommended as an alternative therapy for the treatment of herpes simplex and varicella zoster in pediatric patients when first-line therapy (IV acyclovir) is unavailable. Hematologic toxicity is common with systemic ganciclovir administration; dosage adjustments for neutropenia or thrombocytopenia may be required. Although not FDA-approved, intravenous ganciclovir has been used in pediatric patients as young as neonates for the treatment of congenital CMV infection; the ophthalmic gel is FDA-approved in pediatric patients as young as 2 years.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: cytomegalovirus (CMV), herpes simplex virus type 1, herpes simplex virus type 2
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

This drug may also have activity against the following microorganisms: B virus (cercopithecine herpesvirus), Epstein-Barr virus, human herpesvirus 6 (HHV-6), human herpesvirus 8 (HHV-8), varicella-zoster virus
NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.

For the treatment of viral encephalitis*:
-for herpes simplex or varicella-zoster (herpes zoster) encephalitis as an alternative to acyclovir:
Intravenous dosage:
Neonates: 6 mg/kg/dose IV every 12 hours. The American Academy of Pediatrics (AAP) recommends ganciclovir as the first line alternative when IV acyclovir is unavailable for patients with suspected or proven neonatal herpes simplex disease and herpes simplex/varicella zoster infections in immunocompromised hosts and patients unable to tolerate oral acyclovir or valacyclovir.
Infants 1 to 3 months: 6 mg/kg/dose IV every 12 hours. The American Academy of Pediatrics (AAP) recommends ganciclovir as the first line alternative when IV acyclovir is unavailable for patients with suspected or proven neonatal herpes simplex disease and herpes simplex/varicella zoster infections in immunocompromised hosts and patients unable to tolerate oral acyclovir or valacyclovir.
Infants, Children, and Adolescents 4 months to 17 years: 5 mg/kg/dose IV every 12 hours. The American Academy of Pediatrics (AAP) recommends ganciclovir as the first line alternative when IV acyclovir is unavailable for patients with herpes simplex/varicella zoster infections in immunocompromised hosts and patients unable to tolerate oral acyclovir or valacyclovir.
-for the treatment of cytomegalovirus (CMV) encephalitis or neurological disease, including persons with HIV:
Intravenous dosage:
Neonates: 6 mg/kg/dose IV every 12 hours for 6 weeks. If during the 6 weeks of therapy an infant is identified with confirmed HIV infection, some experts recommend extending the course of therapy beyond 6 weeks.
Infants and Children: 5 mg/kg/dose IV every 12 hours plus IV foscarnet (to stabilize the disease and maximize response). Continue treatment until there is symptomatic improvement, then follow with secondary prophylaxis (chronic maintenance therapy). Acutely, single drug therapy with ganciclovir is not recommended due to therapeutic failures.
Adolescents: 5 mg/kg/dose IV every 12 hours plus IV foscarnet (to stabilize the disease and maximize response); optimal duration has not been established. Routine maintenance therapy is not recommended unless there is concurrent retinitis, there have already been recurrent infections, or severe disease was present initially.
-for encephalitis due to B virus (cercopithecine herpesvirus) infection as an alternative to valacyclovir:
Intravenous dosage:
Infants, Children, and Adolescents: 5 mg/kg/dose IV every 12 hours for a minimum of 14 days or until all CNS symptoms have resolved.

For induction treatment of cytomegalovirus (CMV) retinitis* in immunocompromised patients, including persons with HIV:
Intravenous dosage:
Infants and Children: 5 mg/kg/dose IV every 12 hours for 14 to 21 days; may increase to 7.5 mg/kg/dose IV every 12 hours if needed. For children with sight-threatening disease, the addition of IV foscarnet may also be considered. CMV is not eradicated once contracted; follow induction treatment with secondary prophylaxis (chronic maintenance therapy).
Adolescents: 5 mg/kg/dose IV every 12 hours for 14 to 21 days as a preferred therapy. Systemic therapy may be combined with intravitreal injections of ganciclovir (2 mg/injection) or foscarnet (2.4 mg/injection) for immediate sight-threatening lesions (i.e., within 1,500 microns of the fovea). Follow induction treatment with secondary prophylaxis (chronic maintenance therapy).
Intravitreal dosage:
Adolescents: 2 mg intravitreal injection once weekly until lesion inactivity is achieved is recommended for patients with immediate sight-threatening lesions (i.e., within 1,500 microns of the fovea). Intravitreal injections are given to achieve rapid high intraocular drug concentrations and should be administered in combination with systemic induction therapy.

For chronic suppressive therapy of cytomegalovirus (CMV) disease, including CMV retinitis (i.e., secondary cytomegalovirus (CMV) retinitis prophylaxis*), gastrointestinal disease*, pneumonitis*, or neurological disease*, in persons with HIV:
NOTE: For infants and children, chronic maintenance therapy is indicated for retinitis, disseminated, CNS, or GI disease with relapse. For adolescents, chronic maintenance therapy is indicated for retinitis. Chronic maintenance therapy is not routinely recommended for gastrointestinal disease, pneumonitis, or CNS disease unless there is concurrent retinitis, there have already been recurrent infections, or severe disease was present initially.
Intravenous dosage:
Infants and Children: 5 mg/kg/dose IV once daily is recommended as a preferred maintenance treatment following induction therapy. Patients who experience reactivation or progression of CMV retinitis while receiving maintenance therapy should receive reinduction treatment with the same drug used for maintenance followed by reinstitution of maintenance therapy.Treatment duration depends on the immune status of the patient. Discontinuation of secondary prophylaxis may be considered in pediatric patients who have received at least 6 months of highly active antiretroviral therapy with a sustained increase (more than 6 months) in CD4 percentage of at least 15% (pediatric patients younger than 5 years) or CD4 count more than 100 cells/mm3 (children 6 years and older). For retinitis, the decision to discontinue secondary prophylaxis should be made in consultation with an ophthalmologist. Routine follow-up (every 3 to 6 months) with an ophthalmologist is recommended. Restart maintenance therapy if CD4 percentage is less than 15% in pediatric patients younger than 5 years or if CD4 count is less than 100 cells/mm3 in children 6 years and older.
Adolescents: 5 mg/kg/dose IV once daily is recommended as a preferred maintenance treatment following induction therapy; may switch to oral valganciclovir when the patient is clinically improving and there are no concerns about absorption. Patients who experience reactivation or progression of CMV retinitis while receiving maintenance therapy should receive reinduction treatment with the same drug used for maintenance followed by reinstitution of maintenance therapy. For patients who have had a sustained immune response to highly active antiretroviral therapy (i.e., CD4 counts greater than 100 cells/mm3 for 3 to 6 months), have been on CMV treatment for at least 3 to 6 months, and have no active lesions, secondary CMV retinitis prophylaxis may be discontinued after consultation with an ophthalmologist. Maintenance therapy should be restarted if subsequent CD4 counts drop to less than 100 cells/mm3, as relapse occurs most frequently in those patients whose counts decrease to less than 50 cells/mm3 after stopping treatment. However, because relapses may occur at any CD4 count, all patients who have had maintenance CMV therapy discontinued should continue to undergo regular ophthalmologic monitoring (every 3 months) for early detection of CMV relapse (as well as for immune reconstitution uveitis).

For the treatment of symptomatic congenital cytomegalovirus (CMV) disease*:
Intravenous dosage:
Neonates and Infants: 6 mg/kg/dose IV every 12 hours for 6 weeks. Dosage adjustments for the development of neutropenia may be required. This regimen is also recommended for HIV-infected neonates; if a neonate is confirmed as being HIV-positive during the 6-week treatment course, some experts recommend extending the treatment course beyond 6 weeks. Clinical practice guidelines recommend antiviral treatment only for symptomatic neonates (first 30 days of life) with severe symptomatic focal organ disease or CNS disease.

For the treatment of cytomegalovirus (CMV)-associated gastrointestinal disease* (e.g., colitis, esophagitis) in HIV-infected patients:
Intravenous dosage:
Infants and Children: 5 mg/kg/dose IV every 12 hours for 14 to 21 days is recommended in the HIV guidelines for patients with disseminated disease; the dosage may be increased to 7.5 mg/kg/dose IV every 12 hours if needed.
Adolescents: 5 mg/kg/dose IV every 12 hours is recommended in the HIV guidelines. Therapy may be switched to oral valganciclovir 900 mg PO twice daily once the patient can tolerate PO therapy. The total duration of therapy should be 21 to 42 days or until resolution of signs and symptoms.

For the treatment of cytomegalovirus (CMV) pneumonitis*:
Intravenous dosage:
Infants and Children: 5 mg/kg/dose IV every 12 hours for 14 to 21 days. For HIV-infected patients with disseminated disease, the dose may be increased to 7.5 mg/kg/dose IV every 12 hours if needed. 5 mg/kg/dose IV twice daily for 14 days, then 5 mg/kg/dose IV once daily for 5 to 7 days each week for 3 weeks was used in 3 pediatric patients who developed CMV pneumonitis after allogenic stem cell transplant. Intravenous immunoglobulin was given in addition to ganciclovir in all patients with CMV infection for part of the study period, and then only in patients with subnormal IgG. Two of the 3 patients that developed CMV pneumonitis died; 1 of multiorgan failure and 1 of acute graft versus host disease.
Adolescents: 5 mg/kg/dose IV every 12 hours. For HIV-infected patients, treatment should be considered in patients with well-documented, histologic evidence of CMV pneumonitis. Data for treating CMV pneumonitis in HIV-infected patients is limited and the optimal duration of therapy has not been established. In 3 pediatric patients who developed CMV pneumonitis after allogenic stem cell transplant, 5 mg/kg/dose IV twice daily for 14 days, then 5 mg/kg/dose IV once daily for 5 to 7 days each week for 3 weeks was used. Intravenous immunoglobulin was given in addition to ganciclovir in all patients for part of the study period. Two of the 3 patients that developed CMV pneumonitis died; 1 of multiorgan failure and 1 of acute graft versus host disease.

For cytomegalovirus (CMV) disease prophylaxis* in patients at risk for CMV disease:
-for prophylaxis in allogeneic hematopoietic cell transplant (HCT) recipients:
Intravenous dosage:
Infants, Children, and Adolescents: 5 mg/kg/dose IV twice daily for 5 to 7 days starting at engraftment, followed by 5 mg/kg/dose IV once daily through day 100 post-transplant. Monitor ANC at least twice weekly during ganciclovir therapy. Regimens are transplant center and recipient specific; consult local protocols.
-for preemptive therapy in hematopoietic cell transplant (HCT) recipients who are less than 100 days post HCT:
Intravenous dosage:
Infants, Children, and Adolescents: 5 mg/kg/dose IV twice daily for 7 to 14 days for allogeneic transplant recipients or for 7 days for autologous transplant recipients, then 5 mg/kg/dose IV once daily for maintenance. Continue maintenance therapy until CMV detection methods are negative. The minimum length of therapy is 2 weeks for autologous HCT; for allogenic HCT, the minimum is 2 weeks when 14-day induction is used or 3 weeks when a 7-day induction is used. Preemptive therapy is recommended for all allogeneic transplant recipients with evidence of CMV infection in blood by antigenemia, PCR for CMV DNA, or detection of CMV mRNA and for CMV seropositive autologous transplant recipients at high risk when CMV antigenemia is at least 5 cells/slide (or any level for recipients of CD34+ selected grafts). Regimens are transplant center and recipient specific; consult local protocols.
-for preemptive therapy in hematopoietic cell transplant (HCT) recipients who are more than 100 days post HCT:
Intravenous dosage:
Infants, Children, and Adolescents: 5 mg/kg/dose IV twice daily for 7 to 14 days, then 5 mg/kg/dose IV once daily for 1 to 2 weeks or until the indicator test is negative. The minimum length of therapy is 2 weeks. Preemptive therapy is recommended when allogeneic transplant recipients, patients receiving steroids for GVHD, or patients who received CMV therapy less than 100 days after HCT have an antigenemia at least 5 cells/slide or at least 2 consecutive positive viremia or PCR tests. Regimens are transplant center and recipient specific; consult local protocols.
-for solid organ transplant recipients who are at risk for CMV disease (e.g., CMV-seropositive or CMV-seronegative with a CMV-seropositive donor):
Intravenous dosage:
Children and Adolescents: 5 mg/kg/dose IV once daily starting within 10 days post-transplant and continuing for up to 3 months has been recommended. Some protocols may extend therapy up to 6 months in highest risk patients. Regimens vary by transplant center, type of transplant, and recipient characteristics; consult local protocols. CMV hyperimmune globulin may be added to the ganciclovir regimen and/or the duration of IV therapy may vary.

For the treatment of herpes simplex virus infection* or varicella (chickenpox) infection* due to varicella-zoster virus in hospitalized immunocompromised patients unable to take oral therapy:
NOTE: For CNS disease, see encephalitis.
Intravenous dosage:
Neonates and Infants 1 to 3 months: 6 mg/kg/dose IV every 12 hours. The American Academy of Pediatrics (AAP) recommends ganciclovir as the first line alternative when IV acyclovir is unavailable in suspected or proven neonatal herpes simplex disease or herpes simplex/varicella zoster infections in immunocompromised hosts.
Infants 4 to 11 months, Children, and Adolescents: 5 mg/kg/dose IV every 12 hours. The American Academy of Pediatrics (AAP) recommends ganciclovir as the first line alternative when IV acyclovir is unavailable for herpes simplex/varicella zoster infections in immunocompromised hosts and patients unable to tolerate oral acyclovir or valacyclovir.

For the treatment of neonatal herpes simplex virus infection*:
Intravenous dosage:
Neonates and Infants 1 to 3 months: 6 mg/kg/dose IV every 12 hours. The American Academy of Pediatrics (AAP) recommends ganciclovir as the first line alternative when IV acyclovir is unavailable in cases of suspected or proven neonatal herpes simplex disease.

For the treatment of acute herpes simplex keratitis (dendritic keratitis):
NOTE: Ganciclovir ophthalmic gel is an FDA-designated orphan drug for this indication.
Ophthalmic dosage (0.15% ophthalmic gel):
Children >= 2 years and Adolescents: 1 drop in the affected eye(s) 5 times per day (approximately every 3 hours while awake) until corneal ulcer heals, and then 1 drop in the affected eye(s) 3 times per day for 7 days. In an open-label, randomized, controlled multicenter trial (n = 164) and in randomized, single-masked, controlled, multicenter trials (total n = 213), ganciclovir ophthalmic gel was non-inferior to acyclovir 3% ointment with clinical resolution (healed ulcers) at day 7 in 72-77% of ganciclovir patients and 69-72% of acyclovir patients.

For the treatment of progressive outer retinal necrosis (PORN)* due to varicella zoster virus (VZV)* in persons living with HIV:
Intravenous dosage:
Infants and Children: 5 mg/kg/dose IV every 12 hours plus IV foscarnet plus ganciclovir intravitreal injection and/or foscarnet intravitreal injection. The optimal duration has not been defined; duration should be determined clinically in consultation with an ophthalmologist.
Adolescents: 5 mg/kg/dose IV every 12 hours plus ganciclovir intravitreal injection and/or foscarnet intravitreal injection. The optimal duration has not been defined; duration should be determined clinically in consultation with an ophthalmologist.
Intravitreal dosage:
Infants and Children: 2 mg/0.05 mL intravitreal injection twice weekly, with or without foscarnet intravitreal injection, in combination with systemic therapy (i.e., acyclovir or ganciclovir plus foscarnet). The optimal duration has not been defined; duration should be determined clinically in consultation with an ophthalmologist.
Adolescents: 2 mg/0.05 mL intravitreal injection twice weekly, with or without foscarnet intravitreal injection, in combination with systemic therapy (i.e., ganciclovir or acyclovir). The optimal duration has not been defined; duration should be determined clinically in consultation with an ophthalmologist.

For the treatment of severe human herpesvirus 8 (HHV-8) infection* and associated diseases in HIV-infected patients, including multicentric Castleman's disease (MCD)* and primary effusion lymphoma*:
Intravenous dosage:
Infants, Children, and Adolescents: 5 mg/kg/dose IV every 12 hours based on limited data. The HIV guidelines recommend that ganciclovir or oral valganciclovir be used to treat multicentric Castleman disease (MCD) and may be useful as an adjunct to chemotherapy and antiretroviral therapy for the treatment of primary effusion lymphoma. A treatment course of 3 weeks is recommended for MCD.

For the treatment of acute retinal necrosis (ARN)* due to varicella-zoster virus in persons with HIV:
Intravitreal dosage:
Adolescents: 2 mg/0.05 mL administered intravitreally twice weekly until evidence of treatment response in combination with 10 to 14 days of IV acyclovir, then at least 14 weeks of oral valacyclovir. Involvement of an experienced ophthalmologist is recommended.

For the treatment of encephalitis caused by human herpesvirus 6 (HHV-6) infection* in immunocompromised patients:
Intravenous dosage:
Infants, Children, and Adolescents: 5 mg/kg/dose IV every 12 hours for 1 to 3 weeks, followed by a maintenance dose of 5 mg/kg/dose IV once daily to 5 times weekly, has been effective in small studies and case reports of pediatric and adult patients with HHV-6 encephalitis. Higher doses of ganciclovir (18 to 24 mg/kg/day) have also been used in children, without side effects. Ganciclovir alone or in combination with foscarnet is suggested as reasonable by the IDSA due to the lack of other therapeutic options.

Therapeutic Drug Monitoring:
Dosage adjustments for hematologic toxicity
The following dosage adjustments have been suggested for neonates with congenital CMV :
-If absolute neutrophil count (ANC) decreases to < 500 cells/mm3 and is confirmed on repeat testing, hold dose until ANC recovers to > 750 cells/mm3 and resume normal dose.
-If ANC again decreases to <= 750 cells/mm3 but is > 500 cells/mm3, reduce the dose by 50%.
-If after the dosage adjustment, ANC decreases to <= 500 cells/mm3, consider discontinuing ganciclovir.
-Administration of granulocyte colony-stimulating factor may be considered in an attempt to maintain ANC at acceptable levels.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established; however, doses of 12 mg/kg/day IV have been used off-label for the treatment of congenital CMV disease.
-Infants
Safety and efficacy have not been established; however, doses up to 15 mg/kg/day IV have been used off-label for the treatment of CMV infection.
-Children
1 year: Safety and efficacy have not been established; however, doses up to 15 mg/kg/day IV have been used off-label for the treatment of CMV infection.
2 to 12 years: Safety and efficacy have not been established for IV dosing; however, doses up to 15 mg/kg/day IV have been used off-label for the treatment of CMV infection. Five drops/day ophthalmic gel in each affected eye.
-Adolescents
Safety and efficacy have not been established for IV dosing; however, 10 mg/kg/day IV has been used off-label for the treatment of CMV infection. Five drops/day ophthalmic gel in each affected eye.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
The following dosage adjustments based on creatinine clearance have been recommended in pediatric patients:

Intravenous dosage adjustments (induction)
GFR 30 to 50 mL/minute/1.73 m2: 2.5 mg/kg/dose IV every 24 hours.
GFR 10 to 29 mL/minute/1.73 m2: 1.25 mg/kg/dose IV every 24 hours.
GFR less than 10 mL/minute/1.73 m2: 1.25 mg/kg/dose IV three times a week.

Intravenous dosage adjustments (maintenance)
GFR 30 to 50 mL/minute/1.73 m2: 1.25 mg/kg/dose IV every 24 hours.
GFR 10 to 29 mL/minute/1.73 m2: 0.625 mg/kg/dose IV every 24 hours.
GFR less than 10 mL/minute/1.73 m2: 0.625 mg/kg/dose IV three times a week.

Intermittent hemodialysis or Peritoneal dialysis
Give all doses after dialysis sessions.
Intravenous dosage adjustments (induction): 1.25 mg/kg/dose IV 3 times per week.
Intravenous dosage adjustments (maintenance): 0.625 mg/kg/dose IV 3 times per week.

Continuous renal replacement therapy
Intravenous dosage adjustments (induction): 2.5 mg/kg/dose IV every 24 hours.
Intravenous dosage adjustments (maintenance): 1.25 mg/kg/dose IV every 24 hours.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Ganciclovir is a synthetic analog of 2'-deoxyguanosine and inhibits the replication of viruses, including cytomegalovirus (CMV), herpes simplex virus, and varicella zoster virus. In infected cells, ganciclovir is initially phosphorylated to ganciclovir monophosphate by the viral protein kinase pUL97. Further phosphorylation by protein kinases produces ganciclovir triphosphate. Ganciclovir triphosphate inhibits viral DNA synthesis by competitive inhibition of viral DNA polymerases and incorporation into viral DNA resulting in eventual termination of viral DNA elongation. Since phosphorylation is dependent upon viral protein kinases, ganciclovir is preferentially metabolized in virus-infected cells. Ganciclovir triphosphate concentrations may be 100-fold greater in infected cells than in uninfected cells. As sensitivity tests vary due to many factors, the concentration of ganciclovir to inhibit the growth of virus in cell culture by 50% (IC50) ranges from 0.02-3.48 mcg/ml. Ganciclovir inhibits mammalian cell proliferation (CIC50) in vitro at higher concentrations ranging from 30-725 mcg/ml; however, bone marrow cells are more sensitive (CIC50 0.028-0.7 mcg/ml).

Pharmacokinetics: Ganciclovir is administered intravenously, by topical ophthalmic administration, and by intravitreal injection. Ganciclovir exhibits linear pharmacokinetics with IV doses up to 5 mg/kg. Ganciclovir crosses the blood-brain barrier, producing CSF concentrations that average about 40% (range 24% to 70%) of plasma concentrations. After IV administration of ganciclovir, distribution into body tissues and fluids is extensive including significant intraocular penetration. Protein binding is roughly 1% to 2%. Ganciclovir undergoes little or no metabolism. Ganciclovir is excreted primarily in the urine, with about 90% excreted unchanged by glomerular filtration and active tubular secretion.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Intravenous Route
In adult patients (n = 32) who received 5 mg/kg IV ganciclovir over 1 hour, Cmax ranged from 8.27 +/- 1.02 to 9 +/- 1.4 mcg/mL. The half-life in adult patients with normal renal function is about 3.5 hours after IV administration.

Other Route(s)
Ophthalmic Route
Minimal systemic exposure is expected with topical ophthalmic administration of ganciclovir gel.


-Special Populations
Pediatrics
The pharmacokinetics of IV ganciclovir in pediatric patients are similar to those seen in adults.

Neonates
The Cmax, systemic clearance, and half-life of ganciclovir in 27 neonates (2 to 49 days postnatal age, gestational age not specified) after doses of 4 to 6 mg/kg IV were 5.5 to 7 mcg/mL, 3.14 to 3.56 mL/minute/kg, and 2.4 hours, respectively.

Infants, Children, and Adolescents
The Cmax, systemic clearance, and half-life of ganciclovir in 10 infants and children (9 months to 12 years of age) after doses of 5 mg/kg IV were 7.9 mcg/mL, 4.7 mL/minute/kg, and 2.4 hours, respectively.

Renal Impairment
The half-life of ganciclovir increases and clearance decreases in patients with impaired renal function. The half-life and plasma clearance in 3 pediatric renal transplant patients (9 to 16 years of age) receiving IV ganciclovir with creatinine clearances of 60, 45, and 20 mL/minute/1.73 m2 were 3.9 hours and 2.2 mL/minute/kg; 9.9 hours and 1.1 mL/minute/kg; and 23.7 hours and 0.4 mL/minute/kg, respectively. Hemodialysis reduces ganciclovir concentrations by about 50%.