Ganciclovir (Systemic)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Generic: 500 mg/250 mL (250 mL); 500 mg/10 mL (10 mL)

Solution Reconstituted, Intravenous [preservative free]:

Cytovene: 500 mg (1 ea)

Generic: 500 mg (1 ea)

Pharmacology

Mechanism of Action

Ganciclovir is phosphorylated to a substrate which competitively inhibits the binding of deoxyguanosine triphosphate to DNA polymerase resulting in inhibition of viral DNA synthesis

Pharmacokinetics/Pharmacodynamics

Distribution

V_d: Children 9 months to 12 years: 0.64 ± 0.22 L/kg; Adults: 0.74 ± 0.15 L/kg; widely to all tissues including CSF and ocular tissue

Excretion

Urine (80% to 99% as unchanged drug)

Half-Life Elimination

Neonates 2 to 49 days of age: 2.4 hours

Children 9 months to 12 years: 2.4 ± 0.7 hours

Adults: Mean: IV: 3.5 ± 0.9 hours; Oral: 4.8 ± 0.9 hours; CrCl <25 mL/minute: 10.7 ± 5.7 hours

Protein Binding

1% to 2%

Use in Specific Populations

Special Populations: Renal Function Impairment

Clearance is decreased and half-life is prolonged.

Use: Labeled Indications

Cytomegalovirus disease, prophylaxis (transplant patients): Prevention of cytomegalovirus (CMV) disease in adult transplant recipients at risk for CMV disease.

Cytomegalovirus retinitis (immunocompromised patients): Treatment of CMV retinitis in immunocompromised adult patients, including patients with AIDS.

Use: Off Label

Cytomegalovirus (CMV) esophagitis or colitis treatment in HIV-infected patientsyes

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, ganciclovir is an effective and recommended agent for the treatment of esophagitis or colitis due to CMV disease in HIV-infected patients.

CMV neurological disease in HIV-infected patientsyes

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, ganciclovir is an effective and recommended agent for the treatment of neurological disease due to CMV disease in HIV-infected patients.

CMV retinitis, secondary prevention in HIV-infected patientsyes

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, ganciclovir is an effective and recommended agent for the secondary prophylaxis of CMV retinitis in HIV-infected patients.

CMV disease, preemptive therapy (hematopoietic cell transplant recipients)yes

Based on the American Society for Blood and Marrow Transplantation (ASBMT) Guidelines for Preventing Infectious Complications among Hematopoietic Cell Transplantation Recipients, ganciclovir is an effective and recommended agent in the preemptive management of CMV in bone marrow transplant recipients.

CMV disease, treatment (solid organ transplant recipients)yes

Based on The Transplantation Society International CMV Consensus Group Guidelines, ganciclovir is an effective and recommended agent in the treatment of CMV disease in solid organ transplant recipient.

Varicella-zoster: Acute retinal necrosis (ARN) in HIV-infected patientsyes

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, intravitreal ganciclovir in combination with intravenous acyclovir is an effective and recommended agent in the management of varicella-zoster virus acute retinal necrosis (ARN) in HIV-infected patients.

Varicella-zoster: Progressive outer retinal necrosis (PORN) in HIV-infected patientsyes

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, ganciclovir is an effective and recommended agent in the management of this condition in HIV-infected patients.

Contraindications

Hypersensitivity to ganciclovir, valganciclovir, acyclovir, or any component of the formulation

Dosage and Administration

Dosing: Adult

CMV retinitis (immunocompromised patients):

Manufacturer's labeling:

Induction therapy: IV: 5 mg/kg/dose every 12 hours for 14 to 21 days followed by maintenance therapy

Maintenance therapy: IV: 5 mg/kg/dose once daily for 7 days/week or 6 mg/kg/dose once daily for 5 days/week

Alternate dosing (HHS [OI adult 2017]):

Peripheral lesions (alternative agent): IV: Induction: 5 mg/kg/dose every 12 hours for 14 to 21 days followed by chronic maintenance (secondary prophylaxis)

Immediate sight-threatening lesions (adjacent to the optic nerve or fovea): Intravitreal injection (off-label route): Induction therapy: 2 mg of an extemporaneously prepared solution administered as intravitreal injections for 1 to 4 doses over a period of 7 to 10 days; administer with a concomitant systemically administered agent (oral valganciclovir preferred).

CMV disease prophylaxis in transplant patients: IV:

Manufacturer's labeling:

Induction therapy: 5 mg/kg/dose every 12 hours for 7 to 14 days

Maintenance therapy: 5 mg/kg/dose once daily for 7 days/week or 6 mg/kg/dose once daily for 5 days/week; duration is dependent on clinical condition and degree of immunosuppression

Alternate dosing:

Hematopoietic cell transplant recipients (allogeneic): 5 mg/kg/dose every 12 hours for 5 to 7 days, then 5 mg/kg/dose every 24 hours until day 100 post-transplant (Tomblyn 2009).

Solid organ transplant recipients: 5 mg/kg/dose every 24 hours; duration of prophylaxis is dependent on type of transplant, as well as donor and recipient CMV serostatus (Kotton 2013).

CMV disease, preemptive therapy (hematopoietic cell transplant recipients) (off-label use) (Tomblyn 2009): IV:

<100 days post-transplant: 5 mg/kg/dose every 12 hours for 7 days (autologous transplant) or 7 to 14 days (allogenic transplant), then 5 mg/kg/dose every 24 hours for 1 to 2 weeks or until the indicator test is negative (minimum total induction and maintenance treatment is 2 weeks when 14 days of twice daily is used and 3 weeks when a 7-day induction course is used).

>100 days post-transplant: 5 mg/kg/dose every 12 hours for 7 to 14 days, then 5 mg/kg/dose every 24 hours for 1 to 2 weeks or until the indicator test is negative.

CMV disease, treatment (solid organ transplant recipients) (off-label use): IV: 5 mg/kg/dose every 12 hours until 1 or 2 consecutive undetectable CMV viral load samples are obtained (minimum treatment course: 2 weeks) (Kotton 2013).

UL97 mutation for <5x ganciclovir EC50: 10 mg/kg/dose every 12 hours (Kotton 2013).

Ganciclovir-resistant strains: 5 mg/kg/dose every 24 hours in combination with daily foscarnet and monthly CMV hyperimmunoglobulin (Mylonakis 2002).

CMV esophagitis or colitis in HIV-infected patients (off-label use): IV: 5 mg/kg/dose every 12 hours, then change to oral valganciclovir therapy once oral therapy is tolerated; total duration of therapy: 21 to 42 days or until symptom resolution (HHS [OI adult 2017]).

CMV neurological disease in HIV-infected patients (off-label use): IV: 5 mg/kg/dose every 12 hours plus foscarnet until symptoms improve (HHS [OI adult 2017]).

CMV retinitis, chronic maintenance (secondary prophylaxis) in HIV-infected patients (off-label use; alternative agent): IV: 5 mg/kg/dose 5 to 7 times weekly; continue until sustained CD4 count >100 cells/mm³ in response to ART for 3 to 6 months; discontinue only after consultation with an ophthalmologist) (HHS [OI adult 2017]).

Varicella-zoster: Acute retinal necrosis (ARN) in HIV-infected patients (off-label use): Intravitreal injection (off-label route): 2 mg of an extemporaneously prepared solution administered as an intravitreal injection twice weekly for 1 to 2 doses in combination with IV acyclovir for 10 to 14 days, followed by valacyclovir for 6 weeks (HHS [OI adult 2017]).

Varicella-zoster: Progressive outer retinal necrosis in HIV-infected patients (off-label use): IV: 5 mg/kg/dose every 12 hours (with or without IV foscarnet) plus intravitreal ganciclovir and/or intravitreal foscarnet (HHS [OI adult 2017]).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

CMV infection: Limited data available: IV:

Congenital CMV (symptomatic; CNS-disease); treatment (independent of HIV status): Infants: 6 mg/kg/dose every 12 hours for 6 weeks; if neonate diagnosed as HIV-positive a longer duration of therapy may be considered (CDC, 2009; Redbook, 2009)

CNS infection, treatment (HIV-exposed/-positive): Infants and Children: 5 mg/kg/dose every 12 hours plus foscarnet; continue until symptoms improve, followed by chronic suppression (CDC, 2009)

Disseminated disease and retinitis, treatment:

Induction therapy: Infants ≥3 months and Children: 5 mg/kg/dose every 12 hours for 14-21 days; may be increased to 7.5 mg/kg/dose every 12 hours (CDC, 2009)

Maintenance therapy: Infants ≥ 3 months and Children: 5 mg/kg/dose as a single daily dose for 5-7 days/week (CDC, 2009)

Secondary prevention in HIV-exposed/-infected patients: Infants and Children: 5 mg/kg/dose once daily (CDC, 2009)

Prevention in transplant recipients: Children: Initial: 5 mg/kg/dose every 12 hours for 1-2 weeks, followed by 5 mg/kg/dose once daily 7 days/week or 6 mg/kg/dose once daily 5 days/week for 100 days

Prevention in lung/heart-lung transplant patients (CMV-positive donor with CMV-positive recipient): Children: 6 mg/kg/dose once daily for 28 days

Other CMV infections: Children: Initial: 5 mg/kg/dose every 12 hours for 14-21 days; maintenance therapy: 5 mg/kg/dose once daily for 7 days/week or 6 mg/kg/dose once daily for 5 days/week

Varicella zoster; progressive outer retinal necrosis: Limited data available: IV: Infants, Children, and Adolescents: 5 mg/kg/dose every 12 hours plus systemic foscarnet and intravitreal ganciclovir or foscarnet (CDC, 2009; Kaplan, 2009)

Reconstitution

Reconstitute 500 mg vial with 10 mL unpreserved sterile water (do not use bacteriostatic water; parabens may cause precipitation). Shake vial to dissolve. Typically, dilute in 100 mL D5W or NS to a concentration ≤10 mg/mL for infusion.

Administration

IV: For IV infusion; should not be administered by IM, SubQ, or rapid or bolus IV injection. Administer by slow IV infusion over at least 1 hour. Too rapid infusion can cause increased toxicity due to excessive plasma levels. Flush line well with NS before and after administration.

Dietary Considerations

Some products may contain sodium.

Storage

Store intact vials and premixed solution bags at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Reconstituted solution in the vial is stable at room temperature for 12 hours; do not refrigerate or freeze. Diluted solutions for infusion should be refrigerated and used within 24 hours of preparation; do not freeze.

Drug Interactions

Amphotericin B: Ganciclovir-Valganciclovir may enhance the nephrotoxic effect of Amphotericin B. Monitor therapy

Cladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine. Avoid combination

CycloSPORINE (Systemic): Ganciclovir-Valganciclovir may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Monitor therapy

Didanosine: Ganciclovir-Valganciclovir may increase the serum concentration of Didanosine. Monitor therapy

Imipenem: Ganciclovir-Valganciclovir may enhance the adverse/toxic effect of Imipenem. Specifically, the risk of seizures may be increased. Management: Avoid concomitant use of these agents unless the prospective benefits of therapy outweigh the risks. Consider therapy modification

Mycophenolate: May increase the serum concentration of Ganciclovir-Valganciclovir. Ganciclovir-Valganciclovir may increase the serum concentration of Mycophenolate. Monitor therapy

Probenecid: May increase the serum concentration of Ganciclovir-Valganciclovir. Monitor therapy

Tenofovir Products: May increase the serum concentration of Ganciclovir-Valganciclovir. Ganciclovir-Valganciclovir may increase the serum concentration of Tenofovir Products. Monitor therapy

Zidovudine: Ganciclovir-Valganciclovir may enhance the adverse/toxic effect of Zidovudine. Specifically, hematologic toxicity may be enhanced. Monitor therapy

Adverse Reactions

>10%:

Dermatologic: Hyperhidrosis (12%)

Gastrointestinal: Diarrhea (44%), anorexia (14%), vomiting (13%)

Hematologic & oncologic: Thrombocytopenia (6%; ≤50,000/mcL: 8% to 57%; <25,000/mcL: 3% to 32%), leukopenia (41%), neutropenia (ANC <500/mcL: 4% to 25%; 500 to 1,000/mcL: 14% to 29%), anemia (25%; hemoglobin <6.5 g/dL: 5%)

Infection: Sepsis (15%), infection (13%)

Ophthalmic: Retinal detachment (11%; relationship to ganciclovir not established)

Renal: Increased serum creatinine (2% to 50%; ≥2.5 mg/dL: 2% to 20%)

Miscellaneous: Fever (48%)

1% to 10%:

Central nervous system: Chills (10%), peripheral neuropathy (9%)

Dermatologic: Pruritus (5%)

Infection: Catheter sepsis (8%)

Local: Catheter infection (9%), catheter-site reaction (5%)

Frequency not defined:

Cardiovascular: Cardiac arrhythmia, chest pain, edema, hypertension, hypotension, phlebitis, vasodilation

Central nervous system: Abnormal dreams, abnormality in thinking, agitation, anxiety, confusion, depression, dizziness, drowsiness, fatigue, headache, hypoesthesia, insomnia, malaise, myasthenia, pain, paresthesia, psychosis, seizure

Dermatologic: Alopecia, cellulitis, dermatitis, skin rash, urticaria, xeroderma

Endocrine & metabolic: Weight loss

Gastrointestinal: Abdominal distention, abdominal pain, aphthous stomatitis, constipation, dysgeusia, dyspepsia, dysphagia, eructation, flatulence, gastrointestinal perforation, nausea, oral candidiasis, oral mucosa ulcer, pancreatitis, xerostomia

Genitourinary: Hematuria, urinary frequency, urinary tract infection

Hematologic & oncologic: Bone marrow failure

Hepatic: Abnormal hepatic function tests, increased serum alanine aminotransferase, increased serum aspartate aminotransferase, increased serum alkaline phosphatase

Infection: Candidiasis, influenza

Local: Inflammation at injection site

Neuromuscular & skeletal: Arthralgia, asthenia, back pain, lower limb cramp, muscle spasm, myalgia, tremor

Ophthalmic: Conjunctivitis, eye disease (vitreous disorder), eye pain, macular edema, visual impairment

Otic: Deafness, otalgia, tinnitus

Renal: Decreased creatinine clearance, renal failure syndrome, renal function abnormality

Respiratory: Cough, dyspnea, upper respiratory tract infection

Miscellaneous: Multiorgan failure

<1%, postmarketing, and/or case reports: Acidosis, agranulocytosis, amnesia, anaphylaxis, anosmia, aphasia, arthritis, bronchospasm, cardiac conduction disturbance, cataract, cerebrovascular accident, cholelithiasis, cholestasis, cranial nerve palsy (third), dysesthesia, dysphasia, encephalopathy, exfoliative dermatitis, extrapyramidal reaction, facial nerve paralysis, granulocytopenia, hallucination, hemolytic anemia, hemolytic-uremic syndrome, hepatic failure, hepatitis, hypercalcemia, hypersensitivity reaction, hyponatremia, increased serum triglycerides, infertility, intracranial hypertension, irritability, myelopathy, oculomotor nerve paralysis, pancytopenia, peripheral ischemia, pulmonary fibrosis, renal tubular disease, rhabdomyolysis, SIADH, Stevens-Johnson syndrome, testicular hypotrophy, torsades de pointes, ulcerative bowel lesion, vasculitis, ventricular tachycardia, xerophthalmia

Warnings/Precautions

Concerns related to adverse effects:

• Carcinogenic/teratogenic: [US Boxed Warning]: May cause temporary or permanent inhibition of spermatogenesis and suppression of fertility; has the potential to cause birth defects and cancers in humans. Due to its teratogenic potential, females should undergo pregnancy testing prior to initiation and use effective contraception during treatment and for 30 days after; males should use barrier contraception during treatment and for 90 days after.
• Hematologic toxicity: [US Boxed Warning]: Granulocytopenia (neutropenia), anemia, thrombocytopenia, and pancytopenia may occur. Neutropenia usually occurs during the first 1 to 2 weeks of treatment but may occur at any time; cell counts usually begin to recover within 3 to 7 days of treatment discontinuation. Colony-stimulating factors have been shown to increase neutrophil and white blood cell counts in patients receiving ganciclovir. Use with caution in patients with pre-existing cytopenias and in patients receiving myelosuppressive drugs or irradiation. Frequently monitor complete blood count with differential and platelet counts, especially in patients with renal impairment and in patients who have previously experienced drug-induced leukopenia or who have neutrophil counts <1,000 cells/mm³ at the beginning of treatment. Ganciclovir is not recommended in patients with an absolute neutrophil count (ANC) <500 cells/mm³, hemoglobin <8 g/dL, or platelet count <25,000 cells/mm³.
• Renal toxicity: Increased serum creatinine levels have been reported in elderly patients and transplant patients receiving concomitant nephrotoxic medications (eg, cyclosporine, amphotericin B). Monitor renal function during therapy, especially in elderly patients and those receiving concomitant nephrotoxic agents.

Disease-related concerns:

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment recommended.

Special populations:

• Elderly: Increased serum creatinine levels have been reported; use with caution and closely monitor serum creatinine.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Administration: Ensure patients are adequately hydrated. Avoid rapid infusion. Phlebitis and/or pain may occur at injection site despite adequate dilution; infuse solution into veins with adequate blood flow.

Monitoring Parameters

CBC with differential and platelet count at baseline and twice weekly, serum creatinine at baseline and once weekly (Tice 2004); pregnancy test prior to initiation in females of reproductive potential; frequent ophthalmological exams in patients with CMV retinitis.

Pregnancy

Pregnancy Considerations

Ganciclovir crosses the placenta. [US Boxed Warning]: Based on animal data, ganciclovir has the potential to cause birth defects in humans.

[US Boxed Warning]: Based on animal data and limited human data, ganciclovir may cause temporary or permanent inhibition of spermatogenesis in males and suppression of fertility in females. Female patients of reproductive potential should undergo pregnancy testing prior to initiation and use effective contraception during and for at least 30 days after therapy. Male patients should use a barrier contraceptive during and for at least 90 days after therapy.

Patient Education

What is this drug used for?

• It is used to treat a viral infection of the eyes in people with immune system problems.
• It is used to prevent cytomegalovirus (CMV) disease after organ transplant.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Fatigue
• Lack of appetite
• Nausea
• Vomiting
• Passing gas
• Constipation
• Nightmares
• Dry mouth
• Trouble sleeping
• Hair loss
• Dry skin
• Change in taste
• Back pain
• Muscle pain
• Joint pain
• Muscle spasm
• Leg cramps
• Weight loss
• Diarrhea

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding.
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.
• Pancreatitis like severe abdominal pain, severe back pain, severe nausea, or vomiting.
• Severe headache
• Severe dizziness
• Passing out
• Vision changes
• Severe loss of strength and energy
• Sweating a lot
• Confusion
• Anxiety
• Edema
• Eye pain
• Shortness of breath
• Noise or ringing in the ears
• Abnormal heartbeat
• Behavioral changes
• Hearing loss
• Depression
• Tremors
• Burning or numbness feeling
• Seizures
• Severe abdominal pain
• Abdominal edema
• Chest pain
• Injection site pain or irritation
• Severe eye irritation
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.