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Ganciclovir (Systemic)

Pronunciation

Pronunciation

(gan SYE kloe veer)

Index Terms

  • DHPG Sodium
  • Ganciclovir Sodium
  • GCV Sodium
  • Nordeoxyguanosine

Dosage Forms

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

Solution Reconstituted, Intravenous:

Cytovene: 500 mg (1 ea)

Generic: 500 mg (1 ea)

Solution Reconstituted, Intravenous [preservative free]:

Generic: 500 mg (1 ea)

Brand Names: U.S.

  • Cytovene

Pharmacologic Category

  • Antiviral Agent

Pharmacology

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

Distribution

Vd: 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%

Special Populations: Renal Function Impairment

Clearance is decreased and half-life is prolonged.

Use: Labeled Indications

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

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

Off Label Uses

Cytomegalovirus (CMV) esophagitis or colitis treatment in HIV-infected patients (adolescents and adults)

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 adolescent and adult HIV-infected patients.

CMV neurological disease in HIV-infected patients (adolescents and adults)

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 adolescent and adult HIV-infected patients.

CMV retinitis, secondary prevention in HIV-infected patients (adolescents and adults)

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 adolescent and adult HIV-infected patients.

CMV disease, preemptive therapy (hematopoietic cell transplant recipients)

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)

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 patients (adolescent and adults)

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 adolescent and adult HIV-infected patients.

Varicella-zoster: Progressive outer retinal necrosis (PORN) in HIV-infected patients (adolescents and adults)

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 adolescent and adult HIV-infected patients.

Contraindications

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

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/day as a single daily dose for 7 days/week or 6 mg/kg/day 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/day as a single daily dose for 7 days/week or 6 mg/kg/day 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 retinitis:

Children: IV:

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

Maintenance therapy: 5 mg/kg/day as a single daily dose for 7 days/week or 6 mg/kg/day for 5 days/week

Adolescents: Refer to adult dosing.

CMV disease, chronic maintenance (secondary prophylaxis) in HIV-exposed/-infected patients (off-label use):

Infants and Children: IV: 5 mg/kg/dose daily (CDC 2009)

Adolescents (alternative to preferred therapy): Refer to adult dosing.

CMV disease, prophylaxis (secondary) in transplant patients: Children: IV: Refer to adult dosing.

CMV esophagitis or colitis in HIV-infected patients (off-label use): Adolescents: Refer to adult dosing.

CMV neurological disease in HIV-exposed/-infected patients (off-label use): Infants, Children, and Adolescents: IV: Refer to adult dosing.

Varicella-zoster: Acute retinal necrosis (ARN) in HIV-infected patients (off-label use): Adolescents: Refer to adult dosing.

Varicella-zoster: Progressive outer retinal necrosis in HIV-exposed/-infected patients (off-label use):

Infants and Children: IV: 5 mg/kg/dose every 12 hours plus systemic foscarnet and intravitreal ganciclovir or intravitreal foscarnet (CDC 2009)

Adolescents: Refer to adult dosing.

Dosing: Renal Impairment

Note: Renally adjusted dose recommendations are based on an induction dose of 5 mg/kg/dose every 12 hours and a maintenance dose of 5 mg/kg/dose every 24 hours.

IV (Induction):

CrCl ≥70 mL/minute: No dosage adjustment necessary.

CrCl 50 to 69 mL/minute: Administer 2.5 mg/kg/dose every 12 hours

CrCl 25 to 49 mL/minute: Administer 2.5 mg/kg/dose every 24 hours

CrCl 10 to 24 mL/minute: Administer 1.25 mg/kg/dose every 24 hours

CrCl <10 mL/minute: Administer 1.25 mg/kg/dose 3 times/week following hemodialysis.

IV (Maintenance):

CrCl ≥70 mL/minute: No dosage adjustment necessary.

CrCl 50 to 69 mL/minute: Administer 2.5 mg/kg/dose every 24 hours

CrCl 25 to 49 mL/minute: Administer 1.25 mg/kg/dose every 24 hours

CrCl 10 to 24 mL/minute: Administer 0.625 mg/kg/dose every 24 hours

CrCl <10 mL/minute: Administer 0.625 mg/kg/dose 3 times/week following hemodialysis.

Intermittent hemodialysis (IHD) (administer after hemodialysis on dialysis days): Dialyzable (50%): CMV Infection: IV: Induction: 1.25 mg/kg every 48 to 72 hours; Maintenance: 0.625 mg/kg every 48 to 72 hours. Note: Dosing dependent on the assumption of 3 times/week, complete IHD sessions (Heintz 2009).

Peritoneal dialysis (PD): Dose as for CrCl <10 mL/minute (Aronoff 2007).

Continuous renal replacement therapy (CRRT) (Heintz 2009; Trotman 2005): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug concentrations in relation to target trough (if appropriate). The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1 to 2 L/hour and minimal residual renal function) and should not supersede clinical judgment: CMV Infection:

CVVH: IV: Induction: 2.5 mg/kg every 24 hours; Maintenance: 1.25 mg/kg every 24 hours

CVVHD/CVVHDF: IV: Induction: 2.5 mg/kg every 12 hours; Maintenance: 2.5 mg/kg every 24 hours

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Reconstitution

Reconstitute 500 mg vial with 10 mL unpreserved sterile water not bacteriostatic water because 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

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 and excessive plasma levels. Flush line well with NS before and after administration.

Dietary Considerations

Some products may contain sodium.

Compatibility

See Trissel’s IV Compatibility Database

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. Diluted solutions for infusion should be refrigerated and used within 24 hours of preparation; do not freeze.

Drug Interactions

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: Diaphoresis (12%)

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

Hematologic & oncologic: Thrombocytopenia (57%), leukopenia (41%), anemia (16% to 26%), neutropenia (ANC <500/mm3: 12% to 14%)

Infection: Sepsis (15%)

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

Renal: Increased serum creatinine (2% to 14%)

Miscellaneous: Fever (48%)

1% to 10%:

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

Dermatologic: Pruritus (5%)

<1% (Limited to important or life-threatening): Alopecia, brain disease, bronchospasm, cardiac arrhythmia, cataract, cholestasis, coma, dyspnea, edema, eosinophilia, exfoliative dermatitis, extrapyramidal reaction, hemorrhage, hepatic failure, hepatitis, hypersensitivity reaction (including anaphylaxis), pancreatitis, pancytopenia, psychosis, pulmonary fibrosis, renal failure, rhabdomyolysis, seizure, SIADH (syndrome of inappropriate antidiuretic hormone secretion), Stevens-Johnson syndrome, torsades de pointes, urticaria, vision loss

ALERT: U.S. Boxed Warning

Blood dyscrasias:

The clinical toxicity of ganciclovir IV includes granulocytopenia, anemia and thrombocytopenia. In animal studies ganciclovir was carcinogenic, teratogenic and caused aspermatogenesis.

Appropriate use:

Ganciclovir IV is indicated for use only in the treatment of cytomegalovirus (CMV) retinitis in immunocompromised patients and for the prevention of CMV disease in transplant patients at risk for CMV disease

Carcinogenic/teratogenic:

In animal studies ganciclovir was carcinogenic, teratogenic and caused aspermatogenesis

Warnings/Precautions

Concerns related to adverse effects:

• Blood dyscrasias: [US Boxed Warning]: Granulocytopenia (neutropenia), anemia, and thrombocytopenia may occur. Neutropenia usually occurs during the first 1 to 2 weeks of treatment but may occur at any time; counts generally recover within 3 to 7 days of treatment discontinuation. Use with caution in patients with preexisting hematologic abnormalities or with a history of hematologic abnormalities caused by other drugs, chemicals, or irradiation. Frequently monitor complete blood count with differential and platelet counts, especially in patients who have previously experienced drug-induced leukopenia or who have neutrophil counts <1,000 cells/mm3. Dosage adjustment or interruption of therapy may be necessary; do not administer to patients with an ANC <500 cells/mm3 or platelet count <25,000 cells/mm3.

• Carcinogenic/teratogenic: [US Boxed Warning]: Based on animal data, use may suppress fertility in females, inhibit spermatogenesis in males, and cause birth defects if used in pregnant women.Female patients should undergo pregnancy testing prior to initiation and should 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.

• Renal effects: 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.

• Appropriate use: [US Boxed Warning]: Indicated only for treatment of CMV retinitis in the immunocompromised patient and CMV prevention in transplant patients at risk for CMV disease.

Monitoring Parameters

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

Pregnancy Considerations

[US Boxed Warning]: Based on animal data, use may suppress fertility in females, inhibit spermatogenesis in males, and cause birth defects if used in pregnant women. Ganciclovir crosses the placenta. Female patients 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. The inhibition of spermatogenesis may be temporary or permanent.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, lack of appetite, nausea, vomiting, constipation, nightmares, dry mouth, insomnia, hair loss, dry skin, change in taste, muscle pain, joint pain, leg cramps, weight loss, or diarrhea. Have patient report immediately to prescriber signs of infection,signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; 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), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of pancreatitis (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, shortness of breath, tinnitus, depression, tremors, burning or numbness feeling, seizures, severe abdominal pain, abdominal edema, angina, or injection site pain or irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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