Ganciclovir

( DHPG ) Pronunciation: (gan-SYE-kloe-vir)
Class: Antiviral, Ophthalmic antiviral

Trade Names

Cytovene
- Injection, lyophilized powder for solution 500 mg (as sodium)/vial

Ganciclovir
- Capsules 250 mg
- Capsules 500 mg

Vitrasert
- Intravitreal implant 4.5 mg

Zirgan
- Ophthalmic gel 0.15%

Pharmacology

Inhibits cytomegalovirus (CMV) and other virus replication by competitive inhibition of viral DNA polymerases and direct incorporation into viral DNA.

Pharmacokinetics

Absorption

AUC _0-24 is approximately 15.9 mcg•h/mL (oral); approximately 22.1 to 26.8 mcg•h/mL (IV). Fasting absolute bioavailability is approximately 5%; absolute bioavailability following food is 6% to 9% (oral). C _max is approximately 1.02 to 1.18 mcg/mL (oral); approximately 8.27 to 9 mcg/mL (IV). Time to steady state is 24 h (oral).

Distribution

Approximately 1% to 2% bound to plasma proteins; Vd _ss is approximately 0.74 L/kg (IV).

Elimination

Major route is renal excretion of unchanged drug by glomerular filtration and active tubular secretion. Half-life is approximately 3.5 h (IV) to 4.8 h (oral). Systemic Cl is approximately 3.52 mL/min/kg.

Special Populations

Renal Function Impairment
CrCl 50 to 79 mL/min

Cl is about 128 mL/min; half-life is about 4.6 h.

CrCl 25 to 49 mL/min

Cl is approximately 57 mL/min; half-life is approximately 4.4 h.

CrCl less than 25 mL/min

Cl is approximately 30 mL/min; half-life is approximately 10.7 h.

Hemodialysis

Reduces ganciclovir by about 50% after IV administration.

Elderly

No studies have been conducted in patients older than 65 yr of age.

Children
9 mo to 12 yr of age

Vd _ss was approximately 0.64 L/kg; C _max was approximately 7.9 mcg/mL; systemic Cl was approximately 4.7 mL/min/kg; half-life was approximately 2.4 h.

Neonates (2 to 49 days of age)

C _max was approximately 5.5 to 7 mcg/mL; systemic Cl was approximately 3.14 to 3.56 mL/min/kg; half-life was approximately 2.4 h.

Gender

No differences between men and women were observed.

Race

Black and Hispanic patients trend toward a lower AUC _0-8 and steady-state C _max .

Indications and Usage

IV

Treatment of CMV retinitis in immunocompromised patients, including patients with AIDS; prevention of CMV disease in organ transplant patients at risk for CMV.

Oral

Alternative to the IV formulation for maintenance treatment of CMV retinitis in immunocompromised patients, including patients with AIDS, in whom retinitis is stable following appropriate induction therapy and for whom the risk of more rapid progression is balanced by the benefit associated with avoiding daily IV infusions; prevention of CMV disease in solid organ transplant recipients and in individuals with advanced HIV infection at risk for developing CMV disease.

Intravitreal implant

For the treatment of CMV retinitis in patients with AIDS.

Ophthalmic gel

For the treatment of acute herpetic keratitis (dendritic ulcers).

Unlabeled Uses

Treatment of other CMV infections (eg, pneumonitis, gastroenteritis, hepatitis) in some immunocompromised patients.

Contraindications

Hypersensitivity to ganciclovir or acyclovir; patients with any contraindications for ocular surgery, such as external infection or severe thrombocytopenia (implant).

Dosage and Administration

Acute Herpetic Keratitis

Ophthalmic gel Instill 1 drop in the affected eye(s) 5 times per day (approximately every 3 h while awake) until the corneal ulcer heals, and then 1 drop 3 times per day for 7 days.

CMV Retinitis
Adults IV Induction

5 mg/kg over 1 h every 12 h for 14 to 21 days.

Maintenance

5 mg/kg over 1 h once daily 7 days per wk or 6 mg/kg over 1 h once daily 5 days per wk (max, 6 mg/kg over 1 h).

PO

Following induction treatment with IV ganciclovir, the recommended maintenance dosage of oral ganciclovir is 1,000 mg 3 times/day with food. Alternatively, the dosing regimen of 500 mg 6 times/day every 3 h with food, during waking hours, may be used.

Intravitreal implant

4.5 mg insert designed to release the drug over 5 to 8 mo.

CMV Prevention in Transplant Recipients
Adults

IV 5 mg/kg over 1 h every 12 h for 7 to 14 days, followed by 5 mg/kg once daily 7 days per wk or 6 mg/kg once daily 5 days per wk. PO 1,000 mg 3 times/day with food.

CMV Prevention in Advanced HIV Infection
Adults

PO 1,000 mg 3 times daily with food.

Decreased Renal Function
Adults IV Induction

• CrCl at least 70 mL/min : 5 mg/kg every 12 h;
• CrCl 50 to 69 mL/min: 2.5 mg/kg every 12 h;
• CrCl 25 to 49 mL/min: 2.5 mg/kg every 24 h;
• CrCl 10 to 24 mL/min: 1.25 mg/kg every 24 h;
• CrCl less than 10 mL/min: 1.25 mg/kg 3 times per week following hemodialysis

Maintenance

• CrCl at least 70 mL/min: 5 mg/kg every 24 h;
• CrCl 50 to 69 mL/min: 2.5 mg/kg every 24 h;
• CrCl 25 to 49 mL/min: 1.25 mg/kg every 24 h;
• CrCl 10 to 24 mL/min: 0.625 mg/kg every 24 h;
• CrCl less than 10 mL/min: 0.625 mg/kg 3 times per week following hemodialysis

PO

• CrCl at least 70 mL/min: 1,000 mg 3 times daily or 500 mg every 3 h, 6 times/day;
• CrCl 50 to 69 mL/min: 1,500 mg every day or 500 mg 3 times daily;
• CrCl 25 to 49 mL/min 1,000 mg every day or 500 mg twice daily;
• CrCl 10 to 24 mL/min: 500 mg every day;
• CrCl less than 10 mL/min: 500 mg 3 times per week following hemodialysis

General Advice

• Injection
• For IV infusion only. Do not administer by rapid or bolus IV injection.
• IM or subcutaneous injection may result in severe tissue irritation.
• Reconstitute with 10 mL of sterile water for injection (do not use bacteriostatic water or other solutions), and shake well to dissolve drug. Further dilute reconstituted solution with sodium chloride 0.9%, dextrose 5%, Ringer's injection, or Ringer's lactate injection. Final concentration should not exceed 10 mg/mL.
• Do not mix with other IV medications.
• Discard reconstituted solution within 12 h.
• Do not administer in patients with severe neutropenia (ANC less than 500/mcL) or severe thrombocytopenia (less than 25,000/mcL).
• Dosage reduction should be considered for those with anemia, neutropenia, and/or thrombocytopenia.

• Oral
• Avoid direct contact with the skin or mucous membranes of the powder contained in the capsules. If contact occurs, wash thoroughly with soap and water; rinse eyes thoroughly with plain water.
• Do not open or crush the capsules.

• Implant
• For intravitreal implantation only.
• Handle only by the suture tab to avoid damage to the implant's polymer coating.

Storage/Stability

Store capsules and implant at 59° to 86°F. Protect implant from freezing, excessive heat and light. Store vials below 104°F; refrigerate diluted solution for infusion and discard after 24 h. Store ophthalmic gel at 59° to 77°F.

Drug Interactions

Amphotericin B, cyclosporine, nephrotoxic drugs

May increase serum creatinine.

Cytotoxic drugs

May cause added toxicity.

Didanosine

Ganciclovir may increase didanosine plasma levels. Ganciclovir levels may be decreased when administered 2 h after didanosine but not when given simultaneously.

Imipenem-cilastatin

May cause generalized seizures.

Probenecid

May reduce renal Cl and increase serum levels of ganciclovir.

Zidovudine

Zidovudine and ganciclovir can cause granulocytopenia; combination therapy at full dose may not be tolerated.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

IV/Oral

Hypertension, vasodilatation; cardiac arrest, cardiac conduction abnormality, stroke, torsades de pointes, vasculitis, ventricular tachycardia (postmarketing).

CNS

IV/Oral

Neuropathy (21%); abnormal dreams, abnormal thinking, confusion, depression, dizziness, headache, seizures, somnolence, tremor; encephalopathy, extrapyramidal reaction, facial palsy, hallucinations, intracranial hypertension, rhabdomyolysis (postmarketing).

Dermatologic

IV/Oral

Sweating (14%); pruritus (10%); alopecia; exfoliative dermatitis, Stevens-Johnson syndrome (postmarketing).

GI

IV/Oral

Diarrhea (48%); anorexia (19%); vomiting (14%); GI perforation, pancreatitis; intestinal ulceration (postmarketing).

Genitourinary

IV/Oral

CrCl decreased, kidney failure, kidney function abnormal; hemolytic uremic syndrome, renal tubular disorder, testicular hypertrophy (postmarketing).

Hematologic

IV/Oral

Leukopenia (41%); anemia (25%); thrombocytopenia (6%); pancytopenia; hemolytic anemia (postmarketing).

Hepatic

IV/Oral

Abnormal LFT results; hepatic failure, hepatitis (postmarketing).

Hypersensitivity

Allergic reaction, anaphylactic reaction (postmarketing).

Lab Tests

IV/Oral

Creatinine increased, increased AST and ALT; hypercalcemia, hyponatremia (postmarketing).

Metabolic-Nutritional

IV/Oral

Weight loss; SIADH (postmarketing).

Musculoskeletal

Arthralgia, leg cramps, myalgia, myasthenia; peripheral ischemia, rhabdomyolysis (postmarketing)

Ophthalmic

Gel

Blurred vision (60%); eye irritation (20%); conjunctival hyperemia, punctate keratitis (5%).

Implant

Retinal detachments, visual acuity loss, vitreous hemorrhage (10% to 20%); cataract formation/lens opacities, hyphemas, intraocular pressure spikes, macular abnormalities, optic disc/nerve changes, uveitis (1% to 5%).

IV/Oral

Retinal detachment (8%); oculomotor nerve paralysis (postmarketing).

Respiratory

IV/Oral

Dyspnea, increased cough; bronchospasm, pulmonary fibrosis (postmarketing).

Miscellaneous

IV/Oral

Fever (48%); sepsis (15%); infection (13%); chills (10%); catheter infection (9%); catheter sepsis (8%); multiple organ failure.

Precautions

Warnings IV and oral use Animal data In animal studies, ganciclovir was carcinogenic, teratogenic, and caused aspermatogenesis. Hematological The clinical toxicity of ganciclovir includes granulocytopenia, anemia, and thrombocytopenia. Oral capsules Associated with risk of rapid rate of CMV retinitis progression and should be used as maintenance therapy only in patients who benefit from avoiding daily IV infusions.

Monitor Monitor CBC and platelet counts frequently, especially in patients in whom ganciclovir or other nucleoside analogues have previously resulted in leukopenia, or those with neutrophil counts less than 1,000 cells/mcL. Monitor serum creatinine or CrCl to allow for dosage adjustment in renally impaired patients. Monitor for extraocular CMV disease.

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established in children younger than 2 yr of age (ophthalmic gel); younger than 9 yr of age (implant); younger than 13 yr of age (capsules). Safety and efficacy has not been established in children; however, pharmacokinetic and clinical studies have been conducted in children and neonates (IV).

Elderly

Dose selection should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease.

Renal Function

Use drug cautiously and adjust dose. Carefully monitor renal function, especially when other nephrotoxic drugs are given.

Hematologic effects

Use drug with caution in patients with preexisting cytopenias; granulocytopenia is common.

Hydration

Accompany administration with adequate hydration because ganciclovir is excreted by the kidneys.

IV administration

Phlebitis and/or pain may occur at the site of IV infusion.

Ophthalmic implant complications

Potential complications may include vitreous loss, vitreous hemorrhage, cataract formation, retinal detachment, uveitis, endophthalmitis, and decrease in visual acuity.

Retinal detachment

Has occurred; relationship to drug undetermined.

Overdosage

Symptoms

Acute renal failure, central retinal artery occlusion, hepatitis, irreversible pancytopenia, persistent bone marrow suppression (neutropenia and thrombocytopenia), renal toxicity, reversible neutropenia or granulocytopenia, seizure, temporary loss of vision, worsening GI symptoms, worsening of hematuria.

Patient Information

• Give patient and family members instructions regarding handling of ganciclovir and proper disposal techniques when drug is to be administered at home.
• Inform patient that it is important to drink plenty of fluids.
• Instruct patients to take ganciclovir capsules with food to maximize bioavailability.
• Advise patient that drug is not a cure for CMV retinitis.
• Advise patients of the importance of close monitoring of blood cell counts while on ganciclovir.
• Advise patients with CMV retinitis to have regular ophthalmologic examinations at least every 6 wk during treatment.
• Inform patients that potential complications, including intraocular infection or inflammation, detachment of the retina, and formation of cataract in the natural crystalline lens, may occur following intraocular surgery.
• Advise patients not to wear contact lenses during the course of therapy or if they have signs or symptoms of herpetic keratitis.
• Instruct men to use barrier form of contraception during and for at least 90 days after treatment because ganciclovir is potentially teratogenic. Advise women to use effective contraception during treatment and to avoid the use of ganciclovir during pregnancy.
• Explain to men that drug may cause temporary or permanent male infertility.
• Tell patient to avoid crowds and people with infections.
• Advise patients that ganciclovir causes tumors in animals.
• Instruct patient to report the following symptoms to health care provider: headache; mental status changes; rash; pain at the injection site; fever; nausea; unusual bleeding or bruising; black, tarry stools; other bothersome reactions.
• Following implantation of ganciclovir implant, inform patients that they will experience an immediate and temporary decrease in visual acuity in the implanted eye and that this will last for approximately 2 to 4 wk postoperatively.

Copyright © 2009 Wolters Kluwer Health.