ganciclovir (Rx)

>10%

Neutropenia w/ ANC <1000/cu.mm (25-50%)

Thrombocytopenia (20%)

1-10%

Elevated LFTs

Anemia

Confusion

Headache

Nausea/vomiting

Neuropathy

Paresthesia

Pruritus

Retinal detachment,

Rash

Sepsis

Weakness

Frequency Not Defined

Blood and lymphatic disorders: Pancytopenia, bone marrow failure

Cardiac disorders: Arrhythmias

Ear and labyrinth disorders: Tinnitus, ear pain, deafness

Eye disorders: Visual impairment, vitreous disorders, eye pain, conjunctivitis, macular edema

Gastrointestinal disorders: Abdominal pain, dyspepsia, flatulence, constipation, mouth ulceration, dysphagia, abdominal distention, pancreatitis, gastrointestinal perforation, eructation, dry mouth

General disorders and administration site conditions: Fatigue, injection site inflammation, edema, pain, malaise, asthenia, chest pain, multiple organ failure

Blood Immune system disorders: Hypersensitivity Infections and infestations: Candida infections including oral candidiasis, upper respiratory infection, influenza, urinary tract infections, cellulitis

Investigations: Blood alkaline phosphatase increased, hepatic function abnormal, aspartate aminotransferase increased, alanine aminotransferase increased, creatinine clearance decreased

Metabolism and nutrition disorders: Weight decreased

Musculoskeletal and connective tissue disorders: Back pain, myalgia, arthralgia, muscle spasms, leg cramps, myasthenia

Nervous system disorders: Headache, insomnia, dizziness, paresthesia, hypoaesthesia, seizures, somnolence, dysgeusia (taste disturbance), tremor

Psychiatric disorders: Depression, confusional state, anxiety, agitation, psychotic disorder, thinking abnormal, abnormal dreams

Renal and urinary disorders: Kidney failure, renal function abnormal, urinary frequency, hematuria

Respiratory, thoracic and mediastinal disorders: Cough, dyspnea

Skin and subcutaneous tissues disorders: Dermatitis, alopecia, dry skin, urticaria, rash

Vascular disorders: Hypotension, hypertension, phlebitis, vasodilation

Postmarketing Reports

Hemolytic anemia, agranulocytosis, granulocytopenia

Cardiac arrest, conduction disorder, torsade de pointes, ventricular tachycardia

Congenital anomaly

Inappropriate antidiuretic hormone secretion

Cataracts, dry eyes

Intestinal ulcer

Cholelithiasis, cholestasis, hepatic failure, hepatitis

Anaphylactic reaction, allergic reaction, vasculitis

Blood triglycerides increased

Acidosis, hypercalcemia, hyponatremia Arthritis, rhabdomyolysis

Dysesthesia, dysphasia, extrapyramidal disorder, facial paralysis, amnesia, anosmia, myelopathy, cerebrovascular accident, third cranial nerve paralysis, aphasia, encephalopathy, intracranial hypertension

Irritability, hallucinations

Renal tubular disorder, hemolytic uremic syndrome

Infertility, testicular hypotrophy

Bronchospasm, pulmonary fibrosis

Exfoliative dermatitis, Stevens Johnson syndrome Peripheral ischemia

Contraindications

Hypersensitivity reaction (eg, anaphylaxis) to ganciclovir, valganciclovir, or any component of the formulation

Cautions

Also see Black Box Warnings

Granulocytopenia (neutropenia), anemia, thrombocytopenia and pancytopenia observed; not recommended if the absolute neutrophil count (ANC) <500 cells/mcL, hemoglobin <8 g/dL, or the platelet count <25,000 cells/mcL

Exercise caution patients with pre-existing cytopenias and in patients receiving myelosuppressive drugs or irradiation

Renal impairment should be used with caution in patients with impaired renal function because the half-life and plasma/serum concentrations of ganciclovir will be increased due to reduced renal clearance; increased serum creatinine levels have been reported in elderly patients and in transplant recipients receiving concomitant nephrotoxic medications (eg, cyclosporine and amphotericin B); monitor renal function during therapy is essential, especially for elderly patients and those patients receiving concomitant agents that may cause nephrotoxicity

Based on animal data and limited human data, recommended human dose (RHD) may cause temporary or permanent inhibition of spermatogenesis in males, and may cause suppression of fertility in females (see Pregnancy)

Fetal toxicity may occur when administered to pregnant women based on findings in animal studies (see Pregnancy)

Animal data indicate that ganciclovir is mutagenic and carcinogenic, may potentially be carcinogenic in humans

Drug interactions overview

• Coadministration with imipenem-cilastatin is not recommended because generalized seizures reported
• Monitor renal function when coadministered with cyclosporine or amphotericin B because of potential increase in serum creatinine
• Based on increased risk, monitor for hematological and renal toxicity when concomitantly using mycophenolate mofetil with ganciclovir
• Other drugs associated with myelosuppression or nephrotoxicity: Consider only if the potential benefits outweigh the risks
• Coadministration with didanosine will potentially increase plasma levels and toxicities of didanosine; closely monitor
• Concomitant use with probenecid may increase ganciclovir levels; consider reducing dose of ganciclovir and monitor possible toxicities

Pregnancy

Placental transfer of ganciclovir has been shown to occur based on ex vivo experiments with human placenta and in at least 1 case report in a pregnant woman; however, no adequate human data are available to establish whether ganciclovir poses a risk to pregnancy outcomes

In animal studies, ganciclovir caused maternal and fetal toxicity and embryo-fetal mortality in pregnant mice and rabbits as well as teratogenicity in rabbits at exposures 2 times the exposure at the recommended human dose (RHD)

Disease-associated maternal and/or embryo-fetal risk

• Most maternal CMV infections are asymptomatic or they may be associated with a self-limited mononucleosis-like syndrome; however, in immunocompromised patients, CMV infections may be symptomatic and may result in significant maternal morbidity and mortality
• CMV fetal transmission results from maternal viremia and transplacental infection
• Perinatal infection can also occur from exposure of the neonate to CMV shedding in the genital tract ~10% of children with congenital CMV infection are symptomatic at birth
• Mortality in symptomatic infants is ~10% and ~50-90% of symptomatic surviving newborns experience significant morbidity, including mental retardation, sensorineural hearing loss, microcephaly, seizures, and other medical problems
• Risk of congenital CMV infection resulting from primary maternal CMV infection may be higher and of greater severity than that resulting from maternal reactivation of CMV infection

Contraception

• Test for pregnancy in females of reproductive potential before initiating treatment
• Females: Because of ganciclovir’s mutagenic and teratogenic potential, use effective contraception during treatment and for at least 30 days following treatment
• Males: Because of ganciclovir’s mutagenic and teratogenic potential, use barrier contraception during treatment and for at least 90 days following treatment

Infertility

• Based on animal data and limited human data, may cause temporary or permanent inhibition of spermatogenesis in males, and may cause suppression of fertility in females at recommended human dose (RHD); advise patients that fertility may be impaired with use

Lactation

No data are available regarding the presence of ganciclovir in human milk, the effects on the breastfed infant, or the effects on milk production

Ganciclovir was present in milk in lactating rats following administration

Breastfeeding is not recommended during treatment owing to the potential for serious adverse reactions in nursing infants

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Inhibits of viral DNA polymerases resulting in chain termination

Absorption

AUC: 22.1-26.8 mcg·hr/mL

Distribution

Vd (steady-state): 0.74 L/kg

Diffuses across the placenta

Protein binding: 1-2% over ganciclovir concentrations of 0.5-51 mcg/mL

Elimination

Clearance: 3.2 mL/min/kg (renal); 3.52 mL/min/kg (systemic)

IV Compatibilities

Solution: compatible w/ most common solvents

Y-site (partial list): allopurinol, fluconazole, linezolid, propofol

IV Incompatibilities

Y-site: aldesleukin, amifostine, amsacrine, aztreonam, cefepime, cisatracurium(?), cytarabine, doxorubicin, fludarabine, foscarnet, gemcitabine, ondansetron, piperacillin/tazobactam, sargramostim, tacrolimus, vinorelbine

IV Preparation

Reconstitute vial with 10 mL of Sterile Water for Injection

Do not use bacteriostatic water for injection containing parabens; it is incompatible with ganciclovir and may cause precipitation

Gently swirl the vial in order to ensure complete wetting of the product; continue swirling until a clear reconstituted solution is obtained

Visually inspect solution for particulate matter and discoloration prior to proceeding with infusion

Discard the vial if particulate matter or discoloration is observed

IV Administration

Also see Storage

Same precautions as antineoplastic agents should be followed with ganciclovir

Do not administer IM, SC, rapid infusion or IVP

Administer by slow IV infusion over at least 1 hr at a final concentration not to exceed 10 mg/mL

Too rapid infusion can cause increased toxicity and excessive plasma levels

Handling and disposal

• Exercise caution in the handling and preparation of solutions
• Reconstituted solutions are alkaline (pH 11)
• Avoid direct contact of the skin or mucous membranes with solution
• If such contact occurs, wash thoroughly with soap and water; rinse eyes thoroughly with plain water
• Wearing disposable gloves is recommended
• Because ganciclovir shares some of the properties of antitumor agents (eg, carcinogenicity and mutagenicity), consideration should be given to handling and disposal according to guidelines issued for antineoplastic drugs

Storage

Unused vials: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)

Reconstituted vials: Store at 25°C (77°F) for no longer than 12 hr; do not refrigerate or freeze

Diluted solutions: Refrigerate at 2-8°C (36-46°F) for no longer than 24 hr; do not freeze