valganciclovir (Rx)

>10%

Abdominal pain (15%)

Anemia (8-26%)

Diarrhea (16-41%)

Fever (31%)

Granulocytopenia (11-27%)

Headache (9-22%)

Insomnia (16%)

Nausea (8-30%)

Retinal detachment (15%)

Vomiting (21%)

1-10%

Peripheral neuropathy (9%)

Paresthesia (8%)

Thrombocytopenia (8%)

<5%

• Retinal detachment, eye pain
• Dyspepsia, constipation, abdominal distention, mouth ulceration
• Fatigue, pain, malaise, asthenia, chills, peripheral edema
• Abnormal hepatic function
• Candida infections including oral candidiasis, upper respiratory tract infection, influenza, urinary tract infection, pharyngitis/nasopharyngitis, postoperative wound infection
• Postoperative complications, wound secretion
• Decreased appetite, hyperkalemia, hypophosphatemia, weight decreased
• Back pain, myalgia, arthralgia, muscle spasms
• Insomnia, neuropathy peripheral, dizziness
• Depression, anxiety
• Renal impairment, creatinine clearance renal decreased, blood creatinine increased, hematuria
• Cough, dyspnea
• Dermatitis, night sweats, pruritus
• Hypotension

Postmarketing Reports

Pyrexia, fatigue, tremor, neutropenia, anemia, leukopenia, urinary tract infection, anaphylactic reactions, agranulocytosis

Contraindications

Contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction (eg, anaphylaxis) to valganciclovir, ganciclovir, or any component of the formulation

Cautions

Also see Black Box Warnings

Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, and bone marrow failure including aplastic anemia have reported; use with caution in patients with pre-existing cytopenias and in patients receiving myelosuppressive drugs or irradiation; in patients with severe leukopenia, neutropenia, anemia and/or thrombocytopenia, treatment with hematopoietic growth factors may be considered

Complete blood counts with differential and platelet counts should be performed frequently, especially in patients with renal impairment and in patients in whom ganciclovir or other nucleoside analogues have previously resulted in leukopenia

May be teratogenic or embryotoxic, avoid pregnancy; male patients advised to use barrier method during and for 90 days after treatment (see Pregnancy)

Risk of: hematologic toxicity, female infertility; aspermatogenesis

Females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment because of potential risk to fetus; similarly, males should be advised to use condoms during and for at least 90 days following treatment

Maintain adequate hydration

Acute renal failure may occur in the following: Elderly patients with or without reduced renal function; exercise caution when administering to geriatric patients, and dosage reduction is recommended for those with impaired renal function, patients receiving potential nephrotoxic drugs, patients without adequate hydration

Drug interactions overview

• Imipenem-cilastatin: Seizures were reported in patients receiving ganciclovir and imipenem-cilastatin; concomitant use is not recommended unless the potential benefits outweigh the risks
• Cyclosporine or amphotericin B: Coadministration may increase the risk of nephrotoxicity; monitor renal function
• Mycophenolate mofetil (MMF): Coadministration with valganciclovir may increase the risk of hematological and renal toxicity; monitor for ganciclovir and MMF toxicity
• Other drugs associated with myelosuppression or nephrotoxicity: Due to potential for increased toxicity, consider concomitant use with valganciclovir only if the potential benefits are judged to outweigh the risks
• Didanosine: Ganciclovir coadministered with didanosine may increase didanosine levels; monitor for didanosine toxicity (eg, pancreatitis)
• Probenecid: May increase ganciclovir levels; monitor for evidence of ganciclovir toxicity

Pregnancy

After oral administration, valganciclovir (prodrug) converts to ganciclovir (active drug) and, therefore, valganciclovir is expected to have reproductive toxicity

Clinical considerations

• Most maternal CMV infections are asymptomatic or they may be associated with a self-limited mononucleosis-like syndrome; however, in immunocompromised patients (i.e., transplant patients or patients with AIDS)
• CMV infections may be symptomatic and may result in significant maternal morbidity and mortality; transmission of CMV to the fetus is a result of maternal viremia and transplacental infection; perinatal infection can also occur from exposure of the neonate to CMV shedding in the genital tract; approximately 10% of children with congenital CMV infection are symptomatic at birth; mortality in these infants is about 10% and approximately 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
• Females of reproductive potential should undergo pregnancy testing before initiation of therapy

Contraception

• Females: Because of mutagenic and teratogenic potential, females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment
• Males: Because of its mutagenic potential, males should be advised to use condoms during and for at least 90 days following, treatment

Infertility

• Recommended doses may cause temporary or permanent female and male infertility

Lactation

No data available regarding presence of valganciclovir (prodrug) or ganciclovir (active drug) in human milk, effects on breastfed infant or on milk production; animal data indicate that ganciclovir is excreted in milk of lactating rats

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV; advise nursing mothers that breastfeeding is not recommended during treatment because of potential for serious adverse events in nursing infants and because of potential for transmission of HIV

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

Prodrug, converted to ganciclovir in intestine and liver

Inhibits viral DNA polymerases resulting in chain termination

Absorption

AUC: 29.1 mcg⋅h/mL (healthy subjects); 40.2 mcg⋅h/mL (heart transplant recipients); 46 mcg⋅h/mL (liver transplant recipients); 48.2 mcg⋅h/mL (kidney transplant recipients)

Peak plasma concentration: 5.61 mcg/mL (healthy subjects); 4.9 mcg/mL (heart transplant recipients); 5.4 mcg/mL (liver transplant recipients); 5.3 mcg/mL (kidney transplant recipients)

Distribution

Oral bioavailability: 59.4% (healthy subjects)

Protein bound: Unknown (valganciclovir); 1-2% (ganciclovir over 0.5-51 mcg/mL)

CSF fluid penetration: Unknown (valganciclovir); yes (ganciclovir)

Metabolism

Hydrolyzed by intestinal and liver esterases

Metabolized to ganciclovir

Elimination

Half-life: 4.08 hr (healthy subjects); 6.58 hr (heart transplant recipients); 6.18 hr (liver transplant recipients); 6.77 hr (kidney transplant recipients)

Clearance: 3.21 mL/min/kg (healthy subjects)

Oral Solution Preparation

Wear disposable gloves during reconstitution and when wiping the outer surface of the bottle/cap and the table after reconstitution

Prior to dispensing, oral solution must be prepared by the pharmacist as follows

Measure 91 mL of purified water in a graduated cylinder

Shake bottle to loosen the powder; remove child resistant bottle cap and add approximately half the total amount of water for constitution to the bottle and shake the closed bottle well for about 1 minute

Add the remainder of water and shake the closed bottle well for about 1 minute; prepared solution contains 50 mg/mL

Remove the child resistant bottle cap and push the bottle adapter into the neck of the bottle

The patient package insert, which includes the dosing instructions for patients, and 2 oral dispensers should be dispensed to the patient

Avoid contact with your skin or eyes

If you come in contact with the contents of the oral solution, wash your skin well with soap and water or rinse your eyes well with plain water

Oral Administration

Take with food (improved bioavailability)

Handle and dispose according to guidelines for antineoplastic drugs because ganciclovir (active metabolite) shares some of the properties of antitumor agents (ie, carcinogenicity and mutagenicity)

Storage

Store tablets and undiluted oral solution at 20-25°C (68-77°F); excursions are permitted to 15-30°C (59-86°F)

Reconstituted oral solution

• Refrigerate at 2-8°C (36-46°F) for no longer than 49 days
• Do not freeze
• Write the date of expiration of the constituted oral solution on the bottle label