Dosing & Uses
Dosage Forms & Strengths
tablet
- 450mg
powder for oral solution
- 50mg/mL when reconstituted
Cytomegalovirus Retinitis
Indicated for treatment of CMV retinitis in patients with AIDS
Induction dose: 900 mg PO q12hr for 21 days
Maintenance dose: Following induction treatment, or in adults with inactive CMV retinitis, 900 mg PO qDay
CMV Colitis or Esophagitis in HIV-Infected Patients (Off-label)
Treat initially with ganciclovir 5 mg/kg/dose IV q12hr; once therapy is tolerated, change to valganciclovir 900 mg PO q12hr for 21-42 days or until signs and symptoms have resolved
CMV Prevention in Solid Organ Transplant
Indicated for the prevention of CMV disease in kidney, heart, and kidney-pancreas transplant patients at high risk (donor CMV seropositive/recipient CMV seronegative [D+/R-])
Kidney transplantation
- 900 mg PO qDay
- Begin within 10 days of transplant until 200 days post-transplant
Kidney-pancreas transplantation
- 900 mg PO qDay
- Begin within 10 days of transplant until 100 days post-transplant
Heart transplantation
- 900 mg PO qDay
- Begin within 10 days of transplant until 100 days post-transplant
Dosage Modifications
Hepatic impairment: Safety and efficacy not established
Renal impairment
- CrCl 40-59 mL/min: 450 mg PO q12hr (induction), THEN 450 mg qDay
- CrCl 25-39 mL/min: 450 mg PO qDay (induction), THEN 450 mg q2days
- CrCl 10-24 mL/min: 450 mg PO q2days (induction), THEN 450 mg 2 times/week
- <10 mL/min (on hemodialysis): Not recommended
Dosing Considerations
Adults should use tablets, not oral solution
Lymphoproliferative Disorder (Orphan)
Orphan designation for treatment of post-transplant lymphoproliferative disorder in combination with nanatinostat
Orphan sponsor
- Viracta Therapeutics, Inc; 2533 South Coast Highway, Suite 210; Carlsbad, California 92007
Dosage Forms & Strengths
tablet
- 450mg
powder for oral solution
- 50mg/mL when reconstituted
CMV Prevention in Kidney & Heart Transplant
Kidney transplantation
- <4 months: Safety and efficacy not established
- 4 months to 16 years: Daily dose (mg) = 7 x BSA x CrCl; not to exceed 900 mg/day
- Begin within 10 days of transplant and continue until 200 days post-transplant
Heart transplantation
- <1 month: Safety and efficacy not established
- 1 month to 16 years: Daily dose (mg) = 7 x BSA x CrCl; not to exceed 900 mg/day
- Begin within 10 days of transplant and continue until 100 days post-transplant
Dosing Considerations
Calculation of creatinine clearance for the dose in children is by a modified Schwartz formula
The oral solution is the preferred formulation for children since it provides the ability to administer a dose calculated according to the Schwartz formula
Tablets may be used if the calculated doses are within 10% of available tablet strength (450 mg)
For example, if the calculated dose is between 405 mg and 495 mg, one 450 mg tablet may be taken
Assess children for the ability to swallow tablets
Calculate CrCl by Schwartz equation
- CrCl (mL/min/1.73 m²) = K x height (cm) divided by serum Cr (mg/dL)
- If CrCl exceeds 150 mL/min/1.73 m², then use maximum value of 150 mL/min/1.73 m²; an upper limit of 150 mL/min/1.73 m² helps prevent the potential for over dosing
- If the calculated pediatric dose exceeds 900 mg, a dose of 900 mg should be given to the child
- Where K =
- 0.33 for infants aged <1 yr with low birth weight for gestational age
- 0.45 for infants aged <1 yr with birth weight appropriate for gestational age
- 0.45 for aged 4 months to <1-2 yr
- 0.55 for boys aged 2 to <13 yr and girls aged 2 to <16 yr
- 0.7 for boys aged 13-16 yr
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
>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
Warnings
Black Box Warnings
Hematologic toxicity: Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, and bone marrow failure including aplastic reported
Impaired fertility: Based on animal data and limited human data, valganciclovir may cause temporary or permanent inhibition of spermatogenesis in males and suppression of fertility in females
Fetal toxicity: Based on animal data, valganciclovir has the potential to cause birth defects in humans
Mutagenesis and carcinogenesis: Based on animal data, valganciclovir has the potential to cause cancers in humans
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 & Lactation
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.
Pharmacology
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)
Administration
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
Images
Patient Handout
Formulary
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