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Valganciclovir

FDA Drug Information • Also known as: Valcyte, Valganciclovir, Valganciclovir Hydrochloride

Brand Names
Valcyte, Valganciclovir, Valganciclovir Hydrochloride
Route
ORAL
Dosage Form
TABLET, FILM COATED
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

BOXED WARNING WARNING: HEMATOLOGIC TOXICITY, IMPAIRMENT OF FERTILITY, FETAL TOXICITY, MUTAGENESIS AND CARCINOGENESIS

  • Hematologic Toxicity: Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow aplasia and aplastic anemia have been reported in patients treated with valganciclovir tablets [see Warnings and Precautions ( 5.1 )].
  • Impairment of Fertility: Based on animal data, valganciclovir tablets may cause temporary or permanent inhibition of spermatogenesis [see Warnings and Precautions ( 5.2 )].
  • Fetal Toxicity: Based on animal data, valganciclovir tablets have the potential to cause birth defects in humans [see Warnings and Precautions ( 5.3 )].
  • Mutagenesis and Carcinogenesis: Based on animal data, valganciclovir tablets have the potential to cause cancers in humans [see Warnings and Precautions ( 5.4 )]. WARNING: HEMATOLOGIC TOXICITY, IMPAIRMENT OF FERTILITY, FETAL TOXICITY, MUTAGENESIS AND CARCINOGENESIS See full prescribing information for complete boxed warning.
  • Hematologic Toxicity: Severe leukopenia, neutropenia, anemia thrombocytopenia, pancytopenia, bone marrow aplasia and aplastic anemia have been reported in patients treated with valganciclovir tablets ( 5.1 ).
  • Impairment of Fertility: Based on animal data, valganciclovir tablets may cause temporary or permanent inhibition of spermatogenesis ( 5.2 ).
  • Fetal Toxicity: Based on animal data, valganciclovir tablets have the potential to cause birth defects in humans ( 5.3 ).
  • Mutagenesis and Carcinogenesis: Based on animal data, valganciclovir tablets have the potential to cause cancers in humans ( 5.4 ).

    • Description

    11 DESCRIPTION Valganciclovir tablets, USP contains valganciclovir hydrochloride, USP a hydrochloride salt of the L-valyl ester of ganciclovir that exists as a mixture of two diastereomers. Ganciclovir is a synthetic guanine derivative active against CMV. Valganciclovir tablets, USP are available as a 450 mg tablet for oral administration. Each film coated tablet contains 496.3 mg of valganciclovir hydrochloride, USP (corresponding to 450 mg of valganciclovir), and the inactive ingredients crospovidone, microcrystalline cellulose, povidone and stearic acid. The tablets are coated with Opadry Pink which contains hypromellose, iron oxide red, polyethylene glycol, polysorbate 80 and titanium dioxide. Valganciclovir hydrochloride, USP is a white to off-white powder, slightly hygroscopic with a molecular formula of C 14 H 22 N 6 O 5

  • HCl and a molecular weight of 390.82. The chemical name for valganciclovir hydrochloride, USP is L-Valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-hydroxypropylester, monohydrochloride. Valganciclovir hydrochloride, USP is a polar hydrophilic compound with a solubility of 70 mg/mL in water at 25°C at a pH of 7 and an n-octanol/water partition coefficient of 0.0095 at pH 7. The pKa for valganciclovir hydrochloride, USP is 7.5. The chemical structure of valganciclovir hydrochloride, USP is: All doses in this insert are specified in terms of valganciclovir. valganciclovirstructure

    • What Is Valganciclovir Used For?

    1 INDICATIONS & USAGE Valganciclovir tablets, USP are a cytomegalovirus (CMV) nucleoside analogue DNA polymerase inhibitor indicated for: Adult Patients ( 1.1 )

  • Treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS).
  • Prevention of CMV disease in kidney, heart, and kidney-pancreas transplant patients at high risk. Pediatric Patients ( 1.2 )
  • Prevention of CMV disease in heart transplant patients at high risk. 1.1 Adult Patients Treatment of Cytomegalovirus (CMV) Retinitis : Valganciclovir tablets, USP are indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS) [see Clinical Studies ( 14.1)]. Prevention of CMV Disease : Valganciclovir tablets, USP are 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-]) [see Clinical Studies ( 14.1 )]. 1.2 Pediatric Patients Prevention of CMV Disease : Valganciclovir tablets, USP are indicated for the prevention of CMV disease in heart transplant patients (4 month to 16 years of age) at high risk [see Clinical Studies ( 14.2 )]. Pediatric use information for pediatric kidney transplant patients ages 4 months to 16 years and for pediatric heart transplant patients ages 1 to less than 4 months is approved for Roche Palo Alto LLC' s VALCYTE (valganciclovir hydrochloride) tablets. However, due to Roche Palo Alto LLC' s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

    • Dosage and Administration

    2 DOSAGE & ADMINISTRATION Adult Dosage (2.2) Treatment of CMV retinitis Induction: 900 mg (two 450 mg tablets) twice a day for 21 days Maintenance: 900 mg (two 450 mg tablets) once a day Prevention of CMV disease in heart or kidney-pancreas transplant patients 900 mg (two 450 mg tablets) once a day within 10 days of transplantation until 100 days post-transplantation Prevention of CMV disease in kidney transplant patients 900 mg (two 450 mg tablets) once a day within 10 days of transplantation until 200 days post-transplantation Pediatric Dosage (2.3) Prevention of CMV disease in heart transplant patients 4 months to 16 years of age Dose once a day within 10 days of transplantation until 100 days post-transplantation according to dosage algorithm (note the calculation of creatinine clearance using a modified Schwartz formula in children)

  • Valganciclovir tablets should be taken with food ( 2.1 , 12.3 ).
  • Valganciclovir tablets should not be broken or crushed ( 2.6 ).
  • Adult patients should use valganciclovir tablets, not valganciclovir for oral solution ( 2.1 ).
  • Adults with renal impairment: Adjust dose based on creatinine clearance. For adult patients receiving hemodialysis a dose recommendation cannot be given ( 2.5 , 8.6, 12.3 ). 2.1 General Dosing Information
  • Adult patients should use valganciclovir tablets, not valganciclovir for oral solution.
  • Valganciclovir tablets should be taken with food [see Clinical Pharmacology ( 12.3 )]. 2.2 Recommended Dosage in Adult Patients with Normal Renal Function For dosage recommendations in adult patients with renal impairment [see Dosage and Administration ( 2.5 )]. Treatment of CMV Retinitis:
  • Induction: The recommended dosage is 900 mg (two 450 mg tablets) taken orally twice a day for 21 days.
  • Maintenance: Following induction treatment, or in adult patients with inactive CMV retinitis, the recommended dosage is 900 mg (two 450 mg tablets) taken orally once a day. Prevention of CMV Disease:
  • For adult patients who have received a heart or kidney-pancreas transplant, the recommended dosage is 900 mg (two 450 mg tablets) taken orally once a day starting within 10 days of transplantation until 100 days post-transplantation.
  • For adult patients who have received a kidney transplant, the recommended dosage is 900 mg (two 450 mg tablets) taken orally once a day starting within 10 days of transplantation until 200 days post-transplantation. 2.3 Recommended Dosage in Pediatric Patients Prevention of CMV Disease in Pediatric Heart Transplant Patients : For pediatric heart transplant patients 4 month to 16 years of age, the recommended once daily mg dose (7x BSA x CrCL) should start within 10 days of transplantation until 100 days post-transplantation. The recommended once daily dosage of valganciclovir is based on body surface area (BSA) and creatinine clearance (CrCl) derived from a modified Schwartz formula, and is calculated using the equation below: Pediatric Dose (mg) = 7 x BSA x CrCl...

    • Side Effects (Adverse Reactions)

    6 ADVERSE REACTIONS The following serious adverse events are discussed in greater detail in other sections of the labeling:

  • Hematologic toxicity [see Boxed Warning, Warnings and Precautions ( 5.1 )].
  • Acute renal failure [see Warnings and Precautions ( 5.5 )]. The most common adverse events and laboratory abnormalities reported in at least one indication by greater than or equal to 20% of adult patients treated with valganciclovir tablets are diarrhea, pyrexia, nausea, tremor, neutropenia, anemia, graft rejection, thrombocytopenia, and vomiting. The most common reported adverse events and laboratory abnormalities reported in greater than or equal to 20% of pediatric solid organ transplant recipients treated with valganciclovir tablets are diarrhea, pyrexia, hypertension, upper respiratory tract infection, urinary tract infection, vomiting, neutropenia, leukopenia, and head ache.
  • Adult patients: Most common adverse events and laboratory abnormalities (reported in at least one indication by greater than or equal to 20% of patients) are diarrhea, pyrexia, nausea, tremor, neutropenia, anemia, graft rejection, thrombocytopenia, and vomiting ( 6.1 ).
  • Pediatric patients: Most common adverse events and laboratory abnormalities (reported in greater than or equal to 20% of pediatric solid organ transplant recipients) are diarrhea, pyrexia, hypertension, upper respiratory tract infection, urinary tract infection, vomiting, neutropenia, leukopenia, and headache ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact AvKARE, Inc. at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice. Valganciclovir, a prodrug of ganciclovir, is rapidly converted to ganciclovir after oral administration. Adverse events known to be associated with ganciclovir usage can therefore be expected to occur with valganciclovir tablets. Adverse Events in Adults: Treatment of CMV Retinitis in AIDS Patients : In a clinical study for the treatment of CMV retinitis in HIV-infected patients, the adverse events reported by patients receiving valganciclovir tablets (n=79) or intravenous ganciclovir (n=79) for 28 days of randomized therapy (21 days induction dose and 7 days maintenance dose), respectively, included diarrhea (16%, 10%), nausea (8%, 14%), headache (9%, 5%), and catheter-related infections (3%, 11%). The incidence of adverse events was similar between the group who received valganciclovir tablets and the group who received intravenous ganciclovir, with the exception of catheter-related infections, which occurred with greater frequency in patients randomized to receive intravenous ganciclovir. The frequencies of neutropenia (ANC less than 500/μL) were 11% for patients receiving valganciclovir tablets compared with 13% for patients receiving intravenous ganciclovir. Anemia (Hgb less than 8 g/dL) occurred in 8% of patients in each group. Other laboratory abnormalities occurred with similar frequencies in the two groups. Adverse events and abnormal laboratory values data are available for 370 patients who received maintenance therapy with valganciclovir tablets 900 mg once daily in two open-label clinical trials. Approximately 252 (68%) of these patients received valganciclovir tablets for more than nine months (maximum duration was 36 months). Table 3 and Table 4 show the pooled adverse event data and abnormal laboratory values from these patients. Table 3 Pooled Selected Adverse Events Reported in greater than or equal to 5% of Patients who Received Valganciclovir Tablets Maintenance Therapy for CMV Retinitis Patients with CMV Retinitis Adverse Events According to Body System Valganciclovir Tablets (N=370) % Gastrointestinal system Diarrhea 41 Nausea 30...

    • Drug Interactions

    7 DRUG INTERACTIONS In vivo drug-drug interaction studies were not conducted with valganciclovir. However, because valganciclovir is rapidly and extensively converted to ganciclovir, drug-drug interactions associated with ganciclovir will be expected for valganciclovir tablets. Established and other potentially significant drug interactions conducted with ganciclovir are listed in Table 9. Table 9 Established and Other Potentially Significant Drug Interactions with Ganciclovir Name of the Concomitant Drug Change in the Concentration of Ganciclovir or Concomitant Drug Clinical Comment Zidovudine ↓ Ganciclovir ↑ Zidovudine Zidovudine and valganciclovir tablets each have the potential to cause neutropenia and anemia Probenicid ↑ Ganciclovir Patients taking probenicid and valganciclovir tablets should be monitored for evidence of ganciclovir toxicity Mycophenolate Mofetil (MMF) ↔ Ganciclovir (in patients with normal renal function) ↔ MMF (in patients with normal renal function) Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase Didanosine ↓ Ganciclovir ↑ Didanosine Patients should be closely monitored for didanosine toxicity

  • Zidovudine: Potential to cause neutropenia and anemia. Monitor with frequent tests of white blood cell counts with differential and hemoglobin levels (7 ).
  • Probenecid: May increase ganciclovir levels. Monitor for evidence of ganciclovir toxicity (7 ).
  • Mycophenolate mofetil (MMF): May increase ganciclovir concentrations and levels of MMF metabolites in patients with renal impairment. Monitor for ganciclovir and MMF toxicity ( 7 ).
  • Didanosine: May increase didanosine concentrations. Monitor for didanosine toxicity ( 7 ).

    • Contraindications

    4 CONTRAINDICATIONS Valganciclovir tablets are contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction (e.g., anaphylaxis) to valganciclovir, ganciclovir, or any component of the formulation [see Adverse Reactions ( 6.1 )]. Hypersensitivity to valganciclovir or ganciclovir ( 4 )

    Pregnancy and Breastfeeding

    8.1 Pregnancy Teratogenic Effects Risk Summary After oral administration, valganciclovir (prodrug) is converted to ganciclovir (active drug) and, therefore, valganciclovir tablets are expected to have reproductive toxicity effects similar to ganciclovir. 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 two-times the human exposure. There are no available human data on use of valganciclovir tablets or ganciclovir in pregnant women to establish the presence or absence of drug-associated risk. The background risk of major birth defects and miscarriage for the indicated populations is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and the risk of miscarriage is 15 to 20% of clinically recognized pregnancies. Advice pregnant women of the potential risk to the fetus [see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.3 )]. Clinical Considerations 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 (i.e., transplant patients or patients with AIDS) CMV infections may be symptomatic and may result in significant maternal morbidity and mortality. The 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 to 90% of symptomatic surviving newborns experience significant morbidity, including mental retardation, sensorineural hearing loss, microcephaly, seizures, and other medical problems. The risk of congenital CMV infection resulting from...

    Overdosage

    10 OVERDOSAGE Experience With Valganciclovir Tablets: One adult developed fatal bone marrow depression (medullary aplasia) after several days of dosing that was at least 10-fold greater than recommended for the patient’s estimated degree of renal impairment. An overdose of valganciclovir tablets could also possibly result in increased renal toxicity [see Dosage and Administration ( 2.5 ), Use in Specific Populations ( 8.6 )]. Because ganciclovir is dialyzable, dialysis may be useful in reducing serum concentrations in patients who have received an overdose of valganciclovir tablets [see Clinical Pharmacology ( 12.3 )]. Adequate hydration should be maintained. The use of hematopoietic growth factors should be considered [see Clinical Pharmacology ( 12.3 )]. Experience with Intravenous Ganciclovir: Reports of overdoses with intravenous ganciclovir have been received from clinical trials and during postmarketing experience. The majority of patients experienced one or more of the following adverse events: Hematological toxicity: pancytopenia, bone marrow depression, medullary aplasia, leukopenia, neutropenia, granulocytopenia Hepatotoxicity: hepatitis, liver function disorder Renal toxicity: worsening of hematuria in a patient with pre-existing renal impairment, acute renal failure, elevated creatinine Gastrointestinal toxicity: abdominal pain, diarrhea, vomiting Neurotoxicity: generalized tremor, convulsion

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING contains 496.3 mg of valganciclovir hydrochloride, USP equivalent to 450 mg of valganciclovir. Valganciclovir tablets are supplied as: NDC 50268-787-12 5 tablets per card, 4 cards per carton. Store at 25 o C; excursions permitted between 15 o and 30 o C (59 o and 86 o F). [See USP Controlled Room Temperature.] Dispensed in Unit Dose Material. For Institutional Use Only.

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.