Valganciclovir Hydrochloride

Description

11 DESCRIPTION Valganciclovir for oral solution contains valganciclovir hydrochloride, USP (valganciclovir HCl), 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 HCl, USP is available as a powder for oral solution, which when constituted with water as directed contains 50 mg/mL valganciclovir free base. The inactive ingredients of valganciclovir for oral solution are anhydrous citric acid, mannitol, povidone, saccharin sodium, sodium benzoate, and tutti-frutti flavor. Valganciclovir HCl, USP is a white to off-white crystalline powder with a molecular formula of C 14 H 22 N 6 O 5 ·HCl and a molecular mass of 390.82. The chemical name for valganciclovir HCl, USP is L-Valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-hydroxypropyl ester, monohydrochloride. Valganciclovir HCl, USP is freely soluble in water, sparingly soluble in methanol. The pH for valganciclovir HCl, USP is 3.86 and the pKa for valganciclovir HCl, USP is 7.20. The chemical structure of valganciclovir is: All doses in this insert are specified in terms of valganciclovir. valganciclovirstructure

What Is Valganciclovir Hydrochloride Used For?

1 INDICATIONS AND USAGE Valganciclovir is a deoxynucleoside analogue cytomegalovirus (CMV) DNA polymerase inhibitor indicated for: Adult Patients ( 1.1 )

Dosage and Administration

2 DOSAGE AND 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 kidney transplant patients 4 months to 16 years of age Dose once a day within 10 days of transplantation until 200 days post-transplantation according to dosage algorithm (note the calculation of creatinine clearance using a modified Schwartz formula in children) Prevention of CMV disease in heart transplant patients 1 month 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)

Side Effects (Adverse Reactions)

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

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. Drug-drug interaction studies with ganciclovir were conducted in patients with normal renal function. Following concomitant administration of valganciclovir and other renally excreted drugs, patients with impaired renal function may have increased concentrations of ganciclovir and the coadministered drug. Therefore, these patients should be closely monitored for toxicity of ganciclovir and the coadministered drug. 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 Imipenem-cilastatin Unknown Coadministration with imipenem-cilastatin is not recommended because generalized seizures have been reported in patients who received ganciclovir and imipenem-cilastatin. Cyclosporine or amphotericin B Unknown Monitor renal function when valganciclovir is coadministered with cyclosporine or amphotericin B because of potential increase in serum creatinine [see Warnings and Precautions (5.2)]. Mycophenolate mofetil (MMF) ↔ Ganciclovir (in patients with normal renal function) ↔ MMF (in patients with normal renal function) Based on increased risk, patients should be monitored for hematological and renal toxicity. Other drugs associated with myelosuppression or nephrotoxicity (e.g., adriamycin, dapsone, doxorubicin, flucytosine, hydroxyurea, pentamidine, tacrolimus, trimethoprim/ sulfamethoxazole, vinblastine, vincristine, and zidovudine) Unknown Because of potential for higher toxicity, coadministration with valganciclovir should be considered only if the potential benefits are judged to outweigh the risks. Didanosine ↔ Ganciclovir ↑ Didanosine Patients should be closely monitored for didanosine toxicity (e.g., pancreatitis) Probenecid ↑ Ganciclovir Valganciclovir dose may need to be reduced. Monitor for evidence of ganciclovir toxicity.

Contraindications

4 CONTRAINDICATIONS Valganciclovir for oral solution is 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 Risk Summary After oral administration, valganciclovir (prodrug) is converted to ganciclovir (active drug) and, therefore, valganciclovir is 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 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. Advise 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 primary maternal CMV infection may be...

8.3 Females and Males of Reproductive Potential Pregnancy Testing Females of reproductive potential should undergo pregnancy testing before initiation of valganciclovir [see Use in Specific Populations ( 8.1 )] . Contraception Females Because of the mutagenic and teratogenic potential of valganciclovir, females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with valganciclovir [see Dosage and Administration ( 2.6 ), Warnings and Precautions ( 5.4 , 5.5 ), Nonclinical Toxicology ( 13.1 )] . Males Because of its mutagenic potential, males should be advised to use condoms during and for at least 90 days following, treatment with valganciclovir [see Dosage and Administration ( 2.6 ), Warnings and Precautions ( 5.3 , 5.5 ), Nonclinical Toxicology ( 13.1 )] . Infertility Valganciclovir at the recommended doses may cause temporary or permanent female and male infertility [see Warnings and Precautions ( 5.3 ), Nonclinical Toxicology ( 13.1 )] . Data Human Data In a small, open-label, non-randomized clinical study, adult male renal transplant patients receiving valganciclovir for CMV prophylaxis for up to 200 days post-transplantation were compared to an untreated control group. Patients were followed-up for six months after valganciclovir discontinuation. Among 24 evaluable patients in the valganciclovir group, the mean sperm density at the end of treatment visit decreased by 11 million/mL from...

Overdosage

10 OVERDOSAGE Experience with Valganciclovir Tablets: An overdose of valganciclovir could 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 [see Clinical Pharmacology ( 12.3 )] . Adequate hydration should be maintained. The use of hematopoietic growth factors should be considered [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )] . Reports of adverse reactions after overdoses with valganciclovir, some with fatal outcomes, 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: myelosuppression including pancytopenia, bone marrow failure, leukopenia, neutropenia, granulocytopenia Hepatotoxicity: hepatitis, liver function disorder Renal toxicity: worsening of hematuria in a patient with pre-existing renal impairment, acute kidney injury, elevated creatinine Gastrointestinal toxicity: abdominal pain, diarrhea, vomiting Neurotoxicity: generalized tremor, seizure

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Valganciclovir for oral solution: Supplied as a white to slightly yellow powder blend for constitution, forming a colorless to brownish yellow tutti-frutti flavored solution. Available in glass bottles containing approximately 100 mL of solution after constitution. Each bottle can deliver up to a total of 88 mL of solution. Each bottle is supplied with a bottle adapter and 2 oral dispensers (NDC 72603-174-01). Prior to dispensing to the patient, valganciclovir for oral solution must be prepared by the pharmacist [see Dosage and Administration ( 2.4 )]. Store dry powder at 20°C to 25°C (68°F to 77°F); excursions are permitted to 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Store constituted solution under refrigeration at 2°C to 8°C (36°F to 46°F) for no longer than 49 days. Do not freeze.