VALGANCICLOVIR HYDROCHLORIDE (Page 4 of 10)
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of Valganciclovir. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. As Valganciclovir is rapidly and extensively converted to ganciclovir, any adverse reactions associated with ganciclovir might also occur with valganciclovir.
In general, the adverse reactions reported during the postmarketing use of Valganciclovir were similar to those identified during the clinical trials.
7 DRUG INTERACTIONS
I n 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 imipenemcilastatin is not recommended because generalized seizures have been reported in patients who received ganciclovir and imipenemcilastatin.|
|Cyclosporine or amphotericin B||Unknown||Monitor renal function when Valganciclovir hydrochloride 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 myelosuppresion 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 hydrochloride 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 hydrochloride dose may need to be reduced. Monitor for evidence of ganciclovir toxicity.|
8 USE IN SPECIFIC POPULATIONS
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)].
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 higher and of greater severity than that resulting from maternal reactivation of CMV infection.
Doses resulting in two-times the human exposure of ganciclovir (based on the human AUC following a single intravenous infusion of 5 mg per kg of ganciclovir) resulted in maternal and embryo-fetal toxicity in pregnant mice and rabbits as well as teratogenicity in the rabbits. Fetal resorptions were present in at least 85% of rabbits and mice. Rabbits showed increased embryo-fetal mortality, growth retardation of the fetuses and structural abnormalities of multiple organs of the fetuses including the palate (cleft palate), eyes (anophthalmia/microphthalmia), brain (hydrocephalus), jaw (brachygnathia), kidneys and pancreas (aplastic organs). Increased embryo-fetal mortality was also seen in mice. Daily intravenous doses of approximately 1.7 times the human exposure (based on AUC) administered to female mice prior to mating, during gestation, and during lactation caused hypoplasia of the testes and seminal vesicles in the male offspring, as well as pathologic changes in the nonglandular region of the stomach.
Data from an ex-vivo human placental model showed that ganciclovir crosses the human placenta. The transfer occurred by passive diffusion and was not saturable over a concentration range of 1 to 10 mg/mL.
No data are available regarding the presence of valganciclovir (prodrug) or ganciclovir (active drug) in human milk, the effects on the breastfed infant, or the effects on milk production. Animal data indicate that ganciclovir is excreted in the 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 with valganciclovir because of the potential for serious adverse events in nursing infants and because of the potential for transmission of HIV [see Boxed Warning, Warnings and Precautions(5.1,5.3,5.4,5.5),Nonclinical Toxicology (13.1)].
8.3 Females and Males of Reproductive Potential
Females of reproductive potential should undergo pregnancy testing before initiation of valganciclovir [see Use in Specific Populations (8.1)].
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)].
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)].
Valganciclovir at the recommended doses may cause temporary or permanent female and male infertility [see Warnings and Precautions (5.3),Nonclinical Toxicology (13.1)].
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 baseline; whereas, among 14 evaluable patients in the control group the mean sperm density increased by 33 million/mL. However, at the follow-up visit among 20 evaluable patients in the valganciclovir group the mean sperm density was comparable to that observed among 10 evaluable patients in the untreated control group (the mean sperm density at the end of follow-up visit increased by 41 million/mL from baseline in the valganciclovir group and by 43 million/mL in the untreated group).
All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.