Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VIRACEPT during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
Risk Summary
Published reports of hepatic adverse events ranging from elevated liver enzymes to hepatic failure in pregnant patients exposed to nelfinavir have been reported (see Clinical Considerations). Due to VIRACEPT's overall adverse event profile, including hepatic adverse events, and literature reports of decreased exposures in second and third trimesters, consider alternative antiretroviral drugs during pregnancy.
Available data from the APR suggests a statistically significant increase in overall risks of major birth defects with first trimester exposure with nelfinavir (3.9%) when compared with the background rate of 2.7% in one U.S. reference population (the Metropolitan Atlanta Congenital Defects Program [MACDP]), but the risk is similar to the background rate of 4.2% reported in another U.S. reference population (the Texas Birth Defects Registry [TBDR]). No pattern of defects was identified by the APR. The clinical relevance of this statistical finding is uncertain (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2 to 4% and 15 to 20% respectively.
In animal reproductive studies, no effects on embryo-fetal development were observed when nelfinavir was administered orally to pregnant rats and rabbits during organogenesis at systemic exposures similar to or less than human exposure (based on AUC) at the maximum recommended human dose (MRHD), respectively (see Data).
Maternal Adverse Reactions
There have been reports of hepatic adverse events ranging from elevated liver enzymes to hepatic failure in pregnant patients receiving nelfinavir as part of combination treatment of HIV-1 infection. Consider alternative antiretroviral drugs during pregnancy. If VIRACEPT is used during pregnancy, clinical monitoring is recommended [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)].
Human Data
Based on prospective reports to the APR of over 1,200 live births following first trimester and over 2,700 live births following second and third trimester exposure to nelfinavir-containing regimens, there was an increase in overall rates of major birth defects (n=47) with nelfinavir when compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.9% (95% CI: 2.9% to 5.1%) with first trimester exposure to nelfinavir-containing regimens and 3.1% (95% CI: 2.5% to 3.9%) with the second/third trimester exposure to nelfinavir-containing regimens. The rate for nelfinavir-containing regimens is greater than the overall rates of defects in the MACDP (2.7%) but less than rates of defects in the TBDR (4.2%). Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease; these limitations preclude an accurate comparison of outcomes. The MACDP population is not disease specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation.
Animal Data
Nelfinavir was administered orally to pregnant rats and rabbits during organogenesis, from gestation day 6 to 17 (rats) and 7 to 20 (rabbits). There were no effects on fetal development or maternal toxicity when nelfinavir was administered to pregnant rats at systemic exposures (AUC) similar to human exposure. Administration of nelfinavir to pregnant rabbits resulted in no fetal development effects up to a dose at which a slight decrease in maternal body weight was observed; however, even at the highest dose evaluated, systemic exposure in rabbits was significantly lower than human exposure. Additional studies in rats indicated that exposure to nelfinavir in females from mid-pregnancy through lactation (gestation day 6 to lactation day 20) had no effect on the survival, growth, and development of the offspring. Subsequent reproductive performance of these offspring was also not affected by maternal exposure to nelfinavir.
Risk Summary
The Centers for Disease Control and Prevention recommend that HIV-1 infected patients in the United States not breastfeed their infants to avoid risking potential transmission of HIV-1 infection. Based on limited published data, nelfinavir is present in low levels in human milk, and adverse effects in infants exposed to nelfinavir have been reported. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) the potential for serious adverse reactions in breastfed infants similar to those seen in adults, instruct mothers not to breastfeed if they are receiving VIRACEPT.
Contraception
Use of VIRACEPT may reduce the efficacy of estrogen-based oral contraceptives. Advise patients to use alternative or additional contraceptive measures when oral contraceptives containing ethinyl estradiol or norethindrone and VIRACEPT are coadministered [see Drug Interactions (7.3)].
The safety, tolerability, pharmacokinetic profile and efficacy of VIRACEPT were evaluated in HIV infected pediatric patients from 2 to 13 years of age in multicenter clinical trials, Study 556 and PACTG 337 [see Clinical Pharmacology (12.3) and Clinical Studies (14.3)]. In patients less than 2 years of age, VIRACEPT was found to be safe at the doses studied, but a reliably effective dose could not be established [see Dosage and Administration (2.2), Adverse Reactions (6.2), and Clinical Pharmacology (12.3)]. The pharmacokinetic profile, safety and antiviral activity of VIRACEPT in adolescent patients 13 years and older is supported by data from the adult clinical trials where some trials allowed enrolment of subjects 13 years and older. Thus, the data for adolescents and adults were analyzed collectively [see Adverse Reactions (6.1)].
Clinical studies of VIRACEPT did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
VIRACEPT should not be used in patients with either moderate or severe hepatic impairment (Child-Pugh B or C, score greater than or equal to 7) [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. No dose adjustment of VIRACEPT is necessary for patients with mild hepatic impairment (Child-Pugh A, score 5–6).
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VIRACEPT during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
Risk Summary
Published reports of hepatic adverse events ranging from elevated liver enzymes to hepatic failure in pregnant patients exposed to nelfinavir have been reported (see Clinical Considerations). Due to VIRACEPT's overall adverse event profile, including hepatic adverse events, and literature reports of decreased exposures in second and third trimesters, consider alternative antiretroviral drugs during pregnancy.
Available data from the APR suggests a statistically significant increase in overall risks of major birth defects with first trimester exposure with nelfinavir (3.9%) when compared with the background rate of 2.7% in one U.S. reference population (the Metropolitan Atlanta Congenital Defects Program [MACDP]), but the risk is similar to the background rate of 4.2% reported in another U.S. reference population (the Texas Birth Defects Registry [TBDR]). No pattern of defects was identified by the APR. The clinical relevance of this statistical finding is uncertain (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2 to 4% and 15 to 20% respectively.
In animal reproductive studies, no effects on embryo-fetal development were observed when nelfinavir was administered orally to pregnant rats and rabbits during organogenesis at systemic exposures similar to or less than human exposure (based on AUC) at the maximum recommended human dose (MRHD), respectively (see Data).
Maternal Adverse Reactions
There have been reports of hepatic adverse events ranging from elevated liver enzymes to hepatic failure in pregnant patients receiving nelfinavir as part of combination treatment of HIV-1 infection. Consider alternative antiretroviral drugs during pregnancy. If VIRACEPT is used during pregnancy, clinical monitoring is recommended [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)].
Human Data
Based on prospective reports to the APR of over 1,200 live births following first trimester and over 2,700 live births following second and third trimester exposure to nelfinavir-containing regimens, there was an increase in overall rates of major birth defects (n=47) with nelfinavir when compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.9% (95% CI: 2.9% to 5.1%) with first trimester exposure to nelfinavir-containing regimens and 3.1% (95% CI: 2.5% to 3.9%) with the second/third trimester exposure to nelfinavir-containing regimens. The rate for nelfinavir-containing regimens is greater than the overall rates of defects in the MACDP (2.7%) but less than rates of defects in the TBDR (4.2%). Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease; these limitations preclude an accurate comparison of outcomes. The MACDP population is not disease specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation.
Animal Data
Nelfinavir was administered orally to pregnant rats and rabbits during organogenesis, from gestation day 6 to 17 (rats) and 7 to 20 (rabbits). There were no effects on fetal development or maternal toxicity when nelfinavir was administered to pregnant rats at systemic exposures (AUC) similar to human exposure. Administration of nelfinavir to pregnant rabbits resulted in no fetal development effects up to a dose at which a slight decrease in maternal body weight was observed; however, even at the highest dose evaluated, systemic exposure in rabbits was significantly lower than human exposure. Additional studies in rats indicated that exposure to nelfinavir in females from mid-pregnancy through lactation (gestation day 6 to lactation day 20) had no effect on the survival, growth, and development of the offspring. Subsequent reproductive performance of these offspring was also not affected by maternal exposure to nelfinavir.
Risk Summary
The Centers for Disease Control and Prevention recommend that HIV-1 infected patients in the United States not breastfeed their infants to avoid risking potential transmission of HIV-1 infection. Based on limited published data, nelfinavir is present in low levels in human milk, and adverse effects in infants exposed to nelfinavir have been reported. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) the potential for serious adverse reactions in breastfed infants similar to those seen in adults, instruct mothers not to breastfeed if they are receiving VIRACEPT.
Contraception
Use of VIRACEPT may reduce the efficacy of estrogen-based oral contraceptives. Advise patients to use alternative or additional contraceptive measures when oral contraceptives containing ethinyl estradiol or norethindrone and VIRACEPT are coadministered [see Drug Interactions (7.3)].
The safety, tolerability, pharmacokinetic profile and efficacy of VIRACEPT were evaluated in HIV infected pediatric patients from 2 to 13 years of age in multicenter clinical trials, Study 556 and PACTG 337 [see Clinical Pharmacology (12.3) and Clinical Studies (14.3)]. In patients less than 2 years of age, VIRACEPT was found to be safe at the doses studied, but a reliably effective dose could not be established [see Dosage and Administration (2.2), Adverse Reactions (6.2), and Clinical Pharmacology (12.3)]. The pharmacokinetic profile, safety and antiviral activity of VIRACEPT in adolescent patients 13 years and older is supported by data from the adult clinical trials where some trials allowed enrolment of subjects 13 years and older. Thus, the data for adolescents and adults were analyzed collectively [see Adverse Reactions (6.1)].
Clinical studies of VIRACEPT did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
VIRACEPT should not be used in patients with either moderate or severe hepatic impairment (Child-Pugh B or C, score greater than or equal to 7) [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. No dose adjustment of VIRACEPT is necessary for patients with mild hepatic impairment (Child-Pugh A, score 5–6).
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