Tenofovir alafenamide

7 DRUG INTERACTIONS VEMLIDY is a substrate of P-glycoprotein (P-gp) and BCRP. Drugs that strongly affect P-gp and BCRP activity may lead to changes in VEMLIDY absorption. Consult the full prescribing information prior to and during treatment for potential drug-drug interactions. ( 7 )

7.1 Potential for Other Drugs to Affect VEMLIDY VEMLIDY is a substrate of P-glycoprotein (P-gp) and BCRP. Drugs that strongly affect P-gp and BCRP activity may lead to changes in tenofovir alafenamide absorption (see Table 4 ). Drugs that induce P-gp activity are expected to decrease the absorption of tenofovir alafenamide, resulting in decreased plasma concentrations of tenofovir alafenamide, which may lead to loss of therapeutic effect of VEMLIDY. Coadministration of VEMLIDY with other drugs that inhibit P-gp and BCRP may increase the absorption and plasma concentration of tenofovir alafenamide.

7.2 Drugs Affecting Renal Function Because tenofovir is primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of VEMLIDY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.3) ] .

7.3 Established and Other Potentially Significant Interactions Table 4 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with tenofovir alafenamide or are predicted drug interactions that may occur with VEMLIDY [For magnitude of interaction, see Clinical Pharmacology (12.3) ] . Information regarding potential drug-drug interactions with HIV antiretrovirals is not provided (see the prescribing information for emtricitabine/tenofovir alafenamide for interactions with HIV antiretrovirals). The table includes potentially significant interactions but is not all inclusive.

Table 4 Established and Other Potentially Significant Drug Interactions This table is not all inclusive. Concomitant Drug Class: Drug Name Effect on Concentration ↓ = decrease. Clinical Comment Anticonvulsants: ↓ tenofovir alafenamide When coadministered with carbamazepine, the tenofovir alafenamide dose should be increased to two tablets once daily. Coadministration of VEMLIDY with oxcarbazepine, phenobarbital, or phenytoin is not recommended. Carbamazepine Indicates that a drug interaction study was conducted.

P-gp inducer Oxcarbazepine Phenobarbital Phenytoin Antimycobacterials: ↓ tenofovir alafenamide Coadministration of VEMLIDY with rifabutin, rifampin or rifapentine is not recommended. Rifabutin Rifampin Rifapentine Herbal Products: ↓ tenofovir alafenamide Coadministration of VEMLIDY with St. John's wort is not recommended. St. John's wort (Hypericum perforatum)

7.4 Drugs without Clinically Significant Interactions with VEMLIDY Based on drug interaction studies conducted with VEMLIDY, no clinically significant drug interactions have been observed with: ethinyl estradiol, ledipasvir/sofosbuvir, midazolam, norgestimate, sertraline, sofosbuvir, sofosbuvir/velpatasvir, and sofosbuvir/velpatasvir/voxilaprevir.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VEMLIDY during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Available data from the APR show no statistically significant difference in the overall risk of birth defects for tenofovir alafenamide (TAF) compared with the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data ). The rate of miscarriage is not reported in the APR.

The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. In animal studies, no adverse developmental effects were observed when tenofovir alafenamide was administered during the period of organogenesis at exposure equal to or 51 times (rats and rabbits, respectively) the tenofovir alafenamide exposure at the recommended daily dose of VEMLIDY (see Data ). No adverse effects were observed in the offspring when TDF was administered through lactation at tenofovir exposures of approximately 12 times the exposure at the recommended daily dosage of VEMLIDY.

Data Human Data Based on prospective reports to the APR of over 1330 exposures to TAF-containing regimens during pregnancy resulting in live births (including over 1080 exposed in the first trimester and over 240 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.9% (95% CI: 2.8% to 5.2%) and 4.8% (95% CI: 2.5% to 8.3%) following first and second/third trimester exposure, respectively, to TAF-containing regimens. Methodologic limitations of the APR include the use of MACDP as the external comparator group.

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 less than 20 weeks gestation. Animal Data Embryonic fetal development studies performed in rats and rabbits revealed no evidence of impaired fertility or harm to the fetus. The embryo-fetal NOAELs (no observed adverse effect level) in rats and rabbits occurred at tenofovir alafenamide exposures similar to and 51 times higher than, respectively, the exposure in humans at the recommended daily dose.

Tenofovir alafenamide is rapidly converted to tenofovir; the observed tenofovir exposure in rats and rabbits were 54 (rats) and 85 (rabbits) times higher than human tenofovir…