e the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); zonisamide is a weak in vitro inhibitor of P-gp. Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and sofosbuvir is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
PREGNANCY AND LACTATION
Pregnancy
No adequate human data are available to establish whether or not sofosbuvir; velpatasvir poses a risk to pregnancy outcomes. In animal studies, no adverse effects on fetal development were observed with either sofosbuvir or velpatasvir. Because animal studies are not always predictive of human response, use of the drug during pregnancy should only be considered if the benefits justify the potential risk to the fetus. In certain patient populations, sofosbuvir; velpatasvir is administered with ribavirin. The use of sofosbuvir; velpatasvir in combination with ribavirin is contraindicated in pregnant women and in the male partners of women who are pregnant. Ribavirin may cause birth defects and death of the exposed fetus. Ribavirin therapy also may cause male-mediated teratogenicity and is contraindicated for use during pregnancy, in females who may become pregnant, or in men whose female partners are pregnant. Studies of ribavirin indicate teratogenic (e.g., malformations of skull, palate, eye, jaw, limbs, skeleton, and GI tract) or embryocidal properties in all of the animal species tested. Patients and their partners are required use 2 reliable forms of effective contraception during treatment and for 6 months after use of these combination therapies. Patients who are not willing to practice strict contraception should not receive sofosbuvir; velpatasvir with ribavirin. Females must also undergo a pregnancy test immediately prior to initiation of therapy, monthly during therapy, and for 6 months post-therapy. To monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment, health care providers are encouraged to report any cases to the Ribavirin Pregnancy Registry; telephone (800) 593-2214. For patient who are also infected with HIV and taking concomitant antiretroviral agents, an Antiretroviral Pregnancy Registry is available at (800) 258-4263.
MECHANISM OF ACTION
Sofosbuvir; velpatasvir is active against chronic infections caused by genotypes 1, 2, 3, 4, 5, and 6 hepatitis C virus (HCV). Sofosbuvir is a HCV nucleotide analog NS5B polymerase inhibitor. Velpatasvir is an inhibitor of the HCV NS5A protein.
Sofosbuvir: Sofosbuvir is a nucleotide prodrug that prevents hepatitis C viral (HCV) replication by inhibiting the activity of HCV NS5B RNA polymerase. It undergoes intracellular metabolism to form GS-461203, a pharmacologically active uridine analog triphosphate. Hepatitis C virus NS5B RNA polymerase incorporates this metabolite into the viral RNA, where it acts as a chain terminator. GS-461203 does not inhibit human DNA or RNA polymerase, nor does it block mitochondrial RNA polymerase.
In cell cultures, recombinant NS5B polymerase expressing a S282T substitution displayed a 2- to 18-fold decrease in susceptibility to sofos |
