Elbasvir and grazoprevir

Co-administration of ZEPATIER with moderate CYP3A inducers is not recommended as they may decrease the plasma concentration of ZEPATIER. ( 7 ) Co-administration of ZEPATIER with certain strong CYP3A inhibitors is not recommended as they may increase the plasma concentration of ZEPATIER. ( 7 ) Clearance of HCV infection with direct-acting antivirals may lead to changes in hepatic function, which may impact safe and effective use of concomitant medications. Frequent monitoring of relevant laboratory parameters (INR or blood glucose) and dose adjustments of certain concomitant medications may be necessary.

( 7.2 ) Consult the full prescribing information prior to and during treatment for potential drug interactions. ( 4 , 5.5 , 7 , 12.3 )

7.1 Potential for Drug Interactions Grazoprevir is a substrate of OATP1B1/3 transporters. Co-administration of ZEPATIER with OATP1B1/3 inhibitors that are known or expected to significantly increase grazoprevir plasma concentrations is contraindicated [see Contraindications (4) , Clinical Pharmacology (12.3) , and Table 2 ] . Elbasvir and grazoprevir are substrates of CYP3A and P-gp, but the role of intestinal P-gp in the absorption of elbasvir and grazoprevir appears to be minimal. Co-administration of moderate or strong inducers of CYP3A with ZEPATIER may decrease elbasvir and grazoprevir plasma concentrations, leading to reduced therapeutic effect of ZEPATIER.

Co-administration of ZEPATIER with strong CYP3A inducers or efavirenz is contraindicated [see Contraindications (4) , Clinical Pharmacology (12.3) , and Table 2 ]. Co-administration of ZEPATIER with moderate CYP3A inducers is not recommended [see Warnings and Precautions (5.5) , Clinical Pharmacology (12.3) , and Table 6 ]. Co-administration of ZEPATIER with strong CYP3A inhibitors may increase elbasvir and grazoprevir concentrations. Co-administration of ZEPATIER with certain strong CYP3A inhibitors is not recommended [see Warnings and Precautions (5.5) , Clinical Pharmacology (12.3) , and Table 6 ] .

7.2 Established and other Potentially Significant Drug Interactions If dose adjustments of concomitant medications are made due to treatment with ZEPATIER, doses should be readjusted after administration of ZEPATIER is completed. Clearance of HCV infection with direct-acting antivirals may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications. For example, altered blood glucose control resulting in serious symptomatic hypoglycemia has been reported in diabetic patients in postmarketing case reports and published epidemiological studies.

Management of hypoglycemia in these cases required either discontinuation or dose modification of concomitant medications used for diabetes treatment. Frequent monitoring of relevant laboratory parameters (e.g., International Normalized Ratio [INR] in patients taking warfarin, blood glucose levels in diabetic patients) or drug concentrations of concomitant medications such as CYP450 substrates with a narrow therapeutic index (e.g., certain immunosuppressants) is recommended to ensure safe and effective use. Dose adjustments of concomitant medications may be necessary. Table 6 provides a listing of established or potentially clinically significant drug interactions.

The drug interactions described are based on studies conducted with either ZEPATIER, the components of ZEPATIER (elbasvir [EBR] and grazoprevir [GZR]) as individual agents, or are predicted drug interactions that may occur with ZEPATIER [see Contraindications (4) , Warnings and Precautions (5.5) , and Clinical Pharmacology (12.3) ] . Table 6: Potentially Significant Drug Interactions: Alteration in Dose May Be Recommended Based on Results from Drug Interaction Studies or Predicted Interactions This table is not all inclusive.

Concomitant Drug Class: Drug Name Effect on Concentration ↓ = decrease, ↑ = increase Clinical Comment Antibiotics : Nafcillin ↓ EBR ↓ GZR Co-administration of ZEPATIER with nafcillin may lead to reduced therapeutic effect of ZEPATIER. Co-administration is not recommended. Antifungals: oral Ketoconazole These interactions have been studied in healthy adults. ↑ EBR ↑ GZR Co-administration of oral ketoconazole is not recommended. Endothelin Antagonists: Bosentan ↓ EBR ↓ GZR Co-administration of ZEPATIER with bosentan may lead to reduced therapeutic effect of ZEPATIER. Co-administration is not recommended.

Immunosuppressants: Tacrolimus ↑ tacrolimus Frequent monitoring of tacrolimus whole blood concentrations, changes in renal function, and tacrolimus-associated adverse events upon the initiation of co-administration is recommended. HIV Medications: Etravirine ↓ EBR ↓ GZR Co-administration of ZEPATIER with etravirine may lead to reduced therapeutic effect of ZEPATIER. Co-administration is not recommended. Elvitegravir/ cobicistat/ emtricitabine/ tenofovir (disoproxil fumarate or alafenamide) ↑ EBR ↑ GZR Co-administration of cobicistat-containing regimens is not recommended.

HMG-CoA Reductase Inhibitors See Drug Interactions (7.3) for a list of HMG Co-A reductase inhibitors without clinically relevant interactions with ZEPATIER. : Atorvastatin ↑ atorvastatin The dose of atorvastatin should not exceed a daily dose of 20 mg when co-administered with ZEPATIER. Rosuvastatin ↑ rosuvastatin The dose of rosuvastatin should not exceed a daily dose of 10 mg when co-administered with ZEPATIER. Fluvastatin Lovastatin Simvastatin ↑ fluvastatin ↑ lovastatin ↑ simvastatin Statin-associated adverse events such as myopathy should be closely monitored. The lowest necessary dose should be used when co-administered with ZEPATIER.

Wakefulness-Promoting Agents: Modafinil ↓ EBR ↓ GZR Co-administration of ZEPATIER with modafinil may lead to reduced therapeutic effect of ZEPATIER. Co-administration is not recommended.

7.3 Drugs without Clinically Significant Interactions with ZEPATIER The interaction between the components of ZEPATIER (elbasvir or grazoprevir) or ZEPATIER and the following drugs were evaluated in clinical studies, and no dose adjustments are needed when ZEPATIER is used with the following drugs individually: acid reducing agents (proton pump inhibitors, H2 blockers, antacids), buprenorphine/naloxone, digoxin, dolutegravir, methadone, mycophenolate mofetil, oral contraceptive pills, phosphate binders, pitavastatin, pravastatin, prednisone, raltegravir, ribavirin, rilpivirine, tenofovir disoproxil fumarate, and sofosbuvir [see Clinical Pharmacology (12.3) ] .

No clinically relevant drug-drug interaction is expected when ZEPATIER is co-administered with abacavir, emtricitabine, entecavir, and lamivudine.

8.1 Pregnancy Risk Summary No adequate human data are available to establish whether or not ZEPATIER poses a risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of ZEPATIER (elbasvir or grazoprevir) at exposures greater than those in humans at the recommended human dose (RHD) (see Data ) . During organogenesis in the rat and rabbit, systemic exposures (AUC) were approximately 10 and 18 times (for elbasvir) and 117 and 41 times (for grazoprevir), respectively, the exposure in humans at the RHD.

In rat pre/postnatal developmental studies, maternal systemic exposures (AUC) to elbasvir and grazoprevir were approximately 10 and 78 times, respectively, the exposure in humans at the RHD. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. If ZEPATIER is administered with ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant.

Refer to the ribavirin prescribing information for more information on use in pregnancy. Data Animal Data Elbasvir: Elbasvir was administered orally at up to 1000 mg/kg/day to pregnant rats and rabbits on gestation days 6 to 20 and 7 to 20, respectively, and also to rats on gestation day 6 to lactation/post-partum day 20. No effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at up to the highest dose tested. Systemic exposures (AUC) to elbasvir were approximately 10 (rats) and 18 (rabbits) times the exposure in humans at the RHD.

In both species, elbasvir has been shown to cross the placenta, with fetal plasma concentrations of up to 0.8% (rabbits) and 2.2% (rats) that of maternal concentrations observed on gestation day 20. Grazoprevir: Grazoprevir was administered to pregnant rats (oral doses up to 400 mg/kg/day) and rabbits (intravenous doses up to 100 mg/kg/day) on gestation days 6 to 20 and 7 to 20, respectively, and also to rats (oral doses up to 400 mg/kg/day) on gestation day 6 to lactation/post-partum day 20. No effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at up to the highest dose tested.

Systemic exposures (AUC) to grazoprevir were ≥78 (rats) and 41 (rabbits) times the exposure in humans at the RHD. In both species, grazoprevir has been shown to cross the placenta, with fetal…