Interactions : אינטראקציות

7     DRUG INTERACTIONS
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 (12.4)], 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*
Concomitant Drug             Effect on                         Clinical Comment Class: Drug Name         Concentration†
Antibiotics:                ↓ EBR             Co-administration of ZEPATIER with nafcillin may lead to nafcillin                   ↓ GZR             reduced therapeutic effect of ZEPATIER. Co- administration is not recommended.
Antifungals:                ↑ EBR             Co-administration of oral ketoconazole is not oral ketoconazole‡          ↑ GZR             recommended.
Endothelin                  ↓ EBR             Co-administration of ZEPATIER with bosentan may lead Antagonists:                ↓ GZR             to reduced therapeutic effect of ZEPATIER. Co- bosentan                                      administration is not recommended.
Immunosuppressants:         ↑ tacrolimus      Frequent monitoring of tacrolimus whole blood tacrolimus‡                                   concentrations, changes in renal function, and tacrolimus-associated adverse events upon the initiation of co-administration is recommended.
HIV Medications: etravirine                  ↓ EBR             Co-administration of ZEPATIER with etravirine may lead ↓ GZR             to reduced therapeutic effect of ZEPATIER. Co- administration is not recommended.
elvitegravir/ cobicistat/   ↑ EBR             Co-administration of cobicistat-containing regimens is not emtricitabine/ tenofovir    ↑ GZR             recommended.
(disoproxil fumarate‡ or alafenamide)
HMG-CoA Reductase Inhibitors§: 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                     ↑ fluvastatin         Statin-associated adverse events such as myopathy lovastatin                      ↑ lovastatin          should be closely monitored. The lowest necessary dose simvastatin                     ↑ simvastatin         should be used when co-administered with ZEPATIER.§ Wakefulness-                    ↓ EBR                 Co-administration of ZEPATIER with modafinil may lead Promoting Agents:               ↓ GZR                 to reduced therapeutic effect of ZEPATIER. Co- modafinil                                             administration is not recommended.
*This table is not all inclusive.
†↓ = decrease, ↑ = increase
‡These interactions have been studied in healthy adults.
§See Drug Interactions (7.3) for a list of HMG Co-A reductase inhibitors without clinically relevant interactions with 
ZEPATIER.

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.