Sofosbuvir and Velpatasvir (Page 3 of 11)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of sofosbuvir. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac Disorders

Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with a sofosbuvir-containing regimen [see Warnings and Precautions (5.2) and Drug Interactions (7.3)].

Skin and Subcutaneous Tissue Disorders

Skin rashes, sometimes with blisters or angioedema-like swelling

Angioedema

7 DRUG INTERACTIONS

7.1 Potential for Other Drugs to Affect Sofosbuvir and Velpatasvir

Sofosbuvir and velpatasvir are substrates of drug transporters P-gp and BCRP while GS-331007 (the predominant circulating metabolite of sofosbuvir) is not. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 was observed.

Drugs that are inducers of P-gp and/or moderate to strong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., rifampin, St. John’s wort, carbamazepine) may decrease plasma concentrations of sofosbuvir and/or velpatasvir, leading to reduced therapeutic effect of sofosbuvir and velpatasvir. The use of these agents with sofosbuvir and velpatasvir is not recommended [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. Sofosbuvir and velpatasvir may be coadministered with P-gp, BCRP, and CYP inhibitors.

7.2 Potential for Sofosbuvir and Velpatasvir to Affect Other Drugs

Velpatasvir is an inhibitor of drug transporters P-gp, breast cancer resistance protein (BCRP), OATP1B1, OATP1B3, and OATP2B1. Coadministration of sofosbuvir and velpatasvir with drugs that are substrates of these transporters may increase the exposure of such drugs.

7.3 Established and Potentially Significant Drug Interactions

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 cytochrome P450 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 4 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either sofosbuvir and velpatasvir tablets (400 mg/100 mg), or sofosbuvir and velpatasvir as individual agents, or are predicted drug interactions that may occur with sofosbuvir and velpatasvir [see Warnings and Precautions (5.2, 5.3) and Clinical Pharmacology (12.3)].

Table 4 Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction *
Concomitant Drug Class: Drug Name Effect on Concentration Clinical Effect/Recommendation
DF = disoproxil fumarate.
*
This table is not all inclusive.
↓ = decrease, ↑ = increase.
These interactions have been studied in healthy adults.
Acid Reducing Agents: ↓ velpatasvir Velpatasvir solubility decreases as pH increases. Drugs that increase gastric pH are expected to decrease concentration of velpatasvir.
Antacids (e.g., aluminum and magnesium hydroxide) Separate antacid and sofosbuvir and velpatasvir administration by 4 hours.
H2 -receptor antagonists (e.g., famotidine) H2 -receptor antagonists may be administered simultaneously with or 12 hours apart from sofosbuvir and velpatasvir at a dose that does not exceed doses comparable to famotidine 40 mg twice daily.
Proton-pump inhibitors (e.g., omeprazole) Coadministration of omeprazole or other proton-pump inhibitors is not recommended. If it is considered medically necessary to coadminister, sofosbuvir and velpatasvir should be administered with food and taken 4 hours before omeprazole 20 mg. Use with other proton-pump inhibitors has not been studied.
Antiarrhythmics: amiodarone Effect on amiodarone, sofosbuvir, and velpatasvir concentrations unknown Coadministration of amiodarone with a sofosbuvir-containing regimen may result in serious symptomatic bradycardia. The mechanism of this effect is unknown. Coadministration of amiodarone with sofosbuvir and velpatasvir is not recommended; if coadministration is required, cardiac monitoring is recommended [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].
digoxin ↑ digoxin Therapeutic concentration monitoring of digoxin is recommended when coadministered with sofosbuvir and velpatasvir. Refer to digoxin prescribing information for monitoring and dose modification recommendations for concentration increases of less than 50%.
Anticancers: topotecan ↑ topotecan Coadministration is not recommended.
Anticonvulsants: carbamazepine phenytoinphenobarbital ↓ sofosbuvir↓ velpatasvir Coadministration is not recommended.
Antimycobacterials: rifabutin rifampin rifapentine ↓ sofosbuvir↓ velpatasvir Coadministration is not recommended.
HIV Antiretrovirals: efavirenz ↓ velpatasvir Coadministration of sofosbuvir and velpatasvir with efavirenz-containing regimens is not recommended.
Regimens containing tenofovir DF ↑ tenofovir Monitor for tenofovir-associated adverse reactions in patients receiving sofosbuvir and velpatasvir concomitantly with a regimen containing tenofovir DF. Refer to the prescribing information of the tenofovir DF-containing product for recommendations on renal monitoring.
tipranavir/ritonavir ↓ sofosbuvir↓ velpatasvir Coadministration is not recommended.
Herbal Supplements: St. John’s wort (Hypericum perforatum) ↓ sofosbuvir↓ velpatasvir Coadministration is not recommended.
HMG-CoA Reductase Inhibitors: rosuvastatin ↑ rosuvastatin Coadministration of sofosbuvir and velpatasvir with rosuvastatin may significantly increase the concentration of rosuvastatin, which is associated with increased risk of myopathy, including rhabdomyolysis. Rosuvastatin may be administered with sofosbuvir and velpatasvir at a dose that does not exceed 10 mg.
atorvastatin ↑ atorvastatin Coadministration of sofosbuvir and velpatasvir with atorvastatin may be associated with increased risk of myopathy, including rhabdomyolysis. Monitor closely for HMG-CoA reductase inhibitor-associated adverse reactions, such as myopathy and rhabdomyolysis.

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