Side Effects of Epclusa (sofosbuvir and velpatasvir)

Epclusa (sofosbuvir and velpatasvir) contains two direct-acting antiviral agents used to treat chronic infection with the hepatitis C virus (HCV), genotype 1,2,3,4, 5, or 6 in adults. It also may be combined with ribavirin (Rebetol) for treatment of adults with decompensated cirrhosis. 

Sofosbuvir is converted to an active form in the body before it is effective. The active form of sofosbuvir directly blocks replication of the HVC by interfering with a hepatitis C virus enzyme called NS5B. 

Velpatasvir is an inhibitor of another hepatitis C virus enzyme called NS5A, which also is needed for viral replication. Both drugs in Epclusa interfere with enzymes needed by hepatitis C virus to multiply and make new viruses, thus reducing the overall viral load.

Common side effects of Epclusa include

• tiredness,
• headache,
• nausea,
• diarrhea,
• insomnia,
• anemia,
• weakness,
• irritability,
• rash,
• depressed mood,
• increased blood levels of lipase,
• increased blood levels of creatinine kinase, and
• increased blood levels of indirect bilirubin.

Serious side effects of Epclusa include

• an increased risk of low heart rate (bradycardia) when Epclusa is combined with amiodarone.

Drug interactions of Epclusa include acid reducing agents that are commonly used to treat heartburn, indigestion, and GERD, such as antacids, histamine 2 receptor antagonists.

• For example, famotidine, and proton pump inhibitors (PPIs) because they may decrease the effectiveness of Epclusa treatment by decreasing blood levels of velpatasvir.
• Co-administration of Epclusa and amiodarone is not recommended because the combination may cause serious heart-related side effects including symptomatic slow heart rate.
• Anti-seizure medications including carbamazepine, phenytoin, phenobarbital, and oxcarbazepine may increase the breakdown of Epclusa, leading to reduced therapeutic effectiveness.
• Taking St. John's wort or rifampin with Epclusa may also reduce the effectiveness of treatment and is not recommended.
• Certain medications used to treat tuberculosis infection may decrease the effectiveness of Epclusa treatment.
• Patients taking rifampin, rifabutin, or rifapentine should consult with their doctor or pharmacist before starting Epclusa.
• Co-administration of Epclusa with rosuvastatin or atorvastatin cholesterol lowering medications may significantly increase the blood concentration of rosuvastatin or atorvastatin and increase the risk of side effects such as serious muscle injury.
• Drug interactions between Epclusa and certain HIV antiretroviral therapies such as efavirenz, tenofovir, tipranavir, and ritonavir have also been reported. 

Adequate studies of Epclusa treatment in pregnant women are lacking. Epclusa should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. However, ribavirin which may be combined with Epclusa should not be used by pregnant women or their male partners. 

It is unknown if Epclusa is excreted into breast milk. Due to the lack of conclusive safety data, Epclusa should be used cautiously while breastfeeding.

Common side effects of Epclusa include:

• Tiredness
• Headache
• Nausea
• Diarrhea
• Insomnia
• Anemia

Other side effects of Epclusa include:

• Weakness
• Irritability
• Rash
• Depressed mood

Other less common side effects of Epclusa include:

• Increased blood levels of lipase
• Increased blood levels of creatinine kinase
• Increased blood levels of indirect bilirubin

Possible serious side effects include:

• There is an increased risk of low heart rate (bradycardia) when Epclusa is combined with amiodarone (Cordarone).

The following serious adverse reactions are described below and elsewhere in labeling:

• Serious Symptomatic Bradycardia When Coadministered with Amiodarone.

Clinical Trials Experience

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
• If Epclusa is administered with ribavirin, refer to the prescribing information for ribavirin for a description of ribavirin-associated adverse reactions.

Clinical Trials In Adult Subjects

Adverse Reactions in Subjects without Cirrhosis or with Compensated Cirrhosis

• The adverse reactions data for Epclusa in patients without cirrhosis or with compensated cirrhosis were derived from three Phase 3 clinical trials (ASTRAL-1, ASTRAL-2, and ASTRAL-3) which evaluated a total of 1035 subjects infected with genotype 1, 2, 3, 4, 5, or 6 HCV, without cirrhosis or with compensated cirrhosis, who received Epclusa for 12 weeks. Epclusa was studied in placebo-and active-controlled trials.
• The proportion of subjects who permanently discontinued treatment due to adverse events was 0.2% for subjects who received Epclusa for 12 weeks.
• The most common adverse reactions (adverse events assessed as causally related by the investigator and at least 10%) were headache and fatigue in subjects treated with Epclusa for 12 weeks.
• Adverse reactions, all grades, observed in greater than or equal to 5% of subjects receiving 12 weeks of treatment with Epclusa in ASTRAL-1 include
  • headache (22%),
  • fatigue (15%),
  • nausea (9%),
  • asthenia (5%), and
  •  insomnia (5%).
• Of subjects receiving Epclusa who experienced these adverse reactions, 79% had an adverse reaction of mild severity (Grade 1).
• With the exception of asthenia, each of these adverse reactions occurred at a similar frequency or more frequently in subjects treated with placebo compared to subjects treated with Epclusa (asthenia: 3% versus 5% for the placebo and Epclusa groups, respectively).
• The adverse reactions observed in subjects treated with Epclusa in ASTRAL-2 and ASTRAL-3 were consistent with those observed in ASTRAL-1.
• Irritability was also observed in greater than or equal to 5% of subjects treated with Epclusa in ASTRAL-3.

Adverse Reactions In Subjects Coinfected With HCV And HIV-1

• The safety assessment of Epclusa in subjects with HCV/HIV-1 coinfection was based on an open-label clinical trial (ASTRAL-5) in 106 subjects who were on stable antiretroviral therapy.
• The safety profile in HCV/HIV-1 coinfected subjects was similar to that observed in HCV mono-infected subjects.
• The most common adverse reactions occurring in at least 10% of subjects were
  • fatigue (22%) and
  • headache (10%).

Adverse Reactions In Subjects With Decompensated Cirrhosis

• The safety assessment of Epclusa in subjects infected with genotype 1, 2, 3, 4, or 6 HCV with decompensated cirrhosis was based on one Phase 3 trial (ASTRAL-4) including 87 subjects who received Epclusa with ribavirin for 12 weeks.
• All 87 subjects had Child-Pugh B cirrhosis at screening.
• On the first day of treatment with Epclusa with ribavirin, 6 subjects and 4 subjects were assessed to have Child-Pugh A and Child-Pugh C cirrhosis, respectively.
• The most common adverse reactions (adverse events assessed as causally related by the investigator, all grades with frequency of 10% or greater) in the 87 subjects who received Epclusa with ribavirin for 12 weeks were
  • fatigue (32%),
  • anemia (26%),
  • nausea (15%),
  • headache (11%),
  • insomnia (11%), and
  • diarrhea (10%).
• Of subjects who experienced these adverse reactions, 98% had adverse reactions of mild to moderate severity.
• A total of 4 (5%) subjects permanently discontinued Epclusa with ribavirin due to an adverse event; there was no adverse event leading to discontinuation that occurred in more than 1 subject.
• Decreases in hemoglobin to less than 10 g/dL and 8.5 g/dL during treatment were observed in 23% and 7% of subjects treated with Epclusa with ribavirin for 12 weeks, respectively.
•  Ribavirin was permanently discontinued in 17% of subjects treated with Epclusa with ribavirin for 12 weeks, due to adverse reactions.

Less Common Adverse Reactions Reported In Clinical Trials

• The following adverse reactions occurred in less than 5% of subjects without cirrhosis or with compensated cirrhosis treated with Epclusa for 12 weeks and are included because of a potential causal relationship.

Rash

• In the ASTRAL-1 study, rash occurred in 2% of subjects treated with Epclusa and in 1% of subjects treated with placebo. No serious adverse reactions of rash occurred, and all rashes were mild or moderate in severity.

Depression

• In the ASTRAL-1 study, depressed mood occurred in 1% of subjects treated with Epclusa and was not reported by any subject taking placebo.
• No serious adverse reactions of depressed mood occurred, and all events were mild or moderate in severity.
• The following adverse reactions occurred in less than 10% of subjects with decompensated cirrhosis (ASTRAL-4) treated with Epclusa with ribavirin for 12 weeks and are included because of a potential causal relationship.

Rash

• Rash occurred in 5% of subjects treated with Epclusa with ribavirin.
• No serious adverse reactions of rash occurred, and all rashes were mild or moderate in severity.

Laboratory Abnormalities

Lipase Elevations

• In ASTRAL-1, isolated, asymptomatic lipase elevations of greater than 3xULN were observed in 3% and 1% of subjects treated with Epclusa and placebo for 12 weeks, respectively; and in 6% and 3% of subjects treated with Epclusa in ASTRAL-2 and ASTRAL-3, respectively.
• In the Phase 3 trial of subjects with decompensated cirrhosis (ASTRAL-4), lipase was assessed when amylase values were greater than or equal to 1.5xULN.
• Isolated, asymptomatic lipase elevations of greater than 3xULN were observed in 2% of subjects treated with Epclusa with ribavirin for 12 weeks.

Creatine Kinase

• In ASTRAL-1, isolated, asymptomatic creatine kinase elevations greater than or equal to 10xULN were reported in 1% and 0% of subjects treated with Epclusa and placebo for 12 weeks, respectively; and in 2% and 1% of subjects treated with Epclusa in ASTRAL-2 and ASTRAL-3, respectively.
• In the Phase 3 trial with decompensated cirrhosis (ASTRAL-4), isolated, asymptomatic creatine kinase elevations greater than or equal to 10xULN were reported in 1% of subjects treated with Epclusa with ribavirin for 12 weeks.

Indirect Bilirubin

• Increases in indirect bilirubin up to 3 mg/dL above baseline were noted among HIV-1/HCV coinfected subjects treated with Epclusa and an atazanavir/ritonavir-based antiretroviral regimen.
• The elevated indirect bilirubin values were not associated with clinical adverse events, and all subjects completed 12 weeks of Epclusa without dose adjustment or treatment interruption of either Epclusa or HIV antiretroviral agents.

Adverse Reactions In Adult Liver Transplant Recipients

The safety assessment of Epclusa in liver transplant recipients was based on an open-label clinical trial (Trial 2104) in 79 adults without cirrhosis or with compensated cirrhosis who received Epclusa for 12 weeks. One subject discontinued treatment due to an adverse event on Day 7. The adverse reactions observed were consistent with the known safety profile of Epclusa.

 Adverse reactions occurring in at least 5% of subjects were

• headache (18%),
• fatigue (15%),
• nausea (8%),
• diarrhea (6%), and
• asthenia (5%).

Adverse Reactions In Adults With Severe Renal Impairment Requiring Dialysis

• In an open-label trial (Trial 4062), in which a total of 59 adults with HCV with compensated liver disease (with or without cirrhosis) and ESRD requiring dialysis received Epclusa for 12 weeks, the most common adverse reaction was nausea (7%).

Adverse Reactions In Pediatric Subjects 6 Years Of Age And Older

• The safety assessment of Epclusa in pediatric subjects 6 years of age and older or weighing at least 17 kg is based on data from a Phase 2, open-label clinical trial (Study 1143) that enrolled 175 subjects who were treated with Epclusa for 12 weeks.
• The adverse reactions observed were consistent with those observed in clinical trials of Epclusa in adults.

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.

Skin And Subcutaneous Tissue Disorders

• Skin rashes, sometimes with blisters or angioedema-like swelling Angioedema

Potential For Other Drugs To Affect Epclusa

• 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 Epclusa.
• The use of these agents with Epclusa is not recommended. Epclusa may be coadministered with P-gp, BCRP, and CYP inhibitors.

Potential For Epclusa To Affect Other Drugs

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

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 Epclusa, the components of Epclusa (sofosbuvir and velpatasvir) as individual agents, or are predicted drug interactions that may occur with Epclusa.

Table 4 Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesor Predicted Interaction^a

Drugs Without Clinically Significant Interactions With Epclusa

Based on drug interaction studies conducted with the components of Epclusa (sofosbuvir or velpatasvir) or Epclusa, no clinically significant drug interactions have been observed with the following drugs:

• Epclusa: atazanavir/ritonavir, cyclosporine, darunavir/ritonavir, dolutegravir, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, emtricitabine, raltegravir, or rilpivirine.
• Sofosbuvir: ethinyl estradiol/norgestimate, methadone, or tacrolimus.
• Velpatasvir: ethinyl estradiol/norgestimate, ketoconazole, or pravastatin.

See Table 4 for use of Epclusa with certain HIV antiretroviral regimens.