Drug Safety-related Labeling Changes (SrLC)

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EPCLUSA (NDA-208341)

(SOFOSBUVIR; VELPATASVIR)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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04/27/2022 (SUPPL-19)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions underlined

…

Adverse Reactions in People Who Inject Drugs (PWID), Including Those on Medication- Assisted Treatment (MAT) for Opioid Use Disorder

The safety of EPCLUSA in PWID is based on an open-label Phase 2 trial (SIMPLIFY) that enrolled 103 adult subjects with chronic HCV genotype 1, 2, 3, and 4 infection.

Subjects who self-reported injection drug use within the 6 months prior to starting treatment were eligible and were treated with EPCLUSA for 12 weeks. The trial included a subset of 58 subjects on MAT for opioid use disorder.

The adverse reactions observed from SIMPLIFY both overall and in subjects on MAT were consistent with the known safety profile of EPCLUSA. The most common adverse reactions overall were fatigue (18%), nausea (13%), and headache (11%) [see Use in Specific Populations (8.8) and Clinical Studies (14.7)]. Adverse reactions leading to permanent discontinuation of treatment were not observed in any subjects.

…

7 Drug Interactions

7.4 Drugs without Clinically Significant Interactions with EPCLUSA

Additions underlined

Based on drug interaction studies conducted with the components of EPCLUSA (sofosbuvir or velpatasvir) or EPCLUSA, no clinically significant drug interactions have been observed or are expected with the following drugs [see Clinical Pharmacology (12.3)]:

• EPCLUSA: atazanavir/ritonavir, buprenorphine/naloxone, cyclosporine, darunavir/ritonavir, dolutegravir, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, emtricitabine, methadone, naltrexone, raltegravir, or rilpivirine.

• Sofosbuvir: ethinyl estradiol/norgestimate, or tacrolimus.

• Velpatasvir: ethinyl estradiol/norgestimate, ketoconazole, or pravastatin.

   

  See Table 4 for use of EPCLUSA with certain HIV antiretroviral regimens [see Drug Interactions (7.3)].

8 Use in Specific Populations

8.8 People Who Inject Drugs (PWID), Including Those on Medication-Assisted Treatment (MAT) for Opioid Use Disorder

New subsection added

Based on data from the Phase 2 trial SIMPLIFY, the safety and effectiveness of EPCLUSA in subjects who self-reported injection drug use, including in those on concomitant MAT, were similar to the known safety and effectiveness profile of EPCLUSA. No dosage adjustment of EPCLUSA is recommended for PWID, including those on MAT for opioid use disorder [see Adverse Reactions (6.1) and Clinical Studies (14.7)].

06/10/2021 (SUPPL-17)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

…

Adverse Reactions in Pediatric Subjects 3 Years of Age and Older

The safety assessment of EPCLUSA in pediatric subjects 3 years of age and older is based on data from a Phase 2, open-label clinical trial (Study 1143) that enrolled 216 subjects who were treated with EPCLUSA for 12 weeks [see Clinical Studies (14.7)]. The adverse reactions observed in pediatric subjects 6 years of age and older were consistent with those observed in clinical trials of EPCLUSA in adults.

Among the 41 pediatric subjects less than 6 years of age, gastrointestinal adverse reactions were reported more commonly compared to subjects 6 years of age and older. Vomiting and product use issue (spitting up the drug) were reported in 15% and 10% of subjects, respectively; these adverse reactions were mild (Grade 1 or 2) and led to treatment discontinuation in 5 (12%) subjects [see Use in Specific Populations (8.4) and Clinical Studies (14.7)].

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions underlined)

The pharmacokinetics, safety, and effectiveness of EPCLUSA for treatment of HCV genotype 1, 2, 3, 4, or 6 infection in treatment-naïve and treatment-experienced pediatric patients 3 years of age and older without cirrhosis or with compensated cirrhosis have been established in an open-label, multicenter clinical trial (Study 1143, N=216; 190 treatment-naïve, 26 treatment-experienced). No clinically meaningful differences in pharmacokinetics were observed in comparison to those observed in adults.

The safety and effectiveness in pediatric subjects were comparable to those observed in adults. However, among the 41 pediatric subjects less than 6 years of age, vomiting and product use issue (spitting up the drug) were reported more frequently (15% and 10%, respectively; all Grade 1 or 2) compared to subjects 6 years of age and older. Five subjects (12%) discontinued treatment after vomiting or spitting up the drug [see Dosage and Administration (2.4, 2.5), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.7)].

The safety and effectiveness of EPCLUSA for treatment of HCV genotype 5 in pediatric patients 3 years of age and older without cirrhosis or with compensated cirrhosis are supported by sofosbuvir, GS-331007, and velpatasvir exposures in adults and pediatric patients [see Dosage and Administration (2.2 and 2.4), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.7)]. Similar rationale is used to support dosing recommendations for pediatric patients with HCV genotype 1, 2, 3, 4, 5, or 6 infection who have decompensated cirrhosis (Child-Pugh B or C).

In patients with severe renal impairment, including those requiring dialysis, exposures of GS-331007, the inactive metabolite of sofosbuvir, are increased [see Clinical Pharmacology (12.3)]. No data are available regarding the safety of EPCLUSA in pediatric patients with renal impairment [see Use in Specific Populations (8.6)].

The safety and effectiveness of EPCLUSA have not been established in pediatric patients less than 3 years of age.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV Inform patients that HBV reactivation can occur in patients coinfected with HBV during or after treatment of HCV infection. Advise patients to tell their healthcare provider if they have a history of HBV infection [see Warnings and Precautions (5.1)].

Serious Symptomatic Bradycardia When Coadministered with Amiodarone

Advise patients to seek medical evaluation immediately for symptoms of bradycardia such as near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion, or memory problems [see Warnings and Precautions (5.2), Adverse Reactions (6.2), and Drug Interactions (7.3)].

Drug Interactions

Inform patients that EPCLUSA may interact with other drugs. Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products including St. John’s wort [see Warnings and Precautions (5.2, 5.3) and Drug Interactions (7)].

Administration

Advise patients to take EPCLUSA once daily on a regular dosing schedule with or without food. Inform patients that it is important not to miss or skip doses and to take EPCLUSA for the duration that is recommended by the physician.

For EPCLUSA oral pellets, advise patients or caregivers to read and follow the Instructions for Use for preparing the correct dose [see Dosage and Administration (2.4, 2.5)].

Pregnancy

Advise patients to avoid pregnancy during combination treatment with EPCLUSA and ribavirin and for 6 months after completion of treatment. Inform patients to notify their healthcare provider immediately in the event of a pregnancy [see Use in Specific Populations (8.1)].

PATIENT INFORMATION

(Extensive changes; please refer to label)

07/14/2020 (SUPPL-15)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

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.

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions underlined)

The pharmacokinetics, safety, and effectiveness of EPCLUSA for treatment of HCV genotype 1, 2, 3, 4, or 6 infection in treatment-naïve and treatment-experienced pediatric patients 6 years of age and older or weighing at least 17 kg without cirrhosis or with compensated cirrhosis have been established in an open-label, multicenter clinical trial (Study 1143, N=175; 149 treatment-naïve, 26 treatment-experienced). No clinically meaningful differences in pharmacokinetics were observed in comparison to those observed in adults. The safety and effectiveness were comparable with those observed in adults.

The safety and effectiveness of EPCLUSA for treatment of HCV genotype 5 in pediatric patients 6 years of age and older or weighing at least 17 kg without cirrhosis or with compensated cirrhosis are supported by sofosbuvir, GS-331007, and velpatasvir exposures in adults and pediatric patients. Similar rationale is used to support dosing recommendations for pediatric patients with HCV genotype 1, 2, 3, 4, 5, or 6 infection who have decompensated cirrhosis (Child-Pugh B or C).

In patients with severe renal impairment, including those requiring dialysis, exposures of GS-331007, the inactive metabolite of sofosbuvir, are increased. No data are available regarding the safety of EPCLUSA in pediatric patients with renal impairment.

The safety and effectiveness of EPCLUSA have not been established in pediatric patients less than 6 years of age.

8.6 Renal Impairment

(Additions and/or revisions underlined)

No dosage adjustment of EPCLUSA is recommended for patients with mild, moderate, or severe renal impairment, including ESRD requiring dialysis. No safety data are available in subjects with both decompensated cirrhosis and severe renal impairment, including ESRD requiring dialysis. Additionally, no safety data are available in pediatric patients with renal impairment. Refer to ribavirin tablet prescribing information regarding use of ribavirin in patients with renal impairment.

03/19/2020 (SUPPL-14)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

…

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.

…

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.

7 Drug Interactions

7.3 Established and Potentially Significant Drug Interactions

(Additions and/or revisions underlined)

…

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 Studies or Predicted Interaction

…

7.4 Drugs without Clinically Significant Interactions with EPCLUSA

(Additions and/or revisions underlined)

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

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions underlined)

The pharmacokinetics, safety, and effectiveness of EPCLUSA for treatment of HCV genotype 1, 2, 3, 4, or 6 infection in treatment-naïve and treatment-experienced pediatric patients 6 years of age and older or weighing at least 17 kg without cirrhosis or with compensated cirrhosis have been established in an open-label, multicenter clinical trial (Study 1143, N=175; 149 treatment-naïve, 26 treatment-experienced). No clinically meaningful differences in pharmacokinetics were observed in comparison to those observed in adults. The safety and effectiveness were comparable with those observed in adults.

The safety and effectiveness of EPCLUSA for treatment of HCV genotype 5 in pediatric patients 6 years of age and older or weighing at least 17 kg without cirrhosis or with compensated cirrhosis are supported by sofosbuvir, GS-331007, and velpatasvir exposures in adults and pediatric patients. Similar rationale is used to support dosing recommendations for pediatric patients with HCV genotype 1, 2, 3, 4, 5, or 6 infection who have decompensated cirrhosis (Child-Pugh B or C).

In patients with severe renal impairment, including those requiring dialysis, exposures of GS-331007, the inactive metabolite of sofosbuvir, are increased. No data are available regarding the safety of EPCLUSA in pediatric patients with renal impairment.

The safety and effectiveness of EPCLUSA have not been established in pediatric patients less than 6 years of age.

8.6 Renal Impairment

(Additions and/or revisions underlined)

No dosage adjustment of EPCLUSA is recommended for patients with mild, moderate, or severe renal impairment, including ESRD requiring dialysis. No safety data are available in subjects with both decompensated cirrhosis and severe renal impairment, including ESRD requiring dialysis. Additionally, no safety data are available in pediatric patients with renal impairment. Refer to ribavirin tablet prescribing information regarding use of ribavirin in patients with renal impairment.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

(Additions and/or revisions underlined)

…

What is EPCLUSA?

EPCLUSA is a prescription medicine used to treat adults and children 6 years of age and older or weighing at least 37 lbs (17 kg) with chronic (lasting a long time) hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5, or 6 infection:

• without cirrhosis or with compensated cirrhosis

• with advanced cirrhosis (decompensated) in combination with ribavirin

It is not known if EPCLUSA is safe and effective in children under 6 years of age.

…

How should I take EPCLUSA?

• Take EPCLUSA exactly as your healthcare provider tells you to take it. Do not change your dose unless your healthcare provider tells you to.

• Do not stop taking EPCLUSA without first talking with your healthcare provider.

• Take EPCLUSA with or without food.

• It is important that you do not miss or skip doses of EPCLUSA during treatment.

• For adults the usual dose of EPCLUSA is one 400/100 mg tablet each day.

• For children 6 years of age and older your healthcare provider will prescribe the right dose of EPCLUSA based on your child’s body weight.

• Do not miss a dose of EPCLUSA. Missing a dose lowers the amount of medicine in your blood. Refill your EPCLUSA prescription before you run out of medicine.

If you take too much EPCLUSA, call your healthcare provider or go to the nearest hospital emergency room right away.

…

11/15/2019 (SUPPL-12)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underline)

…

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%).

8 Use in Specific Populations

8.6 Renal Impairment

(additions underlined)

No dosage adjustment of EPCLUSA is recommended for patients with mild, moderate, or severe renal impairment, including ESRD requiring dialysis. No safety data are available in subjects with both decompensated cirrhosis and severe renal impairment, including ESRD requiring dialysis. Refer to ribavirin tablet prescribing information regarding use of ribavirin in patients with renal impairment.

09/19/2019 (SUPPL-13)

Approved Drug Label (PDF)

7 Drug Interactions

7.3 Established and Potentially Significant Drug Interactions

(additions underlined)

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 2 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.

(please refer to label to view Table 2)

11/09/2017 (SUPPL-9)

Approved Drug Label (PDF)

7 Drug Interactions

7.2 Potential for EPCLUSA to Affect Other Drugs

(additions underlined)

…

Fluctuations in INR values may occur in patients receiving warfarin concomitant with HCV treatment, including treatment with EPCLUSA. Frequent monitoring of INR values is recommended during treatment and post-treatment follow-up.

08/31/2017 (SUPPL-7)

Approved Drug Label (PDF)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

Before taking EPCLUSA, tell your healthcare provider about all of your medical conditions, including if you:

Addition of the following:

• have ever had hepatitis B virus infection

08/01/2017 (SUPPL-1)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Serious Symptomatic Bradycardia When Coadministered with Amiodarone (revised subsection title)

Additions and/or revisions underlined:

Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with a sofosbuvir- containing regimen …

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

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 …

6.2 Postmarketing Experience

Cardiac Disorders

Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with a sofosbuvir-containing regimen.

Addition of the following:

Skin and Subcutaneous Tissue Disorders

Skin rashes, sometimes with blisters or angioedema-like swelling

Angioedema

02/14/2017 (SUPPL-2)

Approved Drug Label (PDF)

Boxed Warning

(Newly added section)

WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with EPCLUSA. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

5 Warnings and Precautions

5.1 Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV

(Newly added subsection)

Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals, and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressants or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients.

HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection, reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur.

Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with EPCLUSA. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with EPCLUSA and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV

Inform patients that HBV reactivation can occur in patients coinfected with HBV during or after treatment of HCV infection. Advise patients to tell their healthcare provider if they have a history of HBV infection.

Patient Information

(Additions and/or revisions are underlined)

What is the most important information I should know about EPCLUSA?

EPCLUSA can cause serious side effects, including,

Hepatitis B virus reactivation: Before starting treatment with EPCLUSA, your healthcare provider will do blood tests to check for hepatitis B virus infection. If you have ever had hepatitis B virus infection, the hepatitis B virus could become active again during or after treatment of hepatitis C virus with EPCLUSA. Hepatitis B virus becoming active again (called reactivation) may cause serious liver problems including liver failure and death. Your healthcare provider will monitor you if you are at risk for hepatitis B virus reactivation during treatment and after you stop taking EPCLUSA.

For more information about side effects, see the section “What are the possible side effects of EPCLUSA?”

 

What should I tell my healthcare provider before taking EPCLUSA?

Before taking EPCLUSA, tell your healthcare provider about all of your medical conditions, including if you:

• have ever had hepatitis B virus infection

 

What are the possible side effects of EPCLUSA?

EPCLUSA can cause serious side effects, including:

• Hepatitis B virus reactivation. See “What is the most important information I should know about EPCLUSA?”