Drug Safety-related Labeling Changes (SrLC)

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SOVALDI (NDA-204671)

(SOFOSBUVIR)

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

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03/05/2020 (SUPPL-17)

Approved Drug Label (PDF)

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

PATIENT COUNSELING INFORMATION

(Newly added information)

Administration

Advise patients to take SOVALDI every day at the regularly scheduled time with or

without food. Inform patients that it is important not to miss or skip doses and to take

SOVALDI for the duration that is recommended by the physician.

For SOVALDI oral pellets, advise patients or caregivers to read and follow the

Instructions for Use for preparing the correct dose.

Patient Information

(Newly added information)

See the detailed Instructions for Use for information about how to give or take a dose of

SOVALDI oral pellets.

09/19/2019 (SUPPL-16)

Approved Drug Label (PDF)

7 Drug Interactions

7.1 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.

Information on potential drug interactions with SOVALDI is summarized in Table 7. The table is not all-inclusive.

(please refer to label to view Table 7)

08/28/2019 (SUPPL-14)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(tables are re-numbered)

(additions/revisions are underlined)

Adverse Reactions in Pediatric Subjects 3 Years of Age and Older

The safety assessment of SOVALDI in pediatric subjects 3 years of age and older is based on data from 106 subjects who were treated with SOVALDI plus ribavirin for 12 weeks (genotype 2 subjects) or 24 weeks (genotype 3 subjects) in a Phase 2, open- label clinical trial. The adverse reactions observed were consistent with those observed in clinical studies of SOVALDI plus ribavirin in adults. Among pediatric subjects 3 years to < 12 years of age taking SOVALDI in combination with ribavirin oral solution, decreased appetite was observed in 13%.

7 Drug Interactions

7.1 Potentially Significant Drug Interactions

(additions/revisions are underlined)

Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while the predominant circulating metabolite GS-331007 is not. Drugs that are P-gp inducers in the intestine (e.g., rifampin or St. John’s wort) may decrease sofosbuvir plasma concentration, leading to reduced therapeutic effect of SOVALDI, and thus concomitant use with SOVALDI is not recommended.

Information on potential drug interactions with SOVALDI is summarized in Table 7. The table is not all-inclusive.

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

Table 7          Potentially Significant Drug Interactions: Alteration in Dosage or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction

7.2 Drugs without Clinically Significant Interactions with SOVALDI

(additions/revisions are underlined)

Based on drug interaction studies conducted with SOVALDI, no clinically significant drug interactions have been either observed or are expected when SOVALDI is combined with the following drugs: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone, oral contraceptives, raltegravir, rilpivirine, tacrolimus, or tenofovir disoproxil fumarate.

8 Use in Specific Populations

8.4 Pediatric Use

(additions/revisions are underlined)

The safety, pharmacokinetics, and efficacy of SOVALDI in pediatric patients 3 years of age and older with genotype 2 and 3 infection have been established. SOVALDI was evaluated in an open-label clinical trial (Study 1112), which included 106 subjects (31 genotype 2; 75 genotype 3) 3 years of age and older. The safety, pharmacokinetics, and efficacy were comparable to that observed in adults.

The safety and efficacy of SOVALDI in pediatric patients 3 years of age and older with compensated cirrhosis is supported by comparable sofosbuvir and GS-331007 exposures between: 1) adults and pediatric patients without cirrhosis and 2) adults without cirrhosis and adults with compensated cirrhosis. Thus, similar efficacy would be expected for pediatric patients with compensated cirrhosis as adults with compensated cirrhosis.

The safety and efficacy of SOVALDI have not been established in pediatric patients less than 3 years of age with HCV genotype 2 or 3. The safety and efficacy of SOVALDI have not been established in pediatric patients with HCV genotype 1 or 4.

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

PATIENT INFORMATION

(additions/revisions are underlined)

What is SOVALDI?

SOVALDI is a prescription medicine used with other antiviral medicines to treat adults with chronic (lasting a long time) hepatitis C virus (HCV):

• genotype 1 or 4 infection without cirrhosis or with compensated cirrhosis in combination with peginterferon alfa and ribavirin

• genotype 2 or 3 infection without cirrhosis or with compensated cirrhosis in combination with ribavirin

SOVALDI is used to treat children 3 years of age and older with chronic HCV genotype 2 or 3 infection without cirrhosis or with compensated cirrhosis in combination with ribavirin.

It is not known if SOVALDI is safe and effective in children under 3 years of age with HCV genotype 2 or 3 infection, or with HCV genotype 1 or 4 infection.

It is not known if SOVALDI is safe and effective in people who have had a liver transplant.

…

How should I take SOVALDI?

• Take SOVALDI 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 SOVALDI without first talking with your healthcare provider.

• Take SOVALDI tablets or oral pellets by mouth, with or without food.

• For adults the usual dose of SOVALDI is one 400 mg tablet each day.

• For children 3 years of age and older, your healthcare provider will prescribe the right dose of SOVALDI tablets or oral pellets based on your child’s body weight.

  • Tell your healthcare provider if your child has problems with swallowing tablets.

  • If your healthcare provider prescribes SOVALDI pellets for your child, see “How should I give SOVALDI oral pellets to my child.”

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

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

How should I give SOVALDI oral pellets to my child?

• Administer SOVALDI oral pellets exactly as instructed by your healthcare provider.

• Do not open the packet until ready to use.

• Hold the SOVALDI pellets packet with the cut line on top.

• Shake the SOVALDI pellets packet gently to settle the pellets.

• Tear or cut the SOVALDI packet along the cut line.

• SOVALDI pellets can be taken right in the mouth without chewing, or with food.

• If SOVALDI pellets are taken with food, sprinkle the pellets on one or more spoonfuls of non- acidic soft food at or below room temperature. Examples of non-acidic foods include pudding, chocolate syrup, mashed potato, and ice cream. Take SOVALDI pellets within 30 minutes of gently mixing with food and swallow the entire contents without chewing to avoid a bitter taste.

Do not store any leftover SOVALDI mixture (oral pellets mixed with food) for use at a later time. Throw away any unused portion.

…

How should I store SOVALDI?

• Store SOVALDI tablets or pellets below 86°F (30°C).

• Keep SOVALDI tablets in the original container.

• Do not use SOVALDI tablets if the seal over the bottle opening is broken or missing.

• Do not use SOVALDI pellets if the carton tamper-evident seal, or the pellets packet seal, is broken or damaged.

Keep SOVALDI and all medicines out of the reach of children.

10/23/2018 (SUPPL-13)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Newly added information:

Skin and Subcutaneous Tissue Disorders

Skin rashes, sometimes with blisters or angioedema-like swelling

Angioedema

11/09/2017 (SUPPL-12)

Approved Drug Label (PDF)

7 Drug Interactions

7.1 Potentially Significant Drug Interactions

(additions underlined)

…

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

…

04/07/2017 (SUPPL-6)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Serious Symptomatic Bradycardia When Coadministered with Amiodarone

(Additions and/or revisions are underlined)

Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with a sofosbuvir- containing regimen. A fatal cardiac arrest was reported in a patient taking amiodarone who was coadministered a sofosbuvir-containing regimen (HARVONI [ledipasvir/sofosbuvir]).

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

Adverse Reactions in Adult Subjects

The safety assessment of SOVALDI was based on pooled Phase 3 clinical trial data

(both controlled and uncontrolled) including:…

Adverse events observed in at least 15% of subjects in the Phase 3 clinical trials outlined above are provided in Table 4…

Table 4 Adverse Events (All Grades and without Regard to Causality) Reported in Greater than or Equal to 15% of Subjects with HCV in Any Treatment Arm

With the exception of anemia and neutropenia, the majority of events presented in Table 4 occurred at severity of grade 1 in SOVALDI-containing regimens.

 

Changes in selected hematological parameters are described in Table 5…

Table 5 Percentage of Subjects Reporting Selected Hematological Parameters

 

Adverse Reactions in Pediatric Subjects 12 Years of Age and Older

The safety assessment of SOVALDI in pediatric subjects 12 years of age and older is based on data from 50 subjects who were treated with SOVALDI plus ribavirin for 12 weeks (genotype 2 subjects) or 24 weeks (genotype 3 subjects) in a Phase 2, open- label clinical trial. The adverse reactions observed were consistent with those observed in clinical studies of SOVALDI plus ribavirin in adults.

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

Cardiac Disorders

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

7 Drug Interactions

7.1 Potentially Significant Drug Interactions

(Additions and/or revisions are underlined)

Information on potential drug interactions with SOVALDI is summarized in Table 6. The table is not all-inclusive

Table 6 Potentially Significant Drug Interactions: Alteration in Dosage or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction (superscript a)

(Table has been revised; please refer to label)

7.2 Drugs without Clinically Significant Interactions with SOVALDI

(Additions and/or revisions are underlined)

In addition to the drugs included in Table 6, the interaction between SOVALDI and the following drugs was evaluated in clinical trials and no dose adjustment is needed for either drug:…

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

Risk Summary

If SOVALDI is administered with ribavirin or peginterferon alfa and ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to the ribavirin and/or peginterferon alfa prescribing information for more information on ribavirin- and peginterferon alfa-associated risks of use during pregnancy.

No adequate human data are available to establish whether or not SOVALDI poses a risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with sofosbuvir 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) to the predominant circulating metabolite of sofosbuvir (GS-331007) were ?5 (rats) and 12 (rabbits) times the exposure in humans at the RHD. In the rat pre/postnatal development study, maternal systemic exposure (AUC) to GS-331007 was ?6 times 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.

Data

Animal Data

Sofosbuvir was administered orally to pregnant rats (up to 500 mg/kg/day) and rabbits (up to 300 mg/kg/day) on gestation days 6 to 18 and 6 to 19, respectively, and also to rats (oral doses up to 500 mg/kg/day) on gestation day 6 to lactation/post-partum day 20. No significant effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at the highest doses tested. Systemic exposures (AUC) to the predominant circulating metabolite of sofosbuvir (GS-331007) were ?5 (rats) and 12 (rabbits) times the exposure in humans at the RHD, with exposures increasing during gestation from approximately 5 to 10 (rats) and 12 to 28 (rabbits) times the exposure in humans at the RHD.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

Risk Summary

It is not known whether sofosbuvir or its metabolites are present in human breast milk, affect human milk production or have effects on the breastfed infant. The predominant circulating metabolite of sofosbuvir (GS-331007) was the primary component observed in the milk of lactating rats, without effect on nursing pups.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SOVALDI and any potential adverse effects on the breastfed child from SOVALDI or from the underlying maternal condition.

If SOVALDI is administered with ribavirin, the nursing mother’s information for ribavirin also applies to this combination regimen. Refer to the ribavirin prescribing information for more information on use during lactation.

 

Data

Animal Data

No effects of sofosbuvir on growth and postnatal development were observed in nursing pups at the highest dose tested in rats. Maternal systemic exposure (AUC) to the predominant circulating metabolite of sofosbuvir (GS-331007) was approximately 12 times the exposure in humans at the RHD, with exposure of approximately 2% that of maternal exposure observed in nursing pups on lactation day 10. In a lactation study, sofosbuvir metabolites (primarily GS-331007) were excreted into the milk of lactating rats following administration of a single oral dose of sofosbuvir (20 mg/kg) on lactation day 2, with milk concentrations of approximately 10% that of maternal plasma concentrations observed 1 hour post-dose.

8.3 Females and Males of Reproductive Potential

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

If SOVALDI is administered with ribavirin or peginterferon and ribavirin, the information for ribavirin and peginterferon with regard to pregnancy testing, contraception, and infertility also applies to these combination regimens. Refer to ribavirin and/or peginterferon prescribing information for additional information.

8.4 Pediatric Use

(Additions and/or revisions are underlined)

The safety, pharmacokinetics, and efficacy of SOVALDI in pediatric patients 12 years of age and older or weighing at least 35 kg with genotype 2 and 3 infection have been established. SOVALDI was evaluated in an open-label clinical trial (Study 1112), which included 50 subjects (13 genotype 2; 37 genotype 3) 12 years of age and older. The safety, pharmacokinetics, and efficacy were comparable to that observed in adults.

The safety and efficacy of SOVALDI in pediatric patients 12 years of age and older or weighing at least 35 kg with compensated cirrhosis is supported by comparable sofosbuvir and GS-331007 exposures between: 1) adults and adolescents without cirrhosis and 2) adults without cirrhosis and adults with compensated cirrhosis. Thus, similar efficacy would be expected for adolescent patients with compensated cirrhosis as adults with compensated cirrhosis.

The safety and efficacy of SOVALDI have not been established in pediatric patients less than 12 years of age and weighing less than 35 kg with HCV genotype 2 or 3. The safety and efficacy of SOVALDI have not been established in pediatric patients with HCV genotype 1 or 4.

8.8 Patients with Hepatocellular Carcinoma Awaiting Liver Transplantation

(Additions and/or revisions are underlined)

SOVALDI was studied in HCV-infected adult subjects with hepatocellular carcinoma prior to undergoing liver transplantation in an open-label clinical trial evaluating the safety and efficacy of SOVALDI and ribavirin administered pre-transplant to prevent post-transplant HCV reinfection…

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

Patient Information

(Additions and/or revisions are underlined)

What is SOVALDI?

SOVALDI is a prescription medicine used with other antiviral medicines to treat adults with chronic

(lasting a long time) hepatitis C virus (HCV):

• genotype 1 or 4 infection without cirrhosis or with compensated cirrhosis in combination with peginterferon alfa and ribavirin
• genotype 2 or 3 infection without cirrhosis or with compensated cirrhosis in combination with ribavirin

SOVALDI is used to treat children 12 years of age and older or weighing at least 77 pounds (at least 35 kg) with chronic HCV genotype 2 or 3 infection without cirrhosis or with compensated cirrhosis in combination with ribavirin.

It is not known if SOVALDI is safe and effective in children under 12 years of age and weighing less than 77 pounds (less than 35 kg) with HCV genotype 2 or 3 infection, or with HCV genotype 1 or 4 infection. It is not known if SOVALDI is safe and effective in people who have had a liver transplant.

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

• are pregnant or plan to become pregnant. It is not known if SOVALDI will harm your unborn baby.
• Males and females who take SOVALDI in combination with ribavirin should also read the ribavirin Medication Guide for important pregnancy, contraception, and infertility information.

Tell your healthcare provider about all the medicines you take, including prescription and over-the- counter medicines, vitamins, and herbal supplements. SOVALDI and other medicines may affect each other. This can cause you to have too much or not enough SOVALDI or other medicines in your body. This may affect the way SOVALDI or your other medicines work, or may cause side effects.

Keep a list of your medicines to show your healthcare provider and pharmacist.

• You can ask your healthcare provider or pharmacist for a list of medicines that interact with SOVALDI.
• Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take SOVALDI with other medicines.

02/14/2017 (SUPPL-7)

Approved Drug Label (PDF)

Boxed Warning

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

(Newly added section)

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with SOVALDI. 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

(Newly added section)

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 immunosuppressant 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 SOVALDI. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with SOVALDI 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)

Patient Information SOVALDI® (soh-VAHL-dee) (sofosbuvir) tablets

(Additions and/or revisions are underlined)

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

SOVALDI can cause serious side effects, including,

Hepatitis B virus reactivation: Before starting treatment with SOVALDI, 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 SOVALDI. 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 SOVALDI.

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

SOVALDI, 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 SOVALDI? SOVALDI can cause serious side effects, including:

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

•         Slow heart rate (bradycardia). SOVALDI treatment may result in slowing of the heart rate along with other symptoms when taken with amiodarone (Cordarone®, Nexterone®, Pacerone®), a medicine used to treat certain heart problems. In some cases bradycardia has led to death or the need for a heart pacemaker when amiodarone is taken with SOVALDI. Get medical help right away if you take amiodarone with SOVALDI and get any of the following symptoms:…