Sofosbuvir, Velpatasvir, and Voxilaprevir

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom).

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

This medicine is usually taken once per day for 12 weeks. Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Take this medicine with food, at the same time each day.

You will need frequent blood tests to check your liver function.

Hepatitis C is often treated with a combination of drugs. Use all medications as directed by your doctor. Read all patient information, medication guides, and instruction sheets provided to you. Do not change your doses or medication schedule without your doctor's advice. Every person with chronic hepatitis C should remain under the care of a doctor.

You should not stop using this medicine suddenly. Stopping suddenly could make your condition harder to treat with hepatitis C antiviral medicine.

If you have ever had hepatitis B, this medicine can cause the condition to come back or get worse. You will need liver function tests during treatment and for several months after you stop using sofosbuvir, velpatasvir, and voxilaprevir.

Store this medicine in the original container at room temperature away from moisture and heat.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have new or worsening symptoms such as:

• loss of appetite, upper stomach pain;

• dark urine, clay-colored stools; or

• jaundice (yellowing of the skin or eyes).

If you also take amiodarone: Seek medical help right away if you feel weak, tired, or light-headed, or if you have chest pain, shortness of breath, confusion, or memory problems.

Common side effects may include:

• headache;

• feeling tired; or

• nausea, diarrhea.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Take sofosbuvir, velpatasvir, and voxilaprevir exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

sofosbuvir, velpatasvir, and voxilaprevir should come with a patient information leaflet. Read and follow these instructions carefully. Ask your doctor if you have any questions.

Keep using sofosbuvir, velpatasvir, and voxilaprevir for the full time of treatment, even if you begin to feel better after a few days. Also, it is important to keep the amount of medicine in your body at a steady level. To help keep the amount constant, sofosbuvir, velpatasvir, and voxilaprevir must be used on a regular schedule.

Take sofosbuvir, velpatasvir, and voxilaprevir with food.

If you are taking an antacid containing aluminum or magnesium, take it 4 hours before or after you take sofosbuvir, velpatasvir, and voxilaprevir.

Dosing

The dose of sofosbuvir, velpatasvir, and voxilaprevir will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of sofosbuvir, velpatasvir, and voxilaprevir. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For hepatitis C virus infection that has been previously treated with other medicines:
    • Adults—One tablet (400 milligrams [mg] sofosbuvir, 100 mg velpatasvir, 100 mg voxilaprevir) once a day for 12 weeks.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of sofosbuvir, velpatasvir, and voxilaprevir, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep sofosbuvir, velpatasvir, and voxilaprevir in its original container.

It is very important that your doctor check your progress at regular visits to make sure that sofosbuvir, velpatasvir, and voxilaprevir is working properly. Blood tests may be needed to check for unwanted effects.

Do not take sofosbuvir, velpatasvir, and voxilaprevir together with products containing rifampin (eg, Rifadin®, Rifamate®, Rifater®, Rimactane®).

If you have ever had a hepatitis B infection, the virus could become active again during treatment with sofosbuvir, velpatasvir, and voxilaprevir combination. You should be tested for hepatitis B infection before starting treatment with sofosbuvir, velpatasvir, and voxilaprevir. Talk with your doctor if you have concerns.

Amiodarone can cause serious side effects (including cardiac arrest, slow heartbeat, or conditions that need a pacemaker) if used together with sofosbuvir, velpatasvir, and voxilaprevir or other medicines containing sofosbuvir, or if you have used it recently. This is more likely to occur in patients with heart disease or advanced liver disease. Tell your doctor if you are taking amiodarone before using sofosbuvir, velpatasvir, and voxilaprevir.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal (eg, St. John's wort) or vitamin supplements.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Chest pain or discomfort
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• lightheadedness, dizziness, or fainting
• skin rash, sometimes with blisters or hive-like swelling
• slow or irregular heartbeat
• unusual tiredness or weakness

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Diarrhea
• headache
• lack or loss of strength
• nausea

• Discouragement
• feeling sad or empty
• irritability
• lack of appetite
• loss of interest or pleasure
• tiredness
• trouble concentrating
• trouble sleeping

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Use sofosbuvir, velpatasvir, and voxilaprevir as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take this medicine with food.
• Do not take antacids within 4 hours of sofosbuvir, velpatasvir, and voxilaprevir.
• If you take cimetidine, dexlansoprazole, esomeprazole, famotidine, lansoprazole, nizatidine, omeprazole, pantoprazole, rabeprazole, or ranitidine, ask your doctor or pharmacist how to take it with this medicine.
• Keep taking sofosbuvir, velpatasvir, and voxilaprevir as you have been told by your doctor or other health care provider, even if you feel well.
• It is important that you do not miss or skip a dose of this medicine during treatment.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.
• If you are not sure what to do if you miss a dose, call your doctor.

• Store in the original container at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

• Antihepaciviral, NS5A Inhibitor
• Antihepaciviral, Polymerase Inhibitor (Anti-HCV)
• NS3/4A Inhibitor
• NS5A Inhibitor
• NS5B RNA Polymerase Inhibitor

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Amiodarone: Sofosbuvir may enhance the bradycardic effect of Amiodarone. Avoid combination

Antacids: May decrease the serum concentration of Velpatasvir. Management: Separate administration of velpatasvir and antacids by at least 4 hours. Consider therapy modification

Asunaprevir: OATP1B1/SLCO1B1 Inhibitors may increase the serum concentration of Asunaprevir. Avoid combination

Atazanavir: May increase the serum concentration of Voxilaprevir. Avoid combination

BCRP/ABCG2 Substrates: Voxilaprevir may increase the serum concentration of BCRP/ABCG2 Substrates. Avoid combination

Betrixaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease the betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-glycoprotein inhibitor. Consider therapy modification

Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Management: Consider alternatives when possible; bilastine should be avoided in patients with moderate to severe renal insufficiency who are receiving p-glycoprotein inhibitors. Consider therapy modification

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

CarBAMazepine: May decrease the serum concentration of Sofosbuvir. Avoid combination

Celiprolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. Monitor therapy

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Consider therapy modification

CYP2B6 Inducers (Moderate): May decrease the serum concentration of Velpatasvir. Avoid combination

CYP2C8 Inducers (Strong): May decrease the serum concentration of Velpatasvir. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Velpatasvir. Avoid combination

CYP3A4 Inducers (Strong): May decrease the serum concentration of Velpatasvir. Avoid combination

CYP3A4 Inducers (Strong): May decrease the serum concentration of Voxilaprevir. Avoid combination

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Digoxin: Velpatasvir may increase the serum concentration of Digoxin. Monitor therapy

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

Grazoprevir: OATP1B1/SLCO1B1 Inhibitors may increase the serum concentration of Grazoprevir. Avoid combination

H2-Antagonists: May decrease the serum concentration of Velpatasvir. Monitor therapy

HMG-CoA Reductase Inhibitors: Voxilaprevir may increase the serum concentration of HMG-CoA Reductase Inhibitors. Management: Use the lowest statin dose possible if combined with voxilaprevir and monitor patients for increased statin effects/toxicities. Avoid concomitant use of voxilaprevir with rosuvastatin or pitavastatin, and limit pravastatin doses to 40 mg daily. Consider therapy modification

Lopinavir: May increase the serum concentration of Voxilaprevir. Avoid combination

Modafinil: May decrease the serum concentration of Sofosbuvir. Avoid combination

Naldemedine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine. Monitor therapy

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy

Nilotinib: May decrease the serum concentration of CYP2B6 Substrates. Monitor therapy

OATP1B1/SLCO1B1 Inhibitors: May increase the serum concentration of Voxilaprevir. Avoid combination

OXcarbazepine: May decrease the serum concentration of Sofosbuvir. Avoid combination

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

PAZOPanib: BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of Sofosbuvir. Avoid combination

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of Velpatasvir. Avoid combination

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

PHENobarbital: May decrease the serum concentration of Sofosbuvir. Avoid combination

Pitavastatin: Voxilaprevir may increase the serum concentration of Pitavastatin. Avoid combination

Primidone: May decrease the serum concentration of Sofosbuvir. Avoid combination

Proton Pump Inhibitors: May decrease the serum concentration of Velpatasvir. Avoid combination

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Monitor therapy

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Rifabutin: May decrease the serum concentration of Sofosbuvir. Avoid combination

RifAMPin: May increase the serum concentration of Voxilaprevir. Specifically, a single dose of rifampin may increase voxilaprevir concentrations, while chronic daily use of rifampin may decrease voxilaprevir concentrations. RifAMPin may decrease the serum concentration of Voxilaprevir. Avoid combination

Rifapentine: May decrease the serum concentration of Sofosbuvir. Avoid combination

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy

Ritonavir: May decrease the serum concentration of Velpatasvir. Ritonavir may increase the serum concentration of Velpatasvir. Consider therapy modification

Rosuvastatin: Voxilaprevir may increase the serum concentration of Rosuvastatin. Avoid combination

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tenofovir Disoproxil Fumarate: Velpatasvir may increase the serum concentration of Tenofovir Disoproxil Fumarate. Monitor therapy

Tipranavir: May decrease the serum concentration of Sofosbuvir. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Topotecan: Velpatasvir may increase the serum concentration of Topotecan. Avoid combination

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Vitamin K Antagonists (eg, warfarin): Antihepaciviral NS5B RNA Polymerase Inhibitors may diminish the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Voxilaprevir: OATP1B1/SLCO1B1 Inhibitors may increase the serum concentration of Voxilaprevir. Avoid combination

Also see Sofosbuvir monograph.

>10%:

Central nervous system: Headache (21% to 23%), fatigue (17% to 19%)

Gastrointestinal: Diarrhea (13% to 14%), nausea (10% to 13%)

Hepatic: Increased serum bilirubin (4% to 13%)

1% to 10%:

Central nervous system: Insomnia (3% to 6%), depression (≤1%)

Dermatologic: Skin rash (2%)

Gastrointestinal: Increased serum lipase (2%)

Neuromuscular & skeletal: Weakness (4% to 6%)

<1%, postmarketing, and/or case reports: Increased creatine phosphokinase

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Feeling tired or weak.
• Headache.
• Loose stools (diarrhea).
• Upset stomach.
• Not able to sleep.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.