Mavyret

Taking this medication will not prevent you from passing hepatitis C to other people. Do not have unprotected sex or share razors or toothbrushes. Talk with your doctor about safe ways to prevent HCV transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• carbamazepine;
• efavirenz; or
• St. John's wort.

This list is not complete. Other drugs may interact with glecaprevir and pibrentasvir, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Glecaprevir and pibrentasvir are antiviral medications that prevent hepatitis C virus (HCV) from multiplying in your body.

Glecaprevir and pibrentasvir is a combination medicine used to treat chronic hepatitis C in adults with HCV genotype 1, 2, 3, 4, 5, or 6.

Glecaprevir and pibrentasvir is sometimes given after other medicines have been tried without success.

Glecaprevir and pibrentasvir may also be used for purposes not listed in this medication guide.

Glecaprevir and pibrentasvir has the following uses:

The fixed combination of glecaprevir and pibrentasvir is indicated for the treatment of patients with chronic HCV genotype (GT) 1, 2, 3, 4, 5 or 6 infection without cirrhosis and with compensated cirrhosis (Child-Pugh A). Glecaprevir and pibrentasvir is also indicated for the treatment of adult patients with HCV genotype 1 infection, who previously have been treated with a regimen containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor, but not both. 1

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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.

• Tell all of your health care providers that you take Mavyret. This includes your doctors, nurses, pharmacists, and dentists.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• It is not known if this medicine stops the spread of diseases like hepatitis that are passed through blood or having sex. Do not have any kind of sex without using a latex or polyurethane condom. Do not share needles or other things like toothbrushes or razors. Talk with your doctor.
• This medicine may affect how much of some other drugs are in your body. If you are taking other drugs, talk with your doctor. You may need to have your blood work checked more closely while taking Mavyret with your other drugs.
• Call your doctor right away if you have 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.
• Drugs that contain ethinyl estradiol, like certain birth control pills, must not be used with this medicine. If you use birth control that contains ethinyl estradiol, you will need to use another type of birth control like condoms. Talk with the doctor.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using Mavyret (glecaprevir and pibrentasvir) while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

Each Mavyret tablet contains 100 mg of glecaprevir and 40 mg of pibrentasvir. The tablets are pink, oblong-shaped, film-coated, and debossed with “NXT” on one side.

Mavyret is contraindicated in patients with severe hepatic impairment (Child-Pugh C) [see Dosage and Administration (2.3), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

Mavyret is contraindicated with atazanavir or rifampin [see Drug Interaction (7.3) and Clinical Pharmacology (12.3)].

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of Mavyret cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Overall Adverse Reactions in HCV-Infected Adults Without Cirrhosis or With Compensated Cirrhosis (Child-Pugh A)

The adverse reactions data for Mavyret in subjects without cirrhosis or with compensated cirrhosis (Child-Pugh A) were derived from nine Phase 2 and 3 trials which evaluated approximately 2,300 subjects infected with genotype 1, 2, 3, 4, 5, or 6 HCV who received Mavyret for 8, 12 or 16 weeks [see Clinical Studies (14)].

The overall proportion of subjects who permanently discontinued treatment due to adverse reactions was 0.1% for subjects who received Mavyret for 8, 12 or 16 weeks.

The most common adverse reactions, all grades, observed in greater than or equal to 5% of subjects receiving 8, 12, or 16 weeks of treatment with Mavyret were headache (13%), fatigue (11%), and nausea (8%). In subjects receiving Mavyret who experienced adverse reactions, 80% had an adverse reaction of mild severity (Grade 1). One subject experienced a serious adverse reaction.

Adverse reactions (type and severity) were similar for subjects receiving Mavyret for 8, 12 or 16 weeks. The type and severity of adverse reactions in subjects with compensated cirrhosis (Child-Pugh A) were comparable to those seen in subjects without cirrhosis.

Adverse Reactions in HCV-Infected Adults treated with Mavyret in Controlled Trials

ENDURANCE-2

Among 302 treatment-naïve or PRS treatment-experienced, HCV genotype 2 infected adults enrolled in ENDURANCE-2, adverse reactions (all intensity) occurring in at least 5% of subjects treated with Mavyret for 12 weeks are presented in Table 3. In subjects treated with Mavyret for 12 weeks, 32% reported an adverse reaction, of which 98% had adverse reactions of mild or moderate severity. No subjects treated with Mavyret or placebo in ENDURANCE-2 permanently discontinued treatment due to an adverse drug reaction.

ENDURANCE-3

Among 505 treatment-naïve, HCV genotype 3 infected adults without cirrhosis enrolled in ENDURANCE-3, adverse reactions (all intensity) occurring in at least 5% of subjects treated with Mavyret for 8 or 12 weeks are presented in Table 4. In subjects treated with Mavyret, 45% reported an adverse reaction, of which 99% had adverse reactions of mild or moderate severity. The proportion of subjects who permanently discontinued treatment due to adverse reactions was 0%, < 1% and 1% for the Mavyret 8 week arm, Mavyret 12 week arm and DCV + SOF arm, respectively.

Adverse Reactions in HCV-Infected Adults with Severe Renal Impairment Including Subjects on Dialysis

The safety of Mavyret in subjects with chronic kidney disease (Stage 4 or Stage 5 including subjects on dialysis) with genotypes 1, 2, 3, 4, 5 or 6 chronic HCV infection without cirrhosis or with compensated cirrhosis (Child-Pugh A) was assessed in 104 subjects (EXPEDITION-4) who received Mavyret for 12 weeks. The most common adverse reactions observed in greater than or equal to 5% of subjects receiving 12 weeks of treatment with Mavyret were pruritus (17%), fatigue (12%), nausea (9%), asthenia (7%), and headache (6%). In subjects treated with Mavyret who reported an adverse reaction, 90% had adverse reactions of mild or moderate severity (Grade 1 or 2). The proportion of subjects who permanently discontinued treatment due to adverse reactions was 2%.

Laboratory Abnormalities

Serum bilirubin elevations

Elevations of total bilirubin at least 2 times the upper limit of normal occurred in 3.5% of subjects treated with Mavyret versus 0% in placebo; these elevations were observed in 1.2% of subjects across the Phase 2 and 3 trials. Mavyret inhibits OATP1B1/3 and is a weak inhibitor of UGT1A1 and may have the potential to impact bilirubin transport and metabolism, including direct and indirect bilirubin. No subjects experienced jaundice and total bilirubin levels decreased after completing Mavyret.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis

Glecaprevir and pibrentasvir were not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo rodent micronucleus assays.

Carcinogenicity studies with glecaprevir and pibrentasvir have not been conducted.

Impairment of Fertility

No effects on mating, female or male fertility, or early embryonic development were observed in rodents at up to the highest dose tested. Systemic exposures (AUC) to glecaprevir and pibrentasvir were approximately 63 and 102 times higher, respectively, than the exposure in humans at the recommended dose.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• carbamazepine;

• efavirenz; or

• St. John's wort.

This list is not complete. Other drugs may interact with glecaprevir and pibrentasvir, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Applies to glecaprevir / pibrentasvir: oral tablet

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.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of glecaprevir and pibrentasvir combination in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of glecaprevir and pibrentasvir combination in the elderly.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Atazanavir
• Rifampin

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Atorvastatin
• Carbamazepine
• Cyclosporine
• Dabigatran Etexilate
• Darunavir
• Efavirenz
• Ethinyl Estradiol
• Lopinavir
• Lovastatin
• Ritonavir
• Simvastatin
• St John's Wort

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Digoxin
• Pravastatin
• Rosuvastatin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Hepatitis B infection, history of—Use with caution. May cause this condition to become active again.

• Liver disease, severe—Should not be used in patients with this condition.

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.

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
• itching skin
• lack or loss of strength
• nausea
• unusual tiredness or weakness

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.