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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
MAVYRET (NDA-209394)
(GLECAPREVIR; PIBRENTASVIR)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
06/10/2025 (SUPPL-19)
6 Adverse Reactions
6.1 Clinical Trials Experience
Additions and/or revisions underlined:
. . .
Overall Adverse Reactions in Subjects with Chronic HCV Infection without Cirrhosis or with Compensated Cirrhosis (Child-Pugh A)
. . .
Adverse Reactions in Subjects with Chronic HCV Infection without Cirrhosis
. . .
Adverse Reactions in Subjects with Chronic HCV Infection with Compensated Cirrhosis (Child- Pugh A)
. . .
Adverse Reactions in Subjects with Chronic HCV Infection with Severe Renal Impairment Including Those on Dialysis
. . .
Adverse Reactions in Subjects with Chronic HCV Infection Co-Infected with HIV-1
. . .
Adverse Reactions in Subjects with Chronic HCV Infection with Liver or Kidney Transplant
. . .
Adverse Reactions in People Who Inject Drugs (PWID) and those on Medication-Assisted Treatment (MAT) for Opioid Use Disorder with Chronic HCV Infection
PWID
The safety of MAVYRET in PWID with chronic HCV GT 1, 2, 3, 4, 5, or 6 infection is based on data from adults and adolescents in Phase 2 and 3 trials in which 62 subjects identified as current/recent PWID (defined as self-reported injection drug use within the last 12 months prior to starting MAVYRET) and 3,282 subjects reported no injection drug use (non-PWID).
. . .
MAT
The safety of MAVYRET in subjects with chronic HCV GT 1, 2, 3, 4, 5, or 6 infection reporting concomitant use of MAT for opioid use disorder is based on data from adults and adolescents in Phase 2 and 3 trials in which 225 subjects reported concomitant use of MAT and 4,098 subjects reported no concomitant use of MAT.
Among subjects on MAT, adverse reactions observed in greater than or equal to 5% were headache (15%), fatigue (12%), nausea (11%), and diarrhea (6%).
. . .
Adverse Reactions in Subjects with Acute HCV Infection
The safety of MAVYRET in subjects with acute HCV GT 1, 2, 3, or 4 infection was assessed in 286 adults who received MAVYRET for 8 weeks. Among these subjects, 142 had HIV-1 co- infection, 41 identified as current/recent PWID, and 21 reported concomitant use of MAT. At baseline, 49% of subjects had ALT elevations greater than 3 x upper limit of normal (ULN), 13% had ALT elevations greater than 10 x ULN, and 12% had total bilirubin elevations greater than ULN. The overall safety profile in these subjects was similar to that observed in subjects with chronic HCV infection. Serious adverse reactions and/or adverse reactions leading to treatment discontinuation were not observed among subjects with acute HCV infection.
The most commonly reported adverse reactions were fatigue (3%), asthenia (2%), headache (2%) and diarrhea (2%) [see Use in Specific Populations (8.4), Use in Specific Populations (8.5) Clinical Studies (14.11)].
Adverse Reactions in Pediatric Subjects 3 Years and Older with Chronic HCV Infection
. . .
Laboratory Abnormalities
Serum bilirubin elevations in subjects with chronic HCV infection
. . .
Liver tests in subjects with acute HCV infection
Elevations of total bilirubin at least 2 times ULN occurred in 2.8% of subjects treated with MAVYRET. Subjects with total bilirubin elevations did not have concurrent increases in ALT or AST, or signs of liver decompensation or failure, and these laboratory events did not lead to treatment discontinuation. All subjects with baseline ALT greater than 3 × ULN improved from baseline by the final treatment visit.
8 Use in Specific Populations
8.4 Pediatric Use
Additions and/or revisions underlined:
. . .
The safety, efficacy, and pharmacokinetics of MAVYRET in HCV GT1, 2, 3, or 4 infected pediatric patients 3 years and older is based on data from an open-label trial in 127 subjects with chronic HCV infection, without cirrhosis, and aged 3 years to less than 18 years who were either treatment-naïve (n=114) or treatment-experienced (n=13) and received MAVYRET for 8, 12 or 16 weeks (DORA-Part 1 and Part 2). The adverse reactions observed in subjects 3 years to less than 18 years of age were consistent with those observed in clinical trials of MAVYRET in adults with chronic HCV infection with the exception of vomiting, rash and abdominal pain upper which were observed more frequently in pediatric subjects less than 12 years of age compared to adults [see Adverse Reactions (6.1)].
. . .
Use of MAVYRET in pediatric patients with acute HCV infection is supported by extrapolation of safety and efficacy data from adult patients with acute HCV infection and adult and pediatric patients with chronic HCV infection. It is expected that adult and pediatric patients with acute HCV infection have similar disease response to treatment. No clinically meaningful differences in MAVYRET exposures are expected among pediatric patients with acute HCV infection and pediatric patients with chronic HCV infection [see Clinical Pharmacology (12.3)].
. . .
8.4 Geriatric Use
Additions and/or revisions underlined:
In clinical trials of MAVYRET in subjects with chronic HCV infection, 328 subjects were age 65 years and over (14% of the total number of subjects in the Phase 2 and 3 clinical trials), and 47 (2%) subjects were age 75 and over. In a clinical trial of MAVYRET in subjects with acute HCV infection, 16 subjects were age 65 years and over (6%), and 1 (0.3%) subject was age 75 and over.
. . .
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION
Additions and/or revisions underlined:
. . .
MAVYRET is a prescription medicine used to treat adults and children 3 years of age and older with:
acute (recently infected) or chronic (lasting a long time) hepatitis C virus (HCV) genotypes 1, 2, 3, 4, 5 or 6 infection without cirrhosis or with compensated cirrhosis.
. . .
Swallow the food and oral pellets mixture within 15 minutes of preparation. Do not crush or chew the oral pellets.
10/25/2023 (SUPPL-16)
7 Drug Interactions
7.3 Established and Other Potential Drug Interactions
Changes to table 6; please refer to label for complete information
7.5 Drugs with No Observed Clinically Significant Interactions with MAVYRET
Additions and/or revisions underlined:
No dose adjustment is required when MAVYRET is coadministered with the following medications: abacavir, amlodipine, caffeine, dextromethorphan, dolutegravir, elvitegravir/cobicistat, emtricitabine, ethinyl estradiol of 20 mcg or less, felodipine, lamivudine, lamotrigine, losartan, midazolam, norethindrone or other progestin-only contraceptives, omeprazole, raltegravir, rilpivirine, sofosbuvir, tacrolimus, tenofovir alafenamide, tenofovir disoproxil fumarate, tolbutamide, and valsartan.
06/10/2021 (SUPPL-13)
6 Adverse Reactions
6.1 Clinical Trials Experience(Extensive changes; please refer to label)
7 Drug Interactions
7.3 Established and Other Potential Drug interactions(Additions and/or revisions 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 CYP 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 6 provides the effect of MAVYRET on concentrations of coadministered drugs and the effect of coadministered drugs on glecaprevir and pibrentasvir [see Contraindications (4), Warnings and Precautions (5.3), and Clinical Pharmacology (12.3)]. All interaction studies were performed in adults.
Table 6. Potentially Significant Drug Interactions Identified in Drug Interaction Studies
…
8 Use in Specific Populations
8.4 Pediatric Use(Additions and/or revisions underlined)
No dosage adjustment of MAVYRET is required in pediatric patients 12 years and older or weighing at least 45 kg. The recommended dosage of MAVYRET in pediatric patients 3 to less than 12 years of age is based on weight [see Dosage and Administration (2.2, 2.4), Clinical Pharmacology (12.3) and Clinical Studies (14.10)].
The safety, efficacy, and pharmacokinetics of MAVYRET in HCV GT1, 2, 3, or 4 infected pediatric patients 3 years and older is based on data from an open-label trial in 127 subjects without cirrhosis aged 3 years to less than 18 years who were either treatment-naïve (n=114) or treatment-experienced (n=13) and received MAVYRET for 8, 12 or 16 weeks (DORA-Part 1 and Part 2). The adverse reactions observed in subjects 3 years to less than 18 years of age were consistent with those observed in clinical trials of MAVYRET in adults with the exception of vomiting, rash and abdominal pain upper which were observed more frequently in pediatric subjects less than 12 years of age compared to adults [see Adverse Reactions (6.1)].
The efficacy results observed in this trial were consistent with those observed in clinical trials of MAVYRET in adults [see Clinical Studies (14.10)].
In pediatric patients with cirrhosis, history of a kidney and/or liver transplant, or HCV GT5 or 6 infection, the safety and efficacy of MAVYRET are supported by the comparable glecaprevir and pibrentasvir exposures observed between pediatric subjects and adults [see Clinical Pharmacology (12.3)].
The safety and effectiveness of MAVYRET in children less than 3 years of age have not been studied.
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).
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 hepatitis B virus infection [see Warnings and Precautions (5.1)].
Risk of Hepatic Decompensation/Failure in Patients with Evidence of Advanced Liver Disease
Advise patients to seek medical evaluation immediately for symptoms of worsening liver problems such as nausea, tiredness, yellowing of the skin or white part of the eyes, bleeding or bruising more easily than normal, confusion, loss of appetite, diarrhea, dark or brown urine, dark or bloody stool, swelling of the stomach area (abdomen) or pain in the upper right side of the stomach area, sleepiness, or vomiting of blood [see Warnings and Precautions (5.2)].
Drug Interactions
Inform patients that MAVYRET may interact with some drugs; therefore, patients should be advised to report to their healthcare provider the use of any prescription, non-prescription medication or herbal products [see Contraindications (4), Warnings and Precautions (5.3) and Drug Interactions (7)].
Administration
For MAVYRET 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)].
Inform patients it is important to take all three tablets at the same time once daily with food as directed. Inform patients that it is important not to miss or skip doses and to take MAVYRET for the duration that is recommended by the physician [see Dosage and Administration (2.2)].
If a dose is missed and it is:
Less than 18 hours from the usual time that MAVYRET should have been taken – advise the patient to take the dose as soon as possible and then to take the next dose at the usual time.
More than 18 hours from the usual time that MAVYRET should have been taken – advise the patient not to take the missed dose and to take the next dose at the usual time.
(Extensive changes; please refer to label)
04/10/2020 (SUPPL-10)
6 Adverse Reactions
(Newly added information)
Adverse Reactions in People Who Inject Drugs (PWID) and those on Medication-Assisted Treatment (MAT) for Opioid Use Disorder
The safety of MAVYRET in PWID with HCV GT 1, 2, 3, 4, 5, or 6 infection is based on data from Phase 2 and 3 trials in which 62 subjects identified as current/recent PWID (defined as self- reported injection drug use within the last 12 months prior to starting MAVYRET) and 3,282 subjects reported no injection drug use (non-PWID).
Among current/recent PWID, adverse reactions observed in greater than or equal to 5% of subjects were fatigue (16%), headache (13%), diarrhea (6%), and nausea (6%). Among non- PWID subjects, adverse reactions observed in greater than or equal to 5% were headache (7%) and fatigue (6%). Serious adverse reactions and/or adverse reactions leading to treatment discontinuation occurred in one current/recent PWID subject (2%) compared to less than 1% in non-PWID subjects [see Use in Specific Populations (8.8) and Clinical Studies (14.9)].
Among 225 subjects reporting concomitant use of MAT for opioid use disorder, adverse reactions observed in greater than or equal to 5% were headache (15%), fatigue (12%), nausea (11%), and diarrhea (6%). Among 4,098 subjects who were not on MAT, adverse reactions observed in greater than or equal to 5% were headache (9%), fatigue (8%), and nausea (5%). Serious adverse reactions and/or adverse reactions leading to treatment discontinuation were not observed among subjects on MAT and were experienced by less than 1% of subjects not on MAT [see Use in Specific Populations (8.8) and Clinical Studies (14.9)].
8 Use in Specific Populations
People Who Inject Drugs (PWID) and those on Medication-Assisted Treatment (MAT) for Opioid Use Disorder(Newly added subsection)
No dosage adjustment of MAVYRET is required in PWID or those who are on MAT for opioid use disorder. In clinical trials of MAVYRET, the safety and efficacy were similar between subjects who self-identified as current/recent PWID, those who were former PWID, and those who did not report history of injection drug use. The safety and efficacy of MAVYRET were also similar between subjects who reported concomitant MAT for opioid use disorder and those who did not report concomitant MAT [see Adverse Reactions (6.1), Drug Interactions (7.4) and Clinical Studies (14.9)].
09/26/2019 (SUPPL-7)
4 Contraindications
(additions and/or revisions are underlined)
MAVYRET is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh B or C) or those with any history of prior hepatic decompensation.
MAVYRET is contraindicated with atazanavir or rifampin.
5 Warnings and Precautions
5.2 Risk of Hepatic Decompensation/Failure in Patients with Evidence of Advanced Liver Disease(newly added subsection)
The majority of patients with severe outcomes had evidence of advanced liver disease with moderate or severe hepatic impairment (Child-Pugh B or C) prior to initiating therapy with MAVYRET, including some patients reported as having compensated cirrhosis with mild liver impairment (Child-Pugh A) at baseline but with a prior decompensation event (i.e., prior history of ascites, variceal bleeding, encephalopathy). Rare cases of hepatic decompensation/failure were reported in patients without cirrhosis or with compensated cirrhosis (Child-Pugh A); many of these patients had evidence of portal hypertension. Events also occurred in patients taking a concomitant medication not recommended for coadministration, or in patients with confounding factors such as serious liver-related medical or surgical comorbidities. Cases typically occurred within the first 4 weeks of treatment (median of 27 days).
In patients with compensated cirrhosis (Child Pugh A) or evidence of advanced liver disease such as portal hypertension, perform hepatic laboratory testing as clinically indicated; and monitor for signs and symptoms of hepatic decompensation such as the presence of jaundice, ascites, hepatic encephalopathy, and variceal hemorrhage. Discontinue MAVYRET in patients who develop evidence of hepatic decompensation/failure.
MAVYRET is contraindicated in patients with moderate to severe hepatic impairment (Child- Pugh B or C) or those with any history of prior hepatic decompensation.
6 Adverse Reactions
6.2 Postmarketing Experience(additions and/or revisions are underlined)
The following adverse reactions have been identified during post-approval use of MAVYRET. Because these 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.
Skin and Subcutaneous Tissue Disorders: Angioedema
Hepatobiliary Disorders: Hepatic decompensation, hepatic failure
7 Drug Interactions
7.3 Established and Other Potential Drug Interactions(additions and/or revisions are 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 CYP 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.
(newly added subsection)
No buprenorphine/naloxone or methadone dosage adjustment is required when used concomitantly with MAVYRET. There is insufficient information to make a recommendation regarding the concomitant use of naltrexone with MAVYRET.
8 Use in Specific Populations
8.7 Hepatic Impairment(additions and/or revisions are underlined)
No dosage adjustment of MAVYRET is required in patients with mild hepatic impairment (Child-Pugh A). MAVYRET has not been evaluated and is contraindicated in HCV-infected patients with moderate or severe hepatic impairment (Child-Pugh B or Child-Pugh C) or those with any history of prior hepatic decompensation. Postmarketing cases of hepatic decompensation/failure have been reported in these patients. Higher exposures of both glecaprevir and pibrentasvir occur in subjects with severe hepatic impairment (Child-Pugh C).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION(additions and/or revisions are underlined)
Advise the patient to read the FDA-approved patient labeling (Patient Information).
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 hepatitis B virus infection.
Risk of Hepatic Decompensation/Failure in Patients with Evidence of Advanced Liver Disease
Advise patients to seek medical evaluation immediately for symptoms of worsening liver problems such as nausea, tiredness, yellowing of the skin or white part of the eyes, bleeding or bruising more easily than normal, confusion, loss of appetite, diarrhea, dark or brown urine, dark or bloody stool, swelling of the stomach area (abdomen) or pain in the upper right side of the stomach area, sleepiness, or vomiting of blood.
Drug Interactions
Inform patients that MAVYRET may interact with some drugs; therefore, patients should be advised to report to their healthcare provider the use of any prescription, non-prescription medication or herbal products.
Administration
Inform patients it is important to take all three tablets at the same time once daily with food as directed. Inform patients that it is important not to miss or skip doses and to take MAVYRET for the duration that is recommended by the physician.
If a dose is missed and it is:
Less than 18 hours from the usual time that MAVYRET should have been taken – advise the patient to take the dose as soon as possible and then to take the next dose at the usual time.
More than 18 hours from the usual time that MAVYRET should have been taken – advise the patient not to take the missed dose and to take the next dose at the usual time.
09/26/2019 (SUPPL-8)
6 Adverse Reactions
6.1 Clinical Trials Experience(additions and/or revisions are underlined)
...
Adverse Reactions in Subjects with Compensated Cirrhosis (Child-Pugh A)
The safety of MAVYRET in HCV GT 1, 2, 3, 4, 5, or 6 adults with compensated cirrhosis is based on data from 288 subjects from the Phase 2/3 registrational trials treated with MAVYRET for 12 or more weeks and 343 subjects from EXPEDITION-8 treated with MAVYRET for 8 weeks. The adverse reactions observed were generally consistent with those observed in clinical studies of MAVYRET in non-cirrhotic subjects.
In the Phase 2/3 registrational trials, the adverse reactions reported in greater than or equal to 5% of compensated cirrhotic subjects (n=288) treated across all durations of MAVYRET were fatigue (15%), headache (14%), nausea (8%), diarrhea (6%), and pruritus (6%). In EXPEDITION-8, the adverse reactions reported in greater than or equal to 5% of compensated cirrhotic subjects (n=343) were fatigue (8%), pruritus (7%), and headache (6%). No subjects with compensated cirrhosis in the Phase 2/3 registrational trials (without severe renal impairment) or in EXPEDITION-8 discontinued treatment with MAVYRET due to an adverse reaction.
…
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.
In subjects with compensated cirrhosis (Child-Pugh A), 17% experienced early, transient post- baseline elevations of bilirubin above the upper limit of normal. These bilirubin elevations were typically less than two times the upper limit of normal, generally occurred within the first 2 weeks of treatment and resolved with continued treatment. The subjects with compensated cirrhosis and bilirubin elevations did not have concurrent increases in ALT or AST, or signs of liver decompensation or failure, and these laboratory events did not lead to treatment discontinuation. 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. Few subjects experienced jaundice or ocular icterus and total bilirubin levels decreased after completing MAVYRET.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION(extensive revisions; please refer to labeling for complete information)
04/30/2019 (SUPPL-6)
6 Adverse Reactions
6.1 Clinical Trials Experience(additions underlined)
…
Adverse Reactions in Adolescent Subjects
The safety of MAVYRET in HCV GT1, 2, 3, or 4 infected adolescents is based on data from a Phase 2/3 open-label trial in 47 subjects aged 12 years to less than 18 years without cirrhosis treated with MAVYRET for 8 or 16 weeks (DORA-Part 1). The adverse reactions observed were consistent with those observed in clinical studies of MAVYRET in adults. The only adverse drug reaction observed in greater than or equal to 5% of subjects receiving MAVYRET was fatigue (6%). No subjects discontinued or interrupted treatment with MAVYRET due to an adverse reaction.
…
8 Use in Specific Populations
8.4 Pediatric Use(additions and revisions underlined)
No dosage adjustment of MAVYRET is required in pediatric patients 12 years and older or weighing at least 45 kg.
The safety, efficacy, and pharmacokinetics of MAVYRET in HCV GT1, 2, 3, or 4 infected pediatric patients 12 years and older or weighing at least 45 kg is based on data from an open- label trial in 47 subjects without cirrhosis aged 12-18 years who were either treatment naïve (n=36) or treatment experienced (n=11) and received MAVYRET for 8 or 16 weeks (DORA- Part 1). The safety and efficacy results observed in this trial were consistent with those observed in clinical studies of MAVYRET in adults.
In pediatric patients with cirrhosis, history of a kidney and/or liver transplant, or HCV GT5 or 6 infection, the safety and efficacy of MAVYRET are supported by the comparable glecaprevir and pibrentasvir exposures observed between adolescents and adults .
The safety and effectiveness of MAVYRET in children less than 12 years of age have not been studied.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION(additions underlined)
…
Administration
Inform patients it is important to take all three tablets at the same time once daily with food as directed. Inform patients that it is important not to miss or skip doses and to take MAVYRET for the duration that is recommended by the physician.
...
08/06/2018 (SUPPL-2)
6 Adverse Reactions
6.1 Clinical Trials Experience(Newly added subsection)
…
Adverse Reactions in HCV/HIV-1 Co-infected Subjects
The safety of MAVYRET in subjects with HIV-1 co-infection with genotypes 1, 2, 3, 4 or 6 chronic HCV infection without cirrhosis or with compensated cirrhosis (Child-Pugh A) was assessed in 153 subjects (EXPEDITION-2) who received MAVYRET for 8 or 12 weeks. Thirty- three subjects with HIV-1 coinfection also received 8 or 12 weeks of therapy in ENDURANCE- 1.
The overall safety profile in HCV/HIV-1 co-infected subjects (ENDURANCE-1 and EXPEDITION-2) was similar to that observed in HCV mono-infected subjects. Adverse reactions observed in greater than or equal to 5% of subjects receiving MAVYRET in EXPEDITION-2 for 8 or 12 weeks were fatigue (10%), nausea (8%), and headache (5%).
Adverse Reactions in Subjects with Liver or Kidney Transplant
The safety of MAVYRET was assessed in 100 post-liver or -kidney transplant recipients with genotypes 1, 2, 3, 4, or 6 chronic HCV infection without cirrhosis (MAGELLAN-2). The overall safety profile in transplant recipients was similar to that observed in subjects in the Phase 2 and 3
studies, without a history of transplantation. Adverse reactions observed in greater than or equal to 5% of subjects receiving MAVYRET for 12 weeks were headache (17%), fatigue (16%), nausea (8%) and pruritus (7%). In subjects treated with MAVYRET who reported an adverse reaction, 81% had adverse reactions of mild severity. Two percent of subjects experienced a serious adverse reaction, and no subjects permanently discontinued treatment due to adverse reactions.
…
7 Drug Interactions
7.2 Mechanisms for the Potential Effect of Other Drugs on MAVYRET(Additions and/or revisions are underlined)
…
Carbamazepine, phenytoin, efavirenz, and St. John’s wort may significantly decrease plasma concentrations of glecaprevir and pibrentasvir, leading to reduced therapeutic effect of MAVYRET. The use of these agents with MAVYRET is not recommended.
12/11/2017 (SUPPL-3)
7 Drug Interactions
7.1 Mechanisms for the Potential Effect of MAVYRET on Other Drugs(additions underlined)
Glecaprevir and pibrentasvir are inhibitors of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide (OATP) 1B1/3. Coadministration with MAVYRET may increase plasma concentration of drugs that are substrates of P-gp, BCRP, OATP1B1 or OATP1B3. Glecaprevir and pibrentasvir are weak inhibitors of cytochrome P450 (CYP) 3A, CYP1A2, and uridine glucuronosyltransferase (UGT) 1A1.
Fluctuations in INR values may occur in patients receiving warfarin concomitant with HCV treatment, including treatment with MAVYRET. If MAVYRET is coadministered with warfarin, close monitoring of INR values is recommended during treatment and post-treatment follow-up.