Approved Drug Label (PDF)
6
Adverse Reactions
6.1 Clinical Trials Experience
Additions and/or
revisions underlined:
… If ZEPATIER is administered with ribavirin, refer
to the prescribing information for ribavirin for a description of
ribavirin-associated adverse reactions.
Clinical Trials in Adult Subjects
The safety of ZEPATIER in adult subjects was
assessed based on 2 placebo-controlled trials and 7 uncontrolled Phase 2 and 3
clinical trials in approximately 1700 subjects with chronic hepatitis C virus
infection with compensated liver disease (with or without cirrhosis) [see
Clinical Studies (14)] …
Newly added information
to ending of subsection:
Clinical Trial in Pediatric Subjects
Adverse Reactions in Pediatric Subjects 12 Years of
Age and Older
The safety of ZEPATIER was assessed in pediatric subjects
12 years of age and older based on data from 22 subjects, without cirrhosis,
who were treated with ZEPATIER for 12 weeks in a Phase 2b, open- label clinical
trial (MK-5172-079). The adverse reactions observed were consistent with those
observed in clinical trials of ZEPATIER in adults [see Clinical Studies
(14.6)]. The adverse drug reactions observed in greater than or equal to 5%
of subjects receiving ZEPATIER were headache (14%) and nausea (9%).
8
Use in Specific Populations
8.4 Pediatric Use
Additions and/or
revisions underlined:
The safety, efficacy,
and pharmacokinetics of ZEPATIER was evaluated in an open-label clinical trial
(MK-5172-079), which included 22 subjects (n=21, genotype 1; n=1, genotype 4) 12
years of age and older who received ZEPATIER for 12 weeks. The safety,
pharmacokinetics, and efficacy observed in this trial were comparable to those
observed in adults [see Dosage and Administration (2.2), Adverse Reactions
(6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.6)].
Safety and effectiveness of ZEPATIER have not been established in pediatric patients younger than 12
years of age who weigh less than 30 kg.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION
Additions and/or
revisions underlined:
ZEPATIER is a prescription medicine used with or
without ribavirin to treat chronic (long-lasting) hepatitis C virus (HCV)
genotypes 1 or 4 infection in adults and children 12 years of age and older
or weighing at least 66 pounds (30 kilograms).
ZEPATIER should not be used in children younger
than 12 years of age who weigh less than 66 pounds (30 kilograms).
Approved Drug Label (PDF)
4
Contraindications
(additions
and/or revisions underlined)
…
…
5
Warnings and Precautions
5.3 Risk of Hepatic Decompensation/Failure in Patients with Evidence of Advanced Liver Disease
(new subsection
added)
Postmarketing cases of hepatic
decompensation/failure, including those with fatal outcomes, have been reported
in patients treated with HCV NS3/4A protease inhibitor-containing regimens,
including ZEPATIER.
Reported cases occurred in
patients treated with HCV NS3/4A protease inhibitor-containing regimens with
baseline cirrhosis with and without moderate or severe liver impairment
(Child-Pugh B or C) as well as some patients without cirrhosis. Because these
events 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.
![]()
Hepatic laboratory testing should
be performed in all patients. In patients with compensated cirrhosis
(Child-Pugh A) or evidence of advanced liver disease, such as portal
hypertension, more frequent hepatic laboratory testing may be warranted; and
patients should be monitored for signs
and symptoms of hepatic decompensation such as the presence of jaundice,
ascites, hepatic encephalopathy, and variceal hemorrhage. Discontinue ZEPATIER
in patients who develop evidence of hepatic decompensation/failure.
ZEPATIER 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
underlined)
…
Hepatobiliary
Disorders
Hepatic
decompensation, hepatic failure
7
Drug Interactions
7.2 Established and other 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 CYP450 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.
…
8
Use in Specific Populations
8.9 Hepatic Impairment
(additions
underlined)
… In addition, postmarketing cases of
hepatic decompensation/failure have been reported in patients with advanced
liver disease.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
(additions
underlined)
…
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.
…
PATIENT INFORMATION
(additions
underlined)
…
What
are the possible side effects of ZEPATIER?
…
color changes in
your stool or urine
Confusion
sleepiness
vomiting of blood
bleeding or bruising more easily than
normal
diarrhea
swelling of the stomach area (abdomen)
or pain in the upper right side of the stomach area
…
Approved Drug Label (PDF)
6
Adverse Reactions
6.2 Postmarketing Experience
(new
subsection added)
The following adverse
reactions have been identified during post approval use of ZEPATIER. 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 Subc utaneous
Tissue Disorders Angioedema
Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 Increased Risk of ALT Elevations
(Additions and/or revisions are underlined)
Hepatic laboratory testing should be performed prior to therapy, at
treatment week 8, and as clinically indicated. For patients receiving 16 weeks
of therapy, additional hepatic laboratory testing should be performed at
treatment week 12.
…
- Discontinue
ZEPATIER if ALT elevation is accompanied by signs or symptoms of liver
inflammation or increasing conjugated bilirubin, alkaline phosphatase, or International
Normalized Ratio (INR).
7
Drug Interactions
7.1 Potential for Drug Interactions
(Additions and/or revisions are underlined)
Fluctuations in INR values may occur in patients receiving warfarin
concomitantly with HCV treatment, including treatment with ZEPATIER. Frequent
monitoring of INR values is recommended during treatment and post-treatment
follow-up.
Approved Drug Label (PDF)
Boxed Warning
(Newly added section)
WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN
PATIENTS COINFECTED WITH HCV AND HBV
Test all patients for evidence of current or prior hepatitis
B virus (HBV) infection before initiating treatment with ZEPATIER. HBV
reactivation has been reported in HCV/HBV coinfected patients who were
undergoing or had completed treatment with HCV direct acting antivirals and
were not receiving HBV antiviral therapy. Some cases have resulted in fulminant
hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for
hepatitis flare or HBV reactivation during HCV treatment and post-treatment
follow-up. Initiate appropriate patient management for HBV infection as
clinically indicated.
5
Warnings and Precautions
5.1 Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV
(Newly added subsection)
Hepatitis B virus (HBV) reactivation has been reported in
HCV/HBV coinfected patients who were undergoing or had completed treatment with
HCV direct acting antivirals, and who were not receiving HBV antiviral therapy.
Some cases have resulted in fulminant hepatitis, hepatic failure and death.
Cases have been reported in patients who are HBsAg positive and also in
patients with serologic evidence of resolved HBV infection (i.e., HBsAg
negative and anti-HBc positive). HBV reactivation has also been reported in
patients receiving certain 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
ZEPATIER. In patients with serologic evidence of HBV infection, monitor for
clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV
treatment with ZEPATIER and during post-treatment follow-up. Initiate
appropriate patient management for HBV infection as clinically indicated.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions are underlined)
Risk of Hepatitis B Virus Reactivation in Patients
Coinfected with HCV and HBV
Inform patients that HBV reactivation can occur in
patients coinfected with HBV during or after treatment of HCV infection. Advise
patients to tell their healthcare provider if they have a history of hepatitis
B virus infection.
Patient Information
(Additions and/or revisions are underlined)
What is the most important information I should know
about ZEPATIER?
ZEPATIER can cause serious side effects, including,
Hepatitis B virus reactivation: Before
starting treatment with ZEPATIER, 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 infection
with ZEPATIER. 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 ZEPATIER.
For more information about side effects, see the
section “What are the possible side effects of ZEPATIER?”
What should I tell my
healthcare provider before taking ZEPATIER?
Before taking ZEPATIER, 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 ZEPATIER?
ZEPATIER can cause serious side effects, including:
Hepatitis B virus reactivation. See “What
is the most important information I should know about ZEPATIER?”
Approved Drug Label (PDF)
4
Contraindications
(additions
underlined)
- ZEPATIER is contraindicated with inhibitors of organic anion transporting
polypeptides 1B1/3 (OATP1B1/3) that are known or expected to significantly increase grazoprevir plasma concentrations, strong inducers
of cytochrome P450 3A (CYP3A), and efavirenz.
7
Drug Interactions
7.1 Potential for Drug Interactions
(additions
underlined)
Grazoprevir
is a substrate of OATP1B1/3 transporters. Co-administration of ZEPATIER with OATP1B1/3
inhibitors that are known or expected to significantly increase grazoprevir
plasma concentrations is contraindicated.
Elbasvir
and grazoprevir are substrates of CYP3A and P-gp, but the role of intestinal P-gp
in the absorption of elbasvir and grazoprevir appears to be minimal. Co-administration
of moderate or strong inducers of CYP3A with ZEPATIER may decrease elbasvir and
grazoprevir plasma concentrations, leading to reduced therapeutic effect of ZEPATIER.
Co-administration of ZEPATIER with strong CYP3A inducers or efavirenz is contraindicated. Co-administration
of ZEPATIER with moderate CYP3A inducers is not recommended. Co-administration of ZEPATIER with strong CYP3A inhibitors may increase
elbasvir and grazoprevir concentrations. Co- administration of ZEPATIER with certain
strong CYP3A inhibitors is not recommended.
7.2 Established and other Potentially Significant Drug Interactions
(Extensive
revisions to table 6, please refer to label)
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