Special Warning : אזהרת שימוש

5        WARNINGS AND PRECAUTIONS

5.1 Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV 
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.

5.2      Increased Risk of ALT Elevations
During clinical trials with ZEPATIER with or without ribavirin, 1% of subjects experienced elevations of ALT from normal levels to greater than 5 times the upper limit of normal (ULN), generally at or after treatment week 8. ALT elevations were typically asymptomatic and most resolved with ongoing or completion of therapy. Higher rates of late ALT elevations occurred in the following subpopulations: female sex (2% [10/608]), Asian race (2% [4/164]), and age 65 years or older (2% [3/177]) [see Adverse Reactions (6.1)].

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.
• Patients should be instructed to consult their healthcare professional without delay if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice, or discolored feces.
• Consider discontinuing ZEPATIER if ALT levels remain persistently greater than 10 times the ULN.
• 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).



5.3   Risk of Hepatic Decompensation/Failure in Patients with Evidence of Advanced Liver Disease Postmarketing cases of hepatic decompensation/failure, including those with fatal outcomes, have been reported in patients treated with HCV NS3/4A protease inhibitor-containig 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 [see Warnings and Precautions (5.2)].
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 [see Contraindications (4), Adverse Reactions (6.1), Use in Specific Populations (8.9), and Clinical Pharmacology (12.3)].

5.4   Risks Associated with Ribavirin Combination Treatment
If ZEPATIER is administered with ribavirin, the warnings and precautions for ribavirin, including the pregnancy avoidance warning, also apply to this combination regimen. Refer to the ribavirin prescribing information for a full list of warnings and precautions for ribavirin [see Dosage and Administration (2.2)].

5.5   Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions The concomitant use of ZEPATIER and certain drugs may result in known or potentially significant drug interactions, some of which may lead to:
• Possible clinically significant adverse reactions from greater exposure of concomitant drugs or components of ZEPATIER.
• Significant decrease of elbasvir and grazoprevir plasma concentrations which may lead to reduced therapeutic effect of ZEPATIER and possible development of resistance.
See Tables 2 and 6 for steps to prevent or manage these known or potentially significant drug interactions, including dosing recommendations [see Contraindications (4) and Drug Interactions (7.2)].
6     ADVERSE REACTIONS
The following adverse reaction is described below and elsewhere in the labeling: • Increased Risk of ALT Elevations [see Warnings and Precautions (5.2)].

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

If ZEPATIER is administered with ribavirin, refer to the prescribing information for ribavirin for a description of ribavirin-associated adverse reactions.

The safety of ZEPATIER 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)].

Adverse Reactions with ZEPATIER in Treatment-Naïve Subjects


C-EDGE TN was a Phase 3 randomized, double-blind, placebo-controlled trial in 421 treatment-naïve (TN) subjects with HCV infection who received ZEPATIER or placebo one tablet once daily for 12 weeks.
Adverse reactions (all intensity) occurring in C-EDGE TN in at least 5% of subjects treated with ZEPATIER for 12 weeks are presented in Table 3. In subjects treated with ZEPATIER who reported an adverse reaction, 73% had adverse reactions of mild severity. The type and severity of adverse reactions in subjects with compensated cirrhosis were comparable to those seen in subjects without cirrhosis. No subjects treated with ZEPATIER or placebo had serious adverse reactions. The proportion of subjects treated with ZEPATIER or placebo who permanently discontinued treatment due to adverse reactions was 1% in each group.
Table 3: Adverse Reactions (All Intensity) Reported in ≥5% of Treatment-Naïve Subjects with HCV Treated with ZEPATIER for 12 Weeks in C-EDGE TN
C-EDGE TN
ZEPATIER                                    Placebo
N=316                                      N=105
%                                         %
12 weeks                                   12 weeks
Fatigue                              11%                                        10% Headache                             10%                                         9% 
C-EDGE COINFECTION was a Phase 3 open-label trial in 218 treatment-naïve HCV/HIV co-infected subjects who received ZEPATIER one tablet once daily for 12 weeks. Adverse reactions (all intensity) reported in C-EDGE COINFECTION in at least 5% of subjects treated with ZEPATIER for 12 weeks were fatigue (7%), headache (7%), nausea (5%), insomnia (5%), and diarrhea (5%). No subjects reported serious adverse reactions or discontinued treatment due to adverse reactions. No subjects switched their antiretroviral therapy regimen due to loss of plasma HIV-1 RNA suppression. Median increase in CD4+ T- cell counts of 31 cells per mm3 was observed at the end of 12 weeks of treatment.

Adverse Reactions with ZEPATIER with or without Ribavirin in Treatment-Experienced Subjects C-EDGE TE was a Phase 3 randomized, open-label trial in treatment-experienced (TE) subjects.
Adverse reactions of moderate or severe intensity reported in C-EDGE TE in at least 2% of subjects treated with ZEPATIER one tablet once daily for 12 weeks or ZEPATIER one tablet once daily with ribavirin for 16 weeks are presented in Table 4. No subjects treated with ZEPATIER without ribavirin for 12 weeks reported serious adverse reactions or discontinued treatment due to adverse reactions. The proportion of subjects treated with ZEPATIER with ribavirin for 16 weeks with serious adverse reactions was 1%. The proportion of subjects treated with ZEPATIER with ribavirin for 16 weeks who permanently discontinued treatment due to adverse reactions was 3%. The type and severity of adverse reactions in subjects with cirrhosis were comparable to those seen in subjects without cirrhosis.

Table 4: Adverse Reactions (Moderate or Severe Intensity) Reported in ≥2% of PegIFN/RBV- Experienced Subjects with HCV Treated with ZEPATIER for 12 Weeks or ZEPATIER + Ribavirin for 16 Weeks in C-EDGE TE
C-EDGE TE
ZEPATIER                   ZEPATIER + Ribavirin
N=105                            N=106
%                                %
12 weeks                          16 weeks
Anemia                                       0%                                8% Headache                                     0%                                6% Fatigue                                      5%                                4% Dyspnea                                      0%                                4% Rash or Pruritus                             0%                                4% Irritability                                 1%                                3% Abdominal pain                               2%                                2% Depression                                   1%                                2% Arthralgia                                   0%                                2% 

Diarrhea                                           2%                                   0% 
The type and severity of adverse reactions with ZEPATIER with or without ribavirin in 10 treatment- experienced subjects with HCV/HIV co-infection were comparable to those reported in subjects without HIV co-infection. Median increase in CD4+ T-cell counts of 32 cells/mm3 was observed at the end of 12 weeks of treatment with ZEPATIER alone. In subjects treated with ZEPATIER with ribavirin for 16 weeks, CD4+ T-cell counts decreased a median of 135 cells per mm3 at the end of treatment. No subjects switched their antiretroviral therapy regimen due to loss of plasma HIV-1 RNA suppression. No subject experienced an AIDS-related opportunistic infection.
C-SALVAGE was a Phase 2 open-label trial in 79 PegIFN/RBV/PI-experienced subjects. Adverse reactions of moderate or severe intensity reported in C-SALVAGE in at least 2% of subjects treated with ZEPATIER once daily with ribavirin for 12 weeks were fatigue (3%) and insomnia (3%). No subjects reported serious adverse reactions or discontinued treatment due to adverse reactions.

Adverse Reactions with ZEPATIER in Subjects with Severe Renal Impairment including Subjects on Hemodialysis
The safety of elbasvir and grazoprevir in comparison to placebo in subjects with severe renal impairment (Stage 4 or Stage 5 chronic kidney disease, including subjects on hemodialysis) and chronic hepatitis C virus infection with compensated liver disease (with or without cirrhosis) was assessed in 235 subjects (C-SURFER) [see Clinical Studies (14.4)]. The adverse reactions (all intensity) occurring in at least 5% of subjects treated with ZEPATIER for 12 weeks are presented in Table 5. In subjects treated with ZEPATIER who reported an adverse reaction, 76% had adverse reactions of mild severity. The proportion of subjects treated with ZEPATIER or placebo with serious adverse reactions was less than 1% in each treatment arm, and less than 1% and 3% of subjects, respectively, permanently discontinued treatment due to adverse reactions in each treatment arm.

Table 5: Adverse Reactions (All Intensity) Reported in ≥5% of Treatment-Naïve or PegIFN/RBV- Experienced Subjects with Stage 4 or 5 Chronic Kidney Disease and HCV Treated with ZEPATIER for 12 Weeks in C-SURFER
ZEPATIER                        Placebo
N=122                          N=113
%                              %
12 weeks                       12 weeks
Nausea                                         11%                             8% Headache                                       11%                             5% Fatigue                                         5%                             8% 
Laboratory Abnormalities in Subjects Receiving ZEPATIER with or without Ribavirin 
Serum ALT Elevations
During clinical trials with ZEPATIER with or without ribavirin, regardless of treatment duration, 1% (12/1599) of subjects experienced elevations of ALT from normal levels to greater than 5 times the ULN, generally at or after treatment week 8 (mean onset time 10 weeks, range 6-12 weeks). These late ALT elevations were typically asymptomatic. Most late ALT elevations resolved with ongoing therapy with ZEPATIER or after completion of therapy [see Warnings and Precautions (5.2)]. The frequency of late ALT elevations was higher in subjects with higher grazoprevir plasma concentrations [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. The incidence of late ALT elevations was not affected by treatment duration. Cirrhosis was not a risk factor for late ALT elevations.

Serum Bilirubin Elevations
During clinical trials with ZEPATIER with or without ribavirin, regardless of treatment duration, elevations in bilirubin at greater than 2.5 times ULN were observed in 6% of subjects receiving ZEPATIER with ribavirin compared to less than 1% in those receiving ZEPATIER alone. These bilirubin increases were predominately indirect and generally observed in association with ribavirin co-administration. Bilirubin elevations were typically not associated with serum ALT elevations.


Decreased Hemoglobin
During clinical trials with ZEPATIER with or without ribavirin, the mean change from baseline in hemoglobin levels in subjects treated with ZEPATIER for 12 weeks was –0.3 g per dL and with ZEPATIER with ribavirin for 16 weeks was approximately –2.2 g per dL. Hemoglobin declined during the first 8 weeks of treatment, remained low during the remainder of treatment, and normalized to baseline levels during follow-up. Less than 1% of subjects treated with ZEPATIER with ribavirin had hemoglobin levels decrease to less than 8.5 g per dL during treatment. No subjects treated with ZEPATIER alone had a hemoglobin level less than 8.5 g per dL.

6.2    Postmarketing Experience
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 Subcutaneous Tissue Disorders
Angioedema

Hepatobiliary Disorders
Hepatic decompensation, hepatic failure [see Warnings and Precautions (5.3)] 
Reporting suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il/ 

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