Adverse reactions : תופעות לוואי

4.8.    Undesirable effects

Summary of the safety profile
In pooled Phase 2 and 3 clinical studies of adult subjects receiving Maviret with genotype 1, 2, 3, 4, 5 or 6 HCV infection the most commonly reported adverse reactions (incidence ≥ 10%) were headache and fatigue. Less than 0.1% of subjects treated with Maviret had serious adverse reactions (transient ischaemic attack). The proportion of subjects treated with Maviret who permanently discontinued treatment due to adverse reactions was 0.1%.

Tabulated list of adverse reactions

The following adverse reactions were identified in registrational Phase 2 and 3 studies in HCV- infected adults with or without cirrhosis treated with Maviret for 8, 12 or 16 weeks, or during post- marketing experience. The adverse reactions are listed below by body system organ class and frequency. Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) or not known (cannot be estimated from the available data).

Table 4: Adverse reactions identified with Maviret
Frequency                                                        Adverse reactions Immune system disorders
Uncommon                                                          angioedema Nervous system disorders
Very common                                                      headache Gastrointestinal disorders
Common                                                           diarrhoea, nausea Skin and subcutaneous tissue disorders
Not known                                                         pruritus General disorders and administration site conditions
Very common                                                      fatigue Common                                                           asthenia Investigations
Common                                                           elevation in total bilirubin 
Description of selected adverse reactions

Adverse reactions in subjects with severe renal impairment including subjects on dialysis The safety of Maviret in subjects with chronic kidney disease (including subjects on dialysis) and genotypes 1, 2, 3, 4, 5 or 6 chronic HCV infection with compensated liver disease (with or without cirrhosis) was assessed in adults in EXPEDITION-4 (n=104) and EXPEDITION-5 (n=101). The most common adverse reactions in subjects with severe renal impairment were pruritus (17%) and fatigue (12%) in EXPEDITION-4 and pruritus (14.9%) in EXPEDITION-5.

Adverse reactions in subjects with liver or kidney transplant
The safety of Maviret was assessed in 100 post-liver or -kidney transplant adult recipients with genotypes 1, 2, 3, 4, or 6 chronic HCV infection without cirrhosis (MAGELLAN-2). The overall safety profile in transplant recipients was comparable to that observed in subjects in the Phase 2 and 3 studies. Adverse reactions observed in greater than or equal to 5% of subjects receiving Maviret for 12 weeks were headache (17%), fatigue (16%), nausea (8%) and pruritus (7%).

Safety in HCV/HIV-1 co-infected subjects
The overall safety profile in HCV/HIV-1 co-infected adult subjects (ENDURANCE-1 and EXPEDITION-2) was comparable to that observed in HCV mono-infected adult subjects.

MAV API APR 22_CL                                                                                Page 10 of 25 Paediatric population
The safety of Maviret in HCV GT1-6 infected adolescents is based on data from a Phase 2/3 open- label study in 47 subjects aged 12 years to <18 years treated with Maviret for 8 to 16 weeks (DORA- Part 1). The adverse reactions observed were comparable with those observed in clinical studies of Maviret in adults.

Serum bilirubin elevations
Elevations in total bilirubin of at least 2x upper limit normal (ULN) were observed in 1.3% of subjects related to glecaprevir-mediated inhibition of bilirubin transporters and metabolism. Bilirubin elevations were asymptomatic, transient, and typically occurred early during treatment. Bilirubin elevations were predominantly indirect and not associated with ALT elevations. Direct hyperbilirubinemia was reported in 0.3% of subjects.

Postmarketing Experience
The following adverse reactions have been identified during post-approval use of Maviret. 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.

Hepatobiliary Disorders: Hepatic decompensation, hepatic failure (see sections 4.4).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization 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