Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The safety assessment of Harvoni was mainly based on pooled Phase 3 clinical studies, without a control, in 1952 patients who received Harvoni for 8, 12 or 24 weeks, including 872 patients who received Harvoni in combination with ribavirin.

The proportion of patients who permanently discontinued treatment due to adverse events was 0%, < 1% and 1% for patients receiving ledipasvir/sofosbuvir for 8, 12 and 24 weeks, respectively; and < 1%, 0%, and 2% for patients receiving ledipasvir/sofosbuvir + ribavirin combination therapy for 8, 12 and 24 weeks, respectively.

In clinical studies, fatigue and headache were more common in patients treated with ledipasvir/sofosbuvir compared to placebo. When ledipasvir/sofosbuvir was studied with ribavirin, the most frequent adverse drug reactions to ledipasvir/sofosbuvir + ribavirin combination therapy were consistent with the known safety profile of ribavirin, without increasing the frequency or severity of the expected adverse drug reactions.

Tabulated list of adverse events

The following adverse drug reactions have been identified with Harvoni (Table 4). 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) or very rare (< 1/10,000).

Table 4: Adverse drug reactions identified with Harvoni

Frequency                       Adverse drug reaction
Nervous system disorders:
Very common               headache
Skin and subcutaneous tissue disorders:
Common                    rash
Not known                 angioedema
General disorders:
Very common               fatigue
Patients with decompensated cirrhosis and/or who are awaiting liver transplant or post-liver transplant 
The safety profile of ledipasvir/sofosbuvir with ribavirin for 12 or 24 weeks in patients with decompensated liver disease and/or those post-liver transplant was assessed in an open-label study (SOLAR-1). No new adverse drug reactions were detected among patients with decompensated cirrhosis and/or who were post-liver transplant and who received ledipasvir/sofosbuvir with ribavirin.
Although adverse events, including serious adverse events, occurred more frequently in this study compared to studies that excluded decompensated patients and/or patients who were post-liver transplantation, the adverse events observed were those expected as clinical sequelae of advanced liver disease and/or transplantation or were consistent with the known safety profile of ribavirin (see section 5.1 for details of this study).

Decreases in haemoglobin to < 10 g/dL and < 8.5 g/dL during treatment were experienced by 39% and 13% of patients treated with ledipasvir/sofosbuvir with ribavirin, respectively. Ribavirin was discontinued in 19% of the patients.

10% of liver transplant recipients had a modification of their immunosuppressive agents.

Patients with renal impairment
Ledipasvir/sofosbuvir was administered for 12 weeks to 18 patients with genotype 1 CHC and severe renal impairment in an open-label study (Study 0154). In this limited clinical safety data set, the rate of adverse events was not clearly elevated from what is expected in patients with severe renal impairment.

The safety of Harvoni has been evaluated in a 12-week non-controlled study including 95 patients with ESRD requiring dialysis (Study 4063). In this setting, exposure of sofosbuvir metabolite GS- 331007 is 20-fold increased, exceeding levels where adverse reactions have been observed in preclinical trials. In this limited clinical safety data set, the rate of adverse events and deaths was not clearly elevated from what is expected in ESRD patients.

Paediatric population

The safety and efficacy of Harvoni in children and adolescents aged less than 18 years have not yet been established. No data are available.

Description of selected adverse reactions

Cardiac arrhythmias
Cases of severe bradycardia and heart block have been observed when Harvoni is used with amiodarone and/or other drugs that lower heart rate (see sections 4.4 and 4.5).

Skin disorders
Frequency not known: Stevens-Johnson syndrome

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

You can report any side effects to the Ministry of Health by clicking on the link "Report side effects due to medical treatment" that is located on the Ministry of Health homepage (www.health.gov.il)which redirects to the online form for reporting side effects, or by clicking on the link: https://sideeffects.health.gov.il.

You can also report any side effects directly to the registration holder via email: (DrugSafety.Israel@gilead.com).