Adverse reactions : תופעות לוואי

4.8 Undesirable effects

Summary of the safety profile
In patients with compensated liver disease, the most frequently reported adverse reactions during    48 weeks of adefovir dipivoxil therapy were asthenia (13 %), headache (9 %), abdominal pain (9 %) and nausea (5 %).
In patients with decompensated liver disease, the most frequently reported adverse reactions during up to 203 weeks of adefovir dipivoxil therapy were increased creatinine (7 %) and asthenia (5 %).



Tabulated summary of adverse reactions
Assessment of adverse reactions is based on experience from post-marketing surveillance and from three pivotal clinical studies in patients with chronic hepatitis B:

•     two placebo-controlled studies in which 522 patients with chronic hepatitis B and compensated liver disease received double-blind treatment with 10 mg adefovir dipivoxil (n=294) or placebo (n=228) for 48 weeks.
•     an open-label study in which pre- (n=226) and post-liver transplantation patients (n=241) with lamivudine-resistant HBV were treated with 10 mg adefovir dipivoxil once daily, for up to       203 weeks (median 51 and 99 weeks, respectively).

The adverse reactions considered at least possibly related to treatment are listed below, by body system organ class, and frequency (see Table 1). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100) or not known (identified through post- marketing safety surveillance and the frequency cannot be estimated from the available data).

Table 1: Tabulated summary of adverse reactions associated with adefovir dipivoxil based on clinical study and post-marketing experience

Frequency         Adefovir dipivoxil
Nervous system disorders:
Common:           Headache
Gastrointestinal disorders:
Common:          Diarrhoea, vomiting, abdominal pain, dyspepsia, nausea, flatulence Not known:        Pancreatitis
Skin and subcutaneous tissue disorders:
Common:           Rash, pruritus
Musculoskeletal and connective tissue disorders:
Osteomalacia (manifested as bone pain and infrequently contributing to fractures) Not known: and myopathy, both associated with proximal renal tubulopathy
Renal and urinary disorders:
Very common: Increases in creatinine
Common:           Renal failure, abnormal renal function, hypophosphatemia Uncommon:         Proximal renal tubulopathy (including Fanconi syndrome) General disorders and administration site conditions:
Very common: Asthenia

Description of selected adverse reactions
Exacerbation of hepatitis
Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of treatment with 10 mg adefovir dipivoxil (see section 4.4).

Long-term safety data in patients with compensated disease
In a long-term safety study of 125 HBeAg negative patients with compensated liver disease, the adverse event profile was overall unchanged after a median exposure of 226 weeks. No clinically significant changes in renal function were observed. However, mild to moderate increases in serum creatinine concentrations, hypophosphatemia and a decrease in carnitine concentrations were reported in 3 %, 4 % and 6 % of patients, respectively, on extended treatment.

In a long-term safety study of 65 HBeAg positive patients with compensated liver disease (after a median exposure of 234 weeks), 6 patients (9 %) had confirmed increases in serum creatinine of at least 0.5 mg/dl from baseline with 2 patients discontinuing from the study due to the elevated serum creatinine concentration. Patients with a confirmed increase in creatinine of ≥ 0.3 mg/dl by week 48 were at a statistically significant higher risk of a subsequent confirmed increase in creatinine of 

≥ 0.5 mg/dl. Hypophosphatemia and a decrease in carnitine concentrations were reported each in 3 % of patients on extended treatment.

Based on post-marketing data, long-term treatment with adefovir dipivoxil may lead to progressive alteration of renal function resulting in renal impairment (see section 4.4).

Safety in patients with decompensated disease
Renal toxicity is an important feature of the safety profile of adefovir dipivoxil in patients with decompensated liver disease. In clinical studies of wait-listed and post-liver transplantation patients, four percent (19/467) of patients discontinued treatment with adefovir dipivoxil due to renal adverse events.

Paediatric population
Because of insufficient data on safety and efficacy, Hepsera should not be used in children under the age of 18 years (see Sections 4.2 and 5.1).

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.
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 
Additionally, you should also report to GSK Israel (il.safety@gsk.com).