Adverse reactions : תופעות לוואי

4.8     Undesirable effects

The adverse reaction profile appears similar for adults and children. The most serious adverse reactions include anaemia (which may require transfusions), neutropenia and leucopenia.
These occurred more frequently at higher dosages (1200-1500 mg/day) and in patients with advanced HIV disease (especially when there is poor bone marrow reserve prior to treatment), and particularly in patients with CD4 cell counts less than 100/mm3. Dosage reduction or cessation of therapy may become necessary (see section 4.4).

The incidence of neutropenia was also increased in those patients whose neutrophil counts, haemoglobin levels and serum vitamin B12 levels were low at the start of Retrovir therapy.
The following events have been reported in patients treated with Retrovir.

The adverse events considered at least possibly related to the treatment (adverse drug reactions, ADR) are listed below by body system, organ class and absolute frequency.
Frequencies are defined as 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) and Very rare (<1/10,000).

Blood and lymphatic system disorders
Common: Anaemia, neutropenia and leucopenia
Uncommon: Pancytopenia with bone marrow hypoplasia, thrombocytopenia Rare: Pure red cell aplasia
Very rare: Aplastic anaemia

Metabolism and nutrition disorders
Rare: Lactic acidosis in the absence of hypoxaemia, anorexia

Psychiatric disorders
Rare: Anxiety and depression
Nervous system disorders
Very common: Headache
Common: Dizziness
Rare:Convulsions, loss of mental acuity, insomnia, paraesthesia, somnolence 
Cardiac disorders
Rare: Cardiomyopathy

Respiratory, thoracic and mediastinal disorders
Uncommon: Dyspnoea
Rare: Cough
Gastrointestinal disorders
Very common: Nausea
Common: Vomiting, diarrhoea and abdominal pain
Uncommon: Flatulence
Rare: Oral mucosa pigmentation, taste disturbance and dyspepsia. Pancreatitis.

Hepatobiliary disorders
Common: Raised blood levels of liver enzymes and bilirubin
Rare: Liver disorders such as severe hepatomegaly with steatosis

Skin and subcutaneous tissue disorders
Uncommon: Rash and pruritis
Rare: Urticaria, nail and skin pigmentation, and sweating
Musculoskeletal and connective tissue disorders
Common: Myalgia
Uncommon: Myopathy

Renal and urinary disorders
Rare: Urinary frequency

Reproductive system and breast disorders
Rare: Gynaecomastia
General disorders and administration site disorders
Common: Malaise
Uncommon: Asthenia, fever, and generalised pain
Rare: Chest pain and influenza-like syndrome, chills

Experience with Retrovir IV for Infusion treatment for periods in excess of two weeks is limited, although some patients have received treatment for up to 12 weeks. The most frequent adverse reactions were anaemia, neutropenia and leucopenia. Local reactions were infrequent.

The available data from studies of Retrovir Oral Formulations indicate that the incidence of nausea and other frequently reported clinical adverse reactions consistently decreased over time during the first few weeks of therapy with Retrovir.

Adverse reactions with Retrovir for the prevention of maternal-foetal transmission: 
In a placebo-controlled trial, overall clinical adverse reactions and laboratory test abnormalities were similar for women in the Retrovir and placebo groups. However, there was a trend for mild and moderate anaemia to be seen more commonly prior to delivery in the zidovudine treated women.

In the same trial, haemoglobin concentrations in infants exposed to Retrovir for this indication were marginally lower than in infants in the placebo group, but transfusion was not required. Anaemia resolved within 6 weeks after completion of Retrovir therapy. Other clinical adverse reactions and laboratory test abnormalities were similar in the Retrovir and placebo groups. It is unknown whether there are any long-term consequences of in utero and infant exposure to Retrovir.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of zidovudine (see section 4.4).

Treatment with zidovudine has been associated with loss of subcutaneous fat which is most evident in the face, limbs and buttocks. Patients receiving Retrovir should be frequently examined and questioned for signs of lipoatrophy. When such development is found, treatment with Retrovir should not be continued (see section 4.4).

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4)

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

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).