Combivir Adverse Reactions

Adverse reactions have been reported during therapy for HIV disease with lamivudine and zidovudine separately or in combination. For many of these events, it is unclear whether they are related to lamivudine, zidovudine, the wide range of medicinal products used in the management of HIV disease, or as a result of the underlying disease process.
As Combivir contains lamivudine and zidovudine, the type and severity of adverse reactions associated with each of the compounds may be expected. There is no evidence of added toxicity following concurrent administration of the two compounds.
Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of zidovudine (see Warnings).
Treatment with zidovudine has been associated with loss of subcutaneous fat which is most evident in the face, limbs and buttocks. Patients receiving Combivir should be frequently examined and questioned for signs of lipoatrophy. When such development is found, treatment with Combivir should not be continued (see Precautions).
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see Precautions).
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) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see Precautions).
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 Precautions).
Lamivudine: The adverse reactions considered at least possibly related to the treatment are listed as follows by body system, organ class and absolute frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Blood and lymphatic systems disorders: Uncommon: Neutropenia and anaemia (both occasionally severe), thrombocytopenia.
Very rare: Pure red cell aplasia.
Metabolism and nutrition disorders: Very Rare: Lactic acidosis.
Nervous system disorders: Common: Headache, insomnia.
Very rare: Peripheral neuropathy (or paraesthesiae).
Respiratory, thoracic and mediastinal disorders: Common: Cough, nasal symptoms.
Gastrointestinal disorders: Common: Nausea, vomiting, abdominal pain or cramps, diarrhoea.
Rare: Pancreatitis, rises in serum amylase.
Hepatobiliary disorders: Uncommon: Transient rises in liver enzymes (AST, ALT).
Rare: Hepatitis.
Skin and subcutaneous tissue disorders: Common: Rash, alopecia.
Rare: Angioedema.
Musculoskeletal and connective tissue disorders: Common: Arthralgia, muscle disorders.
Rare: Rhabdomyolysis.
General disorders and administration site conditions: Common: Fatigue, malaise, fever.
Zidovudine: The adverse reactions profile appears similar for adults and adolescents. 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 (see Precautions).
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 zidovudine therapy.
The adverse reactions considered at least possibly related to the treatment are listed as follows by body system, organ class and absolute frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Blood and lymphatic system disorders: Common: Anaemia, neutropenia and leucopenia.
Uncommon: Thrombocyopenia and pancytopenia (with marrow hypoplasia).
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: Insomnia, paraesthesiae, somnolence, loss of mental acuity, convulsions.
Cardiac disorders: Rare: Cardiomyopathy.
Respiratory, thoracic and mediastinal disorders: Uncommon: Dyspnoea.
Rare: Cough.
Gastrointestinal disorders: Very common: Nausea.
Common: Vomiting, abdominal pain and diarrhoea.
Uncommon: Flatulence.
Rare: Oral mucosa pigmentation, taste perversion 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 pruritus.
Rare: Nail and skin pigmentation, urticaria 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 conditions: Common: Malaise.
Uncommon: Fever, generalised pain and asthenia.
Rare: Chills, chest pain and influenza-like syndrome.
The available data from both placebo-controlled and open-label studies indicate that the incidence of nausea and other frequently reported clinical adverse events consistently decreases over time during the first few weeks of therapy with zidovudine.
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.