Combivir Special Precautions

The special warnings and precautions relevant to both lamivudine and zidovudine are included in this section. There are no additional precautions and warnings relevant to the combination COMBIVIR.
It is recommended that separate preparations of lamivudine and zidovudine should be administered in cases where dosage adjustment is necessary. In these cases the physician should refer to the individual prescribing information for these medicinal products.
Patients should be cautioned about the concomitant use of self-administered medications (see Interactions).
Patients should be advised that current antiretroviral therapy, including COMBIVIR, has not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be taken.
Patients treated with COMBIVIR or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection. Therefore patients should remain under close clinical observation by physicians experienced in the treatment of HIV infection.
Haematological adverse reactions: Anaemia, neutropenia and leucopenia (usually secondary to neutropenia) can be expected to occur in patients receiving zidovudine. These occurred more frequently at higher zidovudine dosages (1200-1500 mg/day), in patients with advanced HIV disease and in those who had poor marrow reserve prior to treatment (see Adverse Reactions). Haematological parameters should therefore be carefully monitored (see Contraindications) in patients receiving COMBIVIR.
These haematological effects are not usually observed before four to six weeks therapy. For patients with advanced symptomatic HIV disease, it is generally recommended that blood tests are performed at least every two weeks for the first three months of therapy and at least monthly thereafter. In patients with early HIV disease haematological adverse reactions are infrequent. Depending on the overall condition of the patient, blood tests may be performed less often, for example every one to three months.
Additionally dosage adjustment of zidovudine may be required if severe anaemia or myelosuppression occurs during treatment with COMBIVIR, or in patients with pre-existing bone marrow compromise for example haemoglobin less than 9 g/dl (5.59 mmol/l) or neutrophil count less than 1.0 x 10⁹/l. As dosage adjustment of COMBIVIR is not possible separate preparations of zidovudine and lamivudine should be used (see Contraindications).
Pancreatitis: Cases of pancreatitis have occurred rarely in patients treated with lamivudine and zidovudine. However it is not clear whether these cases were due to treatment with the medicinal products or to the underlying HIV disease. Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers. Discontinue use of COMBIVIR until diagnosis of pancreatitis is excluded.
Lactic acidosis/severe hepatomegaly with steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues either alone or in combination, including lamivudine and zidovudine. A majority of these cases have been in women.
Clinical features which may be indicative of the development of lactic acidosis include generalised weakness, anorexia and sudden unexplained weight loss, gastrointestinal symptoms and respiratory symptoms (dyspnoea and tachypnoea).
Caution should be exercised when administering COMBIVIR particularly to those with known risk factors for liver disease. Treatment with COMBIVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis with or without hepatitis (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Lipoatrophy: Treatment with zidovudine has been associated with loss of subcutaneous fat. The incidence and severity of lipoatrophy are related to cumulative exposure. This fat loss, which is most evident in the face, limbs and buttocks, may be only partially reversible and improvement may take several months when switching to a zidovudine-free regimen. Patients should be regularly assessed for signs of lipoatrophy during therapy with COMBIVIR and other zidovudine containing products (Retrovir), and if feasible therapy should be switched to an alternative regimen if there is suspicion of lipoatrophy development.
Serum lipids and blood glucose: Serum lipid and blood glucose levels may increase during antiretroviral therapy. Disease control and life style changes may also be contributing factors. Consideration should be given to the measurement of serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate.
Immune Reconstitution Syndrome: In HIV-infected patients with severe immune deficiency at the time of initiation of anti-retroviral therapy (ART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of ART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and Pneumocystis jiroveci pneumonia (often referred to as PCP). Any inflammatory symptoms must be evaluated without delay and treatment initiated when necessary. Autoimmune disorders (such as Graves' disease, polymyositis and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution, however the time to onset is more variable, and can occur many months after initiation of treatment and sometimes can be an atypical presentation.
Patients co-infected with Hepatitis B virus: Clinical trial and marketed use of lamivudine, have shown that some patients with chronic hepatitis B virus (HBV) disease may experience clinical or laboratory evidence of recurrent hepatitis upon discontinuation of lamivudine, which may have more severe consequences in patients with decompensated liver disease. If COMBIVIR is discontinued in patients co-infected with Hepatitis B virus, periodic monitoring of both liver function tests and markers of HBV replication should be considered.
Patients co-infected with hepatitis C virus: Exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen used to treat HIV although the exact mechanism remains to be elucidated. Therefore, the co-administration of ribavirin and zidovudine is not advised and consideration should be given to replacing zidovudine in a combination ART regimen if this is already established. This is particularly important in patients with a known history of zidovudine induced anaemia.
Effects on Ability to Drive and Use Machines: There have been no studies to investigate the effect of lamivudine or zidovudine on driving performance or the ability to operate machinery. Further, a detrimental effect on such activities cannot be predicted from the pharmacology of the active substances. Nevertheless, the clinical status of the patient and the adverse event profile of lamivudine and zidovudine should be borne in mind when considering the patient's ability to drive or operate machinery.