Combivir Special Precautions

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.
It is recommended that separate preparations of lamivudine and zidovudine should be administered in cases where dosage adjustment is necessary (see Dosage & Administration). In these cases the physician should refer to the individual prescribing information for these medicinal products.
The concomitant use of stavudine with zidovudine should be avoided (see Interactions).
Opportunistic infections: Patients receiving 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) and in patients with poor bone marrow reserve prior to treatment, particularly with advanced HIV disease. 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 e.g. haemoglobin <9 g/dl (5.59 mmol/l) or neutrophil count <1.0 x 10⁹/l (see Dosage & Administration). As dosage adjustment of Combivir is not possible separate preparations of zidovudine and lamivudine should be used. Physicians should refer to the individual prescribing information for these medicinal products.
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 the antiretroviral treatment or to the underlying HIV disease. Treatment with Combivir should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur.
Mitochondrial dysfunction following exposure in utero: Nucleoside and nucleotide analogues may impact mitochondrial function to a variable degree, which is most pronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues; these have predominantly concerned treatment with regimens containing zidovudine. The main adverse events reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactatemia, hyperlipasemia). These events have often been transitory. Late-onset neurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or permanent is currently unknown. These findings should be considered for any child exposed in utero to nucleoside and nucleotide analogues, who presents with severe clinical findings of unknown etiology particularly neurologic findings. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
Lipoatrophy: Treatment with zidovudine has been associated with loss of subcutaneous fat, which has been linked to mitochondrial toxicity. 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 not be reversible when switching to a zidovudine-free regimen. Patients should be regularly assessed for signs of lipoatrophy during therapy with zidovudine and zidovudine-containing products (Combivir and Trizivir). Therapy should be switched to an alternative regimen if there is suspicion of lipoatrophy development.
Weight and metabolic parameters: An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.
Immune Reactivation Syndrome: In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens 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 CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterium infections, and Pneumocystis jirovecii pneumonia (often referred to as PCP). Any inflammatory symptoms should be evaluated and treatment instituted when necessary. 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.
Liver disease: If lamivudine is being used concomitantly for the treatment of HIV and HBV, additional information relating to the use of lamivudine in the treatment of hepatitis B infection is available in the Zeffix SmPC.
The safety and efficacy of zidovudine has not been established in patients with significant underlying liver disorders.
Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk of severe and potentially fatal hepatic adverse events. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.
If Combivir is discontinued in patients co-infected with hepatitis B virus, periodic monitoring of both liver function tests and markers of HBV replication for 4 months is recommended, as withdrawal of lamivudine may result in an acute exacerbation of hepatitis.
Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.
Patients co-infected with hepatitis C virus: The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see Interactions).
Osteonecrosis: Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Combivir should not be taken with any other medicinal products containing lamivudine or medicinal products containing emtricitabine.
The combination of lamivudine with cladribine is not recommended (see Interactions).
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed.