Abacavir Sulfate/Lamivudine Atlanta Medicare Special Precautions

Hypersensitivity Reaction: In clinical studies approximately 5% of subjects receiving abacavir develop a hypersensitivity reaction. Some of these cases were life-threatening and resulted in a fatal outcome despite taking precautions.
Studies have shown that carriage of the HLA-B*5701 allele is associated with a significantly increased risk of a hypersensitivity reaction to abacavir. Based on the prospective study CNA106030 (PREDICT-1), use of pre-therapy screening for the HLA-B*5701 allele and subsequently avoiding abacavir in patients with this allele significantly reduced the incidence of abacavir hypersensitivity reactions. In populations similar to that enrolled in the PREDICT-1 study, it is estimated that 48% to 61% of patients with the HLA-B*5701 allele will develop a hypersensitivity reaction during the course of abacavir treatment compared with 0% to 4% of patients who do not have the HLA-B*5701 allele.
These results are consistent with those of prior retrospective studies.
As a consequence, before initiating treatment with abacavir, screening for carriage of the HLA-B*5701 allele should be performed in any HIV-infected patient, irrespective of racial origin. Abacavir should not be used in patients known to carry the HLA-B*5701 allele, unless no other therapeutic option is available based on the treatment history and resistance testing.
In any patient treated with abacavir, the clinical diagnosis of suspected hypersensitivity reaction must remain the basis of clinical decision-making. It is noteworthy that among patients with a clinically suspected hypersensitivity reaction, a proportion did not carry HLA-B*5701. Therefore, even in the absence of HLA-B*5701 allele, it is important to permanently discontinue abacavir and not rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on clinical grounds, due to the potential for a severe or even fatal reaction.
Skin patch testing was used as a research tool for the PREDICT-1 study but has no utility in the clinical management of patients and therefore should not be used in the clinical setting.
Clinical Description: Hypersensitivity reactions are characterised by the appearance of symptoms indicating multi-organ system involvement. Almost all hypersensitivity reactions will have fever and/or rash as part of the syndrome.
Other signs and symptoms may include respiratory signs and symptoms such as dyspnoea, sore throat, cough, and abnormal chest x-ray findings (predominantly infiltrates, which can be localised), gastrointestinal symptoms, such as nausea, vomiting, diarrhoea, or abdominal pain, and may lead to misdiagnosis of hypersensitivity as respiratory disease (pneumonia, bronchitis, pharyngitis), or gastroenteritis. Other frequently observed signs or symptoms of the hypersensitivity reaction may include lethargy or malaise and musculoskeletal symptoms (myalgia, rarely myolysis, arthralgia).
The symptoms related to this hypersensitivity reaction worsen with continued therapy and can be life threatening. These symptoms usually resolve upon discontinuation of abacavir.
Clinical Management: Hypersensitivity reaction symptoms usually appear within the first six weeks of initiation of treatment with abacavir, although these reactions may occur at any time during therapy. Patients should be monitored closely, especially during the first two months of treatment with abacavir, with consultation every two weeks.
Patients who are diagnosed with a hypersensitivity reaction whilst on therapy MUST discontinue the fixed-dose combination Abacavir 600 mg / Lamivudine 300 mg tablets immediately.
The fixed-dose combination Abacavir / Lamivudine 600 mg / 300 mg, or any other medicinal product containing abacavir (Ziagen or Trizivir), MUST NEVER be restarted in patients who have stopped therapy due to a hypersensitivity reaction. Restarting abacavir following a hypersensitivity reaction results in a prompt return of symptoms within hours. This recurrence is usually more severe than on initial presentation, and may include life-threatening hypotension and death.
To avoid a delay in diagnosis and minimise the risk of a life-threatening hypersensitivity reaction, the fixed-dose combination Abacavir 600 mg / Lamivudine 300 mg tablets must be permanently discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible (respiratory diseases, flu-like illness, gastroenteritis or reactions to other medicinal products).
Special care is needed for those patients simultaneously starting treatment with the fixed-dose combination Abacavir 600 mg / Lamivudine 300 mg tablets and other medicinal products known to induce skin toxicity (such as non-nucleoside reverse transcriptase inhibitors - NNRTIs). This is because it is currently difficult to differentiate between rashes induced by these products and abacavir related hypersensitivity reactions.
Management after an interruption of the fixed-dose combination Abacavir 600 mg / Lamivudine 300 mg tablets therapy: If therapy with the fixed-dose combination Abacavir 600 mg / Lamivudine 300 mg tablets has been discontinued for any reason and restarting therapy is under consideration, the reason for discontinuation must be established to assess whether the patient had any symptoms of a hypersensitivity reaction. If a hypersensitivity reaction cannot be ruled out, the fixed-dose combination Abacavir 600 mg / Lamivudine 300 mg tablets or any other medicinal product containing abacavir (Ziagen or Trizivir) must not be restarted.
Hypersensitivity reactions with rapid onset, including life-threatening reactions have occurred after restarting abacavir in patients who had only one of the key symptoms of hypersensitivity (skin rash, fever, gastrointestinal, respiratory or constitutional symptoms such as lethargy and malaise) prior to stopping abacavir. The most common isolated symptom of a hypersensitivity reaction was a skin rash. Moreover, on very rare occasions hypersensitivity reactions have been reported in patients who have restarted therapy, and who had no preceding symptoms of a hypersensitivity reaction. In both cases if a decision is made to restart abacavir this must be done in a setting where medical assistance is readily available.
Lactic acidosis: Lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, has been reported with the use of nucleoside analogues. Early symptoms (symptomatic hyperlactatemia) include benign digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (including motor weakness).
Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure, or renal failure.
Lactic acidosis generally occurred after a few or several months of treatment.
Treatment with nucleoside analogues should be discontinued in the setting of symptomatic hyperlactatemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels.
Caution should be exercised when administering nucleoside analogues to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain medicinal products and alcohol). Patients co-infected with hepatitis C and treated with alpha interferon and ribavirin may constitute a special risk.
Patients at increased risk should be followed closely.
Lipodystrophy: Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors (PIs) and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs) has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate.
Pancreatitis: Pancreatitis has been reported, but a causal relationship to lamivudine and abacavir is uncertain.
Triple nucleoside therapy: There have been reports of a high rate of virological failure, and of emergence of resistance at an early stage when abacavir and lamivudine were combined with tenofovir disoproxil fumarate as a once daily regimen.
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 SPC.
The safety and efficacy of the fixed-dose combination Abacavir 600 mg / Lamivudine 300 mg tablets has not been established in patients with significant underlying liver disorders. The fixed-dose combination Abacavir 600 mg / Lamivudine 300 mg tablets is contraindicated in patients with severe hepatic impairment.
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 the fixed-dose combination Abacavir 600 mg / Lamivudine 300 mg tablets is discontinued in patients co-infected with hepatitis B virus, periodic monitoring of both liver function tests and markers of HBV replication is recommended, as withdrawal of lamivudine may result in an acute exacerbation of hepatitis (see Zeffix SPC).
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.
Mitochondrial dysfunction: Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues. The main adverse events reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactatemia, hyperlipasemia). These events are often transitory. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or permanent is currently unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV-negative children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
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 mycobacterial infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.
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.
Opportunistic infections: Patients should be advised that the fixed-dose combination Abacavir 600 mg / Lamivudine 300 mg tablets or any other antiretroviral therapy does not cure HIV infection and that they may still develop opportunistic infections and other complications of HIV infection. Therefore patients should remain under close clinical observation by physicians experienced in the treatment of these associated HIV diseases.
Transmission of HIV: Patients should be advised that current antiretroviral therapy, including the fixed-dose combination Abacavir 600 mg / Lamivudine 300 mg tablets, 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.
Myocardial infarction: Observational studies have shown an association between myocardial infarction and the use of abacavir. Those studied were mainly antiretroviral experienced patients. Data from clinical trials showed limited numbers of myocardial infarction and could not exclude a small increase in risk. Overall the available data from observational cohorts and from randomised trials show some inconsistency so can neither confirm nor refute a causal relationship between abacavir treatment and the risk of myocardial infarction. To date, there is no established biological mechanism to explain a potential increase in risk. When prescribing the fixed-dose combination Abacavir 600 mg / Lamivudine 300 mg tablets, action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).
Excipients: The fixed-dose combination Abacavir 600 mg / Lamivudine 300 mg tablets contains the azo colouring agent sunset yellow, which may cause allergic reactions.
Effects on Ability to Drive and Use Machines: No studies on the effects on ability to drive and use machines have been performed. The clinical status of the patient and the adverse event profile of the fixed-dose combination Abacavir 600 mg / Lamivudine 300 mg tablets should be borne in mind when considering the patient's ability to drive or operate machinery.