FDA Safety Changes: Epzicom, Trizivir, Tracleer

Yael Waknine

April 29, 2009

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April 29, 2009 — The US Food and Drug Administration (FDA) has approved safety labeling revisions to warn of the increased risk for potentially fatal hypersensitivity reactions in patients who carry the human leukocyte antigen allele B*5701 receiving abacavir sulfate, the potential increased risk for myocardial infarction in patients receiving combination antiretroviral therapy, and drug interactions between ritonavir-boosted lopinavir and bosentan that preclude their coadministration.

Genetic Screening Recommended Before Initiating Abacavir-Containing (Epzicom and Trizivir) Therapy

On March 9, the FDA approved safety labeling revisions for abacavir sulfate and lamivudine tablets and abacavir plus lamivudine and zidovudine tablets (Epzicom and Trizivir; GlaxoSmithKline) to warn of the increased risk for potentially fatal hypersensitivity reactions (HSRs) in patients who carry the human leukocyte antigen allele B*5701 (HLA-B*5701).

HSR is a multiorgan syndrome usually characterized by signs or symptoms from at least 2 of the following groups: fever, rash, gastrointestinal tract illness (nausea, vomiting, diarrhea, and abdominal pain), constitutional illness (generalized malaise, fatigue, or achiness), and respiratory tract illness (dyspnea, cough, or pharyngitis).

During the course of 9 clinical trials (n = 2760), the incidence of HSR reactions in abacavir-treated patients was 7.8%. Although symptoms appeared within 6 weeks of initiating therapy in 89% of affected patients, they may occur at any time. Median time to symptom onset was 9 days, with 95% of patients who reported symptoms from 2 or more of the 5 groupings listed above.

Less common signs and symptoms of HSR included lethargy, myolosis, edema, paresthesia, and abnormal findings on chest radiographs (predominantly infiltrates, which can be localized). Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, and death have also been reported.

In some patients, physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and rash. The rash usually appears as maculopapular or urticarial, but some cases of erythema multiforme have been reported.

Laboratory abnormalities associated with HSR may also be present, including elevated liver function tests, elevated creatine phosphokinase levels, elevated creatinine levels, and lymphopenia.

Screening for the allele is recommended before starting or restarting treatment with abacavir and abacavir-containing products. For those who test positive for HLA-B*5701, abacavir should be considered only under exceptional circumstances, when the potential benefit outweighs the risk for having an HSR. Patients in whom an abacavir-related HSR develops require immediate and permanent discontinuation of therapy, the FDA emphasized, noting that this also applies when other diagnoses are possible, and in patients who test negative for the HLA-B*5701 allele.

These recommendations were based in part on data from a prospective, double-blind study, showing that prescreening for HLA-B*5701 significantly decreased the risk for an abacavir-related HSR by 60% (3.4% vs 7.8%; P < .0001). Findings suggest that 61% of patients who test positive for the allele experience an abacavir-related HSR vs only 4.5% of those who test negative.

The findings were supported by data from a retrospective case-control study that demonstrated a strong association between the HLA-B*5701 allele and a clinically suspected abacavir-related HSR in both black and white patients.

The FDA notes that an Abacavir Hypersensitivity Registry has been established to facilitate HSR reporting and information collection. Patients may be registered by calling 1-800-270-0425.

Abacavir plus lamivudine tablets and abacavir plus lamivudine and zidovudine tablets are indicated for use with other antiretroviral agents in the treatment of HIV-1 infection.

Abacavir-Containing Antiretroviral Therapy (Epzicom and Trizivir) May Be Linked to MI Risk

On March 9, the FDA approved safety labeling revisions for abacavir sulfate and lamivudine tablets and abacavir plus lamivudine and zidovudine tablets (Epzicom and Trizivir; GlaxoSmithKline) to warn of the potential increased risk for myocardial infarction (MI) in patients receiving abacavir therapy.

The warning was based on data from a published prospective, observational, epidemiologic study known as D:A:D (Data Collection on Adverse Events of Anti-HIV Drugs), showing that the risk for MI was increased in patients who had received abacavir within the previous 6 months vs those who had not (per 1000 patient-years: 6.1 events vs 2.6 events; Δ = 3.5).

However, no excess risk for MI was observed in a sponsor-conducted pooled analysis of abacavir clinical trials (n = 9600). Although available data from the observational cohort and from clinical trials remain inconclusive, the FDA advises that the underlying risk for coronary heart disease be considered when prescribing antiretroviral therapies and precautions taken to minimize all modifiable risk factors such as hypertension, hyperlipidemia, diabetes mellitus, and smoking.

Abacavir plus lamivudine tablets and abacavir plus lamivudine and zidovudine tablets are indicated for use with other antiretroviral agents in the treatment of HIV-1 infection.

Bosentan (Tracleer) Contraindicated in Patients Receiving Ritonavir-Boosted Lopinavir

On March 17, the FDA approved safety labeling revisions for bosentan tablets (Tracleer; Actelion Pharmaceuticals, Ltd) to warn of drug interactions with ritonavir-boosted lopinavir.

Bosentan is metabolized by cytochrome P 450 hepatic isoenzymes 2C9 and 3A4 (CYP2C9 and CYP3A4). Inhibition of these enzymes may increase the plasma concentration of bosentan.

In a pharmacokinetic study, coadministration of lopinavir with ritonavir increased initial and steady-state bosentan trough plasma concentrations by approximately 48-fold and 5-fold, respectively, vs those achieved with bosentan alone.

According to the FDA, these elevations are most likely explained by inhibition by ritonavir of organic anion transporting polypeptide–mediated uptake into hepatocytes, but the potential for increased toxicity cannot be excluded. Coadministration of bosentan and lopinavir with ritonavir or other ritonavir-containing HIV regimens is contraindicated

Bosentan is indicated for the treatment of pulmonary arterial hypertension (World Health Organization [WHO] Group I) in patients with WHO class III or IV symptoms to improve exercise ability and decrease the rate of clinical worsening.

Ritonavir-boosted lopinavir is indicated with other antiretroviral agents for the treatment of HIV-1 infection.

Epzicom Prescribing Information

Trizivir Prescribing Information

Tracleer Prescribing Information

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