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warnings and cautions
5 WARNINGS AND PRECAUTIONS Failure to administer atovaquone oral suspension with food may result in lower plasma atovaquone concentrations and may limit response to therapy. Patients with gastrointestinal disorders may have limited absorption resulting in suboptimal atovaquone concentrations. ( 5.1 ) Hepatotoxicity: Elevated liver chemistry tests and cases of hepatitis and fatal liver failure have been reported. ( 5.2 ) Severe Cutaneous Adverse Reactions (SCARs): Cases of SCARs such as Stevens-Johnson Syndrome (SJS) have been reported. SCARs can be life-threatening or fatal. If symptoms or signs of SCARs develop, discontinue atovaquone oral suspension immediately and institute appropriate therapy. ( 5.3 ) 5.1 Risk of Limited Oral Absorption Absorption of orally administered atovaquone oral suspension is limited but can be significantly increased when the drug is taken with food. Failure to administer atovaquone oral suspension with food may result in lower plasma atovaquone concentrations and may limit response to therapy. Consider therapy with other agents in patients who have difficulty taking atovaquone oral suspension with food or in patients who have gastrointestinal disorders that may limit absorption of oral medications [see Clinical Pharmacology ( 12.3 ) ]. 5.2 Hepatotoxicity Cases of cholestatic hepatitis, elevated liver enzymes, and fatal liver failure have been reported in patients treated with atovaquone [see Adverse Reactions ( 6.2 ) ]. If treating patients with severe hepatic impairment, closely monitor patients following administration of atovaquone. 5.3 Severe Cutaneous Adverse Reactions Cases of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson Syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and erythema multiforme (EM) have been reported in patients treated with atovaquone [see Adverse Reactions ( 6.2 )]. SCARs can be life-threatening or fatal. If symptoms or signs of SCARs develop, discontinue atovaquone immediately and institute appropriate therapy. Patients who have developed SCARs with the use of atovaquone must not receive atovaquone [see Contraindications ( 4 )].
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adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in another section of the labeling: Hepatotoxicity [see Warnings and Precautions ( 5.2 )] . Severe Cutaneous Adverse Reactions [see Warnings and Precautions ( 5.3 )]. PCP Prevention: The most frequent adverse reactions (≥25% that required discontinuation) were diarrhea, rash, headache, nausea, and fever. ( 6.1 ) PCP Treatment: The most frequent adverse reactions (≥14% that required discontinuation) were rash (including maculopapular), nausea, diarrhea, headache, vomiting, and fever. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact PAI Pharma at 1-800-845-8210 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Additionally, because many subjects who participated in clinical trials with atovaquone had complications of advanced human immunodeficiency virus (HIV) disease, it was often difficult to distinguish adverse reactions caused by atovaquone from those caused by underlying medical conditions. PCP Prevention Trials In 2 clinical trials, atovaquone oral suspension was compared with dapsone or aerosolized pentamidine in HIV-1-infected adolescent (13 to 18 years) and adult subjects at risk of PCP (CD4 count 2%) of Subjects with Selected Adverse Reactions Requiring Discontinuation of Treatment in the Dapsone Comparative PCP Prevention Trial All Subjects Adverse Reaction Atovaquone Oral Suspension 1,500 mg/day (n = 536) % Dapsone 100 mg/day (n = 521) % Rash 6.3 8.8 Nausea 4.1 0.6 Diarrhea 3.2 0.2 Vomiting 2.2 0.6 Aerosolized Pentamidine Comparative Trial: In the aerosolized pentamidine comparative trial (n = 549), the majority of subjects were white (79%), male (92%), and were primary prophylaxis patients at enrollment (58%); the mean age was 38 years. Subjects received atovaquone oral suspension once daily at a dose of 750 mg (n = 188) or 1,500 mg (n = 175) or received aerosolized pentamidine 300 mg every 4 weeks (n = 186); the median durations of exposure were 6.2, 6.0, and 7.8 months, respectively. Table 2 summarizes the clinical adverse reactions reported by ≥20% of the subjects receiving eithe...