MALARONE SIDE EFFECTS

SIDE EFFECTS

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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Because MALARONE contains atovaquone and proguanil hydrochloride, the type and severity of adverse reactions associated with each of the compounds may be expected. The lower prophylactic doses of MALARONE were better tolerated than the higher treatment doses.

Prophylaxis of P. falciparum Malaria

In 3 clinical trials (2 of which were placebo-controlled) 381 adults (mean age 31 years) received MALARONE for the prophylaxis of malaria; the majority of adults were black (90%) and 79% were male. In a clinical trial for the prophylaxis of malaria, 125 pediatric patients (mean age 9 years) received MALARONE; all subjects were black and 52% were male. Adverse experiences reported in adults and pediatric patients, considered attributable to therapy, occurred in similar proportions of subjects receiving MALARONE or placebo in all studies. Prophylaxis with MALARONE was discontinued prematurely due to a treatment-related adverse experience in 3 of 381 (0.8%) adults and 0 of 125 pediatric patients.

In a placebo-controlled study of malaria prophylaxis with MALARONE involving 330 pediatric patients (aged 4 to 14 years) in Gabon, a malaria-endemic area, the safety profile of MALARONE was consistent with that observed in the earlier prophylactic studies in adults and pediatric patients. The most common treatment-emergent adverse events with MALARONE were abdominal pain (13%), headache (13%), and cough (10%). Abdominal pain (13% vs. 8%) and vomiting (5% vs. 3%) were reported more often with MALARONE than with placebo. No patient withdrew from the study due to an adverse experience with MALARONE. No routine laboratory data were obtained during this study.

Non-immune travelers visiting a malaria-endemic area received MALARONE (n = 1,004) for prophylaxis of malaria in 2 active-controlled clinical trials. In one study (n = 493), the mean age of subjects was 33 years and 53% were male; 90% of subjects were white, 6% of subjects were black and the remaining were of other racial/ethnic groups. In the other study (n = 511), the mean age of subjects was 36 years and 51% were female; the majority of subjects (97%) were white. Adverse experiences occurred in a similar or lower proportion of subjects receiving MALARONE than an active comparator (Table 3). Fewer neuropsychiatric adverse experiences occurred in subjects who received MALARONE than mefloquine. Fewer gastrointestinal adverse experiences occurred in subjects receiving MALARONE than chloroquine/proguanil. Compared with active comparator drugs, subjects receiving MALARONE had fewer adverse experiences overall that were attributed to prophylactic therapy (Table 1). Prophylaxis with MALARONE was discontinued prematurely due to a treatment-related adverse experience in 7 of 1,004 travelers.

Table 1: Adverse Experiences in Active-Controlled Clinical Trials of MALARONE for Prophylaxis of P. falciparum Malaria

In a third active-controlled study, MALARONE (n = 110) was compared with chloroquine/proguanil (n = 111) for the prophylaxis of malaria in 221 non-immune pediatric patients (2 to 17 years of age). The mean duration of exposure was 23 days for MALARONE, 46 days for chloroquine, and 43 days for proguanil, reflecting the different recommended dosage regimens for these products. Fewer patients treated with MALARONE reported abdominal pain (2% vs. 7%) or nausea ( < 1% vs. 7%) than children who received chloroquine/proguanil. Oral ulceration (2% vs. 2%), vivid dreams (2% vs. < 1%), and blurred vision (0% vs. 2%) occurred in similar proportions of patients receiving either MALARONE or chloroquine/proguanil, respectively. Two patients discontinued prophylaxis with chloroquine/proguanil due to adverse events, while none of those receiving MALARONE discontinued due to adverse events.

Treatment of Acute, Uncomplicated P. falciparum Malaria

In 7 controlled trials, 436 adolescents and adults received MALARONE for treatment of acute, uncomplicated P. falciparum malaria. The range of mean ages of subjects was 26 to 29 years; 79% of subjects were male. In these studies, 48% of subjects were classified as other racial/ethnic groups, primarily Asian; 42% of subjects were black and the remaining subjects were white. Attributable adverse experiences that occurred in ≥ 5% of patients were abdominal pain (17%), nausea (12%), vomiting (12%), headache (10%), diarrhea (8%), asthenia (8%), anorexia (5%), and dizziness (5%). Treatment was discontinued prematurely due to an adverse experience in 4 of 436 (0.9%) adolescents and adults treated with MALARONE.

In 2 controlled trials, 116 pediatric patients (weighing 11 to 40 kg) (mean age 7 years) received MALARONE for the treatment of malaria. The majority of subjects were black (72%); 28% were of other racial/ethnic groups, primarily Asian. Attributable adverse experiences that occurred in ≥ 5% of patients were vomiting (10%) and pruritus (6%). Vomiting occurred in 43 of 319 (13%) pediatric patients who did not have symptomatic malaria but were given treatment doses of MALARONE for 3 days in a clinical trial. The design of this clinical trial required that any patient who vomited be withdrawn from the trial. Among pediatric patients with symptomatic malaria treated with MALARONE, treatment was discontinued prematurely due to an adverse experience in 1 of 116 (0.9%).

In a study of 100 pediatric patients (5 to < 11 kg body weight) who received MALARONE for the treatment of uncomplicated P. falciparum malaria, only diarrhea (6%) occurred in ≥ 5% of patients as an adverse experience attributable to MALARONE. In 3 patients (3%), treatment was discontinued prematurely due to an adverse experience.

Abnormalities in laboratory tests reported in clinical trials were limited to elevations of transaminases in malaria patients being treated with MALARONE. The frequency of these abnormalities varied substantially across trials of treatment and were not observed in the randomized portions of the prophylaxis trials.

One active-controlled trial evaluated the treatment of malaria in Thai adults (n = 182); the mean age of subjects was 26 years (range 15 to 63 years); 80% of subjects were male. Early elevations of ALT and AST occurred more frequently in patients treated with MALARONE (n = 91) compared to patients treated with an active control, mefloquine (n = 91). On Day 7, rates of elevated ALT and AST with MALARONE and mefloquine (for patients who had normal baseline levels of these clinical laboratory parameters) were ALT 26.7% vs. 15.6%; AST 16.9% vs. 8.6%, respectively. By Day 14 of this 28-day study, the frequency of transaminase elevations equalized across the 2 groups.

Postmarketing Experience

In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of MALARONE. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to MALARONE.

Blood and Lymphatic System Disorders: Neutropenia and anemia. Pancytopenia in patients with severe renal impairment treated with proguanil..

Immune System Disorders: Allergic reactions including anaphylaxis, angioedema, and urticaria, and vasculitis.

Nervous System Disorders: Seizures and psychotic events (such as hallucinations); however, a causal relationship has not been established.

Gastrointestinal Disorders: Stomatitis.

Hepatobiliary Disorders: Elevated liver laboratory tests, hepatitis, cholestasis; hepatic failure requiring transplant has been reported.

Skin and Subcutaneous Tissue Disorders: Photosensitivity, rash, erythema multiforme, and Stevens-Johnson syndrome.