Long-term safety of the tafenoquine antimalarial chemoprophylaxis regimen: A 12-month, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Tafenoquine is a long-acting 8-aminoquinoline approved for antimalarial prophylaxis for ≤6 months. Additional data is needed to establish the drug's longer-term safety profile, including potential ophthalmic or neuropsychiatric effects. METHOD: This was a randomized, double-blind, placebo-controlled trial in 600 healthy adults. Eligible subjects were randomized 1:1 to receive tafenoquine 200 mg weekly (antimalarial prophylactic regimen) or placebo for 52 weeks. Scheduled safety visits occurred at Weeks 4, 12, 24, 52 (dosing completed), and 64 (final follow-up). Safety assessments included ophthalmic changes, general and neuropsychiatric adverse events (AEs), and laboratory value changes. RESULTS: The percentage of subjects with a protocol-defined Serious Ophthalmic Safety Event was lower in the Tafenoquine Group (18.2%) versus the Placebo Group (19%, p = 0.308). There was no significant difference between the percentages of subjects with at least one AE in the Tafenoquine Group (91.0%) versus Placebo (89.9%, p = 0.65). Common AEs seen at a significantly higher incidence for tafenoquine included reversible cornea verticillata (54.5%) and nausea (13.0%), leading to 0.0% and 0.7% discontinuations. Psychiatric AEs occurred at similar percentages in both study groups. Reversible changes in hemoglobin, methemoglobin, creatinine, and blood urea nitrogen (BUN) were noted. CONCLUSIONS: This study supports the safety of extended 52-week tafenoquine prophylaxis. CLINICAL TRIAL REGISTRATION NUMBER/CLINICALTRIALS. GOV IDENTIFIER: NCT03320174.

Tafenoquine for malaria prophylaxis in adults: An integrated safety analysis.

BACKGROUND: Tafenoquine is a new prophylactic antimalarial drug. The current analysis presents an integrated safety assessment of the Tafenoquine Anticipated Clinical Regimen (Tafenoquine ACR) from 5 clinical trials, including 1 conducted in deployed military personnel and 4 in non-deployed residents, which also incorporated placebo and mefloquine comparator groups. METHODS: Adverse events (AEs) were coded according to the Medical Dictionary for Regulatory Activities (MedDRA®, Version 15.0) and summarized. Among all subjects who had received the Tafenoquine ACR, safety findings were compared for subjects who were deployed military personnel from the Australian Defence Force (Deployed ADF) versus non-deployed residents (Resident Non-ADF). RESULTS: The incidence of at least one AE was 80.6%, 64.1%, 67.6% and 94.9% in the mefloquine, placebo, tafenoquine Resident Non-ADF and tafenoquine Deployed ADF groups, respectively. The latter group had a higher incidence of AEs related to military deployment. AEs that occurred at ≥ 1% incidence in both tafenoquine sub-groups and at a higher frequency than placebo included diarrhea, nausea, vomiting, gastroenteritis, nasopharyngeal tract infections, and back/neck pain. CONCLUSIONS: Weekly administration of tafenoquine for up to six months increased the incidence of gastrointestinal AEs, certain infections, and back/neck pain, but not the overall incidence of AEs versus placebo. CLINICAL TRIAL REGISTRATION NUMBERS/CLINICALTRIALS. GOV IDENTIFIERS: NCT02491606; NCT02488980; NCT02488902.

Intravenous Artesunate for the Treatment of Severe and Complicated Malaria in the United States: Clinical Use Under an Investigational New Drug Protocol.

BACKGROUND: Quinidine gluconate, the only U.S. Food and Drug Administration-approved treatment for life-threatening malaria in the United States, has a problematic safety profile and is often unavailable in hospitals. OBJECTIVE: To assess the safety and clinical benefit of intravenous artesunate as an alternative to quinidine. DESIGN: Retrospective case series. SETTING: U.S. hospitals. PATIENTS: 102 patients aged 1 to 72 years (90% adults; 61% men) with severe and complicated malaria. Patients received 4 weight-based doses of intravenous artesunate (2.4 mg/kg) under a treatment protocol implemented by the Centers for Disease Control and Prevention between January 2007 and December 2010. At baseline, 35% had evidence of cerebral malaria, and 17% had severe hepatic impairment. Eligibility required the presence of microscopically confirmed malaria, need for intravenous treatment, and an impediment to quinidine. MEASUREMENTS: Clinical and laboratory data from each patient's hospital records were abstracted retrospectively, including information from baseline through a maximum 7-day follow-up, and presented before a physician committee to evaluate safety and clinical benefit outcomes. RESULTS: 7 patients died (mortality rate, 6.9%). The most frequent adverse events were anemia (65%) and elevated hepatic enzyme levels (49%). All deaths and most adverse events were attributed to the severity of malaria. Patients' symptoms generally improved or resolved within 3 days, and the median time to discharge from the intensive care unit was 4 days, even for patients with severe liver disease or cerebral malaria. More than 100 concomitant medications were used, with no documented drug-drug interactions. LIMITATION: Potential late-presenting safety issues might occur outside the 7-day follow-up. CONCLUSION: Artesunate was a safe and clinically beneficial alternative to quinidine.