Chemical formula: C₂₄H₂₈F₃N₃O₃ Molecular mass: 463.501 g/mol
The use of tafenoquine during pregnancy may cause hemolytic anemia in a fetus who is G6PD deficient. Treatment with tafenoquine during pregnancy is not recommended. Available data with use of tafenoquine in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, there were increased abortions, with and without maternal toxicity, when tafenoquine was given orally to pregnant rabbits at and above doses equivalent to about 0.4 times the clinical exposure based on body surface area comparisons. No fetotoxicity was observed at doses equivalent to the clinical exposure (based on body surface area comparisons) in a similar study in rats.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Malaria during pregnancy increases the risk for adverse pregnancy outcomes, including maternal anemia, prematurity, spontaneous abortion, and stillbirth.
Tafenoquine resulted in dose-related abortions when given orally to pregnant rabbits during organogenesis (Gestation Days 6 to 18) at doses of 7 mg/kg (about 0.4 times the clinical exposure based on body surface area comparisons) and above. Doses higher than 7 mg/kg were also associated with maternal toxicity (mortality and reduced body weight gain). In a similar study in rats, doses of 3, 10, or 30 mg/kg/day resulted in maternal toxicity (enlarged spleen, reduced body weight, and reduced food intake) but no fetotoxicity at the high dose (equivalent to the clinical exposure based on body surface area comparisons). There was no evidence of malformations in either species. In a pre- and postnatal development study in rats, tafenoquine administered throughout pregnancy and lactation produced maternal toxicity and a reversible decrease in offspring body weight gain and decrease in motor activity at 18 mg/kg/day, which is equivalent to about 0.6 times the clinical dose based on body surface area comparisons.
A breastfed infant with G6PD deficiency is at risk for hemolytic anemia from exposure to tafenoquine. Infant G6PD status should be checked before breastfeeding begins. tafenoquine is contraindicated in breastfeeding women when the infant is found to be G6PD deficient or the G6PD status of the infant is unknown.
There is no information regarding the presence of tafenoquine in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. In a breastfed infant with normal G6PD, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tafenoquine and any potential effects on the breastfed infant from tafenoquine or from the underlying maternal condition.
Check the infant’s G6PD status before maternal breastfeeding commences. If an infant is G6PD deficient, exposure to tafenoquine during breastfeeding may result in hemolytic anemia in the infant; therefore, advise the woman with an infant who has G6PD deficiency or whose G6PD status is unknown not to breastfeed for 3 months after the dose of tafenoquine.
Two-year oral carcinogenicity studies were conducted in rats and mice. Renal cell adenomas and carcinomas were increased in male rats at doses of 1 mg/kg/day and above (3 times the clinical exposure based on AUC comparisons). Tafenoquine was not carcinogenic in mice. Given the single-dose administration of tafenoquine, these findings may not represent a carcinogenicity risk to humans.
Tafenoquine did not cause mutations or chromosomal damage in 2 definitive in vitro tests (bacterial mutation assay and mouse lymphoma L5178Y cell assay) or in an in vivo oral rat micronucleus test.
In a rat fertility study, tafenoquine was given orally at 1.5, 5, and 15 mg/kg/day (up to about 0.5 times the human dose based on body surface area comparisons) to males for at least 67 days, including 29 days prior to mating, and to females from 15 days prior to mating through early pregnancy. Tafenoquine resulted in reduced number of viable fetuses, implantation sites, and corpora lutea at 15 mg/kg in the presence of maternal toxicity (mortality, piloerection, rough coat, and reduced body weight).
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.
The safety data described below reflect exposure to 4,129 subjects, of whom 810 received a 300-mg single dose of tafenoquine. Tafenoquine was evaluated in patients with P. vivax malaria (n=483) in 3 randomized, double-blind trials including a placebo-controlled trial comparing tafenoquine plus chloroquine (n=260) with chloroquine alone (Trial 1), a placebo-controlled dose-ranging trial (Trial 2) (n=57), and a hematologic safety trial (Trial 3, NCT02216123) (n=166).
In Trial 1, in patients with P. vivax malaria, the most common adverse reactions reported in ≥5% of patients treated with tafenoquine are listed in Table 1. Patients included in the trial had a mean age of 35 (range: 16 to 79 years), were 75% male and from the following regions: 70% Latin America (Brazil and Peru), 19% Southeast (SE) Asia (Thailand, Cambodia, and the Philippines), and 11% Africa (Ethiopia).
Table 1. Selected Adverse Reactionsa Reported in ≥5% of Patients with P. Vivax Malaria Receiving Tafenoquine in a Randomized, Active-Controlled Trial (Trial 1):
| Adverse Reaction | Chloroquine | Tafenoquine + Chloroquine |
|---|---|---|
| (n=133) | (n=260) | |
| % | % | |
| Dizziness | 3 | 8 |
| Nausea | 7 | 6 |
| Vomiting | 5 | 6 |
| Decreased Hemoglobin | 2 | 5 |
| Headache | 7 | 5 |
a Adverse reactions reported prior to Day 29 as subsequent adverse reactions can be confounded by recurrence of malaria or retreatment with another agent from the quinoline class.
Clinically significant adverse reactions with Tafenoquine 300-mg single dose in clinical trials (n=810) in ≤3% of subjects are listed below:
Psychiatric Disorders: Anxiety, insomnia, abnormal dreams.
Nervous System Disorders: Somnolence.
Laboratory Investigations: Increased blood creatinine, increased blood methemoglobin, increased alanine aminotransferase.
Immune System Disorders: Hypersensitivity reactions (e.g., angioedema, urticaria).
Eye Disorders: Vortex keratopathy, photophobia.
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