Oral: This drug is only recommended for use during pregnancy (especially in the first trimester) when there are no alternatives and the benefit outweighs the risk.
Parenteral: This drug should not be withheld in severe malaria.

AU TGA pregnancy category: Not formally assigned to a pregnancy category.
US FDA pregnancy category: Not assigned.

Risk summary: Insufficient data available on use of this drug in pregnant women to inform a drug-related risk.

Comments:
-A pregnancy exposure registry is available.
-Since severe malaria is particularly hazardous during pregnancy, full dose parenteral therapy should be administered at any stage of pregnancy without delay.

Animal studies have revealed evidence of embryolethality, fetal malformations, and fetotoxicity. Pregnant rats administered a single IV dose at 1.5 mg/kg (about 0.1 times the clinical dose based on body surface area [BSA] comparisons) early during organogenesis resulted in complete postimplantation loss. Pregnant rats, rabbits, and cynomolgus monkeys dosed orally during organogenesis at 6 to 16.7 mg/kg/day (about 0.4- to 1-times the clinical dose based on BSA comparisons), 5 to 12 mg/kg/day (0.7- to 1.6-times the clinical dose based on BSA comparisons), and 12 mg/kg/day (about 1.6-times the clinical dose based on BSA comparisons), respectively, showed: in rats, dose-dependent postimplantation losses, with surviving fetuses showing cardiovascular (ventricular septal defects, abnormal origin of subclavian artery) and skeletal (e.g., bent and/or shortened scapulae, humeri, femurs, and fibulae) malformations with no maternal toxicity; in rabbits, cardiovascular (ventricular septal defects, abnormal origin of subclavian artery), skeletal (e.g., cleft sternebrae, shortened and/or displaced ribs), and brain (dilated ventricles, pons absent) malformations with no maternal toxicity plus (at 12 mg/kg/day) abortions and postimplantation loss; and in cynomolgus monkeys, increased embryonic death with surviving fetuses showing skeletal malformations (e.g., absolute length of ulna decreased). Animal studies suggest placental transfer to the fetus; after a radiolabeled dose was administered to pregnant rats, about 7% of detected radioactivity was found in fetoplacental tissues. Pregnancy outcomes reported from a prospective surveillance study with this IV drug are insufficient to identify a drug-related risk of major birth defects, miscarriage, or fetal death. Based on published literature from randomized controlled trials and cohort studies, no drug-related risk of major birth defects, miscarriage, or adverse maternal/fetal outcomes has been identified during use of the oral formulation and other artemisinin class drugs in pregnant women over several decades. The bioavailability of the oral formulation is expected to be significantly lower than the IV formulation; clinical relevance of studies involving oral exposure to this and other artemisinin class drug is unclear.

Reports of first trimester use of this IV drug, published randomized control trials, observational studies, and cohort studies in more than 1300 and 6500 women exposed in the first and second/third trimesters of pregnancy, respectively, to the oral formulation and other artemisinin class drugs (via various administration routes) have not shown an increase in major birth defects, miscarriage, or adverse maternal/fetal outcomes. Published epidemiologic studies have important methodological limitations which hinder data interpretation, including inability to control for confounders such as malaria infection severity, other underlying maternal diseases, maternal use of concomitant drugs, and missing information on administration route, dose, and duration of use.

To monitor the outcomes of pregnant women exposed to this drug, a pregnancy registry has been established. Healthcare providers are encouraged to report drug exposure and pregnant women are encouraged to report their pregnancy by contacting 1-855-526-4827 or www.amivas.com/our-products.

Malaria during pregnancy increases the risk for adverse pregnancy and neonatal outcomes (including maternal anemia, severe malaria, spontaneous abortion, stillbirths, preterm delivery, low birth weight, intrauterine growth retardation, congenital malaria, maternal and neonatal mortality).

US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

See references

According to limited data, a maternal dose of 200 mg orally produced low levels in milk; harmful effects in the nursing infant (especially if older than 2 months) would not be expected.

After a single 200 mg oral dose to nursing mothers (number not provided), this drug was undetectable in breast milk (less than 5 mcg/L) at any time. The active metabolite (dihydroartemisinin) reached a peak level in breast milk of about 35 mcg/L at 90 minutes after dosing; it was undetectable (less than 2.5 mcg/L) at 6 hours after dosing.

Vomiting occurred more often in breastfed infants given dihydroartemisinin and piperaquine as a malaria treatment than non-breastfed infants given the drugs; whether this finding applies to infants receiving dihydroartemisinin via breast milk has not been studied.

In general, the very small amounts of antimalarial drugs transferred in breast milk are insufficient to provide adequate protection against malaria. If prophylaxis is required, infants should receive recommended doses of antimalarial drugs. Current guidelines should be consulted for additional information.

Caution is recommended; withholding nursing for 6 hours after a dose should markedly reduce the dose received by the infant.

Excreted into human milk: Yes (low levels of active metabolite)

Comments:
-Developmental and health benefits of breastfeeding should be considered as well as the mother's clinical need for this drug.
-The effects in the nursing infant are unknown; potential side effects in the breastfed child due to this drug or the mother's underlying condition should be considered.

See references