Malaria: This drug should not be used during pregnancy unless the benefit outweighs risk to the fetus.
Nocturnal leg cramps: Use is not recommended.

AU TGA pregnancy category: D
US FDA pregnancy category: Not assigned.

Risk summary: Prolonged experience with this drug in pregnant women over several decades have not identified a drug-related risk.

Comments:
-According to some authorities: The use of antimalarials to treat malaria or as prophylaxis in high-risk situations is considered acceptable since the risk to the fetus is outweighed by the benefits to the mother and fetus.
-According to some authorities: Pregnancy in a malaria patient is not generally considered a contraindication to use this drug; it should not be withheld from pregnant women with life-threatening malaria if other agents are inappropriate.
-According to some experts: This drug has been routinely used in the treatment of malaria.
-Large doses of this drug can induce abortion; congenital malformations of the auditory and optic nerves have been reported after this drug failed to induce abortion.

Animal studies have revealed evidence of embryofetal toxicity, teratogenicity, impaired male fertility, and fetal death. Published prospective and retrospective observational studies, surveys, safety and efficacy studies, review articles, case reports, and case series have not identified a drug-related risk of major birth defects, miscarriage, or adverse maternal/fetal outcomes. In studies with more than 893 pregnant women treated with this drug for malaria in the first trimester, no drug-related increases in the incidence of congenital anomalies were observed compared with other antimalarial agents.

Malaria during and after 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).

An increased incidence of hypoglycemia (due to increased pancreatic secretion of insulin) has been reported with use of this drug in pregnant women, especially during the third trimester; glucose levels should be monitored in pregnant women using this drug. Commonly reported side effects with this drug in pregnant women include tinnitus, vomiting, dizziness, and nausea. Pregnant women have risk for a rare triad of complications: massive hemolysis, hemoglobinemia, and hemoglobinuria.

In high doses, this drug causes fetal harm including deafness, development disturbances, and extremity and cranium malformations.

There is no evidence that this drug causes uterine contractions at doses recommended to treat malaria; in doses several times higher than those used for malaria treatment, this drug may stimulate the pregnant uterus.

This drug crosses the placenta with measurable blood levels in the fetus. In 8 women who delivered live infants 1 to 6 days after starting this drug, umbilical cord plasma drug levels were between 1 and 4.6 mg/L (mean 2.4 mg/L) and the mean ratio of cord plasma to maternal plasma drug levels was 0.32. Drug levels in the fetus may not be therapeutic.

During a retrospective study of women with Plasmodium falciparum malaria, difference in the rate of stillbirths at greater than 28 weeks of gestation was not significant in pregnant women treated with quinine sulfate (10 mg/kg orally 3 times a day for 7 days) compared to a control group without malaria or exposure to antimalarial agents during pregnancy. The overall rate of congenital malformations was not different for women treated with this drug (1.4%) compared with the control group (1.7%). The rate of spontaneous abortion was lower in women treated with this drug (3.5%) than in the control group (10.9%).

In an epidemiologic survey, risk of structural birth defects was not increased in 104 mother-child pairs exposed to this drug during the first 4 months of pregnancy; 2 fetal malformations (1.9%) were reported. Case reports describe deafness and optic nerve hypoplasia in children exposed in utero due to maternal ingestion of high doses.

In a published study of 5 men administered 600 mg (as tablets) orally 3 times a day for 1 week, sperm motility decreased and percent sperm with abnormal morphology increased; sperm count and serum testosterone were unaffected.

AU TGA pregnancy category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.

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

Since levels of this drug in breast milk are low, amounts ingested by infants are small and would not be expected to cause harmful effects in the nursing infant. The amount in milk is considerably less than the dose needed to treat an infant for malaria.

In 1 study, this drug was administered to 25 lactating women (10 mg/kg orally every 8 hours for 1 to 10 days); no toxicity was reported in their nursing infants. Drug levels in breast milk were about 31% of drug levels in maternal plasma. It was estimated that breastfed infants would receive less than 2 to 3 mg/day of quinine base (less than 0.4% of maternal dose) via breast milk.

In 1 old study, drug levels in milk from 6 women were measured at various times after 2 to 3 doses (300 or 640 mg). Milk levels ranged from traces to 4.4 mg/L (average about 0.8 mg/L); time to peak milk levels varied from 1.5 to 6.4 hours after dosing.

An unpublished study showed milk levels were about one-third of simultaneous plasma levels; according to author estimation, an infant would receive 1.5 to 3 mg/day of quinine base with maternal therapy.

A group of investigators studied 30 women who received this drug IV or orally while breastfeeding; 2 publications reported data from the same group of women. In 1 paper, milk levels reported after IV administration appeared to be the levels after oral use and vice versa; this was apparently corrected in the later publication. To summarize: after quinine sulfate (600 mg orally every 8 hours for 7 days) in 25 women, random breast milk drug levels averaged 2.6 mg/L (range: 0.5 to 3.6 mg/L); in 3 of the women who had just started lactation, colostrum levels were 0.4, 0.9, and 1.9 mg/L; after quinine dihydrochloride (10 mg salt/kg/day [8.3 mg base/kg/day] IV for 2 to 7 doses) in 5 women, random breast milk drug levels averaged 3.4 mg/L (range: 0.5 to 8 mg/L).

After maternal ingestion of drinks containing quinine (e.g., tonic water), severe hemolysis developed in 4 breastfed infants of 3 mothers (3 boys, 1 girl; 1 set of twins); the 4 infants had low levels of G6PD and were jaundiced on admission. Breastfeeding and tonic water were stopped and with phototherapy and/or transfusion, the jaundice resolved. At discharge, 1 of the infants who was severely jaundiced had abnormal brainstem auditory evoked potentials; at 4 months of age, he had slightly decreased reactivity and profound bilateral deafness. The breast milk of 1 of the mothers was qualitatively positive for quinine.

LactMed: This drug should not be used in mothers with a glucose-6-phosphate dehydrogenase (G6PD)-deficient infant.
WHO and other experts: Use is considered acceptable.
-According to some authorities: Caution is recommended.
-According to some authorities: Use is not recommended unless the benefits outweigh the risks.

Excreted into human milk: Yes (in small amounts)

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.
-At-risk infants should not be breastfed until G6PD deficiency can be ruled out.
-WHO: Infants should be monitored for hemolysis and jaundice, especially if premature or younger than 1 month.
-WHO and other experts: Use should be avoided in G6PD-deficient infants.
-This drug is considered compatible with breastfeeding by the American Academy of Pediatrics.

See references