Antiviral
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >>Embryo/Fetal Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
Reports describing the use of zanamivir during five human pregnancies have been located. Although the animal data suggest low risk, the near absence of human pregnancy experience prevents an assessment of the risk to the embryo–fetus. Nevertheless, if the drug is indicated in a pregnant woman, the maternal benefit outweighs the unknown embryo–fetal risk.
FETAL RISK SUMMARY
Zanamivir is formulated as a powder to be administered by oral inhalation. The agent is thought to act by inhibiting influenza virus neuraminidase with the possibility of alteration of virus particle aggregation and release. Zanamivir is indicated for the treatment of uncomplicated acute illness due to influenza A and B virus in patients who have been symptomatic for no more than 2 days. It is also indicated for prophylaxis of influenza in patients aged 5 years and older. The systemic bioavailability of the drug is approximately 4%–17%, plasma protein binding is <10%, and it is excreted unchanged (no metabolites have been detected) in the urine with a serum elimination half-life of 2.5–5.1 hours (1). In April, 2009, the FDA issued an Emergency Use Authorization to allow zanamivir to be used to treat and prevent influenza in children under 1 year of age, and to provide alternate dosing recommendations for children older than 1 year (2).
Reproduction studies with IV or SC zanamivir have been conducted in rats and rabbits. In pregnant rats, the highest IV daily doses administered produced exposures that were >300 times the human exposure from the clinical dose based on AUC (HE). Drug administration, during gestational days 6–15 or during gestational day 16 until litter day 21–23, revealed no evidence of malformations, embryotoxicity, or maternal toxicity. In a different strain of rats administered SC zanamivir 3 times daily during gestational days 7–17, the highest SC dose produced exposures that were >1000 times the HE. In this study, minor skeletal alterations and variations were observed in the exposed offspring, but the incidence of these effects was within the background rates for the strain studied. In pregnant rabbits, IV doses (identical to the rat doses, but relationship to human dose not specified) administered during gestational days 7–19 revealed no evidence of malformations, embryotoxicity, or maternal toxicity (1).
Zanamivir was not carcinogenic in 2-year studies in mice and rats, was not mutagenic in multiple assays, and did not impair fertility or mating in male and female rats (1).
It is not known if zanamivir crosses the human placenta. The molecular weight (about 332), combined with the lack of metabolism and plasma protein binding, and the moderately long elimination half-life, suggest that the drug will cross to the embryo–fetus. However, the low systemic bioavailability after oral inhalation should limit the amount of drug available for crossing at the maternal:fetal interface.
A 1999 review on the safety of zanamivir briefly described three pregnancies inadvertently exposed during clinical trials (3). The pregnancy outcomes were one spontaneous abortion, one elective abortion, and one healthy baby born 2 weeks early. These results were similar to four pregnancies exposed to placebo in the same clinical trials. A 2009 review concluded that unvaccinated women who come in contact with the H1N1 virus should receive prophylactic antiviral therapy and, although the pregnancy data are limited, it was reassuring (4). Another 2009 review mentioned a woman in Japan who had taken zanamivir at 4 weeks’ gestation and gave birth to a healthy baby at term (no other details provided) (5).
A 2010 case report from Thailand described the fatal outcome of a pregnancy treated with nebulized zanamivir (6). The 25-year-old woman at 26 weeks’ gestation presented with influenza A (H1N1) pneumonia. Treatment with oral oseltamivir, nebulized zanamivir, and IV dexamethasone was started. The patient was ventilated but the ventilator constantly malfunctioned, eventually leading to the patient’s death. The problem was traced to filter blockade caused by the lactose in the double doses of zanamivir (20 mg) commonly used in Thailand at the time (6).
BREASTFEEDING SUMMARY
No reports describing the use of zanamivir during human lactation have been located, but two 2009 reviews consider the drug to be compatible with breastfeeding (4,5). The molecular weight (about 332), moderately long elimination half-life, and the lack of metabolism and plasma protein binding suggest that the drug will be excreted into breast milk. However, the low systemic bioavailability after oral inhalation should limit the amount of drug excreted into breast milk. The effect, if any, of this exposure on a nursing infant is unknown, but the risk of harm appears to be low.
References
1.Product information. Relenza. GlaxoSmithKline, 2013.
2.FDA News Release. FDA authorizes emergency use of influenza medicines, diagnostic test in response to swine flu outbreak in humans. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149571.htm. Accessed October 30, 2013.
3.Freund B, Gravenstein S, Elliott M, Miller I. Zanamivir—a review of clinical safety. Drug Saf 1999;21:267–81.
4.Bozzo P, Djokanovic N, Koren G. H1N1 influenza in pregnancy: risks, vaccines, and antivirals. J Obstet Gynaecol Can 2009;31:1172–5.
5.Tanaka T, Nakajima K, Murashima A, Garcia-Bournissen F, Koren G, Ito S. Safety of neuraminidase inhibitors against novel influenza A (H1N1) in pregnant and breastfeeding women. CMAJ 2009;181:55–8.
6.Kiatboonsri S, Kiatboonsri C, Theerawit P. Fatal respiratory events caused by zanamivir nebulization. Clin Infect Dis 2010;50:620.