NEDOCROMIL SODIUM

Fetal Risk Summary

Nedocromil sodium is an inhaled anti-inflammatory agent used in the prevention of asthma. Because of its mast cell stabilizing properties, it is also available as a 2% ophthalmic solution for the treatment of itching associated with allergic conjunctivitis. Its respiratory action appears to be similar to that of cromolyn sodium. Each activation of the meter delivers 1.75 mg nedocromil from the mouthpiece. In asthmatic patients, the absolute bioavailability after chronic dosing (2 activations four times/day for 1 month) was approximately 5% of the administered dose (1). No accumulation was observed after chronic use. With chronic administration in the eye, less than 4% of the total dose is absorbed systemically (2).

No effects on fertility in male and female mice and rats were observed with a SC dose of nedocromil sodium 100 mg/kg/day, about 30 and 60 times the maximum recommended human daily inhalation dose on a body surface area basis (MRHID), respectively (1). In reproduction studies, no evidence of teratogenicity or fetal harm was revealed when 100 mg/kg/day SC was given to pregnant mice, rats, and rabbits (30, 60, and 116 times the MRHID, respectively) (1). The SC dose was more than 1600 times the maximum recommended human daily ocular dose on a mg/kg basis (2).

It is not known if nedocromil sodium crosses the human placenta. The molecular weight of the drug (about 415) is low enough that transfer to the fetus should be expected. The low systemic bioavailability (e.g., mean peak plasma concentrations in the 1.6- to 2.8-ng/mL range [1]), however, suggests that the amounts reaching the embryo or fetus are clinically insignificant.

A report published in 1988 described three women who became pregnant while enrolled in a trial of nedocromil (3). All three were withdrawn from the study because of their pregnancy. One woman stopped the therapy 5 weeks after her last menstrual period. She and another woman (gestational age when therapy stopped not specified) had normal pregnancies. The third woman stopped nedocromil therapy at 8 weeks' gestation and had a spontaneous abortion 5 days later. The abortion was thought to be unrelated to treatment (3).

A 1998 non-interventional observational cohort study described the outcomes of pregnancies in women who had been prescribed one or more of 34 newly marketed drugs by general practitioners in England (4). Data were obtained by questionnaires sent to the prescribing physicians 1 month after the expected or possible date of delivery. In 831 (78%) of the pregnancies, a newly marketed drug was thought to have been taken during the 1st trimester with birth defects noted in 14 (2.5%) singleton births of the 557 newborns (10 sets of twins). In addition, two birth defects were observed in aborted fetuses. However, few of the aborted fetuses were examined. Nedocromil was taken during the 1st trimester in 35 pregnancies. The outcomes of these pregnancies included 1 spontaneous abortion; 8 elective abortions; 3 cases lost to follow-up; 22 normal, term infants; and 1 newborn with a birth defect (4). The birth defect, in an infant born to a 22-year-old woman, was categorized as congenital heart disease (no details given). Other maternal drug exposures in this case included aminophylline, corticosteroids, and salbutamol. Although the cause of the one major congenital malformation observed is unknown, the study lacks the sensitivity to identify minor anomalies because of the absence of standardized examinations. Late-appearing major defects may also have been missed because of the timing of the questionnaires.

In summary, the absence of animal embryo/fetal toxicity, the limited human systemic bioavailability, and the outcomes of the exposed human pregnancies appear to indicate that nedocromil sodium is not a major teratogenic risk. Although this assessment is based on limited pregnancy experience, the benefits in preventing maternal asthma probably outweigh any potential fetal harm. Because of the greater pregnancy experience, cromolyn sodium may be the preferred choice (see Cromolyn Sodium).

Breast Feeding Summary

No reports describing the use of nedocromil sodium during human lactation have been located. After IV administration, the drug is excreted into the milk of lactating rats (2). Although the molecular weight of the drug (about 415) is low enough to allow excretion into human breast milk, the very small amounts in the systemic circulation (see above) suggests that the potential for harm in a nursing infant is nil.

References

1. Product information. Tilade. Rhone-Poulenc Rorer Pharmaceuticals, 2000.
2. Product information. Alocril. Allergan, 2001.
3. Carrasco E, Sepulveda R. The acceptability, safety and efficacy of nedocromil sodium in long-term clinical use in patients with perennial asthma. J Int Med Res 1988;16:394–401.
4. Wilton LV, Pearce GL, Martin RM, Mackay FJ, Mann RD. The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. Br J Obstet Gynaecol 1998;105:882–9.