32 Clinical Rounds Women’s Health I NTERNAL M EDICINE N EWS • July 15, 2005

D RUGS, PREGNANCY, FDA Downgrades Efavirenz A ND L ACTATION To Pregnancy Category D Migraine Drugs

BY JANE SALODOF MACNEIL live births after second- or third-trimester igraine symptoms improve in around the time of conception, and ex- Southwest Bureau exposures. Dr. Lewis-Hall did not de- up to 70% of women during posure in the third trimester is associ- scribe the birth defects, except to say Mpregnancy, usually during the ated with premature closure of the he Food and Drug Administration they were not neural tube defects, which, second and third trimesters. But in 4%- ductus arteriosus with the risk of per- has downgraded efavirenz to preg- so far, have only been seen in retrospec- 8% of women, migraines worsen, and sistent pulmonary hypertension of the Tnancy category D, “Positive Evi- tive reports. as many as 16% of all migraine cases newborn. dence of Fetal Risk,” and is urging women “Although a causal relationship of these during pregnancy may be new onset. Since aspirin causes irreversible inhi- to avoid becoming pregnant while taking events to the use of Sustiva has not been A 2002 review identified drugs or drug bition of platelet function and other the antiretroviral drug. established, similar defects have been ob- classes used for preventing migraine at- clotting disorders, its use near term The new package label stems from four served in preclinical studies of efavirenz,” tacks (N. Engl. J. Med. 2002;346:257-70), may enhance maternal blood loss at de- retrospective reports of women who gave she wrote. Her letter cited a preclinical including four drugs available in the livery and increase the incidence of in- birth to infants with neural tube defects af- animal study that reported malforma- United States that were considered well- tracranial hemorrhage in premature ter first trimester exposure to efavirenz tions in 3 of 20 fetuses from cynomolgus accepted treatments or had proved to be infants. Use of corticosteroids in the (Sustiva). Three infants were diagnosed monkeys treated with efavirenz through- effective: metoprolol, pro- first trimester is associat- with meningomyelocele and one with out pregnancy. pranolol, amitriptyline, ed with a low risk of oral Dandy Walker syndrome. Gerald G. Briggs, B. Pharm., told this and valproate. Verapamil clefts. Ergot alkaloid Physicians are being asked to report newspaper that data from pregnancy reg- (Calan, Isoptin) and selec- preparations are con- pregnant patients exposed to efavirenz to istries and retrospective reports should be tive serotonin-reuptake in- traindicated in pregnancy the Antiretroviral Pregnancy Registry viewed as identifying possible signals and hibitors (SSRIs) also were because of dose-related (800-258-4263), which was established to raising hypotheses. “Follow-up controlled widely used, but the re- developmental toxicity monitor fetal outcomes. The drug had pre- studies are needed to determine if the as- viewers concluded that and oxytocic properties. viously been labeled category C: “Risk of sociation is causative,” said Mr. Briggs, a there was poor evidence of In the United States, Fetal Harm Cannot Be Ruled Out.” pharmacist clinical specialist at Women’s benefit. Gabapentin (Neu- seven triptans indicated Bristol-Myers Squibb Co., Princeton, Pavilion at Miller Children’s Hospital, rontin) and topiramate for the short-term treat- N.J., alerted health care providers to the la- Long Beach, Calif. (Topamax), were consid- ment of migraine with bel change in a letter dated March 2005 He did not rule out prescribing ered promising for mi- BY GERALD G. or without aura are avail- and made public in June. Signed by Freda efavirenz for a pregnant woman who is graine prophylaxis. BRIGGS, B. PHARM. able: sumatriptan (Im- C. Lewis-Hall, M.D., senior vice president positive for HIV. If she cannot take an al- Only amitriptyline, ver- itrex), almotriptan (Ax- for medical affairs, the letter urged preg- ternative nonnucleoside reverse tran- apamil, and low-dose propranolol (30-40 ert), eletriptan (Relpax), frovatriptan nancy testing before women start on scriptase inhibitor and has done well on mg/day) have sufficient data to be clas- (Frova), naratriptan (Amerge), riza- efavirenz. efavirenz, he recommended continuing sified as low risk throughout pregnancy. triptan (Maxalt), and zolmitriptan “Though there are no adequate, well- her on the drug. But higher doses of propranolol may (Zomig). Triptans do not appear to be controlled studies in pregnant women, “Taken in sum, the data suggest that cause intrauterine growth retardation major teratogens in humans, but more Sustiva should be used during the first there may be a small risk of neural tube (IUGR) and other fetal/neonatal toxici- data are needed to adequately assess trimester of pregnancy only if the poten- defects and other defects, but no neural ty. Based on the drug class (antihista- this risk. tial benefit justifies the potential risk to the tube defects were observed in 188 prospec- mine and calcium channel blocker), flu- In animal studies at doses or sys- fetus, such as in pregnant women without tive cases, so the risk must be low,” he said. narizine is probably compatible with temic exposures 10 times the human other therapeutic options,” Dr. Lewis-Hall As in all potential pregnancies, he added, pregnancy. Gabapentin and topiramate dose, triptans caused developmental advised. “Barrier contraception should al- the woman should be taking folic acid be- should be avoided in the first trimester toxicity. Human data, primarily from ways be used in combination with other fore conception. “It may not be preven- because of inadequate human data to pregnancy registries, are available only contraceptive methods.” tive,” Mr. Briggs said, “but based on the assess their risk. Valproate is known to for naratriptan, sumatriptan, and riza- Dr. Lewis-Hall described a prospective potential signal, I would recommend the cause neural tube defects and other triptan. As of early 2004, about 500 review of pregnancy outcomes for 206 same folic acid dose used for anticonvul- structural anomalies if used in the first women had been prospectively en- women who carried 207 fetuses, while ex- sants known to cause neural tube defects trimester, and use of metoprolol during rolled, about 90% with first-trimester posed to efavirenz. Five of 188 infants and for women with a history of giving the second and third trimesters is asso- exposure. Except for a small cluster of born after first-trimester exposure had birth to an infant with a neural tube defect: ciated with an increased risk of IUGR. five ventricular septal defects, a com- birth defects; none were observed in 13 4 or 5 mg per day.” ■ Use of the SSRIs in the third trimester mon heart condition, there was no may cause newborn toxicity, and methy- consistent pattern of defects to suggest sergide and other ergot alkaloids are a common cause. contraindicated in pregnancy. Other than ergot drugs (contraindi- Pregnant Smokers: Cutting Back in Many other drugs have been used in cated) and amitriptyline (concern for treating migraines, including: aceta- long-term neurotoxicity), all antimi- Third Trimester Is Better Than Never minophen (alone, or in combination graine agents appear to be compatible with caffeine and butalbital, aspirin and with breast-feeding. However, there are L OS A NGELES — A pregnant smoker 18.2 cigarettes a day. They had already cut caffeine, or isometheptene and dichlo- few or no data available for gabapentin who cuts back by just one cigarette a day down to 6.7 cigarettes per day by the time ralphenazone); NSAIDs, including as- and topiramate. Ergot alkaloids may in- in her third trimester can hope to increase they enrolled in the study, which was at 12 pirin; chlorpromazine (Thorazine); hibit lactation, and high doses have her newborn’s birth weight by 24 g, ac- weeks’ gestation on average. By 28 weeks, dimenhydrinate (Dramamine); diphen- been associated with toxicity in nursing cording to a prospective study reported at they were down to 4.8 cigarettes daily. hydramine (Benadryl); morphine; infants. The effect of triptans on a nurs- the annual meeting of the Society for Gy- All had singleton pregnancies with a meperidine; intranasal butorphanol ing infant is unknown, but the small necologic Investigation. mean birth weight of 3,266 g. The mean (Stadol); and corticosteroids. amount of drug found in milk does not The message is, “Don’t stop trying to get gestational age at delivery was 38.6 weeks, Combination products with butal- appear to represent a risk and it is prob- women to reduce their smoking volume,” with 17 babies born preterm. bital are not recommended because in able that they are all compatible with said Ira M. Bernstein, M.D., who present- Smoking in the third trimester account- studies, the butalbital component did breast-feeding. ed data on 160 women and their offspring. ed for 10% of variance in birthweight. Dr. not increase efficacy. Acetaminophen, The mothers were enrolled in a ran- Bernstein reported a linear relationship in caffeine, dimenhydrinate, diphenhy- MR. BRIGGS is pharmacist clinical domized, prospective trial of a voucher which babies weighed 24 g less at birth for dramine, narcotic analgesics, lidocaine, specialist, Women’s Pavilion at Miller system designed to help pregnant women every cigarette their mothers smoked per and butorphanol are compatible (i.e., Children’s Hospital, Long Beach; clinical stop smoking or stay cigarette free. Dr. day in the third trimester. The data support very low risk) in pregnancy. However, professor of pharmacy, University of Bernstein of the University of Vermont, the idea that the third trimester is more im- frequent, prolonged use of narcotic California, San Francisco; and adjunct Burlington, said that a woman’s smoking portant than the first, he said. analgesics may result in maternal and professor of pharmacy, University of volume was assessed using self-reports as The National Institutes of Health and a fetal addiction. Southern California, Los Angeles. He is well as measurement of urinary cotinine General Clinical Research Center grant NSAIDs, including aspirin, have been also coauthor of the reference book and exhaled carbon monoxide levels. supported the study. associated with miscarriage when used “Drugs in Pregnancy and Lactation.” Before pregnancy, the group averaged —Jane Salodof MacNeil