TERATOLOGY 44:l-6 (1991)

Recommendations for lsotretinoin Use in Women of Childbearing Potential RECOMMENDATIONS

Isotretinoin, marketed under the trade name of Accutane, is a n effective treatment for severe recalcitrant cystic acne and has been approved by the FDA only for this condition. Isotretinoin is also a potent human developmental toxicant. Despite category X classification and patient package insert warnings, malformed babies attributable to isotretinoin exposure have been reported every year since 1983. It is necessary, therefore, to limit isotretinoin use among fertile women to those who absolutely require this drug and to those who will reliably use adequate contraception. Thus the Teratology Society recommends that: 1. Hoffmann La Roche should insure appropriate means to limit distribution of isotretinoin so that women of childbearing potential with a n FDA-approved indication are identified and properly educated about the risks of taking isotretinoin before initiating therapy with this agent. 2. Implantable progesterone-type contraceptive agents should be strongly recommended for female isotretinoin users because these contraceptives reduce the risk of pregnancy up to 10-fold when compared to oral contraceptives. Furthermore, the FDA should allow the use of injectable versions of these contraceptives since the implantable products may not be financially affordable for some women. 3. Postmarketing surveillance should be continued and rigorously evaluated. If this study design cannot determine accurately the rate of exposed pregnancies, the reasons for the exposures, and the fate of those pregnancies, then a new monitoring system should be established. 4. If implementation of these recommendations cannot assure the prevention of birth defects, then the manufacturer and the FDA must consider further restricted availability of isotretinoin.

These recommendations are meant to complement and extend the stringent con0

1991 WILEY-LISS, INC

ditions printed in the recently released package insert by the manufacturer (Physicians’ Desk Reference, 44th ed., 1990, p. 1770). These state that a woman of childbearing potential must meet all of the following conditions: 1. “has severe disfiguring cystic acne that is recalcitrant to standard therapies 2. is reliable in understanding and carrying out instructions 3. is capable of complying with the mandatory contraceptive measures 4. has received both oral and written warnings of the hazards of taking Accutane’” during pregnancy and the risk of possible contraception failure and has acknowledged her understanding of these warnings in writing 5. has had a negative serum pregnancy test within 2 weeks prior to beginning therapy (it is also recommended that pregnancy testing and contraception counseling be repeated on a monthly basis) 6. will begin therapy only on the second or third day of the next normal menstrual period.” An additional precaution suggested by the manufacturer is the use of a n effective form of contraception for 1 month after isotretinoin therapy has been stopped. All of these conditions and recommendations apply only to isotretinoin. Other therapeutic retinoids require separate consideration be-

Received February 5, 1991; accepted February 5, 1991. Address reprint requests to Chairperson, Public Affairs Committee, The Teratology Society, 9650 Rockville Pike, Bethesda, MD 20814. The initial draft of this document was written by a committee of experts which included Jose Cordero, M.D., M.P.H.,from the Centers for Disease Control in Atlanta; David Kochhar, Ph.D., from Thomas Jefferson University in Philadelphia; and Alan Fantel, Ph.D., from the University of Washington in Seattle. Subsequently the document was reviewed by more than 30 scientists with expertise in a wide variety of basic, clinical, and regulatory disciplines. The final version published here has been approved by the Public Affairs Committee and the Council of the Teratology Society.

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TERATOLOGY SOCIETY COOH COOH

all-trans-Retinoic acid

F

O

13-c&Retinoic acid (isotretinoin)

H

Retinol

COOH

0 4-OXO-l3-c&-Retinoic acid

Fig. 1. Isotretinoin is the 13-cis-isomer of all-trans-retinoic acid.

cause of differing pharmacologic and teratologic characteristics.

skens et al., '82; Levine et al., '84; Hong et al., '90).

INTRODUCTION

DEVELOPMENTAL TOXICITY

Laboratory animals Isotretinoin is a synthetic retinoid and is the 13-cis-isomer of all-trans-retinoic acid Isotretinoin causes developmental toxic(Fig. 1). Both differ in chemical structure ity in all common laboratory species. A listfrom retinol (vitamin A) in possessing a n ing of doses and organ systems affected is acidic group in place of a n alcoholic function found in Table 1. Of interest is the very high at the polar terminus in the side chain of the dose of isotretinoin needed to induce develmolecule. Both drugs were synthesized in opmental toxicity in rats and mice, about a n the laboratory before they were shown to order of magnitude greater than other laboccur in small amounts in blood and other oratory animals and two orders of magnitissues as natural metabolites of ingested tude greater than humans. Creech Kraft et vitamin A (Emerick et al., '67; DeRuyter et al. ('87) have indicated that, in mice, this al., '79; McCormick and Napoli, '82; Anon- lack of potency may be related to a low level ymous, '88). After oral doses, isotretinoin of placental transfer when compared with rapidly appears in the plasma of human pa- all-trans-retinoic acid. In fact, these authors tients, but the peak concentrations vary suggest that the developmental toxicity of greatly between individuals. The drug has isotretinoin in mice may be caused by cona n elimination half-life of 10-20 h r which version of the parent compound to the alldoes not change with repeated dosing (Braz- trans-isomer with subsequent passage of zell et al., '83). Its major metabolite in the this isomer and its 4-0x0-metabolite into the blood is 4-0x0-13-cis-retinoic acid, which is embryo. present a t concentrations exceeding those of Consideration of isotretinoin conversion isotretinoin after repeated dosing (Brazzell to 4-0x0-isotretinoin is important since this et al., '83; Hill and Struck, '83). Addi- metabolite is itself a developmental toxin. tionally, considerable amounts of all-trans- In vivo the metabolite is more potent than retinoic acid and 4-0x0-all-trans-retinoic the parent compound in mice (Kochhar and acid were found in the serum of a woman Penner, '87), whereas in vitro the two are of being treated with isotretinoin (Creech nearly equal potency toward rat embryos (Webster e t al., '86). In mice (Creech Kraft Kraft et al., '90). Isotretinoin is a uniquely effective treat- et al., '871, hamsters (Howard et al., '891, ment for severe, recalcitrant, cystic acne and humans (Brazzell et al., '83) the level of (Peck et al., '79), and it is for this indication 4-0x0-isotretinoin is 2-5 times higher than that the drug has received FDA approval. It isotretinoin. The general opinion is that i t is also has been used experimentally in the the combination of these two plus that treatment of disorders of keratinization converted to all-trans-retinoic acid and its (Arndt, '86) and in neoplastic and preneo- 4-0x0-metabolite which determines teratoplastic diseases (Haydey et al., '80; Mey- logic response.

RECOMMENDATIONS FOR ISOTRETINOIN USE IN WOMEN

SDecies Human Monkey Rabbit

Rat Hamster Mouse

3

TABLE 1 , Lowest teratogenic dose (mglkgldavi of isotretinoin in animals and man Dose (melke) Dads) Svstemk) affected Reference 0.4 Variable Craniofacial, cardiovascular Lammer et al., '85 5 10-27 Craniofacial, cardiovascular Hummler et al., '90 10 7-18 Skeletal, nervous system, other soft tissues Kamm et al., '84 75 8-10 Craniofacial Agnish [personal communication I 25 8 Craniofacial, skeletal, renal Willhite and Shealy, '84 100 6-15 Craniofacial Agnish [personal communication1

Most, if not all, teratogenic retinoids induce a recognizable pattern of central nervous system, craniofacial, and cardiovascular malformations which is demonstrable across species lines. Isotretinoin is no exception, inducing craniofacial and cardiovascular malformations in mice (Webster et al., '86). In hamsters, Willhite and Shealy ('84) reported a variety of craniofacial malformations, but did not search for cardiovascular malformations. The reports of isotretinoin teratogenicity in rats and rabbits are of insufficient detail to state unequivocally their resemblance to a retinoid pattern of malformations, but in vitro results in rats (Webster et al., '86) suggest a close similarity. Hummler et al. ('90) have shown that isotretinoin causes craniofacial malformations in non-human primates. Cynomolgus monkeys treated during early gestation (days 10-27) yielded fetuses with otic, thymic, and cardiovascular malformations th at can be regarded as typical of retinoid exposure. In addition to major structural malformations, vitamin A (Butcher et al., '72; Hutchings et al., '73; Vorhees, '74; Vorhees et al., '78) and all-trans-retinoic acid (Nolen, '86) have been shown to cause functional nervous system deficits, raising the possibility that isotretinoin would have similar effects. Recently, Jensh et al. ('90) reported behavioral effects in rats exposed to isotretinoin on days 11-13 of gestation. Humans Isotretinoin causes a pattern of dysmorphogenesis which includes craniofacial defects, malformations of the cardiovascular and central nervous systems (CNS), and defects of the thymus (Table 2). At least 85 malformed babies have been reported resulting from maternal exposure to isotretinoin during pregnancy [Rosa, personal communication, '881. A number of reports (Lammer et al., '85; Rosa et al., '86; Willhite et al., '86; Lynberg et al., '90) have summa-

rized the developmental toxicity of isotretinoin in the human. In a prospective study of 57 pregnancies exposed during the first trimester, 9 resulted in spontaneous abortions, 1in a malformed stillbirth, 10 in malformed livebirths, and 37 in livebirths without evidence of major malformations (Lammer et al., '88). This represents a risk for malformations of 23% for fetuses that reach 20 weeks gestation. Among the 21 malformed infants reported by Lammer et al. ('851, 17 had craniofacial defects, 12 had anomalies of the heart, 18 had malformations of the CNS, and 7 had thymus anomalies. A combination of defects was reported in 10 of the 21 infants. The most common craniofacial malformations were facial asymmetry, microtia, and/ or anotia usually associated with atresia or stenosis of the ear canal. In the reported cases, ear malformations nearly always occurred bilaterally but the severity may be asymmetric. However, Lammer [personal communication, '881 observed two patients with essentially unilateral ear malformations associated with isotretinoin exposure. Maldevelopment of the cranial bones, micrognathia, and cleft palate also have been reported. In isotretinoin embryopathy the cardiovascular defects can be classified as conotruncal or branchial arch mesenchymal tissue defects. Conotruncal defects observed in eight infants included transposition of the great vessels, tetralogy of Fallot, truncus arteriosus communis, and supracristal ventricular septa1 defects. The branchial arch mesenchymal tissue defects observed in seven infants included type B aortic arch interruption, retroesophageal right subclavian artery, and hypoplasia of the aorta (Lammer and Opitz, '86). CNS defects included hydrocephalus and structural malformations of the cerebral cortex and the cerebellum. Nine infants were afflicted with hydrocephalus, both communicating and noncommunicating

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TABLE 2. Major malformations associated with human isotretinoin exposure' Craniofacial defects (continued) Central nervous system Hydrocephalus Micrognathia Cleft palate (U-shape) Aqueductal stenosis Hypertelorism Communicating Cardiovascular defects Fourth ventricle cyst Conotruncal malformations Holoprosencephaly Transposition of the great vessels Malformations of the brain Double-outlet right ventricle Cerebellar hypoplasia Tetralogy of Fallot Cerebellar microdysgenesis "runcus arteriosus communis Megacysterna magna Craniofacial defects Supracristal ventricular defects Branchial arch mesenchymal tissue defects Microtia Type B aortic arch interruption Agenesis or hypoplasia of the ear canal Retroesophageal right subclavian artery Maldevelopment of the facial and calvarium bones Aortic arch hypoplasia 'Data from Lammer et al. ('85) and Lammer et al. ('88)

types being observed. The cortical anomalies included focal cortical agenesis, focal agyria, heterotopias, and calcifications. The cerebellar anomalies were hypoplasia, absence of the vermis, and microdysgenesis. Follow-up of the children evaluated by Lammer et al. ('85) is not complete, but preliminary findings indicate that 52% of 5year-olds exposed during the first trimester had intellectual deficits, and of these 37.5% had no major malformations (Adams, '90; Adams and Lammer, '91). Neurobehavioral deficits may also be expected in children exposed to isotretinoin after the most sensitive period for malformations because of the protracted development of the nervous system (Lammer et al., '90). The reasons for inadvertent exposure to isotretinoin during pregnancy were reported by Lammer et al. ('85). Among 99 pregnancies for which there was information available about contraceptive use, one-third were pregnant before starting therapy, one-third were not practicing contraception while using isotretinoin, and one-third conceived while reputedly using contraception. Contraceptive failures included the entire gamut of available methods. The mechanisms by which isotretinoin produces developmental toxicity still remain unresolved. Some clues are available from the fact that a combination of ear, thymus, great vessel, and brain abnormalities forms the core of the isotretinoin embryopathy (Lammer e t al., '85; Rosa et al., '86). This suggests a specific sensitivity of some neuroectrodermal cell populations, including the cranial neural crest. Cytosolic binding proteins as well as nuclear receptors for

retinoids are present in several types of embryonic cells (Maden et al., '89; Oro et al., '89). Their role, if any, in mediating aberrant development is still a matter of debate (Kochhar, '87; Thaller and Eichele, '88). CONCLUSIONS

Since its introduction isotretinoin has been classified by the FDA a s pregnancy category X, (Roche Laboratories, '82). Although no human experience was available at the time of licensure, the animal developmental toxicity studies consistently suggested that isotretinoin was likely to be a developmental toxin. In June 1983 the manufacturer reported the first malformed babies resulting from exposure to isotretinoin during pregnancy. This initial report was followed by a number of case reports, a summary of FDA case reports (Stern et al., ,841, and the study by Lammer e t al. ('85). The unusually high percentage of malformed babies among exposed pregnancies, the specific pattern of malformations, and the consistency with the pattern of defects induced by retinoids in experimental animals provided sufficient evidence to conclude that isotretinoin was a human teratogen. Recently Rosa1 [personal communication] indicated that, as of November 1988, 85 fetuses and infants with malformations attributable to isotretinoin exposure had been reported to the FDA. Thus the measures taken to prevent pregnancy during isotretinoin exposure have not been totally

'Dr. Franz Rosa, Epidemiologist, FDA.

RECOMMENDATIONS FOR ISOTRETINOIN USE IN WOMEN

satisfactory, although the number of reported cases of isotretinoin-induced birth defects has declined in recent years. The continued birth of malformed children led the manufacturer to introduce a new effort to reduce such cases. In 1988 Roche Laboratories developed a new package insert with larger print containing six criteria that women should meet in order to receive a n isotretinoin prescription. In addition, isotretinoin capsules are now marketed in individual blister packages, each of which contains a pregnancy warning. Finally, Roche Laboratories has prepared a pregnancy prevention program kit. These kits have been delivered to all dermatologists and other identified isotretinoin prescribers. The effectiveness of these new measures in preventing inadvertent exposure to isotretinoin during pregnancy cannot yet be fully evaluated. Recently David Graham of the FDA estimated that there are less than 4,000 women per year aged 15-44 who have a n approved indication for isotretinoin therapy, yet 65,000 women of reproductive age are given a prescription for this drug (FDA Joint Advisory Committee Hearing, May 21,1990). This discrepancy has been consistent since the mid-1980s. Thus, to minimize exposure of fertile women to isotretinoin the Teratology Society recommends that the manufacturer pursue development of a plan to limit distribution of isotretinoin to those patients with a n FDA-approved indication. To further reduce the risk of isotretinoin developmental toxicity the Teratology Society recommends that female isotretinoin users be strongly urged to utilize implantable progesterone contraceptive agents. The use of this contraceptive is reputed to be costly; therefore the Teratology Society further recommends that the FDA attempt to make injectable progesterone contraceptives available for their lower cost but equally efficient contraception. Finally, postmarketing surveillance to detect inadvertent use is essential to monitor the success of the first two recommendations. The present system should be continued or replaced by a more rigorous program if necessary. Isotretinoin is a valuable therapeutic agent. However, its inadvertent use during pregnancy is likely to cause serious adverse consequences to the conceptus. The recommendations described herein represent a n effort to maintain the availability of isotre-

5

tinoin for its intended use while reducing its use during pregnancy. LITERATURE CITED Adams, J. (1990) High incidence of intellectual deficits in 5 year old children exposed to isotretinoin “in utero.” Teratology, 41:614. Adams, J., and E.J. Lammer (1991) Relationship between dysmorphology and neuropsychological function in children exposed to isotretinoin “in utero.” In: Functional Neuroteratology of Short Term Exposure t o Drugs. T. Fujii and G.J. Boer, eds. Teikyo University Press, Tokyo, in press. Anonymous (1988) Retinoic acid biosynthesis from retinol. Nutr. Rev., 46:30-31. Arndt, K. (1986) The Management of Dermatologic Therapy. 111. Little, Brown & Co., Boston, pp. 11-12, 237-238. Brazzell, R.K., F.M. Vane, C.W. Ehmann, and W.A. Colburn (1983) Pharmacokinetics of isotretinoin during repetitive dosing to patients. Eur. J . Clin. Pharmacol., 24:695-702. Butcher, R.E., R.L. Brunner. T. Roth. and C.A. Kimmel (1972) A learning impairment associated with maternal hypervitaminosis-A in rats. Life Sci., 11r141-145. Creech Kraft, J., D.M. Kochhar, W.J. Scott, and H. Nau (1987) Low teratogenicity of 1 3 4 s retinoic acid (isotretinoin) in the mouse corresponds to low concentrations during organogenesis: Comparison to the all-trans isomer. Toxicol. Appl. Pharmacol., 87r474482. Creech Kraft, J., W. Slikker, J . Bailey, L. Roberts, B. Fischer, W. Wittfoht, and H. Nau (1990)Plasma pharmacokinetics and metabolism of 13-cis and all transretinoic acid in the cynomolgus monkey and the identification of 13-cis and all-trans retinoyl-2-glucuronides: A comparison to one human case study with isotretinoin. Drug Metab. Dispos., in press. DeRuyter, M.G., W.E. Lambert, and A.P. DeLeenheer (1979) Retinoic acid An endogenous compound of human blood. Unequivocal demonstration of endogenous retinoic acid in normal physiological conditions. Anal. Biochem., 98:402-409. Emerick, R.F., M. Zile, and H.F. DeLuca (1967) Formation of retinoic acid from retinol in the rat. Biochem. J., 102:606-611. Haydey, R.P., M.L. Reed, L.M. Dzubow et al. (1980) Treatment of keratoacanthomas with oral 13cis-retinoic acid. N. Engl. J. Med., 303560-562. Hill, D.L., and R.F. Struck (1983) Pharmacologic disposition of chemo-preventive retinoids. Anticancer Res., 3;171-180. Hong, W.K., et al. (1990) Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N. Engl. J . Med., 323r795-801. Howard, B., C. Willhite, S. Omage, and R. Sharma (1989) Comparative distribution, pharmacokinetics and placental permeabilities of all-trans-retinoic acid, 13-cis-retinoic acid, all trans-4-0x0-retinoic acid, retinyl acetate and 9-cis-retinol in hamsters. Arch. Toxicol., 63r112-120. Hummler, H., R. Korte, and A. Hendrickx (1990) Induction of malformations in the cynomolgus monkey with 13-cis retinoic acid. Teratology, 42:263-272. Hutchings, D.E., J . Gibbon, and M.A. Kaufman (1973) Maternal vitamin A excess during the early fetal period: Effects on learning and development in the offspring. Dev. Psychol., 20r523-532. Jensh, R.P., D.M. Kochhar, M.K. Till, and M.B. Eskesen

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(1990) Postnatal behavioral sequelae of prenatal exposure to 13-cisretinoic acid. Teratology, 41 t621-622. Kamm, J.J., K.O. Ashenfelter, and C.W. Ehmann (1984) Preclinical and clinical toxicology of selected retinoids. In: The Retinoids. M. Sporn, A.B. Roberts, and D.S. Goodman, eds. Academic Press, New York. Vol. 2, pp. 287-326. Kochhar, D.M. (1987) Mechanisms by which retinoids intercept developmental events of the mammalian limb. In: Approaches to Elucidate Mechanisms of Teratogenesis. F. Welsch, ed. Hemisphere Publ. Corp., Washington, pp. 197-213. Kochhar, D.M., and J.D. Penner (1987) Developmental effects of isotretinoin and 4-0x0-isotretinoin: The role of metabolism in teratogenicity. Teratology, 36:67-75. Lammer, E.L., and J. Opitz (1986)The Di George anomaly as a developmental field defect. Am. J . Med. Genet., 2(Suppl.j: 113-127. Lammer, E.J., D.T. Chen, R.M. Hoar, N.D. Agnish, P.J. Benke. J.T. Braun. C.J. Currv. P.M. Fernhoff. A.W. Grix, Jr., I.T. Lott,'et al. (1985) Retinoic acid embryopathy. N. Engl. J. Med., 3132337-841. Lammer, E.L., A.M. Hayes, A. Schunior, and L.B. Holmes (1988) Unusually high risk for adverse outcomes of pregnancy following fetal isotretinoin exposure. Am. J. Hum. Genet., 43:A58. Lammer, E., A. Schunior, and L. Holmes (1990) Retinoic acid fetopathy. Proc. Greenwd. Genet. Ctr., 9t68. Levine, N., R.C. Miller, and F.L. Meyskens (1984) Oral 13-cis-retinoic acid therapy for multiple cutaneous squamous cell carcinomas and keratoacanthomas. Arch. Dermatol., 120:1215-1217. Lynberg, M., M. Khoury, E. Lammer, K. Waller, J . Cordero, and D. Erickson (1990) Sensitivity, specificity and positive predictive value of multiple malformations in isotretinoin embryopathy surveillance. Teratology, 42t513-519. Maden. M.. D. Ona. D. Summerbell. and F. Chvtil (1989)The role of retinoid binding proteins in the ;eneration of patterns in the developing limb, the regenerating limb and the nervous system. Development, I07~suppz.!:109-120. McCormick, A.J., and J.L. Napoli (1982) Identification of 5,6-epoxy-retinoic acid as a n endogenous retinol metabolite. J. Biol. Chem., 257t1730-1735.

Meyskens, F.L., Jr., E. Gilmartin, D.S. Alberts, N.S. Levine, R. Brooks, S.E. Salmon, and E.A. Surwit (1982) Activity of isotretinoin against squamous cell cancers and preneoplastic lesions. Cancer Treatment Rep., 66t1315-1319. Nolen, G.A. (1986) The effects of prenatal retinoic acid on the viability and behavior of the offspring. Neurobehav. Toxicol. Teratol., 8t643-654. Oro, A., K. Umesono, and R. Evans (1989) Steroid hormone receptor homologs in development. Development, 107(SuppZ.):133-140. Peck, G.L., T.G. Olson, F.W. Yoder, et al. (1979) Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid. N. Engl. J . Med., 300t329-335. Roche Laboratories (1982) Accutane'" Package. Rosa, F.W. (1983)Teratogenicity of isotretinoin. Lancet, 2.513. Rosa, F.W., A.L. Wilk, and F.O. Kelsey (1986) Teratogen update: Vitamin A congeners. Teratology, 33: 355-364. Stern, R.S., F. Rosa, and C. Baum (1984) Isotretinoin and pregnancy. J. Am. Acad. Dermatol., IOr851-854. Thaller, C., and G. Eichele (1988) Characterization of retinoid metabolism in the developing chick limb bud. Development, 103:473-483. Vorhees, C.V. (1974) Some behavioral effects of maternal hypervitaminosis A in rats. Teratology, IOt269274. Vorhees, C.V., R.L. Brunner, C.F. McDaniel, and R.E. Butcher (1978) The relationship of gestational age to vitamin A induced postnatal dysfunction. Teratology, 17:271-276. Webster, W.S., M.C. Johnston, E.J. Lammer, and K.K. Sulik (1986) Isotretinoin embryopathy and the cranial neural crest: An in vivo and in vitro study. J. Craniofac. Genet. Dev. Biol., 6t211-222. Willhite, C.C., and Y.F. Shealy (1984) Amelioration of embryotoxicity by structural modification of the terminal group of cancer chemopreventive retinoids. J . Natl. Cancer Inst., 72t689-695. Willhite, C.C., R.M. Hill, and D.W. Irving (1986) Isotretinoin-induced craniofacial malformations in humans and hamsters. J . Craniofac. Genet. Dev. Biol., Z(Supp1.i: 193-209.