Class: Skin and Mucous Membrane Agents, Miscellaneous
VA Class: DE751
Chemical Name: 13-cis-retinoic acid
Molecular Formula: C20H28O2
CAS Number: 4759-48-2
Brands: Amnesteem, Claravis, Sotret
iPLEDGE restricted distribution program is in effect to help ensure that fetal exposure does not occur.201 203 The iPLEDGE program specifies monthly requirements for the prescribing clinician, patient, and pharmacist.201 (See Restricted Distribution under Dosage and Administration.)
Contraindicated in female patients who are or may become pregnant and in female patients of childbearing potential, unless they comply with all the special conditions required by the iPLEDGE restricted distribution program.201 202 203
If pregnancy occurs, immediately discontinue drug and refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.201 202 203 (See Pregnancy under Cautions.)
FDA approved a REMS for isotretinoin to ensure that the benefits outweigh the risks. (See Restricted Distribution under Dosage and Administration.) The REMS may apply to one or more preparations of isotretinoin and consists of the following: medication guide, elements to assure safe use, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center ().
Uses for Isotretinoin
Severe Nodular Acne
Disorders of Keratinization†
Has been used in the prevention, treatment, and adjunctive treatment of various cutaneous and extracutaneous malignant neoplasms† (of epithelial origin); however, the specific role of isotretinoin, if any, not established.4 46 58 63 64 65 66 94 97 118 160 161
Isotretinoin Dosage and Administration
Severe Nodular Acne
Individualize dosage according to severity of the disease, the patient’s weight, and/or appearance of adverse effects (e.g., dose-related cheilitis or hypertriglyceridemia).105
Prior to increasing isotretinoin dosage, ascertain whether patient has been compliant with instructions on taking the drug with food since failing to do so will substantially decrease absorption of the drug.105 111
A centralized risk management program, called iPLEDGE, for all isotretinoin preparations was approved by FDA; this program replaced previous restricted distribution programs sponsored by various manufacturers.201 202 203 204 The program requires registration of wholesalers, prescribers, pharmacies, and patients; all must agree to accept specific responsibilities designed to minimize pregnancy exposures in order to distribute, prescribe, dispense, or use isotretinoin.201 202 203
The iPLEDGE program strengthened processes to ensure appropriately timed and properly documented pregnancy testing and counseling of patients before, during, and following isotretinoin therapy; the program is computer based and uses verifiable, trackable links between prescriber, patient, pharmacy, and wholesaler in a single registry to control prescribing, distribution, dispensing, and patient use of isotretinoin.201 202 203
To obtain detailed information on all requirements for patients (e.g., contraception, pregnancy testing), prescribing clinicians (e.g., program enrollment, patient registration, patient education), and dispensing pharmacists (e.g., obtaining dispensing authorization, providing patient medication guides), see the iPLEDGE program website at .201 202 203
To facilitate pregnancy testing and counseling in accordance with the iPLEDGE program, clinicians must not prescribe more than a 30-day supply of drug.201 203 Telephone, fax, and electronic transmission (e.g., e-mail) of prescriptions are permitted.202 Refills require a new prescription and another authorization from the iPLEDGE program; automatic refills are not allowed.201 203
Pharmacists must dispense prescriptions prior to the date specified by the iPLEDGE system (7 days from the office visit date) and record this date on the prescription bag sticker.201 203 Patients must pick up prescriptions no later than this date; if not picked up by that date, pharmacists must return the drug to stock.201
To decrease the risk of esophageal irritation, swallow capsules whole with a full glass of liquid; do not suck or chew the capsules.105
Severe Nodular Acne
Adolescents ≥12 years of age: usual initial dosage is 0.5–1 mg/kg daily given in 2 divided doses with food.105 Adjust subsequent dosage after ≥2 weeks of treatment according to individual tolerance and response, using the lowest possible effective dosage.105
Usual duration of therapy: 15–20 weeks; discontinue therapy sooner if the total number of cysts has been reduced by more than 70%.102
A second course of therapy may be initiated if severe nodular acne persists and it is thought that the patient could benefit from further treatment; optimum interval between initial and subsequent courses of isotretinoin therapy has not been defined for adolescents who have not completed skeletal growth.105
Severe Nodular Acne
Usual initial dosage: 0.5–1 mg/kg daily given in 2 divided doses with food.105 Adjust subsequent dosage after ≥2 weeks of treatment according to individual tolerance and response, using the lowest possible effective dosage.105 If disease is severe or is mainly evident on the chest and back, instead of the face, dosages up to 2 mg/kg daily may be required.105
Usual duration of therapy: 15–20 weeks; discontinue therapy sooner if the total number of cysts has been reduced by more than 70%.102
A second course of therapy may be initiated if severe nodular acne persists and it is thought that the patient could benefit from further treatment; however, at least 2 months should elapse between courses in adults to assess the degree of improvement and the need for further therapy.105
Severe Nodular Acne
Maximum 2 mg/kg daily.105
Severe Nodular Acne
Maximum 2 mg/kg daily.105
Cautions for Isotretinoin
Female patients who are or may become pregnant.203 (See Fetal/Neonatal Morbidity and Mortality under Cautions and also see Boxed Warning.)
Female patients of childbearing potential, unless they comply with all the special conditions required by the manufacturer and the iPLEDGE restricted distribution program.201 202 203 (See Boxed Warning and also see Restricted Distribution under Dosage and Administration.)
Fetal/Neonatal Morbidity and Mortality
Extremely high risk of severe birth defects (possibly life-threatening) if pregnancy occurs while receiving isotretinoin in any amount even for short periods of time; teratogenicity generally characterized by malformations involving craniofacial, cardiovascular, thymus and parathyroid gland, and CNS structures.100 143 144 145 146 147 173 203 Cases of IQ scores <85 with or without obvious CNS abnormalities also have been reported.203 Spontaneous abortions and premature births also reported.203 Contraindicated in female patients who are or who may become pregnant.201 203 (See Boxed Warning and also see Advice to Patients.) Distribution is restricted.201 203 (See Restricted Distribution under Dosage and Administration.)
Potential risk to the developing fetus from exposure to transfused blood containing isotretinoin; blood donation not recommended for both male and female patients during isotretinoin therapy and for at least 1 month following discontinuance of the drug.203
May cause depression, psychosis, and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors;185 186 187 188 189 203 etiology not known.203 Prescribing clinicians should be familiar with manifestations of psychiatric disorders in adolescents and young adults and alert to the warning signs of psychiatric disorders in order to guide patients to receive the help they need.203
Prior to initiating therapy, ask patients and family members about any history of psychiatric disorder.203 At each visit during therapy, assess patients for symptoms of depression, mood disturbance, psychosis, or aggression to determine whether further evaluation is necessary.203
Patients who experience symptoms of depression, mood disturbance, psychosis, or aggression after initiating isotretinoin therapy should discontinue the drug and the patient or family member should promptly contact their prescribing clinician without waiting for the next scheduled visit.203 Discontinuance of the drug may be insufficient and further evaluation of the patient may be needed.203
Such monitoring may not detect all patients at risk.203 If a patient reports mental health problems or a family history of psychiatric disorders, discuss with the patient and/or the patient’s family; may need to refer patient to a mental health professional in some cases.203 Consider whether isotretinoin therapy is appropriate; for some patients, potential risks may outweigh potential benefits.203
Pseudotumor cerebri (benign intracranial hypertension), usually associated with headache, visual disturbances, and papilledema, reported; some patients with pseudotumor cerebri were receiving concomitant tetracycline therapy.105 107 141
Screen patients who develop manifestations of pseudotumor cerebri (e.g., headache, nausea and vomiting, visual disturbances) for the presence of papilledema and, if present, discontinue the drug immediately and refer to a neurologist for further evaluation and care.105
Possible acute, life-threatening pancreatitis (e.g., hemorrhagic pancreatitis) with either elevated or normal serum triglyceride concentrations;105 108 132 133 use with caution in patients with preexisting elevated fasting serum triglyceride concentrations and in patients with increased tendency to develop hypertriglyceridemia (e.g., patients with diabetes mellitus, obesity, increased alcohol intake).105 108
If serum triglyceride concentrations cannot be controlled at an acceptable level or if symptoms of pancreatitis occur, discontinue therapy.105
Clinical hepatitis reported; mild to moderate elevations of hepatic enzymes reported, which resolved despite continued therapy in some patients.105 Perform pretreatment and follow-up liver function tests at weekly or biweekly intervals until response to isotretinoin is established.105
If hepatitis is suspected or abnormal liver function test results develop and persist during isotretinoin therapy, discontinue the drug and investigate the cause of the abnormality.105
Effects on Lipoproteins
Possible lipid abnormalities (e.g., hyperlipidemia, elevated fasting triglycerides and cholesterol, decreased HDL-cholesterol); usually reversible with cessation of therapy.105
Monitor fasting blood lipid levels prior to initiating therapy and at weekly or biweekly intervals until lipid response is established.1 105 If alcohol is consumed prior to testing, at least 36 hours should elapse before these determinations are made.105
Use with caution in patients with diabetes mellitus, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder.105 More frequent serum lipid and/or glucose monitoring recommended in such patients.105
Inflammatory Bowel Disease
Possible arthralgias, hyperostosis, premature epiphyseal closure, osteoporosis, osteopenia, bone loss or fractures, and delayed healing of bone fractures; do not exceed recommended dosage and/or duration of treatment.105
Participation in sports with repetitive impact, where the risks of spondylolisthesis with and without pars fractures and hip growth plate injuries in early and late adolescence are known, may increase the risk of developing such adverse effects.105 196 197
Use with caution in patients with a genetic predisposition for age-related osteoporosis; a history of childhood osteoporosis conditions, osteomalacia, or other disorders of bone metabolism; in patients diagnosed with anorexia nervosa; and in those receiving chronic drug therapy with agents that induce osteoporosis/osteomalacia and/or affect vitamin D metabolism (e.g., systemic corticosteroids, anticonvulsants).105 196 197
Hearing impairment or tinnitus reported, sometimes persisting even after discontinuance of isotretinoin.105 If such otic effects occur during therapy, discontinue the drug and consult an appropriate specialist for further evaluation.105
Possible anaphylactic or allergic reactions; cutaneous allergic reactions and serious allergic vasculitis, often with purpura of extremities and extracutaneous involvement (e.g., renal).105
If such reactions occur, discontinue therapy and institute appropriate treatment.105
Some formulations contain parabens; contraindicated in sensitive patients.203
Possible anemia, thrombocytopenia, neutropenia, and (rarely) agranulocytosis; discontinue the drug if clinically important decreases in leukocyte counts occur.203
Possible scarring; avoid wax epilation and skin resurfacing procedures (such as dermabrasion, laser) during therapy and for at least 6 months thereafter.105
Report all pregnancies during or up to 1 month following therapy to FDA Medwatch Program at 1-800-FDA-1088 and also to the iPLEDGE pregnancy registry at 1-866-495-0654 or through the program’s website ().201 202 203 (See Fetal/Neonatal Morbidity and Mortality under Cautions and also see Boxed Warning.)
Not known whether isotretinoin is distributed into milk; contraindicated in nursing women.105
Possible increased risk for adverse musculoskeletal effects (e.g., arthralgias, back pain, premature closure of the epiphyses); use with caution in adolescents 12–17 years of age, particularly those with known metabolic or structural bone disease.105 (See Musculoskeletal Effects under Cautions.)
Perform appropriate evaluations of the musculoskeletal system if symptoms of such effects occur during or after a course of isotretinoin therapy.105 If any substantial abnormality is found, consider discontinuing therapy.105
Titrate dosage carefully; do not exceed recommended dosage and duration of treatment.105 196 197 Effects of long-term or multiple courses of isotretinoin therapy on the developing musculoskeletal system remain to be established.105
Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.105
Common Adverse Effects
Cheilitis, conjunctivitis, hypertriglyceridemia, and adverse musculoskeletal effects (e.g., bone or joint pain, generalized muscle aches, arthralgia).105
Interactions for Isotretinoin
Possible risk of contraceptive failure, particularly in female patients using a single contraceptive method or when used concomitantly with St. John’s wort203
Use 2 effective forms of contraception simultaneously, at least 1 of which must be a primary form 203
St. John’s wort (Hypericum perforatum)
Possible risk of hormonal contraceptive failure during concomitant use203
Avoid concomitant use203
Possible additive adverse effects105
Avoid concomitant use105
Actual oral bioavailability not yet determined in humans; in animals, oral bioavailability is about 25%, possibly because of biodegradation of the drug in the GI lumen and/or metabolism of the drug during absorption (in the GI mucosa) and first pass through the liver.53
Food appears to increase the bioavailability of isotretinoin without altering its disposition.105
Following oral administration in animals, the drug is distributed into many tissues including liver, ureters, adrenals, ovaries, and lacrimal glands.1 Distributed into bile in humans.53 54 113 Unlike vitamin A, isotretinoin is not stored in the liver.7
It is not known if isotretinoin is distributed into milk.1
Plasma Protein Binding
>99%, principally albumin.105
Metabolized in the liver by CYP microsomal enzyme system, principally by CYP2C8, CYP2C9, CYP3A4, and CYP2B6 isoenzymes, to several active metabolites (e.g., 4-oxo-isotretinoin, retinoic acid [tretinoin], and 4-oxo-retinoic acid [4-oxo-tretinoin]).105
Excreted in urine and feces in relatively equal amounts as conjugates of isotretinoin and its metabolites.105
Has pharmacologic actions similar to those of other retinoids (e.g., vitamin A, tretinoin);7 principal pharmacologic effect appears to be regulation of cell (e.g., epithelial) proliferation and differentiation.8 9
Exact mechanism(s) of action in treatment of neoplasms has not been conclusively determined7 42 48 90 but may involve effects mediated via cytosol-binding proteins,42 inhibition of ornithine decarboxylase activity,48 49 50 51 52 and effects on the immune system.65 78
Has teratogenic and abortifacient effects.105 (See Boxed Warning.)
Advice to Patients
Describe risk of birth defects.203 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.105 Necessity of advising women of child-bearing potential to avoid pregnancy by using 2 methods of contraception simultaneously for ≥1 month prior to, throughout, and for ≥1 month after isotretinoin therapy.201 203 At least one method of contraception must be a primary form: tubal sterilization, vasectomized partner, intrauterine device, or oral, injectable, inserted, transdermal, or implanted hormonal contraceptive.201 203 (See Boxed Warning.)
Importance of warning both male and female patients not to share isotretinoin with anyone else (even if the other individual has similar symptoms) and not to donate blood while receiving isotretinoin and for at least 1 month afterward.191 196 197 203
Importance of promptly reporting symptoms of depression, mood disturbance, psychosis, or aggression to clinician; importance of discussing any personal or family history of psychiatric illness with clinician before beginning treatment.203
Risk of sudden, decreased night vision; importance of being cautious when driving or operating any vehicle at night.105
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription or OTC drugs and herbal supplements (e.g., St. John’s wort), as well as concomitant illnesses.203
Importance of informing patients of other important precautionary information.105 (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Isotretinoin is available only through a restricted distribution program.201 (See Restricted Distribution under Dosage and Administration.)
Sotret (with parabens)
Sotret (with parabens)
Sotret (with parabens)
Sotret (with parabens)
AHFS DI Essentials. © Copyright, 2004-2015, Selected Revisions October 1, 2015. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
Only references cited for selected revisions after 1984 are available electronically.
1. Roche Laboratories. Accutane (isotretinoin) capsules package insert. Nutley, NJ; 1982 May.
2. Roche Laboratories. Accutane (isotretinoin/Roche) comprehensive product information. Nutley, NJ; 1982.
3. Mayer H, Bollag W, Hanni R et al. Retinoids: a new class of compounds with prophylactic and therapeutic activities in oncology and dermatology. Experientia. 1978; 34:1105-19. [PubMed 363444]
4. Sporn MB, Newton DL, Smith JM et al. Retinoids and cancer prevention: the importance of the terminal group of the retinoid molecule in modifying activity and toxicity. In: Griffin AC, Shaw CR, eds. Carcinogens: identification and mechanisms of action. New York: Raven Press; 1979:441-53.
5. Sporn MB, Dunlop NM, Newton DL et al. Relationships between structure and activity of retinoids. Nature. 1976; 263:110-3. [PubMed 987541]
6. Windhorst DB, Nigra T. General clinical toxicology of oral retinoids. J Am Acad Dermatol. 1982(4 Part 2); 6:675-82.
7. Elias PM, Williams ML. Retinoids, cancer, and the skin. Arch Dermatol. 1981; 117:160-80. [IDIS 139502] [PubMed 7011212]
8. Voorhees JJ, Orfanos CE. Oral retinoids: broad-spectrum dermatologic therapy for the 1980’s. Arch Dermatol. 1981; 117:418-21. [IDIS 136346] [PubMed 6455092]
9. Orfanos CE. Oral retinoids—present status. Br J Dermatol. 1980; 103:473-81. [IDIS 125749] [PubMed 6449212]
10. Zil JS. Vitamin A acid effects on epidermal mitotic activity, thickness, and cellularity in the hairless mouse. J Invest Dermatol. 1972; 59:228-32. [PubMed 5055185]
11. Yuspa SH, Eigjo K, Morse MA et al. Retinyl acetate modulation of cell growth kinetics and carcinogen-cellular interaction in mouse epidermal cell cultures. Chem Biol Interact. 1977; 16:251-64. [PubMed 862128]
12. Zachman RD. The stimulation of RNA synthesis in vivo and in vitro by retinol in the intestine of vitamin A deficient rats. Life Sci. 1967; 6:2207-13. [PubMed 6061006]
13. Johnson BC, Kennedy M, Chiba N. Vitamin A and nuclear RNA synthesis. Am J Clin Nutr. 1969; 22:1048-58. [PubMed 5805213]
14. Sporn MB, Dunlop NM, Yuspa SH. Retinyl acetate: effect on cellular content of RNA in epidermis in cell culture in chemically defined medium. Science. 1973; 182:722-3. [PubMed 4752212]
15. Tsai CH, Chytil F. Effect of vitamin A deficiency on RNA synthesis in isolated cat liver nuclei. Life Sci. 1978; 23:1466-72.
16. Smith KB. Early effects of vitamin A on protein synthesis in the epidermis of embryonic chick skin cultured in serum-containing medium. Dev Biol. 1973; 30:241-8. [PubMed 4703676]
17. De Luca LM. The direct involvement of vitamin A in glycol transfer reactions of mammalian membranes. Vitam Horm. 1977; 34:1-57.
18. Hassell JR, Silverman-Jones CS, De Luca LM. Stimulation of mannose incorporation into specific glycolipids and glycopeptides of rat liver by high doses of retinyl palmitate. J Biol Chem. 1978; 253:1627-31. [PubMed 627560]
19. Wolf G, Kiorpes TC, Masushige S et al. Recent evidence for the participation of vitamin A in glycoprotein synthesis. Fed Proc. 1979; 38:2540-3. [PubMed 90625]
20. Pochi PE. Oral retinoids in dermatology. Arch Dermatol. 1982; 118:57-61.
21. Ziboh VA, Price B, Fulton J. Effects of retinoic acid on prostaglandin biosynthesis in guinea-pig skin. J Invest Dermatol. 1975; 65:370-4. [PubMed 1176787]
22. Aso K, Rabinowitz I, Farber EM. The role of prostaglandin E, cyclic AMP, and cyclic GMP in the proliferation of guinea-pig ear skin stimulated by topical application of vitamin A acid. J Invest Dermatol. 1976; 67:231-4. [PubMed 181494]
23. Ziboh VA. Regulation of prostaglandin E2 biosynthesis in guinea pig skin by retinoic acid. Acta Derm Venereol. 1975; 55(Suppl 74):56-60.
24. Ong DE, Chytil F. Specificity of cellular retinol-binding protein for compounds with vitamin A activity. Nature. 1975; 255:74-5. [PubMed 1128671]
25. Sani BP, Donovan MK. Localization of retinoic acid-binding protein in nuclei and the uptake of retinoic acid. Cancer Res. 1979; 39:2492-6. [PubMed 221105]
26. Van Der Wateren AR, Cormane RH. Oral retinoic acid as therapy for erythrokeratoderma variabilis. Br J Dermatol. 1977; 97:83-5. [IDIS 89994] [PubMed 142506]
27. Roels OA, Anderson OR, Lui NST et al. Vitamin A and membranes. Am J Clin Nutr. 1969; 22:1020-32. [PubMed 5805210]
28. Wang CC, Straight S, Hill DL. Destabilization of mouse liver lysosomes by vitamin A compounds and analogues. Biochem Pharmacol. 1976; 25:471-5. [PubMed 938574]
29. Peck GL, Olsen TG, Yoder FW et al. Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid. N Engl J Med. 1979; 300:329-33. [IDIS 90600] [PubMed 153472]
30. Goldstein JA, Socha-Szott A, Thomsen RJ et al. Comparative effect of isotretinoin and etretinate on acne and sebaceous gland secretion. J Am Acad Dermatol. 1982; 6(4 Part 2):760-5. [IDIS 154900] [PubMed 6461679]
31. Strauss JS, Stranieri AM, Farrell LN et al. The effect of marked sebum production with 13cis-retinoic acid on skin surface lipid composition. J Invest Dermatol. 1980; 74:66-7. [IDIS 110980] [PubMed 6444323]
32. Jones H, Blanc D, Cunliffe WJ. 13-cis-retinoic acid and acne. Lancet. 1980; 2:1048-9. [IDIS 155246] [PubMed 6107678]
33. Farrell LN, Strauss JS, Stranieri AM. The treatment of severe cystic acne with 13-cis-retinoic acid: evaluation of sebum production and the clinical response in a multiple-dose trial. J Am Acad Dermatol. 1980; 3:602-11. [PubMed 6451637]
34. Pochi PE, Strauss JS, Downing DT. Skin surface lipid composition, acne, pubertal development, and urinary excretion of testosterone and 17-ketosteroids in children. J Invest Dermatol. 1977; 69:485-9. [PubMed 143498]
35. Strauss JS, Peck GL, Olsen TG et al. Sebum composition during oral 13-cis-retinoic acid administration. J Invest Dermatol. 1978; 70:228.
36. Smith JG Jr. Dermatology—acne, retinoids, and other skin diseases. JAMA. 1979; 241:1376-7. [PubMed 155165]
37. Heel RC, Brogden RN, Speight TM et al. Vitamin A acid: a review of its pharmacological properties and therapeutic use in the topical treatment of acne vulgaris. Drugs. 1977; 14:401-19. [IDIS 91973] [PubMed 145940]
38. Esterly NB, Furey NL. Acne: current concepts. Pediatrics. 1978; 62:1044-55. [IDIS 119051] [PubMed 153517]
39. Entwisle B. Oral 13-cis-retinoic acid in severe acne. Med J Aust. 1979; 2:119-20.
40. Jones DH, Blanc D, Cunliffe WJ. The effect of 13-cis-retinoic acid in acne. Paper presented at International Dermatology Symposium on Retinoids. Berlin: 1980.
41. Gomez EC. Effects of 13-cis-retinoic acid on the hamster flank organ. J Invest Dermatol. 1980; 74:392-7. [PubMed 7381230]
42. Chytil F, Ong DE. Mediation of retinoic acid-induced growth and anti-tumor activity. Nature. 1976; 260:49-51. [PubMed 944375]
43. Prutkin L. Mucous metaplasia and gap junctions in the vitamin A acid-treated skin tumor, keratoacanthoma. Cancer Res. 1975; 35:364-9. [PubMed 1109802]
44. Elias PM, Friend DS. Vitamin A-induced mucous metaplasia: an in vitro system for modulating tight and gap junction differentiations. J Cell Biol. 1976; 68:173-88. [PubMed 1245547]
45. McNutt NS. Freeze-fracture techniques and applications to the structural analysis of the mammalian plasma membrane. In: Poste G, Nicolson GL, eds. Cell surface reviews. Amsterdam: North-Holland Publishing Co; 1977:75-126.
46. Peck GL, Olsen TG, Butkus D et al. Treatment of basal cell carcinomas with 13-cis-retinoic acid. Proc Annu Meet Am Assoc Cancer Res Proc Annu Meet Am Soc Clin Oncol. 1979; 20:56.
47. Elias PM, Grayson S, Gross EG et al. Influence of topical and systemic retinoids on basal cell carcinoma cell membranes. Cancer. 1981; 48:932-8. [IDIS 136154] [PubMed 7272935]
48. Boutwell RK, Verma AK. Effects of vitamin A and retinoids on the biochemical processes linked to carcinogenesis. Pure Appl Chem. 1979; 51:857-66.
49. O’Brien TG, Simsiman REC, Boutwell RK. Induction of the polyamine-biosynthetic enzymes in mouse epidermis and their specificity for tumor promotion. Cancer Res. 1975; 34:2426-33.
50. O’Brien TG. The induction of ornithine decarboxylase as an early, possibly obligatory, event in mouse skin carcinogenesis. Cancer Res. 1976; 36(7 Part 2):2644-53. [PubMed 1277170]
51. Verma AK, Boutwell RK. Vitamin A acid (retinoic acid): a potent inhibitor of 12-o-tetradecanoyl-phorrbol-13-acetate-induced ornithine decarboxylase activity in mouse epidermis. Cancer Res. 1977; 37:2196-201. [PubMed 861945]
52. Verma AK, Shapas BG, Rice HM et al. Correlation of the inhibition by retinoids of tumor promotorinduced mouse epidermal ornithine decarboxylase activity and of skin tumor promotion. Cancer Res. 1979; 39:419-25. [PubMed 761215]
53. Brazzell RK, Colburn WA. Pharmacokinetics of the retinoids isotretinoin and etretinate. J Am Acad Dermatol. 1982; 6(4 Part 2):643-51. [IDIS 154899] [PubMed 6461675]
54. Hoffmann-La Roche Inc. Data on file. Nutley, NJ.
55. Kochar DM. Transplacental passage of label after administration of [3H] retinoic acid (vitamin A acid) to pregnant mice. Teratology. 1976; 14:53-63. [PubMed 960011]
56. Vane FM, Bugge CJL. Identification of 4-oxo-13-cis-retinoic acid as the major metabolite of 13-cis-retinoic acid in human blood. Drug Metab Dispos. 1981; 6:515-20.
57. Peck GL, Olsen TG, Butkus D et al. Isotretinoin versus placebo in the treatment of cystic acne: a randomized double-blind study. J Am Acad Dermatol. 1982; 6(4 Part 2):735-45. [IDIS 154901] [PubMed 6461677]
58. Peck GL, Yoder FW, Olsen TG et al. Treatment of Darier’s disease, lamellar ichthyosis, PRP, cystic acne and basal cell carcinoma with oral 13-cis-retinoic acid. Dermatologica. 1978; 157(Suppl 1):11-3. [IDIS 154896] [PubMed 150981]
59. Dicken CH, Bauer EA, Hazen PG et al. Isotretinoin treatment of Darier’s disease. J Am Acad Dermatol. 1982; 6(4 Part 2):721-6. [PubMed 7040515]
60. Bergfeld WF, Derbes VJ, Elias PM et al. The treatment of keratosis palmaris et plantaris with isotretinoin: a multicenter study. J Am Acad Dermatol. 1982; 6(4 Part 2):727-31. [PubMed 6461676]
61. Goerz G, Orfanos CE. Systemic treatment of psoriasis with a new aromatic retinoid. Dermatologica. 1978; 157(Suppl 1):38-44. [PubMed 357217]
62. Katz RA. Treatment of acanthosis nigricans with oral isotretinoin. Arch Dermatol. 1980; 116:110-1. [IDIS 110585] [PubMed 7352756]
63. Sporn MB, Dunlop NM, Newton DL et al. Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids). Fed Proc. 1976; 35:1332-8. [PubMed 770206]
64. Sporn MB, Newton DL. Chemoprevention of cancer with retinoids. Fed Proc. 1979; 38:2528-34. [PubMed 488376]
65. Lotan R. Effects of vitamin A and its analogues (retinoids) on normal and neoplastic cells. Biochim Biophys Acta. 1980; 605:33-91. [PubMed 6989400]
66. Michscke M, Cermi C, Kokron O et al. Stimulation of immune response in lung cancer patients by vitamin A therapy. Oncology. 1977; 34:234-8. [PubMed 917457]
67. Peck GL. Retinoids in dermatology—an interim report. Arch Dermatol. 1980; 116:283-4. [IDIS 109822] [PubMed 7369742]
68. Haydey RP, Reed ML, Dzubow LM et al. Treatment of keratoacanthomas with oral 13-cis-retinoic acid. N Engl J Med. 1980; 303:560-2. [IDIS 124959] [PubMed 6931285]
69. Kamm JJ. Toxicology, carcinogenicity, and teratogenicity of some orally administered retinoids. J Am Acad Dermatol. 1982; 6(4 Part 2):652-9. [PubMed 7040511]
70. Blackman HF, Peck GL, Olsen TG et al. Blepharoconjunctivitis: a side effect of oral 13-cis-retinoic acid therapy for dermatologic diseases. Ophthalmology (Rochester). 1979; 86:753-9.
71. Bring SV, Ricard CA, Zaehringer MV. Relationship between cholesterol and vitamin A metabolism in rats fed at different levels of vitamin A. J Nutr. 1965; 85:400-6. [PubMed 14273741]
72. Gerber LE, Erdman JW. Hypertriglyceridemia in rats administered all-trans or 13-cis retinoic acid. Fed Proc. 1979; 38:761.
73. Katz RA, Jorgensen H, Nigra TP. Elevation of serum triglyceride levels from oral isotretinoin in disorders of keratinization. Arch Dermatol. 1980; 116:1369-72. [IDIS 126918] [PubMed 6161583]
74. Dicken CH, Connolly SM. Eruptive xanthomas associated with isotretinoin (13-cis-retinoic acid). Arch Dermatol. 1980; 116:951-2. [IDIS 123277] [PubMed 6931550]
75. Weiss J, Degnan M, Leupold R et al. Bilateral corneal opacities: occurrence in a patient treated with oral isotretinoin. Arch Dermatol. 1981; 117:182-3. [IDIS 139503] [PubMed 6938168]
76. Wagner A, Plewig G. 13-cis-Retinsaure: Pharmakologische und toxikologische Untersuchungen bei der Behandlung schwerster Akneformen. (German; with English abstract.) Muench Med Wochenschr. 1980; 122:1294-1300.
77. Farb RM, Lazarus GM, Chiaramonti A et al. The effect of 13-cis-retinoic acid on epidermal lysosomal hydrolase activity in Darier’s disease and pityriasis rubra pilaris. J Invest Dermatol. 1980; 75:133-5. [IDIS 119644] [PubMed 6997395]
78. Lotan R, Dennert G. Stimulatory effects of vitamin A analogs on induction of cell-mediated cytotoxicity in vivo. Cancer Res. 1979; 39:55-8. [PubMed 761198]
79. Anon. Isotretinoin (Accutane) for acne. Med Lett Drugs Ther. 1982; 24:79-81. [PubMed 6213842]
80. Elias PM, Fritsch P, Lampe MA et al. Effects of systemic retinoids on epidermal barrier function, proliferation, structure, and glycosylation. Clin Res. 1980; 28:248.
81. Strauss JS, Stranieri AM. Changes in long-term sebum production from isotretinoin therapy. J Am Acad Dermatol. 1982; 6(4 Part 2):751-5. [PubMed 6461678]
82. Plewig G, Nikolowski J, Wolff HH. Action of isotretinoin in acne rosacea and gram-negative folliculitis. J Am Acad Dermatol. 1982; 6(4 Part 2):766-85. [PubMed 6461680]
83. Brinckerhoff CE, Nagase H, Nagel JE et al. Effects of all-trans-retinoic acid (retinoic acid) and 4-hydroxyphenylretinamide on synovial cells and articular cartilage. J Am Acad Dermatol. 1982; 6(4 Part 2):591-602. [PubMed 6279710]
84. Bauer EA, Seltzer JL, Eisen AZ. Inhibition of collagen degradative enzymes by retinoic acid in vitro. J Am Acad Dermatol. 1982; 6(4 Part 2):603-7. [PubMed 6279711]
85. Colburn WA (Roche Laboratories, Nutley, NJ): Personal communication; 1982 Oct.
86. Roche Laboratories. Roche Scientific Summary. Accutane (isotretinoin/Roche) in the treatment of severe, recalcitrant cystic acne. Nutley, NJ; 1982.
87. Baden HP, Buxman MM, Weinstein GD et al. Treatment of ichthyosis with isotretinoin. J Am Acad Dermatol. 1982; 6(4 Part 2):716-20. [PubMed 7040514]
88. Goldsmith LA, Weinrich AE, Shupack J. Pityriasis rubra pilaris response to 13-cis-retinoic acid (isotretinoin). J Am Acad Dermatol. 1982; 6(4 Part 2):710-5. [PubMed 7040513]
89. Boyland JI (Roche Laboratories, Nutley, NJ): Personal communication; 1982 Nov.
90. Meyskens FL Jr, Gilmartin E, Alberts DS et al. Activity of isotretinoin against squamous cell cancers and preneoplastic lesions. Cancer Treat Rep. 1982; 66:1315-9. [IDIS 152860] [PubMed 6211233]
91. Weissmann A, Wagner A, Plewig G. Reduction of bacterial skin flora during treatment with 13-cis-retinoic acid. Arch Dermatol Res. 1981; 270:179-83. [IDIS 154890] [PubMed 6454395]
92. Reviewers’ comments (personal observations); 1982.
93. Peck GL, Yoder FW. Treatment of lamellar ichthyosis and other keratinising dermatoses with an oral synthetic retinoid. Lancet. 1976; 2:1172-4. [PubMed 62999]
94. Peck GL, Gross EG, Butkus D et al. Chemoprevention of basal cell carcinoma with isotretinoin. J Am Acad Dermatol. 1982; 6(4 Part 2):815-23. [PubMed 6950957]
95. Moon RC, McCormick DL. Inhibition of chemical carcinogenesis by retinoids. J Am Acad Dermatol. 1982; 6(4 Part 2):809-14. [PubMed 7068981]
96. Camisa C, Eisenstat B, Ragaz A et al. The effects of retinoids on neutrophil functions in vitro. J Am Acad Dermatol. 1982; 6(4 Part 2):620-9. [PubMed 6279712]
97. Yoder FW. Isotretinoin: a word of caution. JAMA. 1983; 249:350-1. [IDIS 162893] [PubMed 6217354]
98. Roche Laboratories. Important information concerning your treatment with Accutane. Nutley, NJ; 1985 Jun.
99. Meyskens FL Jr, Goodman GE, Alberts DS. 13-cis-Retinoic acid: pharmacology, toxicology, and clinical applications for the prevention and treatment of human cancer. CRC Crit Rev Oncol Hematol. 1985; 3:75-101.
100. Anon. Update on birth defects with isotretinoin. FDA Drug Bull. 1984; 14:15-6. [PubMed 6592122]
101. Colburn WA, Gibson DM. Isotretinoin kinetics after 80 to 320 mg oral doses. Clin Pharmacol Ther. 1985; 37:411-4. [IDIS 198816] [PubMed 3856501]
102. Roche Laboratories. Accutane prescribing information. Nutley, NJ; 1985 May.
103. Stamatos MN. Accutane: New Clinical Information/Revised Package Insert (isotretinoin/Roche). Letter to pharmacists. Roche Laboratories. Nutley, NJ; 1985 Jun.
104. Strauss JS, Rapini RP, Shalita AR et al. Isotretinoin therapy for acne: results of a multicenter dose-response study. J Am Acad Dermatol. 1984; 10:490-6. [PubMed 6233335]
105. Roche Laboratories. Accutane (isotretinoin) capsules prescribing information. Nutley, NJ; 2004 Aug.
106. Rofsky HE. Accutane: New Safety Information. Letter to physicians. Roche Laboratories. Nutley, NJ; 1986 Sep.
107. Anon. Adverse effects with isotretinoin. FDA Drug Bull. 1983; 13:21-3. [PubMed 6581108]
108. Ward A, Brogden RN, Heel RC et al. Isotretinoin: a review of its pharmacological properties and therapeutic efficacy in acne and other skin disorders. Drugs. 1984; 28:6-37. [IDIS 186816] [PubMed 6235105]
109. Harms M, Philippe I, Ceyrac D et al. Isotretinoin ineffective topically. Lancet. 1985; 1:398. [IDIS 196482] [PubMed 2857449]
110. Khoo KC, Reik D, Colburn WA. Pharmacokinetics of isotretinoin following a single oral dose. J Clin Pharmacol. 1982; 22:395-402. [IDIS 157847] [PubMed 6957421]
111. Colburn WA, Gibson DM, Wiens RE et al. Food increases the bioavailability of isotretinoin. J Clin Pharmacol. 1983; 23:534-9. [IDIS 180499] [PubMed 6582073]
112. Brazzell RK, Vane FM, Ehmann CW et al. Pharmacokinetics of isotretinoin during repetitive dosing to patients. Eur J Clin Pharmacol. 1983; 24:695-702. [IDIS 172015] [PubMed 6575917]
113. Colburn WA, Vane FM, Bugge CJL et al. Pharmacokinetics of14C-isotretinoin in healthy volunteers and volunteers with biliary T-tube drainage. Drug Metab Dispos. 1985; 13:327-32. [IDIS 200755] [PubMed 2861992]
114. Gilgor RS, Chiaramonti A, Goldsmith LA et al. Evaluation of 13-cis-retinoic acid in lamellar ichthyosis, pityriasis rubra pilaris and Darier’s disease. Cutis. 1980; 25:380-1,385. [IDIS 154887] [PubMed 6928816]
115. Sofen HL, Moy RL, Lowe NJ. Treatment of generalized pustular psoriasis with isotretinoin. Lancet. 1984; 1:40. [IDIS 180326] [PubMed 6140356]
116. Moy RL, Kingston TP, Lowe NJ. Isotretinoin vs etretinate therapy in generalized pustular and chronic psoriasis. Arch Dermatol. 1985; 121:1297-1301. [IDIS 206025] [PubMed 3862363]
117. Hönigsmann H, Wolff K. Isotretinoin-PUVA for psoriasis. Lancet. 1983; 1:236. [IDIS 164712] [PubMed 6130263]
118. Levine N, Miller RC, Meyskens FL Jr. Oral isotretinoin therapy: use in a patient with multiple cutaneous squamous cell carcinomas and keratoacanthomas. Arch Dermatol. 1984; 120:1215-7. [IDIS 190583] [PubMed 6591861]
119. Kessler JF, Meyskens FL Jr, Levine N et al. Treatment of cutaneous T-cell lymphoma (mycosis fungoides) with 13-cis-retinoic acid. Lancet. 1983; 1:1345-7. [IDIS 172519] [PubMed 6134133]
120. Warrell RP Jr, Coonley CJ, Kempin SJ et al. Isotretinoin in cutaneous T-cell lymphoma. Lancet. 1983; 2:629. [IDIS 175683] [PubMed 6136780]
121. Kessler JF, Jones SE, Levine N et al. Isotretinoin and cutaneous helper T-cell lymphoma (mycosis fungoides). Arch Dermatol. 1987; 123:201-4. [IDIS 225172] [PubMed 2949706]
122. Neely SM, Mehlmauer M, Feinstein DI. The effect of isotretinoin in six patients with cutaneous T-cell lymphoma. Arch Intern Med. 1987; 147:529-31. [IDIS 227160] [PubMed 3493744]
123. Gold EJ, Mertelsmann RH, Itri LM et al. Phase I clinical trial of 13-cis-retinoic acid in myelodysplastic syndromes. Cancer Treat Rep. 1983; 67:981-6. [IDIS 181584] [PubMed 6580071]
124. Greenberg BR, Durie BGM, Barnett TC et al. Phase I-II study of 13-cis-retinoic acid in myelodysplastic syndrome. Cancer Treat Rep. 1985; 69:1369-74. [IDIS 211094] [PubMed 3865701]
125. Picozzi VJ Jr, Swanson GF, Morgan R et al. 13-cis Retinoic acid treatment for myelodysplastic syndromes. J Clin Oncol. 1986; 4:589-95. [PubMed 3514807]
126. Clark RE, Jacobs A, Lush CJ et al. Effect of 13-cis-retinoic acid on survival of patients with myelodysplastic syndrome. Lancet. 1987; 1:763-5. [IDIS 228018] [PubMed 2882180]
127. Buzaid AC, Garewal HS, Greenberg BR. Management of myelodysplastic syndromes. Am J Med. 1986; 80:1149-57. [IDIS 217661] [PubMed 3524212]
128. Koch HF. Biochemical treatment of precancerous oral lesions: the effectiveness of various analogues of retinoic acid. J Maxillofac Surg. 1978; 6:59-63. [PubMed 274508]
129. Hong WK, Endicott J, Itri LM et al. 13-cis-Retinoic acid in the treatment of oral leukoplakia. N Engl J Med. 1986; 315:1501-5. [IDIS 223468] [PubMed 3537787]
130. Shah JP, Strong EW, DeCosse JJ et al. Effect of retinoids on oral leukoplakia. Am J Surg. 1983; 146:466-70. [IDIS 176940] [PubMed 6578687]
131. Lyons F, Laker MF, Marsden JR et al. Effect of oral 13-cis-retinoic acid on serum lipids. Br J Dermatol. 1982; 107:591-5. [IDIS 161141] [PubMed 6215057]
132. Zech LA, Gross EG, Peck GL et al. Changes in plasma cholesterol and triglyceride levels after treatment with oral isotretinoin: a prospective study. Arch Dermatol. 1983; 119:987-93. [IDIS 178557] [PubMed 6228196]
133. Bershad S, Rubinstein A, Paterniti JR Jr et al. Changes in plasma lipids and lipoproteins during isotretinoin therapy for acne. N Engl J Med. 1985; 313:981-5. [IDIS 205735] [PubMed 2931603]
134. Matsuoka LY, Wortsman J, Pepper JJ. Acute arthritis during isotretinoin treatment for acne. Arch Intern Med. 1984; 144:1870-1. [IDIS 189838] [PubMed 6236765]
135. Pennes DR, Ellis CN, Madison KC et al. Early skeletal hyperostoses secondary to 13-cis-retinoic acid. AJR. 1984; 142:979-83. [IDIS 184566] [PubMed 6609585]
136. Ellis CN, Madison KC, Pennes DR et al. Isotretinoin therapy is associated with early skeletal radiographic changes. J Am Acad Dermatol. 1984; 10:1024-9. [PubMed 6588057]
137. Pittsley RA, Yoder FW. Retinoid hyperostosis: skeletal toxicity associated with long-term administration of 13-cis-retinoic acid for refractory ichthyosis. N Engl J Med. 1983; 308:1012-4. [IDIS 169275] [PubMed 6403861]
138. Milstone LM, McGuire J, Ablow RC. Premature epiphyseal closure in a child receiving oral 13-cis-retinoic acid. J Am Acad Dermatol. 1982; 7:663-6. [PubMed 6958690]
139. Novick NL, Lawson W, Schwartz IS. Bilateral nasal bone osteophytosis associated with short-term oral isotretinoin therapy for cystic acne vulgaris. Am J Med. 1984; 77:736-9. [IDIS 191620] [PubMed 6237578]
140. Hodak E, Gadoth N, David M et al. Muscle damage induced by isotretinoin. BMJ. 1986; 293:425-6. [IDIS 220114] [PubMed 3091143]
141. Fraunfelder FT, LaBraico JM, Meyer SM. Adverse ocular reactions possibly associated with isotretinoin. Am J Ophthalmol. 1985; 100:534-7. [IDIS 209281] [PubMed 2931989]
142. Weleber RG, Denman ST, Hanifin JM et al. Abnormal retinal function associated with isotretinoin therapy for acne. Arch Dermatol. 1986; 104:831-7.
143. Benke PJ. The isotretinoin teratogen syndrome. JAMA. 1984; 251:3267-9. [IDIS 186330] [PubMed 6587131]
144. de la Cruz E, Sun S, Vangvanichyakorn K et al. Multiple congenital malformations associated with maternal isotretinoin therapy. Pediatrics. 1984; 74:428-30. [IDIS 189774] [PubMed 6591112]
145. Lammer EJ, Chen DT, Hoar RM et al. Retinoic acid embryopathy. N Engl J Med. 1985; 313:837-41. [IDIS 204599] [PubMed 3162101]
146. Rosa FW, Wilk AL, Kelsey FO. Teratogen update: vitamin A congeners. Teratology. 1986; 33:355-64. [PubMed 3461576]
147. Cohen M, Rubinstein A, Li JK et al. Thymic hypoplasia associated with isotretinoin embryopathy. Am J Dis Child. 1987; 141:263-6. [IDIS 226304] [PubMed 3492909]
148. Chalker DK, Lesher JL, Smith JG et al. Efficacy of topical isotretinoin 0.05% gel in acne vulgaris: results of a multicenter, double-blind investigation. J Am Acad Dermatol. 1987; 17:251-4. [PubMed 2957398]
149. American Academy of Dermatology. Guidelines for prescribing isotretinoin (Accutane) in the treatment of female acne patients of childbearing potential. Evanston, IL; 1988 Jul.
150. Young FE. Letter sent to Oddis JA (ASHP) regarding isotretinoin. Rockville, MD: Food and Drug Administration; 1988 Jul.
151. McLearn D. Isotretinoin (Accutane) restrictions. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 1988 May 27.
152. Peterson F. Isotretinoin (Accutane) birth defects. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 1988 Mar 30.
153. Anon. Birth defects caused by isotretinoin—New Jersey. MMWR Morb Mortal Wkly Rep. 1988; 37:171-72,177. [PubMed 3126387]
154. Ayme S, Julian C, Gambarelli D et al. Isotretinoin dose and teratogenicity. Lancet. 1988; 1:655. [IDIS 240205] [PubMed 2894594]
155. Rosa F. Isotretinoin dose and teratogenicity. Lancet. 1987; 2:1154. [IDIS 235512] [PubMed 2890055]
156. Torok L, Kadar L, Kasa M. Spermatological investigations in patients treated with etretinate and isotretinoin. Andrologia. 1987; 19:629-33. [PubMed 3481225]
157. Vogt HJ, Ewers R. [13-cis-Retinoic acid and spermatogenesis: spermatological and impulse cytophotometric studies.] (German; with English abstract.) Hautarzt. 1985; 36:281-6.
158. Zachariae H. Delayed wound healing and keloid formation following argon laser treatment or dermabrasion during isotretinoin treatment. Br J Dermatol. 1988; 118:703-6. [IDIS 243698] [PubMed 2969261]
159. Roenigk HH Jr. Dermabrasion and isotretinoin. JAMA. 1988; 259:3479.
160. Lippman SM, Meyskens FL Jr. Treatment of advanced squamous cell carcinoma of the skin with isotretinoin. Ann Intern Med. 1987; 107:499-501. [IDIS 234488] [PubMed 3477106]
161. Kraemer KH, DiGiovanna JJ, Moshell AN et al. Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med. 1988; 318:1633-7. [IDIS 242488] [PubMed 3287161]
162. Rubenstein R, Roenigk HH Jr, Stegman SJ et al. Atypical keloids after dermabrasion of patients taking isotretinoin. J Am Acad Dermatol. 1986; 15:280-95. [PubMed 3018052]
163. Anon. Accutane risks evaluated: strong precautions needed. FDA Drug Bull. 1990; 20:5-6.
164. Crawford SY. Meeting of joint FDA advisory committees on Accutane (meeting report). Bethesda, MD: American Society of Health-System Pharmacists, Inc.; 1990 Jun 15.
165. Crawford SY. Meeting with Roche Dermatologics to discuss Accutane (meeting report). Bethesda, MD: American Society of Health-System Pharmacists, Inc.; 1990 Oct 10.
166. David M, Hodak E, Lowe NJ. Adverse effects of retinoids. Med Toxicol Adverse Drug Exp. 1988; 3:273-88. [IDIS 246855] [PubMed 3054426]
167. Besa EG, Abraham JL, Bartholomew MJ et al. Treatment with 13-cis-retinoic acid in transfusion-dependent patients with myelodysplastic syndrome and decreased toxicity with addition of alpha-tocopherol. Am J Med. 1990; 89:739-47. [IDIS 275904] [PubMed 2252043]
168. McElwee NE, Schumacher MC, Johnson SC et al. An observational study of isotretinoin recipients treated for acne in a health maintenance organization. Arch Dermatol. 1991; 127:341-6. [IDIS 278916] [PubMed 1825596]
169. Hesdorffer CS, Weltman MD, Raftopoulos H et al. Thrombocytopenia caused by isotretinoin. S Afr Med J. 1986; 70:705. [IDIS 232958] [PubMed 3466373]
170. Johnson TM, Rapini RP. Isotretinoin-induced thrombocytopenia. J Am Acad Dermatol. 1987; 17:838-9. [PubMed 2960702]
171. Rees JL, Cox NH. Effect of isotretinoin on eccrine gland function. Br J Dermatol. 1988; 119:79-82. [IDIS 249479] [PubMed 3165666]
172. Orfanos CE, Ehlert R, Gollnick H. The retinoids: a review of their clinical pharmacology and therapeutic use. Drugs. 1987; 34:459-503. [IDIS 236537] [PubMed 3315625]
173. Braun JT, Franciosi RA, Mastri AR et al. Isotretinoin dysmorphic syndrome. Lancet. 1984; 1:506-7. [IDIS 183081] [PubMed 6142222]
174. Hill RM. Isotretinoin teratogenicity. Lancet. 1984; 1:1465. [IDIS 187185] [PubMed 6145899]
175. Hersh JH, Danhauer DE, Hand ME et al. Retinoic acid embryopathy: timing of exposure and effects on fetal development. JAMA. 1985; 254:909-10. [IDIS 203556] [PubMed 4021019]
176. Anon. The teratogenicity of retinoids. Reprod Toxicol. 1986; 5:5-8.
177. Rappaport EB, Knapp M. Isotretinoin embryopathy: a continuing problem. J Clin Pharmacol. 1989; 29:463-5. [IDIS 255942] [PubMed 2738179]
178. Kizer KW, Fan AM, Bankowska J et al. Vitamin A: a pregnancy hazard alert. West J Med. 1990; 152:78-81. [IDIS 262619] [PubMed 2309485]
179. Stern RS. When a uniquely effective drug is teratogenic: the case of isotretinoin. N Engl J Med. 1989; 320:1007-9. [IDIS 252962] [PubMed 2522591]
180. Faich G, Rosa F. When a uniquely effective drug is teratogenic: the case of isotretinoin. N Engl J Med. 1989; 321:756-7.
181. Swensen RE. Avoiding pregnancy in isotretinoin users. West J Med. 1990; 152:406. [PubMed 18750719]
182. Cogenital Abnormalities Subcommittee of the Australian Drug Evaluation Committee. Isotretinoin: birth defects. Aust Prescriber. 1989; 12:26-7.
184. Anon. Continued reports of birth defects with isotretinoin engender labeling, packaging changes. FDA Drug Bull. 1988; 18:27-8.
185. Anon. Roche relabels Accutane after independent review of MedWatch reports. F-D-C Rep. 1998; Mar 2.
186. Anon. Isotretinoin (Accutane) safety information. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 1998 Feb 25.
187. Ellison RH. Dear doctor letter regarding reports of psychiatric disorders with use of Accutane. Nutley, NJ: Roche Laboratories; 1998 Feb.
188. Ault A. Isotretinoin use may be linked with depression. Lancet. 1998; 351:730.
189. Anon. Side effects prompt stronger warning on acne drug. FDA Consumer. 1998; 32:3.
190. Hong J. Dear healthcare provider and pharmacist letter: Important prescribing information: new medication guide and informed consent documents for Accutane (isotretinoin). Nutley, NJ: Roche Laboratories; 2001 Jan.
191. Roche Laboratories Inc. Accutane (isotretinoin) System to Manage Accutane Related Teratogenicity (SMART) guide to best practices. Nutley, NJ; updated. From the FDA website.
192. Food and Drug Administration. Dermatologic and Ophthalmic Drugs Advisory Committee. Sept. 18-19, 2000 [accessed November 8, 2001]. Appendix II (Overview of Accutane and Pregnancy Exposure Performance of the Current Pregnancy Prevention Program) From the FDA website.
193. Food and Drug Administration. Division of dermatologic and dental Drug Products Center for Drug Evaluation and Research letter to the boards of pharmacy regarding Accutane prescriptions under the S.M.A.R.T. (System to Manage Accutane Related Teratogenicity) program. Rockville, MD; October 30, 2001. From FDA website.
194. DiGiovanna JJ. Isotretinoin effects on bone. J Am Acad Dermatol. 2001 (Suppl); 45:S176-82.
195. Castrow FF. Isotretinoin update. Washington, DC; 2002 Dec 9. Press release from the American Academy of Dermatology Association (AAD) government affairs website.
196. Bertek Pharmaceuticals, Inc. Amnesteem (isotretinoin) capsules prescribing information. Research Triangle Park, NC; 2002 Sep.
197. Ranbaxy Pharmaceuticals, Inc. Sotret (isotretinoin) capsules prescribing information. Princeton, NJ; 2002 Dec.
198. Barr Laboratories, Inc. Claravis (isotretinoin) capsules prescribing information Pomona, NY; 2003 Feb.
199. Food and Drug Administration. FDA announces enhancement to isotretinoin risk management program. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 2004 Nov 23. From FDA website.
200. Food and Drug Administration. Accutane (isotretinoin) questions and answers. Rockville, MD: Food and Drug Administration; 2004 Nov 23. From FDA website.
201. The iPLEDGE Program Guide to Best Practices for Isotretinoin. 2005. From the iPLEDGE website.
202. Food and Drug Administration. Public Health Advisory. Strengthened risk management program for isotretinoin. Rockville, MD; revised October 28, 2005. From the FDA website.
203. Roche Laboratories. Accutane (isotretinoin) capsules prescribing information. Nutley, NJ; 2005 Aug.
204. Houn, F. Letter sent to Carey E (Hoffmann-La Roche) concerning implementation dates for the iPLEDGE RiskMAP program. Rockville, MD: Food and Drug Administration; 2005 Oct 27.
205. Food and Drug Administration. Public Health Advisory. Isotretinoin (marketed as Accutane) capsule information: iPLEGDE update. Rockville, MD; October 6, 2006. From the FDA website.
206. Bottini PB, Mundkur C, Birgerson L et al. Dear healthcare provider letter: Effective immediately: elimination of the 23 day lock-out period for males and females of nonchildbearing potential. October 6, 2006. From the iPLEDGE website.