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: Accutane, Amnesteem, Claravis, Sotret
Special Alerts:
[Posted 10/06/2006] FDA and the iPLEDGE program notified healthcare professionals and patients of an update to iPLEDGE, a risk management program to reduce the risk of fetal exposure to isotretinoin, that will eliminate one element of the program, the 23 day lock-out period for males and females of non-child bearing potential. This change does not affect female patients of child-bearing potential. For more information visit the FDA website at: , , and .
REMS:
FDA approved a REMS for isotretinoin to ensure that the benefits of a drug outweigh the risks. 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 ().
Known human teratogen; extremely high risk of severe birth defects if administered during pregnancy; may be life-threatening.201 203 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
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
Pregnancy must be excluded by monthly negative serum or urine pregnancy test results and prevented by simultaneous use of 2 forms of reliable contraception.201 203 (See Advice to Patients.)
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.)
Introduction
Synthetic retinoid; anti-acne drug.1 2 93 108
Uses for Isotretinoin
See the MedWatch notification at the beginning of the monograph.
Severe Nodular Acne
Treatment of severe recalcitrant nodular (cystic) acne unresponsive to conventional acne therapies, including oral and/or topical anti-infectives.1 29 30 31 32 33 104 105
Safety and efficacy not established for less severe forms of acne.79 89 108
Disorders of Keratinization†
Has been used for the treatment of cutaneous disorders of keratinization† unresponsive to conventional therapies (e.g., corticosteroids, topical tretinoin).58 59 60 87 88 93 108 114
Psoriasis†
Has been used alone and in combination with a psoralen and UVA light (PUVA therapy) in the treatment of psoriasis†.61 93 108 115 116 117
Neoplasms†
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
General
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
Transient exacerbation (or flare) of acne may occur during the first weeks of therapy,108 203 but this initial exacerbation usually subsides by 4–6 weeks.92
If a patient misses a dose, the next dose should not be doubled.98 105
Do not exceed recommended dosage and duration of treatment.105 196 197
Administration
Restricted Distribution
Distribution of isotretinoin is restricted because of known, severe teratogenic effects.201 203 (See Boxed Warning and also see Fetal/Neonatal Morbidity and Mortality under Cautions.)
A centralized risk management program, called iPLEDGE, for Accutane (isotretinoin) and all generic 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
Oral Administration
Administer orally twice daily with meals;1 105 111 once-daily dosing not recommended.105 196 197
To decrease the risk of esophageal irritation, swallow capsules whole with a full glass of liquid; do not suck or chew the capsules.105
Dosage
Pediatric Patients
Severe Nodular Acne
Oral
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
Adults
See the MedWatch notification at the beginning of the monograph.
Severe Nodular Acne
Oral
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
Prescribing Limits
Pediatric Patients
Severe Nodular Acne
Oral
Maximum 2 mg/kg daily.105
Adults
Severe Nodular Acne
Oral
Maximum 2 mg/kg daily.105
Cautions for Isotretinoin
Contraindications
Female patients who are or may become pregnant.203 (See Fetal/Neonatal Morbidity and Mortality under Cautions and also see Boxed Warning.)
Nursing women.203
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.)
Known hypersensitivity to isotretinoin or any ingredient in the formulation.203 Some formulations contain parabens; contraindicated in sensitive patients.203
Warnings/Precautions
Warnings
See the MedWatch notification at the beginning of the monograph.
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.)
Blood Donations
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
Psychiatric Disorders
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
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
Pancreatitis
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
Hepatitis
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
Inflammatory bowel syndrome (including regional ileitis) has been reported in patients without a history of intestinal disorders.105 105
If abdominal pain, rectal bleeding, or severe diarrhea occurs, immediately discontinue therapy.105 Symptoms may persist even after discontinuance of isotretinoin therapy.105
Musculoskeletal Effects
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
Otic Effects
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
Ocular Effects
Possible corneal opacities, cataracts, and decreased night vision.105 If visual difficulties occur during therapy, discontinue the drug and perform an ophthalmologic examination.105
Sensitivity Reactions
Hypersensitivity Reactions
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
Paraben Sensitivity
Some formulations contain parabens; contraindicated in sensitive patients.203
Photosensitivity
Photosensitivity reactions reported;1 6 29 105 minimize exposure of treated areas to natural or artificial (e.g., sunlamps) sunlight.105
General Precautions
Hematologic Effects
Possible anemia, thrombocytopenia, neutropenia, and (rarely) agranulocytosis; discontinue the drug if clinically important decreases in leukocyte counts occur.203
Dermatologic Effects
Possible scarring; avoid wax epilation and skin resurfacing procedures (such as dermabrasion, laser) during therapy and for at least 6 months thereafter.105
Specific Populations
Pregnancy
Category X.203
See the MedWatch notification at the beginning of the monograph.
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.)
Lactation
Not known whether isotretinoin is distributed into milk; contraindicated in nursing women.105
Pediatric Use
Safety and efficacy not established in children <12 years of age.105 No substantial differences in efficacy of the drug in adolescents ≥12 years of age relative to adults.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
Geriatric Use
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
Metabolized principally by CYP2C8, 2C9, 3A4, and 2B6.105 Does not inhibit CYP2C9.105
Specific Drugs
Drug | Interaction | Comment |
|---|---|---|
Corticosteroids | Possible additive effects on bone loss196 197 203 | Use with caution196 197 203 |
Hormonal contraceptives | 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 |
Phenytoin | Possible additive effects on bone loss196 197 203 | Use with caution196 197 203 |
St. John’s wort (Hypericum perforatum) | Possible risk of hormonal contraceptive failure during concomitant use203 | Avoid concomitant use203 |
Tetracyclines | Possible increased risk for pseudotumor cerebri (benign intracranial hypertension)105 196 197 | Avoid concomitant use105 196 197 |
Vitamin A | Possible additive adverse effects105 | Avoid concomitant use105 |
Isotretinoin Pharmacokinetics
Absorption
Bioavailability
Rapidly absorbed from the GI tract following an initial lag time of about 0.5–2 hours.53 110 111 112
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
Food appears to increase the bioavailability of isotretinoin without altering its disposition.105
Distribution
Extent
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
Crosses the placenta in animals.1 55
It is not known if isotretinoin is distributed into milk.1
Distributes into semen of male patients taking the drug; however, the amount delivered to a female partner in semen would be about 1 million times lower than an oral dose of 40 mg.105 191
Plasma Protein Binding
>99%, principally albumin.105
Elimination
Metabolism
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
Elimination Route
Excreted in urine and feces in relatively equal amounts as conjugates of isotretinoin and its metabolites.105
Half-life
Biphasic; initial phase half-life (t½α) averages 0.5 hours53 and the half-life in the terminal phase (t½β) averages 10–20 hours (range: 7–39 hours).53 108 110 112
Stability
Storage
Oral
Capsules
15–30°C in tight, light-resistant containers.2 105
Actions
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 the treatment of nodulocystic acne is not fully understood but appears to include inhibition of sebaceous gland function and follicular keratinization.1 8 29 30 93
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
See the MedWatch notification at the beginning of the monograph.
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.)
Provide patients with a copy of the medication guide and explain procedures necessary for obtaining the drug.201 202 203
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 advising patients who wear contact lenses that they may experience decreased tolerance to the lenses during or after therapy with the drug.102 105
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.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Isotretinoin is available only through a restricted distribution program.201 (See Restricted Distribution under Dosage and Administration.)
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules, liquid-filled | 10 mg | Accutane (with parabens) | Roche |
Amnesteem | Mylan | |||
Claravis | Barr | |||
Sotret (with parabens) | Ranbaxy | |||
20 mg | Accutane (with parabens) | Roche | ||
Amnesteem | Mylan | |||
Claravis | Barr | |||
Sotret (with parabens) | Ranbaxy | |||
30 mg | Sotret (with parabens) | Ranbaxy | ||
40 mg | Accutane (with parabens) | Roche | ||
Amnesteem | Mylan | |||
Claravis | Barr | |||
Sotret (with parabens) | Ranbaxy |
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
References
Only references cited for selected revisions after 1984 are available electronically.
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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.
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