section name header

Introduction ⬇

AHFS Class:

Generic Name(s):

Notification

REMS:

FDA approved a REMS for isotretinoin to ensure that the benefits outweigh the risks. (See Dosage and Administration: Restricted Distribution Program.) 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 ([Web]).

Isotretinoin is a synthetic retinoid.1,2,93,108

Uses ⬆ ⬇

[Section Outline]

Severe Nodular Acne !!navigator!!

Isotretinoin is used for the treatment of severe recalcitrant nodular (cystic) acne.1,29,30,31,32,33,104,105 Nodules are inflammatory lesions with a diameter of 5 mm or greater.1 Such nodules may become suppurative or hemorrhagic.1 The term “severe” as defined by the manufacturers means “many” as opposed to “few or several ” nodules.1 Because of the risk of adverse effects, which may be severe (e.g., skeletal abnormalities), the drug should be reserved for patients who are unresponsive to conventional acne therapies, including oral and/or topical anti-infectives.1 In addition, isotretinoin is indicated only for female patients of childbearing potential who are not and will not become pregnant and have complied with all special conditions required by the manufacturers.1,203 (See Cautions: Precautions.) Treatment of severe nodular acne should be individualized and occasionally modified depending on severity of the disease and response to therapy.1 Although isotretinoin has not been compared directly with conventional acne therapies, isotretinoin has been effective in the treatment of severe nodular and/or conglobate acne that was unresponsive to oral and/or topical anti-infectives, topical tretinoin, topical benzoyl peroxide, or other acne therapies.29,32,33,57 Unlike tretinoin and other conventional acne therapies, isotretinoin has usually been associated with continued improvement and prolonged remission after discontinuance of therapy in patients with severe nodular and/or conglobate acne.1,29,32,33,57 The safety and efficacy of isotretinoin in patients with less severe forms of acne have not been established.79,89,108

In patients with severe nodular and/or conglobate acne, isotretinoin therapy reduces the number of existing cysts, decreases erythema and tenderness of new and existing inflamed lesions, and decreases oiliness of the skin;29,30,32,57 lesions clear almost completely in most patients.29,57 Comedones and noncystic lesions (e.g., papules, pustules) also decrease in number during treatment with the drug.29,57 In these patients, facial lesions respond more rapidly than those of the back and chest.29,57 Lesions in females appear to respond more rapidly and completely.57 Based on limited published reports, a single course of therapy may be sufficient to produce prolonged remission in many patients; some patients benefit from an additional course of therapy, but at least 8 weeks should elapse after the first course to assess the degree of improvement and the need for further therapy.1 The duration of remission and rate of relapse remain to be determined.79,108 Cures (remission persisting for 5 years or longer after discontinuance of therapy) have occurred in some patients.79 Based on limited published data, relapse appears to be age and dose dependent, occurring more commonly in patients younger than 20 years of age and in those treated with low dosages.29,33,57,108

In patients with severe nodular and/or conglobate acne and other concomitant dermatologic conditions, such as hidradenitis suppurativa† or dissecting cellulitis of the scalp†, the dermatologic response of these concomitant conditions may be decreased or delayed with isotretinoin therapy.20,29,57 These patients may require prolonged treatment and/or higher than usual dosages of the drug.20,29,57 Additional studies are required to determine the safety and efficacy of isotretinoin in the treatment of these combined dermatologic conditions†.

Disorders of Keratinization !!navigator!!

Isotretinoin has been used in the treatment of cutaneous disorders of keratinization† that are resistant to treatment with other agents (e.g., corticosteroids, topical tretinoin); however, the specific role of isotretinoin in the treatment of these disorders and the safety of long-term use and high dosages of the drug have not been determined.58,59,60,87,88,93,108,114 (See Cautions: Musculoskeletal Effects.)

Isotretinoin has been used in the treatment of a limited number of patients with keratosis follicularis† (Darier's disease),58,59,93,108,114 lamellar ichthyosis†,58,87,93,108,114 pityriasis rubra pilaris (PRP)†,58,88,93,108,114 and keratosis palmaris et plantaris†.60 In the treatment of lamellar ichthyosis†, isotretinoin appears to increase the patient's ability to perspire, improve the ectropion, and reduce the severity of erythema, scaling, induration, and crusting.20,58,87,93,108,114

Although some improvement has been observed in most patients with disorders of keratinization† following treatment with isotretinoin, responses have been variable and higher than currently recommended dosages of the drug have been required to obtain a response.20,58,59,60,77,87,93,108,114 Unlike the response seen in patients with severe nodular acne, treatment of these cutaneous disorders has generally not been associated with prolonged remission; symptoms usually return to pretreatment severity following discontinuance of the drug, suggesting that long-term therapy with isotretinoin may be necessary.20,58,59,60,87,93,108,114 Because of the apparent risk of hyperostosis when prolonged therapy with high dosages of isotretinoin is used, some clinicians recommend that, pending further accumulation of data regarding long-term safety, the drug be used in the treatment of disorders of keratinization only if the disease is severe.92 These clinicians also recommend that if isotretinoin is used in these disorders, the dosage be as low as possible and the drug be given intermittently, combined with intensive topical therapy with other drugs, in order to limit total isotretinoin dosage.92

Isotretinoin has been administered with good results in at least one patient with acanthosis nigricans†; however, following discontinuance of therapy, the patient's condition returned to pretreatment severity, and long-term administration of the drug was necessary to maintain a response.62

Psoriasis !!navigator!!

Isotretinoin 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 Based on limited data, isotretinoin appears to be substantially less effective than etretinate when used alone for the treatment of chronic plaque psoriasis.93,115,116 Isotretinoin alone appears to be effective in controlling pustulation and systemic symptoms in patients with pustular psoriasis,115,116 but additional therapy may be required to produce complete clearing of lesions.116 Limited data suggest that isotretinoin used in combination with PUVA may be as effective as etretinate and PUVA in the treatment of severe psoriasis.117 In patients with severe psoriasis, isotretinoin in combination with PUVA therapy accelerates the response of psoriatic lesions to PUVA, reduces the number of exposures and treatment time required for lesions to clear, and greatly reduces the cumulative dose of UVA.117

Neoplasms !!navigator!!

Isotretinoin has been used in a limited number of patients in the prevention, treatment, and adjunctive treatment of various cutaneous and extracutaneous malignant neoplasms (of epithelial origin)†; however, the specific role of the drug in the treatment of these conditions has not been determined and additional study is needed.4,46,58,63,64,65,66,94,97,118,160,161

Based on limited reports in humans, isotretinoin appears to be of some value in the prevention and treatment of basal cell carcinoma†;46,58,67,94 however, long-term maintenance therapy appears necessary for successful prophylaxis.20,46,58,94 In animals, isotretinoin has been shown to prevent chemically induced epithelial tumors of the mammary gland, esophagus, and urinary bladder; this effect is observed if the drug is administered prophylactically before or after exposure to a carcinogen.20

Isotretinoin has been effective in the adjunctive treatment of some patients with inoperable neoplasms such as squamous cell carcinoma of the lung†65,66 and for the treatment of advanced squamous cell carcinoma of the skin† that was refractory to standard therapy.160 The drug has also been used with good results alone118 or as an adjunct to surgery68 in a few patients for the management of keratoacanthomas†; however, long-term maintenance therapy with the drug may be necessary to prevent recurrence of the lesions.68,118 Isotretinoin has also produced partial and complete responses in some patients with advanced cutaneous T-cell lymphomas†, including mycosis fungoides and Sézary syndrome,119,120,121,122 and has exhibited a beneficial effect in preventing skin cancers in patients with xeroderma pigmentosum†,161 but further evaluation is needed.

Limited data suggest that isotretinoin may produce beneficial hematologic responses in some patients with myelodysplastic syndromes†, but additional study is needed.123,124,125,126,127 Pending further accumulation of data, some clinicians recommend that therapy with the drug be considered principally in patients whose clinical course is indolent.127 Limited data also suggest that oral128,129 or topical130 isotretinoin therapy may be effective for the treatment of oral leukoplakia†, but further evaluation is needed.128,129,130

Dosage and Administration ⬆ ⬇

[Section Outline]

Administration !!navigator!!

Isotretinoin is administered orally with meals to maximize GI absorption.1,105,111 Isotretinoin should be administered in 2 divided doses.105 The manufacturers state that safety of once-daily dosing of isotretinoin has not been established and is not recommended.105,196,197

To decrease the risk of esophageal irritation, isotretinoin capsules should be swallowed whole with a full glass of liquid.105 Patients should be instructed not to suck or chew the capsules.105

Dosage !!navigator!!

Severe Recalcitrant Nodular Acne

The initial dosage of isotretinoin for the treatment of severe recalcitrant nodular (cystic) acne in adults and adolescents 12 years of age and older should be individualized according to severity of the disease and the patient's weight.105 Subsequent dosage should be carefully adjusted after 2 or more weeks of treatment according to individual tolerance and response, using the lowest possible effective dosage.105 If a patient misses a dose, the next dose should not be doubled.98,105

For the treatment of severe recalcitrant nodular acne in adults and adolescents 12 years of age and older, the usual initial dosage of isotretinoin is 0.5-1 mg/kg daily given in 2 divided doses with food.105 Relapse, with the need for a second course of therapy, appears to be inversely related to the initial dosage regimen.103,104,105 In clinical studies comparing dosages of 0.1, 0.5, and 1 mg/kg daily, all 3 dosages resulted in initial clearing of disease but there was a greater need for retreatment with decreasing dosage (about 40, 20, and 10% of the patients, respectively, required a second course of therapy).103,104,105 Adults whose disease is severe or is mainly evident on the chest and back, instead of the face, may require up to the maximum recommended dosage of 2 mg/kg daily.105 However, clinicians should ascertain whether patients have been compliant with instructions on taking the drug with food before increasing isotretinoin dosages, since failing to take isotretinoin capsules with food will substantially decrease absorption of the drug.105,111

The usual duration of a course of isotretinoin therapy in the treatment of severe recalcitrant nodular acne is 15-20 weeks; however, therapy may be discontinued 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 The optimum interval between initial and subsequent courses of isotretinoin therapy has not been defined for children who have not completed skeletal growth.105 (See Cautions: Musculoskeletal Effects.) The manufacturers state that recommended dosage and duration of treatment should not be exceeded.105,196,197 Long-term use of isotretinoin, even in low dosages, has not been studied and is not recommended.105

Disorders of Keratinization

For the treatment of disorders of keratinization†, isotretinoin dosages up to 4 mg/kg daily have been used by most clinicians;7,26,58,59,60,62,87,88,93,108,114 however, the effective dosage in the treatment of these disorders appears to be variable and depends on several factors, including the specific disease and its severity.26,58,59,60,87,88,93,108,114 In addition, the safety of long-term use and high dosages of the drug has not been established.26,58,59,60,62,87,88,93,108,114 (See Cautions: Musculoskeletal Effects.) Clinicians should consult published protocols for the dosage and duration of isotretinoin therapy in the treatment of specific disorders.

Restricted Distribution Program !!navigator!!

Because isotretinoin is a known human teratogen and can cause severe, life-threatening birth defects if administered during pregnancy, commercially available isotretinoin has been prescribed and distributed under restricted distribution programs (e.g., the System to Manage Accutane Related Teratogenicity [SMART], System to Prevent Isotretinoin-Related Issues of Teratogenicity [SPIRIT], Isotretinoin Medication Program Alerting you to the Risks of Teratogenicity [IMPART], Adverse Event Learning & Education Regarding Teragenicity [ALERT]), which were designed to help ensure that fetal exposure to the drug does not occur. 105,191,196,197,198 Such programs controlled access to isotretinoin and educated program participants (clinicians, pharmacists, patients) about the risks associated with isotretinoin and the procedural requirements for safe use of the drug.105,191,196,197,198 In August 2005, the US Food and Drug Administration (FDA) announced approval of a strengthened, centralized pregnancy risk management program for all isotretinoin preparations.201,202 The new program, called iPLEDGE, requires registration of wholesalers, prescribing clinicians, dispensing pharmacies, and patients, all of whom agree to accept specific responsibilities designed to minimize exposure to isotretinoin during pregnancy.201,202,203 The iPLEDGE program involves strengthened processes to ensure appropriately timed and properly documented pregnancy testing and counseling of patients before, during, and following isotretinoin therapy.201,202,203 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 In addition, the sponsors of the iPLEDGE program will implement a system for reporting and collecting information on serious adverse events associated with isotretinoin therapy through this program.201,202,203

The iPLEDGE program has been gradually implemented and overlapped with previous restricted distribution programs to allow for a smooth transition from the previous distribution programs to the iPLEDGE program.202,204 Wholesalers and dispensing pharmacies should have been registered with and activated in the iPLEDGE program by December 30, 2005.202,204 Patients were allowed to register and qualify in this program beginning December 30, 2005.202,204 As of March 1, 2006, only prescribers registered and activated in iPLEDGE can prescribe isotretinoin, and the drug can only be dispensed to patients registered and qualified in the iPLEDGE program.202,204 Additional information on the iPLEDGE program may be obtained at the program's website at [Web].201,202,203

Prescribing Clinicians

In order to prescribe isotretinoin under the special restricted distribution program called iPLEDGE in the US, clinicians must first register in this program and have their registration activated.201,202,203 Only prescribers who have been registered and activated in this program may prescribe isotretinoin.202,204 Prescribing clinicians can register by completing, signing, and returning the iPLEDGE registration form.201,202,203 Prescribers then must activate their registration by affirming that they meet the initial requirements for prescribing isotretinoin and will comply with all iPLEDGE program requirements; this activation can be done on the program's website or by telephone and must be repeated on an annual basis.201,202,203

Prescribing clinicians in the iPLEDGE program are responsible for registering every patient who meets the program's requirements through the automated system.201,203 Prescribers also are responsible for educating patients about the adverse effects of isotretinoin and the high risk of birth defects for female patients of childbearing potential if they are or become pregnant while receiving the drug.201,203 As part of this process, prescribing clinicians are responsible for counseling patients about the monthly steps they must follow to continue to receive isotretinoin.201,203 Prescribers must agree to assume the responsibility for pregnancy-prevention counseling of all female patients of childbearing potential before the drug is prescribed initially and every month thereafter.201,202,203 In addition, prescribing clinicians must obtain and enter into the iPLEDGE system negative pregnancy test results for female patients of childbearing potential prior to prescribing isotretinoin as well as during and after treatment.201,202,203 Prescribers also must document the 2 forms of contraception being used by the female patient at each monthly visit.201,203 Participating clinicians also must obtain a completed patient information/informed consent document (signed by the patient and prescriber).201,203 Telephone, fax, and electronic transmission (e.g., e-mail) of prescriptions for isotretinoin are permitted in this program.202

Prescribing clinicians must immediately report all pregnancies that occur in female patients during isotretinoin therapy or within one month of the last dose to the FDA MedWatch Program at 1-800-FDA-1088 and to the iPLEDGE pregnancy registry at 1-866-495-0654 or via the program's website ([Web]).201,202,203 (See Cautions: Precautions and Contraindications.) In addition, the prescriber should report any pregnancy in the partner of a male patient receiving the drug to the iPLEDGE program.201 (See Pregnancy, Fertility, and Lactation: Pregnancy, under Cautions.)

Prescribing clinicians should be alert to the warning signs of psychiatric disorders in patients receiving isotretinoin.203 At each visit during therapy, patients should be assessed for symptoms of depression, mood disturbance, psychosis or aggression to determine whether further evaluation may be necessary.203 (See Cautions: Precautions and Contraindications.)

Clinicians must agree to write each prescription for no more than a 30-day supply of isotretinoin at a time (with no refills) and inform the patient that each prescription must be filled within 7 days of the office visit date.201,203 The restricted distribution program does not allow automatic prescription refills, and the clinician must ensure that patients return for monthly office visits to obtain subsequent prescriptions for isotretinoin.196,197,201,203 At each monthly visit and before a new prescription for the drug is issued, the clinician must confirm that each patient has received counseling and education; for female patients of childbearing potential, the clinician must enter the 2 contraception methods chosen by the patient and the result of the monthly pregnancy test.201,203

For additional information on available educational materials and the specific requirements for prescribers in the iPLEDGE program (including which tasks can be delegated to designated office staff), the program's website should be consulted at [Web].201,203

Dispensing Pharmacies

In accordance with the risk management goals of the iPLEDGE restricted distribution program in the US, pharmacies must be registered and activated with the iPLEDGE program to dispense isotretinoin.201,203 The pharmacist designated as the responsible site pharmacist must register the pharmacy by signing and returning the completed registration form.201,203 Following registration, the responsible site pharmacist can activate the pharmacy registration in the iPLEDGE program by affirming that he or she meets the requirements of the program and will comply with all iPLEDGE program requirements.201,203

In order to dispense isotretinoin in the iPLEDGE program, a pharmacist must receive training from the responsible site pharmacist concerning the program's requirements.201,203 In addition, the pharmacist must obtain authorization from the iPLEDGE program via the program's website ([Web]) or telephone (1-866-495-0654) for every isotretinoin prescription.201,203 Authorization indicates that the patient has met all iPLEDGE program requirements and is qualified to receive isotretinoin.201,203 Following authorization, the dispensing pharmacist should record the Risk Management Authorization (RMA) number directly on the patient's prescription.201,203

Isotretinoin must be dispensed in a 30-day supply or less with no automatic refills.201,203 Isotretinoin is commercially available in blister packs containing 10 capsules; the pharmacist cannot break open a blister pack.201 Pharmacists are required by law to dispense an FDA-approved medication guide for isotretinoin, which contains safety information written for all patients taking the drug, with each isotretinoin prescription.201,203 (See REMS.) Isotretinoin prescriptions must be dispensed prior to the date specified by the iPLEDGE system (7 days from the office visit date); the pharmacist should record this date on the prescription bag sticker.201,203 Prescriptions for isotretinoin must be picked up by the patient no later than this date; if the prescription is not picked up by that date, then the prescription should be returned to stock.201 Although male patients and female patients of non-childbearing potential may fill an isotretinoin prescription after the 7-day period from the office visit date has elapsed, such patients and their clinicians must complete the qualification process again, including confirmation of patient counseling in the iPLEDGE system.205,206 However, female patients of childbearing potential cannot start the qualification process for another prescription for 23 days after the end of the 7-day period has elapsed.205,206 Telephone, fax, and electronic transmission (e.g., e-mail) of prescriptions for isotretinoin are permitted in this program.202 Refills for isotretinoin require a new prescription and another authorization from the iPLEDGE program.201,203

Isotretinoin must not be prescribed, dispensed, or otherwise obtained through the Internet or by any other means outside of the iPLEDGE program in the US.201,203 Only FDA-approved isotretinoin products may be distributed, prescribed, dispensed, and used.201,203 Patients may only fill isotretinoin prescriptions written in the US at US licensed pharmacies that are registered in the iPLEDGE program.201,203 A database of such pharmacies is available on the program's website and via the automated telephone line.201 For additional information on the specific requirements for pharmacists in the iPLEDGE program, the program's website should be consulted at [Web].201,203

Patients

To receive commercially available isotretinoin in the iPLEDGE restricted distribution program, all patients must first qualify and be registered by their clinician.201,203 All patients in this program must understand that severe birth defects can occur with isotretinoin use by female patients during pregnancy, and they must be reliable in understanding and carrying out instructions.201,203 In addition, all patients must sign a patient information/informed consent form containing warnings about the potential risks associated with the drug.201,203 Patients must also be instructed to read the other iPLEDGE program patient educational materials.201,203 Both male and female patients must agree not to share their isotretinoin with anyone else (even if the other individual has similar symptoms) and not to donate blood while receiving isotretinoin and for 1 month after completion of isotretinoin treatment.201,203 Patients who receive prescriptions for isotretinoin must fill them within 7 days of the office visit and should understand that refills are not allowed.201,203 Patients can receive a maximum of a 30-day supply of isotretinoin in each prescription.201,203 Although male patients and female patients of non-childbearing potential may fill an isotretinoin prescription after the 7-day period from the office visit date has elapsed, such patients and their clinicians must complete the qualification process again, including confirmation of patient counseling in the iPLEDGE system.205,206 However, female patients of childbearing potential can not start the qualification process for another prescription for 23 days after the end of the 7-day period has elapsed.205,206

Female patients of childbearing potential must comply with additional requirements that are not necessary for male patients and female patients who are not of childbearing potential.201,203 Female patients in the iPLEDGE restricted distribution program who are of childbearing potential (unless the patient commits to continuous abstinence from heterosexual contact, has undergone a hysterectomy or bilateral oophorectomy, or has been medically confirmed to be postmenopausal) must agree to use 2 different forms of effective contraceptive measures simultaneously for at least 1 month prior to, throughout, and for 1 month after completion of isotretinoin therapy.201,203 These women also must have 2 confirmed negative urine or blood pregnancy tests prior to receiving the first isotretinoin prescription and must agree to have monthly pregnancy tests throughout therapy prior to receiving additional isotretinoin prescriptions.201,203 (See Pregnancy under Cautions: Pregnancy, Fertility, and Lactation.)

At each monthly visit to the prescribing clinician and before a new prescription for the drug is issued and authorized by the iPLEDGE restricted distribution program, female patients of childbearing potential must receive additional counseling about the use of appropriate contraception and undergo a urine or serum pregnancy test.201,203 In addition, she must answer questions in the iPLEDGE system about the program requirements and enter the 2 forms of birth control she is using in the automated system in order to continue receiving monthly prescriptions.201,203 A pregnancy test also must be ordered at the completion of isotretinoin therapy (after the last dose) and repeated 1 month after the last dose in female patients of childbearing potential.201,203 For additional information on the specific requirements for patients in the iPLEDGE program, the program's website should be consulted at [Web].201,203

Wholesalers

In the iPLEDGE restricted distribution program, the term “wholesaler” refers to the wholesaler, distributor, and/or chain pharmacy distributor.203 In order to distribute isotretinoin, wholesalers must be registered with iPLEDGE and agree to meet all iPLEDGE requirements for wholesale distribution of the drug.203 Wholesalers must register with iPLEDGE by signing and returning the iPLEDGE wholesaler agreement that affirms they will comply with all program requirements for distribution of isotretinoin.203 For additional information on the specific requirements for wholesalers in the iPLEDGE program, the program's website should be consulted at [Web].201,203

Cautions ⬆ ⬇

[Section Outline]

Isotretinoin appears to share some of the adverse effects of other retinoids1,6,69,108 and many of the adverse effects observed or expected with isotretinoin are similar to those occurring with high dosages of systemically administered vitamin A;105 however, isotretinoin appears to have a greater benefit-to-risk ratio and fewer adverse CNS effects than systemically administered vitamin A or tretinoin.6 Other adverse systemic effects, including acute hepatotoxic reactions, also appear to occur less frequently with isotretinoin than with systemic vitamin A or tretinoin.6,93 Adverse mucocutaneous effects occur frequently with isotretinoin therapy and appear to occur more commonly than with vitamin A or tretinoin therapy.1,6,29,93 The frequency and severity of adverse reactions associated with the use of these retinoids have not been compared directly.92 Some adverse reactions to isotretinoin (e.g., cheilitis, conjunctivitis, hypertriglyceridemia) appear to be dose related.102,108 Adverse effects usually subside with a reduction in dosage and are usually reversible following discontinuance of therapy;1,29 however, some adverse effects have persisted after cessation of therapy.102

Mucocutaneous Effects !!navigator!!

Adverse mucocutaneous effects occur frequently with isotretinoin1 and most of these effects are similar to those associated with hypervitaminosis A.79,108 The most frequent adverse effect of isotretinoin is cheilitis (inflammation of the lips), which occurs in more than 90% of patients receiving the drug for acne.1,6,29,69,108 Other frequent mucocutaneous effects of isotretinoin include xerosis,1,6,29,108 xerostomia,1,6,69,108 dry nose,1,6,29 epistaxis,1,6,29,69 and pruritus.1,6 These adverse reactions are apparently caused by a mucocutaneous drying effect of the drug.1,6,29 Since dry skin is generally a component of disorders of keratinization, adverse mucocutaneous effects of isotretinoin are more commonly recognized in patients with severe nodular acne than in patients with disorders of keratinization.1,6,29

Conjunctivitis (including blepharoconjunctivitis) and irritation of the eyes occur in about 40% of patients receiving isotretinoin for acne.1,29,70,108,141 The drug may aggravate preexisting blepharoconjunctivitis in some patients.70,141 Isotretinoin-induced conjunctivitis or blepharoconjunctivitis may require a dosage reduction or discontinuance of therapy; it also may resolve despite continued therapy at the same dosage level and often subsides within a week of dosage reduction, although a few months may be required in some patients.70,141 Dry eyes has been reported in some patients and in rare instances has persisted following discontinuance of therapy.102 Eyelid inflammation also has been reported.105 Patients who wear contact lenses may experience decreased tolerance to the lenses during and/or after isotretinoin therapy.102,141

Thinning of the hair1,6,29,108 (which has persisted in rare instances),102 palmoplantar desquamation,1,6,29 skin fragility,1,6,29 infections of the skin (e.g., paronychial infections),1,6,29 rash (including erythema, seborrhea, and eczema),6,105,166,167,168 and photosensitivity1,6,29 occur in about 5-10% of patients receiving isotretinoin.1,6,29,108 As may occur with healing severe nodular acne lesions, an occasional exaggerated healing response, manifested as exuberant granulation tissue with crusting, has occurred in patients receiving isotretinoin; in a number of cases, this effect was shown to be pyogenic granuloma.105 Delayed wound healing and keloid formation have been reported following dermabrasion or argon laser therapy in several patients treated with the drug.158,159,162 Hypopigmentation or hyperpigmentation,1 urticaria,1 erythema nodosum,105 bruising,1 paronychia,105 nail dystrophy,102 bleeding and inflammation of the gums,105 hirsutism,102 flushing,105 and hair problems (other than thinning)1 have been reported rarely; however, these effects have not been directly attributed to the drug.1,102,105

Metabolic Effects !!navigator!!

Hypertriglyceridemia (i.e., serum triglyceride concentrations greater than 500 mg/dL) was reported in about 25% of patients receiving isotretinoin in clinical studies and was associated with acute pancreatitis in some cases.1,6,73,131,132,133 Serum lipid concentrations should be monitored in patients receiving the drug.1,108,132 (See Cautions: Precautions and Contraindications.)

Although administration of vitamin A to animals has been associated with hepatic accumulation of triglycerides,71,72 such an effect has not been observed to date in animals or humans receiving isotretinoin. In patients with isotretinoin-induced hypertriglyceridemia, serum lipoprotein electrophoresis usually indicates an increase in very low-density lipoprotein (VLDL) concentration.73 Decreases in serum high-density lipoprotein (HDL) concentration have occurred in about 15% of patients, and increases in serum cholesterol concentration have occurred in about 7% of patients receiving the drug.1,73 During therapy with currently recommended dosages of isotretinoin, serum triglyceride concentrations generally increase by about 50-70%,132,133 serum cholesterol concentrations by about 15-20%,131,132,133 serum VLDL cholesterol concentrations by about 50-60%,132 serum low-density lipoprotein (LDL) cholesterol concentrations by about 15-20%,132,133 and serum HDL cholesterol concentrations generally decrease by about 10-20%.131,132,133 The ratio of LDL-cholesterol to HDL-cholesterol is increased during therapy with the drug.133 Maximum increases in serum triglyceride concentrations usually occur by 4 weeks of therapy in males and by 12 weeks of therapy in females.133 Maximum increases in serum cholesterol concentrations usually occur by 4 weeks of therapy.133 Despite the increases, serum cholesterol concentrations usually remain within the normal range.73,108,132,133

Isotretinoin's effects on serum lipoprotein, triglyceride, and cholesterol concentrations appear to be dose related, occur most frequently at dosages greater than 1 mg/kg daily, and are reversible upon discontinuance of the drug.1,6,73,131,132,133 These effects on serum lipids may also be related to the duration of therapy.73,133 The short- and long-term effects of isotretinoin-induced alterations of serum lipid concentrations with usual courses of therapy are not known,6,73,108,131,132,133 but should be considered potentially serious if long-term therapy is contemplated.133 At least one patient has developed eruptive xanthomas associated with increased serum triglyceride concentrations during isotretinoin therapy.74 Based on limited published reports, it appears that isotretinoin-induced increases in serum triglyceride concentrations can be reversed during continued therapy in some patients by reduction in body weight, restriction of dietary fat and alcohol intake, or reduction in dosage.57,73

Increases in fasting serum glucose concentrations have been reported in some patients receiving isotretinoin.1 In addition, diabetes mellitus has developed during isotretinoin therapy in patients with no history of the disease, although a causal relationship has not been established.105

Hyperuricemia, which is usually asymptomatic but may be associated with symptoms of gout (e.g., painful great toe), has been reported in a few patients receiving isotretinoin.107 Treatment with phenylbutazone during continued administration of isotretinoin was successful in the symptomatic management of 2 patients.107

Musculoskeletal Effects !!navigator!!

Adverse musculoskeletal effects (e.g., bone or joint pain, generalized muscle aches, arthralgia) occur in about 16% of patients receiving isotretinoin.6,105 Adverse musculoskeletal effects have generally been mild to moderate in severity but have occasionally required discontinuance of the drug.105 Less frequently, transient pain in the chest has occurred.102 Acute arthritis of the knee with joint effusion has occurred rarely,105,134 and the drug has been associated with reversible skeletal muscle damage in a patient with severe nodular acne.140 Isotretinoin-induced adverse musculoskeletal effects generally subside rapidly following discontinuance of the drug but rarely have persisted.105

Skeletal abnormalities, similar to those occurring with high dosages of systemically administered vitamin A,194 have occurred in patients receiving isotretinoin therapy.1,105,108,135,136,137,138 Some evidence suggests that long-term, high-dosage, or multiple courses of isotretinoin therapy may have more of an effect on the musculoskeletal system than a single course of therapy.105 A high prevalence of skeletal hyperostosis (with spine degeneration) resembling diffuse idiopathic skeletal hyperostosis has occurred in several adults and children with disorders of keratinization receiving high dosages of isotretinoin (generally 2 mg/kg daily or higher) for periods ranging from 6 months to several years.1,105,108,135,136,137 Diffuse idiopathic skeletal hyperostosis is a disorder of osteophytes and bony bridge formation that occurs predominantly in the spine.194 However, minimal skeletal hyperostosis (e.g., nasal bone osteophytosis139 ) and calcification of tendons and ligaments also have been observed radiographically in patients with severe nodular acne who received a single course of isotretinoin therapy at recommended dosages.102,103,105 Risk of developing hyperostosis appears to increase with increasing age and dose and/or duration of isotretinoin therapy.194 In one clinical study, hyperostosis was not observed in adolescents 12-17 years of age who received 1 mg/kg daily of isotretinoin, given in 2 divided doses, for 16-20 weeks.105 However, hyperostosis may require a longer time frame to develop.105 The clinical course and importance of skeletal hyperostosis in isotretinoin-treated patients with severe nodular acne remains unknown.105

Spontaneous reports of osteoporosis, osteopenia, bone fractures, and delayed healing of bone fractures also have been observed in isotretinoin-treated patients.105 Therefore, the manufacturers state that patients who participate 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 be at increased risk for these adverse effects.105,196,197 The manufacturers state that while a causal relationship between these effects and isotretinoin use has not been established, such an effect also cannot be ruled out.105,196,197 In an open-label clinical study, decreases (based on data adjusted for body mass index) in lumbar spine bone mass density (BMD) measurements exceeding 4% or decreases exceeding 5% in total hip BMD measurements reportedly occurred in about 8 or 11% of patients, respectively.105 Follow-up studies performed in 8 of the patients with decreased BMD for up to 11 months thereafter demonstrated increasing bone density in 5 patients at the lumbar spine, while the other 3 patients had lumbar spine bone density measurements below baseline values.105 Total hip BMD, however, remained below baseline (range: 1.6-7.6% below baseline) in 62.5% of these patients.105 In a separate open-label extension study in a limited number of patients, decreases in mean lumbar spine BMD of up to 3.25% were observed in 20% of adolescents 13-18 years of age who started a second course of isotretinoin 4 months after the first course.105 Effects of long-term or multiple courses of isotretinoin on the developing musculoskeletal system are as yet unknown.105 (See Cautions: Pediatric Precautions.)

Increases in serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations have occurred in some patients with severe nodular acne who engage in vigorous physical activity while receiving isotretinoin.102,103 The clinical importance of these increases is not known.105,103 In one clinical trial, transient elevations in CK concentrations were observed in 12% of adolescents 12-17 years of age who received isotretinoin for the management of severe recalcitrant nodular acne, including those engaged in strenuous physical activity who reported adverse musculoskeletal effects such as back pain, arthralgia, limb injury, or muscle sprain.105 In these patients, approximately half of the elevated CK concentrations returned to normal within 2 weeks and the other half returned to normal within 4 weeks.105 Although rhabdomyolysis was not reported in this trial, there have been rare postmarketing reports of rhabdomyolysis, some of which were associated with strenuous physical activity.105

Hematologic Effects !!navigator!!

Increased erythrocyte sedimentation rates, often in patients with preexisting baseline elevations, occur in about 40% of patients receiving isotretinoin.1,6 Other adverse hematologic effects occur in about 10-20% of patients receiving the drug and include decreased hemoglobin concentration and hematocrit, decreased erythrocyte and leukocyte counts, and increased platelet count.1,6 Increased or decreased reticulocyte counts,86 anemia,105 decreases in leukocyte counts (including severe neutropenia and rare reports of agranulocytosis),105 and thrombocytopenia105,169,170 also have been reported.

Nervous System Effects !!navigator!!

Adverse nervous system effects of isotretinoin include lethargy,6 fatigue,1,6 and headache.1,6,29

Depression, psychosis, and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors have been reported during postmarketing surveillance of isotretinoin; emotional instability also has been reported.185,186,187,188,189,203 In some cases, mental depression has subsided with discontinuance of the drug and recurred with reinstitution of therapy.106,185,186,187,188,189,203 However, discontinuance of isotretinoin therapy alone may be insufficient, and further evaluation may be necessary.203 Other signs and symptoms of depression and mental disturbances that may be associated with isotretinoin therapy include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment.203 The etiology of these isotretinoin-associated nervous system effects has not been elucidated;189,203 however, some patients using the drug may already be at risk for depression.189 (See Cautions: Precautions and Contraindications.)

Seizures, malaise, insomnia, nervousness, weakness, paresthesias, and dizziness also have been reported, but these effects have not been directly attributed to isotretinoin.102

Pseudotumor cerebri (benign intracranial hypertension), usually associated with headache, visual disturbances, and papilledema, has been reported in patients receiving isotretinoin.105,107,141 (See Cautions: Precautions and Contraindications.) Several of these patients were receiving tetracycline or minocycline concomitantly.105,107,141 (See Drug Interactions: Tetracyclines.) A few patients with isotretinoin-induced pseudotumor cerebri developed retinal hemorrhages.107

GI Effects !!navigator!!

Adverse GI effects of isotretinoin include anorexia,29 nausea and vomiting,6 increased appetite,29 and thirst.6,29 The drug has also been temporally associated with inflammatory bowel syndrome (including regional ileitis) in patients without a history of intestinal disorders.105,107 (See Cautions: Precautions and Contraindications.) Weight loss and mild GI bleeding have also been reported rarely in patients receiving isotretinoin, but these effects have not been directly attributed to the drug.1

Hepatic Effects !!navigator!!

Although isotretinoin is thought to be less hepatotoxic than oral vitamin A or tretinoin,6,93 clinical hepatitis, possibly or probably related to isotretinoin, has occurred in a few patients receiving the drug.105 Minimal, transient increases in serum concentrations of alkaline phosphatase, lactate dehydrogenase, γ-glutamyl transferase (GGT), AST (SGOT), and/or ALT (SGPT) occur in about 10-20% of patients receiving isotretinoin.1,6,7,29,93,102,105 Abnormalities in liver function test results occasionally resolved despite continued therapy or following dosage reduction.105 If these abnormalities persist or if hepatitis is suspected, the drug should be discontinued and the cause investigated.105

Ocular and Otic Effects !!navigator!!

In addition to conjunctivitis and irritation of the eyes (see Cautions: Mucocutaneous Effects), isotretinoin therapy has been associated with the development of corneal opacities in patients with severe nodular acne and more frequently in patients with disorders of keratinization when higher dosages of the drug were used.75,105 Cataracts have also been reported in patients receiving the drug.105,106 Isotretinoin-associated corneal opacities are diffuse, fine, white to gray, subepithelial deposits that may occur in various patterns involving the peripheral and central cornea and may range in number from a few hundred to several thousand.141 The deposits do not stain with fluorescein, but tear film irregularity over the involved area is commonly present.141 Corneal changes have been observed in animals during long-term administration of isotretinoin at a dosage of 60 mg/kg daily, but these changes have resolved partially following discontinuance of the drug.1 In humans, the risk of long-term sequelae from corneal opacities is not known.89,141 Isotretinoin-associated corneal opacities have either resolved completely105,141 or were resolving at follow-up 6-7 weeks after discontinuance of the drug.105

Visual disturbances have also been reported in patients receiving isotretinoin.105,106,141 Visual disturbances have been manifested principally as decreased visual acuity or blurred vision,106,141 but tunnel vision,106 temporary loss of vision,106 double vision,106 photophobia,105 color vision disorder,105 and difficulty in seeing106 have also occurred.106 Only about 25% of the cases of visual disturbances have been associated with objective findings; in another 10% of cases, corrective glasses or lenses were required.106 A decrease in night vision has also been reported in some patients with severe nodular acne receiving isotretinoin and has persisted in rare instances following discontinuance of the drug.103,105,142 Optic neuritis has also been reported rarely, but a causal relationship to the drug has not been established.105,106,141

Any visual problem that develops during isotretinoin therapy should be monitored carefully.105

Hearing impairment has been reported in patients receiving isotretinoin and, in some cases, impaired hearing persisted following discontinuance of the drug.105 Although the etiology of this adverse effect and a causal relationship to the drug have not been established, patients experiencing tinnitus or hearing impairment should discontinue the drug and consult an appropriate specialist for further evaluation.105

Other Adverse Effects !!navigator!!

Acute pancreatitis, including rare cases of fatal hemorrhagic pancreatitis, has been reported in patients with elevated or normal serum triglyceride concentrations receiving isotretinoin.105 (See Cautions: Precautions and Contraindications.)

Disseminated herpes simplex, edema, respiratory infections, bronchospasm (with or without a history of asthma),105 sweating, tinnitus, voice changes, abnormal menses, lymphadenopathy, tachycardia, palpitation, and Wegener's granulomatosis have been reported in a few patients receiving isotretinoin; however, a causal relationship to the drug has not been established.105,106,171 Some patients receiving isotretinoin also have developed presence of leukocytes in urine,105 proteinuria,1,105 microscopic or gross hematuria,105,106 glomerulonephritis,105 and nonspecific urogenital findings.1

Focal calcification, fibrosis, and inflammation of the myocardium; calcification of coronary, pulmonary, and mesenteric arteries; and metastatic calcification of the gastric mucosa have occurred in animals receiving isotretinoin dosages of 8 or 32 mg/kg daily for 18 months or longer.1 It is not known if these effects are likely to occur in humans.

Precautions and Contraindications !!navigator!!

Because of the risk of adverse effects, which may be severe (e.g., skeletal abnormalities), isotretinoin therapy should be reserved for patients with severe nodular acne who are unresponsive to conventional acne therapies, including oral and/or topical anti-infectives.1,203 Isotretinoin therapy should be initiated in such patients only after they acknowledge in writing (i.e., patient information/informed consent form) an understanding and a willingness to comply with the clinician's instructions and iPLEDGE program requirements on the use of the drug (e.g., monthly office visits, prescriptions limited to 30-day supply of the drug) and the risks involved (e.g., depression, suicide) with the treatment.201,203 Patients also must agree not to share their isotretinoin with anyone else because of the risk of serious adverse effects.201,203 (See Dosage and Administration: Restricted Distribution Program.) Isotretinoin therapy has been associated frequently with adverse effects including cheilitis, conjunctivitis, and, rarely, corneal opacities; elevations in serum lipid concentrations; increased erythrocyte sedimentation rate and platelet count; pseudotumor cerebri; and inflammatory bowel syndrome.105 Therefore, a copy of the medication guide for isotretinoin provided by the manufacturer that explains the risks associated with the drug must be distributed by the pharmacist to the patient each time a prescription for isotretinoin is dispensed.201,203 (See REMS.)

Because acute pancreatitis, including rare cases of fatal hemorrhagic pancreatitis, has been reported in patients with either elevated or normal serum triglyceride concentrations, serum triglyceride concentrations should be carefully monitored in patients receiving isotretinoin.105,108,132,133 Isotretinoin therapy should be discontinued in patients with hypertriglyceridemia whose serum triglyceride concentrations cannot be controlled at an acceptable level or if symptoms of pancreatitis occur.105 In addition, the drug should be used with caution in patients with preexisting elevated fasting serum triglyceride concentrations and in patients with an increased tendency to develop hypertriglyceridemia, such as those with diabetes mellitus, obesity, or increased alcohol intake.105,108 Pretreatment and follow-up fasting serum lipid determinations should be obtained in all patients; if alcohol was consumed prior to testing, at least 36 hours should elapse before these determinations are made.105 The manufacturers recommend that these tests be performed at weekly or biweekly intervals until the lipid response to isotretinoin is established;105,196,197 this usually occurs within the first 4 weeks of therapy.105,133 The short- and long-term effects of isotretinoin-induced alterations of serum lipid concentrations with usual courses of therapy are not known,6,73,108,131,132,133 but should be considered potentially serious if long-term therapy is contemplated.133 In patients with known or suspected diabetes mellitus, blood glucose concentration should be determined periodically during isotretinoin therapy.102

The possibility of adverse hepatic effects should be considered in patients receiving the drug.105 If hepatitis is suspected or abnormal liver function test results develop and persist during isotretinoin therapy, the drug should be discontinued and the cause of the abnormality investigated.105 Since elevations in serum liver enzyme concentrations have been reported in patients receiving isotretinoin, pretreatment and follow-up liver function tests should be performed at weekly or biweekly intervals until response to isotretinoin is established.105

In addition, although a causal relationship between isotretinion use and bone loss has not been established (see Cautions: Musculoskeletal Effects), the manufacturers recommend that the drug be used 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.105,196,197 Isotretinoin also should be used with caution 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

Because hearing impairment, including some cases persisting after discontinuance of the drug, has been reported in patients receiving isotretinoin, patients who experience tinnitus or impaired hearing should discontinue the drug and consult an appropriate specialist for further evaluation.105

Since isotretinoin has been associated with corneal opacities, cataracts, and other adverse ocular effects, patients experiencing visual difficulties during isotretinoin therapy should discontinue the drug, and an ophthalmologic examination should be performed.105 Because decreased night vision can develop suddenly during isotretinoin therapy, patients should be advised of this potential effect and warned to be cautious when driving or operating any vehicle at night.105 Patients receiving isotretinoin who wear contact lenses also should be advised that they may experience decreased tolerance to the lenses during or after therapy with the drug.102,105

Isotretinoin has been temporally associated with inflammatory bowel syndrome (including regional ileitis) in patients without a history of intestinal disorders.105 In some instances, symptoms have been reported to persist even after discontinuance of isotretinoin therapy.105 Therefore, the drug should be discontinued immediately if abdominal pain, rectal bleeding, or severe diarrhea occurs.105

Patients receiving isotretinoin who develop signs and/or symptoms of pseudotumor cerebri (e.g., headache, nausea and vomiting, visual disturbances) should be examined for the presence of papilledema and, if present, should be informed to discontinue the drug immediately and should be referred to a neurologist for further evaluation and care.105

Isotretinoin may cause depression, psychosis, and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors.185,186,187,188,189,203 The etiology of these isotretinoin-associated nervous system effects has not been elucidated.203 Prescribing clinicians should be familiar with manifestations of psychiatric disorders in adolescents and young adults and should be alert to the warning signs of psychiatric disorders in order to guide patients to receive the help they need.203 Prior to initiating isotretinoin therapy, patients and family members should be asked about any history of psychiatric disorder, and at each visit during isotretinoin therapy patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine whether further evaluation of such symptoms is necessary.203 Signs and symptoms of depression include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment.203 Patients who experience depression, mood disturbance, psychosis, or aggression after initiating isotretinoin therapy should discontinue the drug, and the patient or a family member should promptly contact their prescribing clinician without waiting for the next scheduled visit to the clinician.203 Discontinuance of isotretinoin therapy alone may be insufficient, and further evaluation of the patient may be necessary.203 Although such monitoring may be helpful, it may not detect all patients at risk.203 If a patient reports mental health problems or a family history of psychiatric disorders, such reports should be discussed with the patient and/or the patient's family.203 A referral to a mental health professional may be necessary in some cases.203 The clinician should consider whether isotretinoin therapy is appropriate in this setting; for some patients, the potential risks for these psychiatric disorders may outweigh the potential benefits of therapy with the drug.203

Patients with severe nodular acne should be advised that an occasional exaggerated healing response, manifested by exuberant granulation tissue with crusting, may occur during treatment with isotretinoin.1 Patients also should be advised that 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

Because of the possibility of scarring, wax epilation and skin resurfacing procedures (such as dermabrasion, laser) should be avoided during isotretinoin therapy and for at least 6 months thereafter.105 Patients also should be advised to avoid prolonged exposure to UV light or sunlight.105

Patients should be informed that approximately 16% of patients receiving isotretinoin in a clinical trial developed musculoskeletal symptoms (including arthralgia) during treatment.105 These symptoms usually were mild to moderate, but occasionally required discontinuance of the drug.105 Transient chest pain has been reported less frequently.105 Although such symptoms generally resolved rapidly following discontinuance of isotretinoin, in some cases they persisted.105 (See Cautions: Musculoskeletal Effects.)

Because neutropenia and rare cases of agranulocytosis have been reported, isotretinoin should be discontinued if clinically important decreases in leukocyte counts occur.105

Because anaphylactic reactions and other allergic reactions, including cutaneous allergic reactions and serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement (including renal), have been reported in patients receiving isotretinoin, patients exhibiting such severe allergic reactions should discontinue therapy and receive appropriate medical management.105

If a patient who is receiving isotretinoin donates blood and the donated blood, blood components, or plasma is transfused into a woman who is or soon becomes pregnant, there may be a risk to the developing fetus because of isotretinoin in the transfused blood.100 Taking into consideration the potency of isotretinoin as a teratogen and the possibility that the drug may be present in blood for long periods, patients receiving isotretinoin should not donate blood during therapy and for at least 1 month following discontinuance of the drug.100,105

Isotretinoin is contraindicated in female patients who are or may become pregnant or are breast-feeding (see Cautions: Pregnancy, Fertility, and Lactation) and in those who are hypersensitive to the drug or any component in the formulation.1,203 Isotretinoin should not be given to patients who are sensitive to parabens, which are used as preservatives in some commercially available liquid-filled gelatin capsules of the drug.203

Teratogenicity Contraindications and Precautions

Because of the teratogenic and abortifacient effects of isotretinoin and to minimize fetal exposure to the drug (see Cautions: Pregnancy, Fertility, and Lactation), isotretinoin therapy is contraindicated in female patients who are or who may become pregnant.201,203 Isotretinoin is approved for marketing in the US only under the special iPLEDGE restricted distribution program, which has been approved by the US Food and Drug Administration (FDA).201,203 (See REMS.)

Isotretinoin may be used in female patients who are not pregnant only for disfiguring severe nodular acne that has been demonstrated to be recalcitrant to adequate trials with other standard therapies (e.g., anti-infectives).149,150,151,184,203 Prescription of isotretinoin for such use should be limited to clinicians who are registered and activated with the iPLEDGE program, are knowledgeable in the diagnosis and treatment of the various presentations of acne, understand the risk and severity of fetal injury and birth defects associated with isotretinoin, understand the risk factors for unplanned pregnancy and the effective measures for avoidance of unplanned pregnancy, and have the expertise to provide the patient with detailed pregnancy prevention counseling or are willing to refer patients for such counseling (which is reimbursed by the manufacturer of isotretinoin).201,203 Prescribing clinicians must be willing to comply with all iPLEDGE program requirements.201,203 (See Dosage and Administration: Restricted Distribution Program.) Isotretinoin therapy should be initiated in such women only after the prescriber has registered them in the iPLEDGE program, having determined that they understand that severe birth defects can occur when isotretinoin is used by female patients and that they are reliable in understanding and carrying out instructions; in addition, the prescribing clinician must ensure that the patient has signed a Patient Information/Informed Consent About Birth Defects form.201,203 These patients also should be informed by their clinician about the confidential iPLEDGE Program Pregnancy Registry.201,203

Contraceptive Measures

It is critically important that female patients of childbearing potential choose and commit to simultaneous use of 2 forms of effective contraceptive measures (at least one of which must be a primary form) for at least 1 month prior to, throughout, and for 1 month after isotretinoin therapy, unless the patient commits to continuous abstinence from heterosexual contact, has undergone a hysterectomy or bilateral oophorectomy, or has been medically confirmed to be postmenopausal.201,203

Primary forms of contraception include tubal sterilization, vasectomized partner, intrauterine devices, and oral, injectable, inserted, transdermal, or implanted hormonal contraceptives.201,203 Secondary barrier forms of contraception include diaphragms, male latex condoms, and cervical caps; each must always be used with a spermicide.201,203 Vaginal sponges containing spermicide are another secondary form of contraception.201,203

Clinicians who prescribe isotretinoin should use the iPLEDGE patient education kits provided by the manufacturer to counsel patients.201,203 Female patients of childbearing potential should understand the critical responsibility they assume in deciding to begin therapy with isotretinoin and that any form of birth control can fail unless complete abstinence is used.201,203 These patients also must receive written warnings about the rates of contraceptive failure; this information is included in the iPLEDGE patient education kits along with information about a referral program offering female patients free contraception counseling for one visit (which is reimbursed by the manufacturer) by a healthcare professional with expertise in pregnancy prevention and a copy of the Patient Information/Informed Consent About Birth Defects form.201,203 The iPLEDGE Program Birth Control Workbook must be read by female patients of childbearing potential; it includes information about the types of contraceptive methods, the selection and use of appropriate and effective contraception, the rates of possible contraceptive failure, and a toll-free and confidential contraception counseling line that patients can use 24 hours a day, 7 days a week (1-866-495-0654).201,203 In addition, such patients should be given an opportunity to view the educational video material that is provided by the manufacturer to the prescriber.201,203

These women must have had 2 negative serum or urine pregnancy tests with a sensitivity of at least 25 mIU/mL prior to receiving the initial isotretinoin prescription.201,203 The first pregnancy test (a screening test) must be obtained by the prescribing clinician when the decision is made to pursue qualification of the patient for isotretinoin therapy.201,203 The second pregnancy test (a confirmation test) must be done by a Clinical Laboratory Improvement Amendment (CLIA)-certified laboratory.201,203 The interval between these 2 tests should be at least 19 days.201,203 For patients with regular menstrual cycles, the second pregnancy test should be done during the first 5 days of the menstrual period and within 7 days of the office visit, immediately preceding the beginning of isotretinoin therapy and after the patient has used 2 forms of contraception for 1 month.201,203 For patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding, the second pregnancy test must be done within 7 days after the office visit, immediately preceding the beginning of isotretinoin therapy, and after the patient had used 2 forms of contraception for 1 month.201,203 Female patients of childbearing potential must have a negative result from a urine or serum pregnancy test (in a CLIA-certified laboratory) each month prior to receiving each prescription.201,203 Counseling about contraception and behaviors associated with an increased risk of pregnancy must be repeated monthly during therapy with the drug prior to receipt of isotretinoin prescriptions.201,203

Although contraceptives containing estrogenic and/or progestinic steroids are considered reliable methods of contraception, there have been reports of pregnancy in women receiving oral, topical, injectable, implantable, or insertable contraceptives concurrently with isotretinoin and it is not known whether isotretinoin might affect efficacy of such contraceptives.203 However, reports of pregnancy were more frequent for women who used only a single method of contraception.203 Clinicians are advised to consult the package insert of any medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products.203 Patients should be prospectively cautioned in particular not to self-administer the herbal supplement St. John's wort because breakthrough bleeding and pregnancies have been reported in women who received hormonal contraceptives in conjunction with St. John's wort.203 Clinicians must report immediately any suspected fetal exposure during or up to 1 month following therapy to the US Food and Drug Administration (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 ([Web]).201,202,203

In addition, patients should be warned not to share isotretinoin with anyone else, even if they have similar symptoms, because of the risk of birth defects and other serious adverse effects.201,203 If a patient who is receiving isotretinoin donates blood and the donated blood, blood components, or plasma is transfused into a woman who is or soon becomes pregnant, there may be a risk to the developing fetus because of isotretinoin in the transfused blood.100 Taking into consideration the potency of isotretinoin as a teratogen and the possibility that the drug may be present in blood for long periods, it is recommended that patients receiving isotretinoin not donate blood during therapy and for at least 1 month following discontinuance of the drug.100,201,203

Pediatric Precautions !!navigator!!

Safety and efficacy of isotretinoin in children younger than 12 years of age have not been established.105 Although isotretinoin has been shown in a clinical study to be equally effective in treating severe recalcitrant nodular acne in both adolescents 13-17 years of age and adults, the manufacturers state that use in adolescents 12-17 years of age should be given careful consideration, particularly for those with known metabolic or structural bone disease.105 (See Cautions: Precautions and Contraindications.)

In clinical studies, adverse effects of isotretinoin reported in adolescents 12-17 years of age were similar to those described in adults except for the increased incidence of back pain and arthralgia (both of which were sometimes severe) and myalgia reported in adolescent patients.105 In these studies, arthralgias or back pain reportedly occurred in approximately 22 or 29% of adolescents treated with isotretinoin, respectively, and were considered severe in 8-14% of the cases.105 Back pain occurred at a higher frequency in female than in male patients.105 Appropriate evaluation of the musculoskeletal system should be performed in patients who present with these symptoms during or after a course of isotretinoin therapy.105 If any substantial abnormality is found, discontinuance of the drug should be considered.105

Premature closure of the epiphyses also has been reported in pediatric patients receiving recommended dosages of isotretinoin for the management of acne.105 The risk for developing premature epiphyseal closure appears to increase with increasing dosage and duration of isotretinoin therapy.194 The effect of multiple courses of isotretinoin therapy on epiphyseal closure is as yet unknown.105 In addition, effects of long-term or multiple courses of isotretinoin on the developing musculoskeletal system remain to be established.105 (See Cautions: Musculoskeletal Effects.)

Geriatric Precautions !!navigator!!

Clinical studies of isotretinoin did not include a sufficient number of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.105 While other clinical experience has not revealed age-related differences in response, effects of aging might be expected to increase some risks associated with isotretinoin therapy.105

Mutagenicity and Carcinogenicity !!navigator!!

In vitro tests generally have not shown isotretinoin to be mutagenic.69,105,172 The results of Ames microbial mutagen tests were negative in one study and a weakly positive response was reported in another study in a single strain of Salmonella typhimurium (assay with metabolic activation); no dose-response effect was observed, and all other strains were negative.105 Other mutagenicity tests designed to assess genotoxicity (e.g., Chinese hamster cell test, mouse micronucleus test, Saccharomyces cerevisiae test, unscheduled DNA synthesis assay, in vitro clastogenicity assay in human lymphocytes) did not reveal evidence of mutagenic potential.105

Although pheochromocytoma and adrenal medullary hyperplasia occurred in animals receiving isotretinoin dosages of 8 or 32 mg/kg daily for more than 18 months, the validity of these findings has been questioned since pheochromocytoma occurs at a relatively high frequency in the species of animals tested.1 A decreased incidence of hepatic adenomas and angiomas and leukemia also was observed in these animals.1 The clinical importance of these findings is not known.1

Pregnancy, Fertility, and Lactation !!navigator!!

Pregnancy

Isotretinoin is a known human teratogen, and can cause severe, life-threatening birth defects or fetal death if taken during pregnancy.100,143,144,145,146,147,201,203 Since the risks clearly outweigh any possible benefits in female patients who are or may become pregnant or who intend to become pregnant during treatment, female patients of childbearing potential should not receive isotretinoin until pregnancy is excluded and other conditions of use have been met.144,145,149,150,151,152,184,201,203 (See Teratogenicity Contraindications and Precautions under Cautions: Precautions and Contraindications.) There is an extremely high risk that severe birth defects will result if pregnancy occurs while receiving isotretinoin in any amount even for short periods of time.201 203 There are no accurate means of determining whether an exposed fetus has been affected following isotretinoin exposure.201,203 Therefore, patients who become pregnant, miss their expected menstrual period, stop using birth control, or have sexual intercourse without the use of 2 separate contraceptive measures should immediately discontinue isotretinoin and notify their clinician.203 Such patients should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.201,202,203 Clinicians must immediately report any suspected fetal exposure during or up to 1 month following therapy to the US Food and Drug Administration (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 ([Web]).201,202,203 The iPLEDGE Program Pregnancy Registry collects data on pregnancies that occur in female patients who become pregnant while taking isotretinoin or within 1 month after the last dose.201,203 Data from this registry are used to evaluate further ways to reduce fetal exposure to isotretinoin; the information gathered in the registry will be used for statistical purposes only and will be held in the strictest confidence.201,203

Since becoming commercially available in the US in 1982, isotretinoin has been labeled as being contraindicated during pregnancy, with warnings that use in women of childbearing potential be initiated only after advising them of the teratogenic risks, excluding the possibility of pregnancy, and ensuring the use of an effective means of contraception during isotretinoin therapy.163,184 Despite the stated contraindication and warnings and subsequent strengthening of precautionary information in the drug's labeling, the FDA, the US Centers for Disease Control and Prevention (CDC), and the manufacturer of Accutane® continued to receive reports of infants with congenital abnormalities born to women who had received isotretinoin during pregnancy.153,163,184 FDA states that there is some evidence that overprescribing (e.g., for patients without severe, recalcitrant nodular acne) for women of childbearing potential is partly responsible for such continued reports.184 However, because isotretinoin has been proven to be uniquely effective for use in severe, recalcitrant nodular acne, with therapeutic benefits for this condition that exceed those of other currently available drugs, FDA, at the recommendation of its Dermatologic Drugs Advisory Group, decided that the drug can remain available for use in the US once the manufacturer of Accutane® adopted the recommendations made by this Group and the FDA Fertility and Maternal Health Drugs Advisory Committee for a pregnancy prevention program that included changes in the professional labeling, patient labeling, and packaging; initiation of strengthened education of the patient that includes written informed consent and supervised viewing of an educational videocassette at the time of prescribing; expansion of patient referrals to obstetrician-gynecologists for pregnancy testing; and ensurance by the manufacturer that all unused isotretinoin be returned by the patient.105,163,164,184 Unfortunately, suboptimal participation (40% or less of women who received isotretinoin) and substantial noncompliance with critical elements of the manufacturer-supported pregnancy prevention program (e.g., 25% did not receive a pregnancy test prior to treatment and 33% initiated therapy prior to receiving their pregnancy test results) has been reported to the FDA.192 Of the 1995 documented cases of isotretinoin-exposed pregnancies reported by the manufacturer of Accutane®, 958 pregnancies were identified after the previous pregnancy prevention program was in place.192 According to a 1999 report to the FDA by this manufacturer, approximately 11% of the pregnant women identified by a patient survey conducted by the Slone Epidemiology Unit of Boston University School of Public Health were pregnant at initiation of isotretinoin therapy and another 14% became pregnant during the first 3 weeks of treatment.191,192 Because of such limitations in the previous pregnancy prevention program, the manufacturer of Accutane®, working with the FDA, developed a restricted distribution system, the System to Manage Accutane Related Teratogenicity (SMART), as an additional component of a risk management program to prevent fetal exposure to isotretinoin.105,191 As nonproprietary (generic) isotretinoin preparations became commercially available, additional restricted distribution programs were developed by other manufacturers.196,197 The SMART program included mandatory contraceptive measures for women, as well as mandatory pregnancy testing to confirm that a woman is not pregnant before isotretinoin therapy is initiated and does not become pregnant during or immediately after therapy with the drug.105,191

Existing restricted distribution programs designed to reduce the risk of fetal exposure to isotretinoin, including the SMART program, were assessed in 2004 by FDA, and the results of this assessment were presented at a joint meeting of the Drug Safety and Risk Management and Dermatologic and Ophthalmic Drugs Advisory Committees.202 Those committees strongly recommended the need for improvements in the isotretinoin risk management program to strengthen processes to ensure pregnancy testing and counseling of patients prior to and during therapy to reduce the risk of fetal exposure in the US.202 The resulting FDA-approved iPLEDGE risk management program is a single, mandatory, computer-based, closed system of registered wholesalers, prescribers, pharmacies, and patients for all commercially available isotretinoin preparations.202 The iPLEDGE program links access to isotretinoin by female patients of childbearing potential with negative results of pregnancy testing to lower the risk of possible fetal exposure to the drug during pregnancy.202

Although isotretinoin has been found in the semen of male patients taking the drug, the amount delivered to a female partner has been found to be about 1 million times lower than an oral dose of 40 mg.201,203 While the no-effect limit for isotretinoin-induced embryopathy is unknown, 20 years of postmarketing reports include 4 with isolated defects compatible with features of retinoid-exposed fetuses.201,203 However, 2 of these reports were incomplete, and 2 had other possible explanations for the defects observed.201,203 Nevertheless, clinicians should report any pregnancy in the partner of a male patient receiving the drug to the iPLEDGE program.201 (See Dosage and Administration: Restricted Distribution Program.)

Teratogenic Effects

Teratogenicity of the drug is generally characterized by malformations involving craniofacial, cardiovascular, thymus and parathyroid gland, and CNS structures.100,143,144,145,146,147,173,203 Abnormalities of the external ear including absent (anotia), small (micropinna), or deformed external ears and small or absent external auditory canals;143,144,145,146,147,153,154,173,174,175,177,178,184,203 facial dysmorphia, including micrognathia and cleft palate;143,145,146,153,154,174,175,177,184,203 CNS abnormalities,153,154,173,203 including cerebral abnormalities,203 cerebellar malformations,203 hydrocephalus,143,145,146,153,154,175,176,177,203 agyria (lissencephaly),144,153 cranial nerve deficit,141,145,174,203 skull abnormalities,145,174,203 and microcephaly;143,144,145,146,147,153,177,203 eye abnormalities,141,145,203 including microphthalmia;143,144,146,153,203 thymus gland abnormalities (ectopia, hypoplasia, or aplasia);145,146,147,154,203 parathyroid hormone deficiency,203 and cardiovascular abnormalities (principally conotruncal defects, ventricular and atrial septal defects, or aortic-arch abnormalities)143,144,145,146,147,153,154,173,174,177,184,203 have been reported. IQ scores below 85, with or without CNS abnormalities, also have been reported.203 Most malformed infants have several of these abnormalities,143,144,145,146,147,153,154,173,174,175,177 and death occasionally has been associated with some of the abnormalities.203 In addition, spontaneous abortions100,145,146,153,155,163,176,179,180,181,203 and premature births144,182,203 have occurred. The mechanisms of isotretinoin-induced teratogenicity remain to be fully elucidated, but a deleterious effect on fetal cephalic neural crest cell activity may be involved in the craniofacial, thymic, and cardiac malformations.145

Fertility

Reproduction studies in male and female rats using isotretinoin dosages up to 16 times the maximum recommended human dosage have not revealed evidence of impaired fertility.1,105 However, reproduction studies in male dogs using chronic isotretinoin dosages 10-30 times the maximum recommended human dosage showed testicular atrophy and microscopic evidence of appreciable depression of spermatogenesis.1,105 Although the effect of isotretinoin on fertility in humans has not been determined, no clinically important changes have been observed in the number or motility of spermatozoa in the ejaculate of human males receiving isotretinoin for the treatment of severe nodular acne.105,156,157

Lactation

It is not known whether isotretinoin is distributed into milk.1 Because of the potential for serious adverse reactions to isotretinoin in nursing infants, isotretinoin should not be administered to women who are breast-feeding.105

Drug Interactions ⬆ ⬇

[Section Outline]

Vitamin A !!navigator!!

Because of the potential for additive adverse effects, patients receiving isotretinoin should be warned to avoid concomitant use of preparations containing vitamin A or its derivatives.105

Tetracyclines !!navigator!!

Because some cases of pseudotumor cerebri (benign intracranial hypertension) associated with use of isotretinoin have involved patients also receiving tetracycline or minocycline, which have also been reported to cause increased intracranial pressure, such concomitant use of isotretinoin and tetracyclines should be avoided.105

Oral Contraceptives !!navigator!!

Microdosed progesterone preparations (minipills) may be an inadequate method of contraception during isotretinoin therapy.203 Although other hormonal contraceptives are highly effective, there have been reports of pregnancy from female patients who have used oral contraceptives, as well as injectable, implantable, topical, or insertable contraceptive products. These reports are more frequent for female patients who use only a single method of contraception.203 It is not known if hormonal contraceptives differ in their effectiveness when used with isotretinoin.203 Therefore, it is critically important that female patients of childbearing potential use two effective forms of contraception simultaneously, at least one of which must be a primary form.203

Concomitant use of isotretinoin (1 mg/kg daily) and an oral ethinyl estradiol and norethindrone contraceptive (OrthoNovum® 7/7/7) in premenopausal female patients reportedly did not produce clinically important effects on the pharmacokinetics of the contraceptive hormones or on the serum concentrations of progesterone, follicle-stimulating hormone (FSH), or luteinizing hormone (LH) in one clinical study.203

Phenytoin !!navigator!!

Although clinical studies have not been conducted to evaluate the effects on bone loss when phenytoin, which is known to cause osteomalacia, and isotretinoin are used concurrently, the manufacturers recommend exercising caution when these 2 drugs are used concomitantly.196,197,203 Isotretinoin has not been shown in vitro or in vivo to alter the pharmacokinetics of phenytoin.203

Corticosteroids !!navigator!!

Although clinical studies have not been conducted to evaluate the effects on bone loss when systemic corticosteroids, which are known to cause osteoporosis, and isotretinoin are used concurrently, the manufacturers recommend exercising caution when these 2 drugs are used concomitantly.196,197,203

Other Information ⬆ ⬇

[Section Outline]

Acute Toxicity

Limited information is available on the acute toxicity of isotretinoin. The oral LD50 of isotretinoin is greater than 4 g/kg in rats and mice and approximately 2 g/kg in rabbits.1 Overdosage of isotretinoin would be expected to produce effects that are principally extensions of common adverse reactions.1 (See Cautions.) Overdosage to date has been associated with headache, vomiting, facial flushing, cheilosis, abdominal pain, dizziness, and ataxia; symptoms resolved quickly and without apparent residual effects.105

Because isotretinoin can cause teratogenic effects at any dosage, female patients of childbearing potential who present with an isotretinoin overdosage must be evaluated for pregnancy.203 Patients who are pregnant should receive counseling about the risks to the fetus (see Cautions: Pregnancy, Fertility, and Lactation), and patients who are not pregnant must be warned to avoid pregnancy for at least 1 month and receive contraceptive counseling (see Contraceptive Measures under Precautions and Contraindications: Teratogenicity Precautions and Contraindications, in Cautions).203 Educational materials for such patients can be obtained by calling the manufacturer.203 Because an overdosage would be expected to result in higher concentrations of isotretinoin in semen than found during a normal treatment course, male patients should be instructed to use a condom or avoid reproductive sexual activity with a female patient who is or might become pregnant for 30 days after the overdose.203 In addition, all patients with isotretinoin overdosage should not donate blood for at least 30 days.203

Pharmacology

Isotretinoin has pharmacologic actions similar to those of other retinoids (e.g., vitamin A, tretinoin).7 The principal pharmacologic effect of isotretinoin appears to be regulation of cell (e.g., epithelial) proliferation and differentiation.8,9 The drug also affects the function of monocytes and lymphocytes, resulting in modulation of cellular immune responses in mesenchymal tissue.9 Isotretinoin exhibits some anti-inflammatory20,76 and antineoplastic activity.7,42,48,90 The exact mechanism(s) of action has not been fully elucidated, but data from in vitro studies indicate that retinoids increase cellular mitotic activity,10,11 DNA and RNA synthesis,12,13,14,15 protein synthesis,16 and post-translational glycosylation of proteins.17,18,19

Although the actions of isotretinoin and other retinoids are generally similar, the specific pharmacologic effects of these drugs differ.7,24 Differences in these effects may result from the complexity of the mechanism(s) of action, individual or disease-specific differences in response to the drugs,7,20,24 or differences in cytosol-binding proteins in various tissues.24,25 Intracellular cytosol-binding proteins have been identified for retinol (vitamin A) and retinoic acid (tretinoin, isotretinoin).7,20,24 These receptor proteins are similar in molecular weight and composition but possess distinctly different binding specificities.20,24 Differences in the affinity of retinoids for these receptor proteins generally parallel differences in their pharmacologic effects.27 The exact role of cytosol-binding proteins in mediating the action of retinoids is not fully understood, but the retinoid-binding protein complex (i.e., cytosol-binding protein and retinoid) distributes into the cell nucleus where it affects DNA, RNA, protein, and glycoprotein synthesis.8,20,26

At high concentrations, retinoids exert a detergent-like effect on cell membranes that results in decreased membrane stability.28 In vitro, the drugs disrupt lysosomal membranes, resulting in the release of lysosomal enzymes.27,28 Although the actual in vivo effects of retinoids on lysosomal membranes remain to be clearly determined, it has been suggested that some adverse effects of retinoids may result from their detergent-like activity.64 Binding of isotretinoin to its specific cytosol-binding protein may prevent this detergent-like effect,7 and at low concentrations, the drug may actually stabilize cell membranes.27

Effects on Acne !!navigator!!

The exact mechanism(s) of action of isotretinoin in the treatment of nodulocystic acne is not fully understood but appears to include inhibition of sebaceous gland function and follicular keratinization; however, the drug's effect on follicular keratinization has not been fully characterized.1,8,29,30,93 Although some data suggest that isotretinoin does not possess substantial activity when applied topically (as an alcoholic solution or cream),89,109 other data indicate that topical therapy with the drug (as a 0.05% gel) may reduce inflammatory and noninflammatory lesions associated with acne.148 The mechanism of the drug's topical effect has not been fully elucidated.148

Isotretinoin reduces the size of sebaceous glands and inhibits sebum production, apparently by a direct effect on the glands;6,30,31,32,33 the drug also inhibits sebaceous-gland differentiation.1 Isotretinoin may reduce the production of sebum by as much as 90% in some patients with severe nodular or conglobate acne.6,29,31 The decrease in sebum production is dose related and reversible (sometimes slowly) following discontinuance of the drug.29,30,36 The duration of inhibition of sebum production following discontinuance of the drug appears to be directly related to the duration of isotretinoin therapy; however, further study is needed to confirm this.29,30 Isotretinoin does not appear to exert its effects on sebaceous glands via an antiandrogenic mechanism.41 Because of isotretinoin's inhibition of sebaceous gland function, the lipid composition on the surface of the skin is altered during treatment with the drug and resembles that of prepubertal skin;34 the percentage of squalene and wax esters (mainly of sebaceous origin) is decreased, and the percentage of free and esterified cholesterol (mainly of epidermal origin) is increased.29,31,35 Lipid composition on the surface of the skin returns to pretreatment composition following discontinuance of isotretinoin therapy even though sebum production may not completely return to pretreatment levels.29 In patients with severe nodular acne, prolonged remissions frequently occur following discontinuance of isotretinoin; the exact mechanism of this persistent effect is not known but may include a prolonged effect of the drug on the sebaceous glands.30

It has been suggested that isotretinoin inhibits follicular keratinization in patients with acne, but such an effect has not been fully characterized.80 Tretinoin appears to act as an irritant on follicular epithelium when applied topically, preventing horny cells from sticking together.80 This effect causes horny cells to be readily sloughed and expelled from the follicular orifice, thereby inhibiting formation of additional comedones.38 It is not known whether orally administered isotretinoin has a similar effect.

The pathogenesis of acne also involves bacterial colonization (principally by Propionibacterium acnes ) of the pilosebaceous apparatus;37,38,39 the bacteria produce enzymes (e.g., lipases, proteases, hyaluronidases) that may evoke an inflammatory reaction.38 Although isotretinoin does not inhibit the growth of P. acnes in vitro,91 in large doses, isotretinoin therapy is associated with a reduction in the concentration of P. acnes on the surface of the skin.40 It has been suggested that the reduction in the bacterial flora results not from a direct effect of the drug on the bacteria but from a drug-induced reduction in sebum production.40,82

Isotretinoin has some anti-inflammatory activity that might contribute to its effect on acne.20,76,82,83 The anti-inflammatory effect of the drug may be associated with inhibition of the synthesis of collagenase and prostaglandin E2.20,21,22,23,76

Antineoplastic Effect !!navigator!!

Although the exact mechanism(s) of action has not been conclusively determined, isotretinoin has an antineoplastic effect.7,42,48,90 The antineoplastic activity of the drug 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

Retinoids exhibit immunoadjuvant activity.65,78 In animals, the drugs increase the antibody response to various antigenic stimuli.65 In humans, isotretinoin stimulates the production and cytotoxic effect of lymphocytes (i.e., killer T cells).65,78 Unlike topically applied tretinoin, oral isotretinoin has not been shown to stimulate synthesis of the gap junction, an intercellular membrane structure that connects adjacent epithelial cells and is thought to be involved in the regulation of tissue organization, coordination, and growth.43,44,45,46,47

Pharmacokinetics

Absorption !!navigator!!

Following oral administration of isotretinoin, there is an apparent lag time of about 0.5-2 hours before the drug appears in systemic circulation.53,110,111,112 The lag time is thought to result from disintegration of the capsule and subsequent dissolution of the drug in GI contents.85 Absorption of the drug after this lag time is rapid.53,110,111,112 The actual bioavailability of orally administered isotretinoin has not been determined in humans, but studies in animals indicate that about 25% of an oral dose of the drug reaches systemic circulation as unchanged isotretinoin.53 The low bioavailability observed in animals may result from 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 and/or milk increase GI absorption of isotretinoin.105,111 Peak blood isotretinoin concentrations are slightly delayed and substantially increased and the area under the blood concentration-time curve (AUC) of the drug is approximately 1.5-2 times greater when isotretinoin is administered 1 hour before, concomitantly with, or 1 hour after a meal than when the drug is administered in the fasting state.111 Because of its high lipophilicity, oral absorption of isotretinoin is enhanced when the drug is administered with a high-fat meal.105 In a crossover study of 74 healthy adults who received a single 80-mg isotretinoin dose (as two 40-mg capsules) under fasted and fed conditions, both the peak plasma concentration and total area under the plasma concentration-time curve (AUC) of the drug were more than doubled when isotretinoin was administered immediately after a standardized high-fat meal compared with administration in the fasted state.105 Because the observed elimination half-life of the drug remained unchanged, it is suggested that food appears to increase the bioavailability of isotretinoin without altering its disposition.105 The time to peak concentration was also increased with food and may be related to a longer absorption phase.105 Consequently, the manufacturers recommend that isotretinoin capsules always be administered with food.105,196,197

Following oral administration of a single 80-mg isotretinoin dose (as two 40-mg capsules) to healthy adults, peak plasma isotretinoin concentrations of 167-459 ng/mL occurred at an average of 3.2 hours and peak plasma 4-oxo-isotretinoin (a principal metabolite of isotretinoin) concentrations of 87-399 ng/mL occurred at 6-20 hours.53 In these patients, plasma concentrations of 4-oxo-isotretinoin generally exceeded those of isotretinoin after 6 hours.53 Following oral administration to fasting, healthy adults, peak blood concentrations and the AUCs of isotretinoin and 4-oxo-isotretinoin increase proportionally with single isotretinoin doses of 80, 160, and 240 mg (as 40-mg capsules) but plateau at higher doses.101

Clinical studies have shown that there is no difference in the pharmacokinetics of isotretinoin between adults with normal skin and those with nodular acne.105 In addition, no substantial differences in the pharmacokinetics of the drug were found between adults and children 12-15 years of age with severe recalcitrant nodular acne.105

A therapeutic range for plasma isotretinoin concentrations in patients with acne has not been clearly established.85,86

Distribution !!navigator!!

Distribution of isotretinoin into human body tissues and fluids has not been fully characterized.53 Following oral administration of isotretinoin in animals, the drug is distributed into many tissues including liver, ureters, adrenals, ovaries, and lacrimal glands.1 Isotretinoin and its metabolites are distributed into bile in humans,53,54,113 principally as glucuronide conjugates;113 biliary concentration of the drug is proportional to hepatobiliary function and may be negligible in the presence of obstructive biliary disease.53 The drug has also been detected in synovial fluid.134 Unlike vitamin A, isotretinoin is not stored in the liver.7

In vitro, isotretinoin is 99.9% bound to plasma proteins, principally albumin, at plasma drug concentrations of 0.08-2.3 mcg/mL.1,53 Isotretinoin does not appear to be displaced from binding sites by its metabolites.53

Although it is not known if isotretinoin crosses the placenta in humans, the drug readily crosses the placenta in animals.1,55 It is not known if isotretinoin is distributed into milk.1

Elimination !!navigator!!

Blood concentrations of isotretinoin decline in a biphasic manner.53 In adults with normal renal function, the half-life in the initial phase (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 Following oral administration of radiolabeled isotretinoin in healthy adults, radioactivity in blood declined with a half-life of 90 hours;1,53,113 the prolonged radioactivity probably represented unidentified metabolites.53,113

Isotretinoin is metabolized in the liver by the cytochrome P-450 (CYP) microsomal enzyme system, principally by CYP2C8, CYP2C9, CYP3A4, and CYP2B6 isoenzymes, to several metabolites (e.g., 4-oxo-isotretinoin, retinoic acid [tretinoin], and 4-oxo-retinoic acid [4-oxo-tretinoin]).105 Retinoic acid and 13- cis -retinoic acid are geometric isomers and show reversible interconversion, and the administration of one isomer will give rise to the other.105 Isotretinoin also is irreversibly oxidized to 4-oxo-isotretinoin, which forms its own geometric isomer, 4-oxo-tretinon.105 All of these metabolites possess retinoid activity that is more than that of the parent compound in some in vitro models.105 However, the clinical importance of these models is unknown.105 Concurrent administration of food has been shown to increase the extent of formation of all metabolites in plasma when compared to administration of isotretinoin under fasted conditions.105 In addition, the exposure of patients to 4-oxo-isotretinoin at steady-state under fasted and fed conditions was approximately 3.4 times higher than that of isotretinoin.105

Isotretinoin and its metabolites are conjugated, possibly with glucuronic acid, before being excreted in urine and feces. 53,105,113 Excretion of unchanged isotretinoin in urine appears to be negligible.108,110 Isotretinoin appears to be excreted in feces mainly as unchanged drug.108,110 Limited data suggest that isotretinoin and its metabolites are excreted in feces via biliary elimination and that the drug and its metabolites also undergo enterohepatic circulation.53,110,112,113 In adults with normal renal and hepatic function, 65-85% of a single, radiolabeled 80-mg oral dose of isotretinoin is excreted in urine and feces in approximately equal proportions.1,113

Chemistry and Stability

Chemistry !!navigator!!

Isotretinoin is a synthetic retinoid.1,2,93,108 The drug is the 13- cis -isomer of naturally occurring all- trans -retinoic acid (tretinoin).1,2 Modification of the terminal carboxy group of retinoic acid to the cis -configuration is associated with fewer adverse effects and enhanced biologic activity compared to the all- trans -configuration.3,4,5

Isotretinoin occurs as a yellow-orange to orange, crystalline powder.2 The drug is insoluble in water2,89 and sparingly soluble in alcohol.89 Isotretinoin is commercially available as soft gelatin capsules containing a suspension of the drug in soybean oil.53,89 The capsules contain parabens as preservatives.1,2

Stability !!navigator!!

Isotretinoin is photosensitive and will degrade when exposed to light.2 Commercially available isotretinoin liquid-filled capsules should be stored at 15-30°C in tight, light-resistant containers.2,105

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations ⬆ ⬇

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 Dosage and Administration: Restricted Distribution Program.)

ISOtretinoin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, liquid-filled

10 mg

Amnesteem®

Mylan

Claravis®

Barr

Sotret®

Ranbaxy

20 mg

Amnesteem®

Mylan

Claravis®

Barr

Sotret®

Ranbaxy

30 mg

Sotret®

Ranbaxy

40 mg

Amnesteem®

Mylan

Claravis®

Barr

Sotret®

Ranbaxy

Copyright ⬆ ⬇

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions May 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 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.

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. [PubMed 7011212]

8. Voorhees JJ, Orfanos CE. Oral retinoids: broad-spectrum dermatologic therapy for the 1980's. Arch Dermatol . 1981; 117:418-21. [PubMed 6455092]

9. Orfanos CE. Oral retinoids—present status. Br J Dermatol . 1980; 103:473-81. [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]

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