Isotretinoin, AHFS DRug Information

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Introduction
Isotretinoin is a synthetic retinoid.1 2 93 108
Uses

Severe Nodular Acne
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
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
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
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

Administration
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
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 Programs
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 Accutane® (isotretinoin) and all generic 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 Existing risk management programs for distributing, prescribing, and dispensing commercially available isotretinoin (i.e., SMART, SPIRIT, IMPART, and ALERT), including the use of yellow adhesive qualification stickers on each written prescription for isotretinoin, continued through February 28, 2006 thereby permitting simultaneous new patient registration and qualification in iPLEDGE as well as transitioning existing isotretinoin-treated patients from the existing programs into iPLEDGE.204 Additional information on the iPLEDGE program may be obtained at the program’s website at http://www.ipledgeprogram.com.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 (http://www.ipledgeprogram.com).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.)

It is essential that clinicians review the materials in the iPLEDGE educational kit.201 202 The iPLEDGE Program Guide to Best Practices for Isotretinoin describes the program requirements for prescribing clinicians as well as male and female patients.201 202 The iPLEDGE Program Prescriber Contraception Counseling Guide provides an overview of effective forms of contraception and is a companion to the patient iPLEDGE Program Birth Control Workbook.201 202 These and other materials can be viewed on the iPLEDGE web site.201 202 In addition, the prescribing clinician should distribute the iPLEDGE Program Patient Introductory Brochure and the patient educational kits, which provide information about the iPLEDGE program requirements.201 202 For additional information on other 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 http://www.ipledgeprogram.com.201 203
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.)

In addition, 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

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 (http://www.ipledgeprogram.com) 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 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 The iPLEDGE Program Pharmacist Guide for Isotretinoin also is available on the program’s website and includes information on the teratogenic potential of isotretinoin and the required procedure to obtain authorization to dispense an isotretinoin prescription.201 203 For additional information on the specific requirements for pharmacists in the iPLEDGE program, the program’s website should be consulted at http://www.ipledgeprogram.com.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 http://www.ipledgeprogram.com.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 http://www.ipledgeprogram.com.201 203

Cautions
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
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
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
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
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
Adverse nervous system effects of isotretinoin include lethargy,6 fatigue,1 6 and headache.1 6 29
D
epression, 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
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
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
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
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
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 Programs.) 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

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
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 Programs.) 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 tol