Accutane (Oral)

Soft gelatin capsules, 10 mg (light pink), imprinted %medicine_name% (isotretinoin) 10 ROCHE. Boxes of 100 containing 10 Prescription Paks of 10 capsules (NDC 0004-0155-49).

Soft gelatin capsules, 20 mg (maroon), imprinted %medicine_name% (isotretinoin) 20 ROCHE. Boxes of 100 containing 10 Prescription Paks of 10 capsules (NDC 0004-0169-49).

Soft gelatin capsules, 40 mg (yellow), imprinted %medicine_name% (isotretinoin) 40 ROCHE. Boxes of 100 containing 10 Prescription Paks of 10 capsules (NDC 0004-0156-49).

Storage

Store at controlled room temperature (59° to 86°F, 15° to 30°C). Protect from light.

REFERENCES

1. Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid. N Engl J Med 300:329-333, 1979.

2. Pochi PE, Shalita AR, Strauss JS, Webster SB. Report of the consensus conference on acne classification. J Am Acad Dermatol 24:495-500, 1991.

3. Farrell LN, Strauss JS, Stranieri AM. The treatment of severe cystic acne with 13-cis-retinoic acid: evaluation of sebum production and the clinical response in a multiple-dose trial. J Am Acad Dermatol 3:602-611, 1980.

4. Jones H, Blanc D, Cunliffe WJ. 13-cisretinoic acid and acne. Lancet 2:1048-1049, 1980.

8. Strauss JS, Rapini RP, Shalita AR, et al. Isotretinoin therapy for acne: results of a multicenter dose-response study. J Am Acad Dermatol 10:490-496, 1984.

Distributed by: Roche Laboratories Inc., 340 Kingsland Street, Nutley, New Jersey 07110-1199. PI Revised: January 2010.

Severe Recalcitrant Nodular Acne

%medicine_name% (isotretinoin) is indicated for the treatment of severe recalcitrant nodular acne. Nodules are inflammatory lesions with a diameter of 5 mm or greater. The nodules may become suppurative or hemorrhagic. “Severe,” by definition,² means “many” as opposed to “few or several” nodules. Because of significant adverse effects associated with its use, %medicine_name% (isotretinoin) should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition, %medicine_name% (isotretinoin) is indicated only for those female patients who are not pregnant, because %medicine_name% (isotretinoin) can cause severe birth defects (see Boxed CONTRAINDICATIONS AND WARNINGS).

A single course of therapy for 15 to 20 weeks has been shown to result in complete and prolonged remission of disease in many patients.^1,3,4 If a second course of therapy is needed, it should not be initiated until at least 8 weeks after completion of the first course, because experience has shown that patients may continue to improve while off %medicine_name% (isotretinoin). The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth (see WARNINGS: Skeletal: Bone Mineral Density, Hyperostosis, and Premature Epiphyseal Closure).

%medicine_name% (isotretinoin) should be administered with a meal (see PATIENT INFORMATION).

The recommended dosage range for %medicine_name% (isotretinoin) is 0.5 to 1.0 mg/kg/day given in two divided doses with food for 15 to 20 weeks. In studies comparing 0.1, 0.5, and 1.0 mg/kg/day,⁸ it was found that all dosages provided initial clearing of disease, but there was a greater need for retreatment with the lower dosages. During treatment, the dose may be adjusted according to response of the disease and/or the appearance of clinical side effects — some of which may be dose related. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dose adjustments up to 2.0 mg/kg/day, as tolerated. Failure to take %medicine_name% (isotretinoin) with food will significantly decrease absorption. Before upward dose adjustments are made, the patients should be questioned about their compliance with food instructions.

The safety of once daily dosing with %medicine_name% (isotretinoin) has not been established. Once daily dosing is not recommended.

If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, the drug may be discontinued. After a period of 2 months or more off therapy, and if warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Long-term use of %medicine_name% (isotretinoin) , even in low doses, has not been studied, and is not recommended. It is important that %medicine_name% (isotretinoin) be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of %medicine_name% on bone loss is unknown (see WARNINGS: Skeletal: Bone Mineral Density, Hyperostosis, and Premature Epiphyseal Closure).

Contraceptive measures must be followed for any subsequent course of therapy (see PRECAUTIONS).

Table 4 : %medicine_name% (isotretinoin) Dosing by Body Weight (Based on Administration With Food)

INFORMATION FOR PHARMACISTS

Access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866495-0654) to obtain an authorization and the “do not dispense to patient after” date. %medicine_name% (isotretinoin) must only be dispensed in no more than a 30-day supply.

REFILLS REQUIRE A NEW PRESCRIPTION AND A NEW AUTHORIZATION FROM THE iPLEDGE SYSTEM.

An %medicine_name% (isotretinoin) Medication Guide must be given to the patient each time %medicine_name% (isotretinoin) is dispensed, as required by law. This %medicine_name% (isotretinoin) Medication Guide is an important part of the risk management program for the patient.

Pregnancy

Category X. See Boxed CONTRAINDICATIONS AND WARNINGS.

Allergic Reactions

%medicine_name% (isotretinoin) is contraindicated in patients who are hypersensitive to this medication or to any of its components. %medicine_name% (isotretinoin) should not be given to patients who are sensitive to parabens, which are used as preservatives in the gelatin capsule (see PRECAUTIONS: Hypersensitivity).

WARNINGS

Psychiatric Disorders

%medicine_name% (isotretinoin) may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors. No mechanism of action has been established for these events (see ADVERSE REACTIONS: Psychiatric). Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin. Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. Therefore, prior to initiation of %medicine_name% (isotretinoin) therapy, patients and family members should be asked about any history of psychiatric disorder, and at each visit during therapy patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation may be necessary. Signs and symptoms of depression, as described in the brochure (“Recognizing Psychiatric Disorders in Adolescents and Young Adults”), 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. Patients should stop %medicine_name% (isotretinoin) and the patient or a family member should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression, without waiting until the next visit. Discontinuation of %medicine_name% (isotretinoin) therapy may be insufficient; further evaluation may be necessary. While such monitoring may be helpful, it may not detect all patients at risk. Patients may report mental health problems or family history of psychiatric disorders. These reports should be discussed with the patient and/or the patient's family. A referral to a mental health professional may be necessary. The physician should consider whether %medicine_name% (isotretinoin) therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of %medicine_name% (isotretinoin) therapy.

Pseudotumor Cerebri

%medicine_name% (isotretinoin) use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines. Concomitant treatment with tetracyclines should therefore be avoided. Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea and vomiting, and visual disturbances. Patients with these symptoms should be screened for papilledema and, if present, they should be told to discontinue %medicine_name% (isotretinoin) immediately and be referred to a neurologist for further diagnosis and care (see ADVERSE REACTIONS: Neurological).

Serious Skin Reactions

There have been post-marketing reports of erythema multiforme and severe skin reactions [eg, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)] associated with isotretinoin use. These events may be serious and result in death, life-threatening events, hospitalization, or disability. Patients should be monitored closely for severe skin reactions, and discontinuation of %medicine_name% (isotretinoin) should be considered if warranted.

Pancreatitis

Acute pancreatitis has been reported in patients with either elevated or normal serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. %medicine_name% (isotretinoin) should be stopped if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur.

Lipids

Elevations of serum triglycerides in excess of 800 mg/dL have been reported in patients treated with %medicine_name% (isotretinoin). Marked elevations of serum triglycerides were reported in approximately 25% of patients receiving %medicine_name% (isotretinoin) in clinical trials. In addition, approximately 15% developed a decrease in high-density lipoproteins and about 7% showed an increase in cholesterol levels. In clinical trials, the effects on triglycerides, HDL, and cholesterol were reversible upon cessation of %medicine_name% (isotretinoin) therapy. Some patients have been able to reverse triglyceride elevation by reduction in weight, restriction of dietary fat and alcohol, and reduction in dose while continuing %medicine_name% (isotretinoin).⁵

Blood lipid determinations should be performed before %medicine_name% (isotretinoin) is given and then at intervals until the lipid response to %medicine_name% (isotretinoin) is established, which usually occurs within 4 weeks. Especially careful consideration must be given to risk/benefit for patients who may be at high risk during %medicine_name% (isotretinoin) therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If %medicine_name% (isotretinoin) therapy is instituted, more frequent checks of serum values for lipids and/or blood sugar are recommended (see PRECAUTIONS: Laboratory Tests).

The cardiovascular consequences of hypertriglyceridemia associated with %medicine_name% (isotretinoin) are unknown. Animal Studies: In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 to 5.3 times the recommended clinical dose of 1.0 mg/kg/day after normalization for total body surface area) for 18 months or longer, the incidences of focal calcification, fibrosis and inflammation of the myocardium, calcification of coronary, pulmonary and mesenteric arteries, and metastatic calcification of the gastric mucosa were greater than in control rats of similar age. Focal endocardial and myocardial calcifications associated with calcification of the coronary arteries were observed in two dogs after approximately 6 to 7 months of treatment with isotretinoin at a dosage of 60 to 120 mg/kg/day (30 to 60 times the recommended clinical dose of 1.0 mg/kg/day, respectively, after normalization for total body surface area).

Hearing Impairment

Impaired hearing has been reported in patients taking %medicine_name% (isotretinoin) ; in some cases, the hearing impairment has been reported to persist after therapy has been discontinued. Mechanism(s) and causality for this event have not been established. Patients who experience tinnitus or hearing impairment should discontinue %medicine_name% (isotretinoin) treatment and be referred for specialized care for further evaluation (see ADVERSE REACTIONS: Special Senses).

Hepatotoxicity

Clinical hepatitis considered to be possibly or probably related to %medicine_name% (isotretinoin) therapy has been reported. Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15% of individuals treated during clinical trials, some of which normalized with dosage reduction or continued administration of the drug. If normalization does not readily occur or if hepatitis is suspected during treatment with %medicine_name% (isotretinoin) , the drug should be discontinued and the etiology further investigated.

Inflammatory Bowel Disease

%medicine_name% (isotretinoin) has been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. In some instances, symptoms have been reported to persist after %medicine_name% (isotretinoin) treatment has been stopped. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue %medicine_name% immediately (see ADVERSE REACTIONS: Gastrointestinal).

Skeletal

Bone Mineral Density

Effects of multiple courses of %medicine_name% (isotretinoin) on the developing musculoskeletal system are unknown. There is some evidence that long-term, high-dose, or multiple courses of therapy with isotretinoin have more of an effect than a single course of therapy on the musculoskeletal system. In an open-label clinical trial (N=217) of a single course of therapy with %medicine_name% (isotretinoin) for severe recalcitrant nodular acne, bone density measurements at several skeletal sites were not significantly decreased (lumbar spine change > -4% and total hip change > -5%) or were increased in the majority of patients. One patient had a decrease in lumbar spine bone mineral density > 4% based on unadjusted data. Sixteen (7.9%) patients had decreases in lumbar spine bone mineral density > 4%, and all the other patients (92%) did not have significant decreases or had increases (adjusted for body mass index). Nine patients (4.5%) had a decrease in total hip bone mineral density > 5% based on unadjusted data. Twenty-one (10.6%) patients had decreases in total hip bone mineral density > 5%, and all the other patients (89%) did not have significant decreases or had increases (adjusted for body mass index). Follow-up studies performed in 8 of the patients with decreased bone mineral density 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. Total hip bone mineral densities remained below baseline (range –1.6% to –7.6%) in 5 of 8 patients (62.5%).

In a separate open-label extension study of 10 patients, ages 13-18 years, who started a second course of %medicine_name% (isotretinoin) 4 months after the first course, two patients showed a decrease in mean lumbar spine bone mineral density up to 3.25% (see PRECAUTIONS: Pediatric Use).

Spontaneous reports of osteoporosis, osteopenia, bone fractures, and delayed healing of bone fractures have been seen in the %medicine_name% (isotretinoin) population. While causality to %medicine_name% (isotretinoin) has not been established, an effect cannot be ruled out. Longer term effects have not been studied. It is important that %medicine_name% (isotretinoin) be given at the recommended doses for no longer than the recommended duration.

Hyperostosis

A high prevalence of skeletal hyperostosis was noted in clinical trials for disorders of keratinization with a mean dose of 2.24 mg/kg/day. Additionally, skeletal hyperostosis was noted in 6 of 8 patients in a prospective study of disorders of keratinization.⁶ Minimal skeletal hyperostosis and calcification of ligaments and tendons have also been observed by x-ray in prospective studies of nodular acne patients treated with a single course of therapy at recommended doses. The skeletal effects of multiple %medicine_name% (isotretinoin) treatment courses for acne are unknown.

In a clinical study of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, hyperostosis was not observed after 16 to 20 weeks of treatment with approximately 1 mg/kg/day of %medicine_name% (isotretinoin) given in two divided doses. Hyperostosis may require a longer time frame to appear. The clinical course and significance remain unknown.

Premature Epiphyseal Closure

There are spontaneous reports of premature epiphyseal closure in acne patients receiving recommended doses of %medicine_name% (isotretinoin). The effect of multiple courses of %medicine_name% (isotretinoin) on epiphyseal closure is unknown.

Vision Impairment

Visual problems should be carefully monitored. All %medicine_name% (isotretinoin) patients experiencing visual difficulties should discontinue %medicine_name% (isotretinoin) treatment and have an ophthalmological examination (see ADVERSE REACTIONS: Special Senses).

Corneal Opacities

Corneal opacities have occurred in patients receiving %medicine_name% (isotretinoin) for acne and more frequently when higher drug dosages were used in patients with disorders of keratinization. The corneal opacities that have been observed in clinical trial patients treated with %medicine_name% (isotretinoin) have either completely resolved or were resolving at follow-up 6 to 7 weeks after discontinuation of the drug (see ADVERSE REACTIONS: Special Senses).

Decreased Night Vision

Decreased night vision has been reported during %medicine_name% (isotretinoin) therapy and in some instances the event has persisted after therapy was discontinued. Because the onset in some patients was sudden, patients should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at night.

PRECAUTIONS

%medicine_name% (isotretinoin) must only be prescribed by prescribers who are registered and activated with the iPLEDGE program. %medicine_name% (isotretinoin) must only be dispensed by a pharmacy registered and activated with iPLEDGE, and must only be dispensed to patients who are registered and meet all the requirements of iPLEDGE. Registered and activated pharmacies must receive %medicine_name% (isotretinoin) only from wholesalers registered with iPLEDGE.

iPLEDGE program requirements for wholesalers, prescribers, and pharmacists are described below:

Wholesalers

For the purpose of the iPLEDGE program, the term wholesaler refers to wholesaler, distributor, and/or chain pharmacy distributor. To distribute %medicine_name% (isotretinoin) , wholesalers must be registered with iPLEDGE, and agree to meet all iPLEDGE requirements for wholesale distribution of isotretinoin products. Wholesalers must register with iPLEDGE by signing and returning the iPLEDGE wholesaler agreement that affirms they will comply with all iPLEDGE requirements for distribution of isotretinoin. These include:

• Registering prior to distributing isotretinoin and re-registering annually thereafter
• Distributing only FDA approved isotretinoin product
• Only shipping isotretinoin to
  • wholesalers registered in the iPLEDGE program with prior written consent from the manufacturer or
  • pharmacies licensed in the US and registered and activated in the iPLEDGE program
• Notifying the isotretinoin manufacturer (or delegate) of any non-registered and/or nonactivated pharmacy or unregistered wholesaler that attempts to order isotretinoin
• Complying with inspection of wholesaler records for verification of compliance with the iPLEDGE program by the isotretinoin manufacturer (or delegate)
• Returning to the manufacturer (or delegate) any undistributed product if registration is revoked by the manufacturer or if the wholesaler chooses to not re-register annually

Prescribers

To prescribe isotretinoin, the prescriber must be registered and activated with the pregnancy risk management program iPLEDGE. Prescribers can register by signing and returning the completed registration form. Prescribers can only activate their registration by affirming that they meet requirements and will comply with all iPLEDGE requirements by attesting to the following points:

• I know the risk and severity of fetal injury/birth defects from isotretinoin.
• I know the risk factors for unplanned pregnancy and the effective measures for avoidance of unplanned pregnancy.
• I have the expertise to provide the patient with detailed pregnancy prevention counseling or I will refer her to an expert for such counseling, reimbursed by the manufacturer.
• I will comply with the iPLEDGE program requirements described in the booklets entitled The Guide to Best Practices for the iPLEDGE Program and The iPLEDGE Program Prescriber Contraception Counseling Guide.
• Before beginning treatment of female patients of childbearing potential with isotretinoin and on a monthly basis, the patient will be counseled to avoid pregnancy by using two forms of contraception simultaneously and continuously one month before, during, and one month after isotretinoin therapy, unless the patient commits to continuous abstinence.
• I will not prescribe isotretinoin to any female patient of childbearing potential until verifying she has a negative screening pregnancy test and monthly negative CLIA-certified (Clinical Laboratory Improvement Amendment) pregnancy tests. Patients should have a pregnancy test at the completion of the entire course of isotretinoin and another pregnancy test 1 month later.
• I will report any pregnancy case that I become aware of while the female patient is on isotretinoin or 1 month after the last dose to the pregnancy registry.

To prescribe isotretinoin, the prescriber must access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) to:

1. Register each patient in the iPLEDGE program.
2. Confirm monthly that each patient has received counseling and education.
3. For female patients of childbearing potential:
   • Enter patient's two chosen forms of contraception each month.
   • Enter monthly result from CLIA-certified laboratory conducted pregnancy test.

Isotretinoin must only be prescribed to female patients who are known not to be pregnant as confirmed by a negative CLIA-certified laboratory conducted pregnancy test.

Isotretinoin must only be dispensed by a pharmacy registered and activated with the pregnancy risk management program iPLEDGE and only when the registered patient meets all the requirements of the iPLEDGE program. Meeting the requirements for a female patient of childbearing potential signifies that she:

• Has been counseled and has signed a Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form that contains warnings about the risk of potential birth defects if the fetus is exposed to isotretinoin. The patient must sign the informed consent form before starting treatment and patient counseling must also be done at that time and on a monthly basis thereafter.
• Has had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial isotretinoin prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for isotretinoin. The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the 2 tests should be at least 19 days.
  • For patients with regular menstrual cycles, the second pregnancy test should be done during the first 5 days of the menstrual period immediately preceding the beginning of isotretinoin therapy and after the patient has used 2 forms of contraception for 1 month.
  • For patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding, the second pregnancy test must be done immediately preceding the beginning of isotretinoin therapy and after the patient has used 2 forms of contraception for 1 month.
• Has had a negative result from a urine or serum pregnancy test in a CLIA-certified laboratory before receiving each subsequent course of isotretinoin. A pregnancy test must be repeated every month, in a CLIA-certified laboratory, prior to the female patient receiving each prescription.
• Has selected and has committed to use 2 forms of effective contraception simultaneously, at least 1 of which must be a primary form, unless the patient commits to continuous abstinence from heterosexual contact, or the patient has undergone a hysterectomy or bilateral oophorectomy, or has been medically confirmed to be post-menopausal. Patients must use 2 forms of effective contraception for at least 1 month prior to initiation of isotretinoin therapy, during isotretinoin therapy, and for 1 month after discontinuing isotretinoin therapy. Counseling about contraception and behaviors associated with an increased risk of pregnancy must be repeated on a monthly basis.
  If the patient has unprotected heterosexual intercourse at any time 1 month before, during, or 1 month after therapy, she must:
  1. Stop taking %medicine_name% (isotretinoin) immediately, if on therapy
  2. Have a pregnancy test at least 19 days after the last act of unprotected heterosexual intercourse
  3. Start using 2 forms of effective contraception simultaneously again for 1 month before resuming %medicine_name% (isotretinoin) therapy
  4. Have a second pregnancy test after using 2 forms of effective contraception for 1 month as described above depending on whether she has regular menses or not.

Effective forms of contraception include both primary and secondary forms of contraception:

Any birth control method can fail. There have been reports of pregnancy from female patients who have used oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products; these pregnancies occurred while these patients were taking %medicine_name% (isotretinoin). These reports are more frequent for female patients who use only a single method of contraception. Therefore, it is critically important that female patients of childbearing potential use 2 effective forms of contraception simultaneously. Patients must receive written warnings about the rates of possible contraception failure (included in patient education kits).

Using two forms of contraception simultaneously substantially reduces the chances that a female will become pregnant over the risk of pregnancy with either form alone. A drug interaction that decreases effectiveness of hormonal contraceptives has not been entirely ruled out for %medicine_name% (see PRECAUTIONS: DRUG INTERACTIONS). Although hormonal contraceptives are highly effective, prescribers 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.

Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John's Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John's Wort.

If a pregnancy does occur during isotretinoin treatment, isotretinoin must be discontinued immediately. The patient should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure during or 1 month after isotretinoin therapy must be reported immediately to the FDA via the MedWatch number 1-800-FDA-1088 and also to the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com).

All Patients

Isotretinoin is contraindicated in female patients who are pregnant. To receive isotretinoin all patients must meet all of the following conditions:

• Must be registered with the iPLEDGE program by the prescriber
• Must understand that severe birth defects can occur with the use of isotretinoin by female patients
• Must be reliable in understanding and carrying out instructions
• Must sign a Patient Information/Informed Consent (for all patients) form that contains warnings about the potential risks associated with isotretinoin
• Must fill and pick up the prescription within 7 days of the date of specimen collection for the pregnancy test for female patients of childbearing potential
• Must fill and pick up the prescription within 30 days of the office visit for male patients and female patients not of childbearing potential
• Must not donate blood while on isotretinoin and for 1 month after treatment has ended
• Must not share isotretinoin with anyone, even someone who has similar symptoms

Female Patients of Childbearing Potential

Isotretinoin is contraindicated in female patients who are pregnant. In addition to the requirements for all patients described above, female patients of childbearing potential must meet the following conditions:

• Must NOT be pregnant or breast-feeding
• Must comply with the required pregnancy testing at a CLIA-certified laboratory
• Must fill and pick up the prescription within 7 days of the date of specimen collection for the pregnancy test
• Must be capable of complying with the mandatory contraceptive measures required for isotretinoin therapy, or commit to continuous abstinence from heterosexual intercourse, and understand behaviors associated with an increased risk of pregnancy
• Must understand that it is her responsibility to avoid pregnancy one month before, during and one month after isotretinoin therapy
• Must have signed an additional Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form, before starting isotretinoin, that contains warnings about the risk of potential birth defects if the fetus is exposed to isotretinoin
• Must access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654), before starting isotretinoin, on a monthly basis during therapy, and 1 month after the last dose to answer questions on the program requirements and to enter the patient's two chosen forms of contraception
• Must have been informed of the purpose and importance of providing information to the iPLEDGE program should she become pregnant while taking isotretinoin or within 1 month of the last dose

Pharmacists

To dispense isotretinoin, pharmacies must be registered and activated with the pregnancy risk management program iPLEDGE.

The Responsible Site Pharmacist must register the pharmacy by signing and returning the completed registration form. After registration, the Responsible Site Pharmacist can only activate the pharmacy registration by affirming that they meet requirements and will comply with all iPLEDGE requirements by attesting to the following points:

• I know the risk and severity of fetal injury/birth defects from isotretinoin.
• I will train all pharmacists, who participate in the filling and dispensing of isotretinoin prescriptions, on the iPLEDGE program requirements.
• I will comply and seek to ensure all pharmacists who participate in the filling and dispensing of isotretinoin prescriptions comply with the iPLEDGE program requirements described in the booklet entitled Pharmacist Guide for the iPLEDGE Program.
• I will obtain %medicine_name% (isotretinoin) product only from iPLEDGE registered wholesalers.
• I will not sell, buy, borrow, loan or otherwise transfer isotretinoin in any manner to or from another pharmacy.
• I will return to the manufacturer (or delegate) any unused product if registration is revoked by the manufacturer or if the pharmacy chooses to not reactivate annually.
• I will not fill isotretinoin for any party other than a qualified patient.

To dispense isotretinoin, the pharmacist must:

1. be trained by the Responsible Site Pharmacist concerning the iPLEDGE program requirements.
2. obtain authorization from the iPLEDGE program via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) for every isotretinoin prescription. Authorization signifies that the patient has met all program requirements and is qualified to receive isotretinoin.
3. write the Risk Management Authorization (RMA) number on the prescription.

%medicine_name% (isotretinoin) must only be dispensed:

• in no more than a 30-day supply
• with an %medicine_name% Medication Guide
• after authorization from the iPLEDGE program
• prior to the “do not dispense to patient after” date provided by the iPLEDGE system (within 30 days of the office visit for male patients and female patients not of childbearing potential and within 7 days of the date of specimen collection for female patients of childbearing potential)
• with a new prescription for refills and another authorization from the iPLEDGE program (No automatic refills are allowed)

An %medicine_name% Medication Guide must be given to the patient each time %medicine_name% (isotretinoin) is dispensed, as required by law. This %medicine_name% Medication Guide is an important part of the risk management program for the patients.

%medicine_name% (isotretinoin) must not be prescribed, dispensed or otherwise obtained through the internet or any other means outside of the iPLEDGE program. Only FDA-approved %medicine_name% (isotretinoin) products must be distributed, prescribed, dispensed, and used. Patients must fill %medicine_name% (isotretinoin) prescriptions only at US licensed pharmacies.

A description of the iPLEDGE program educational materials available with iPLEDGE is provided below. The main goal of these educational materials is to explain the iPLEDGE program requirements and to reinforce the educational messages.

1. The Guide to Best Practices for the iPLEDGE Program includes: isotretinoin teratogenic potential, information on pregnancy testing, and the method to complete a qualified isotretinoin prescription.
2. The iPLEDGE Program Prescriber Contraception Counseling Guide includes: specific information about effective contraception, the limitations of contraceptive methods, behaviors associated with an increased risk of contraceptive failure and pregnancy and the methods to evaluate pregnancy risk.
3. The Pharmacist Guide for the iPLEDGE Program includes: isotretinoin teratogenic potential and the method to obtain authorization to dispense an isotretinoin prescription.
4. The iPLEDGE program is a systematic approach to comprehensive patient education about their responsibilities and includes education for contraception compliance and reinforcement of educational messages. The iPLEDGE program includes information on the risks and benefits of isotretinoin which is linked to the Medication Guide dispensed by pharmacists with each isotretinoin prescription.
5. Female patients not of childbearing potential and male patients, and female patients of childbearing potential are provided with separate booklets. Each booklet contains information on isotretinoin therapy including precautions

SIDE EFFECTS

Clinical Trials and Postmarketing Surveillance

The adverse reactions listed below reflect the experience from investigational studies of %medicine_name% (isotretinoin) , and the postmarketing experience. The relationship of some of these events to %medicine_name% (isotretinoin) therapy is unknown. Many of the side effects and adverse reactions seen in patients receiving %medicine_name% (isotretinoin) are similar to those described in patients taking very high doses of vitamin A (dryness of the skin and mucous membranes, eg, of the lips, nasal passage, and eyes).

Dose Relationship

Cheilitis and hypertriglyceridemia are usually dose related. Most adverse reactions reported in clinical trials were reversible when therapy was discontinued; however, some persisted after cessation of therapy (see WARNINGS and ADVERSE REACTIONS).

Body as a Whole

allergic reactions, including vasculitis, systemic hypersensitivity (see PRECAUTIONS: Hypersensitivity), edema, fatigue, lymphadenopathy, weight loss

Cardiovascular

palpitation, tachycardia, vascular thrombotic disease, stroke

Endocrine/Metabolic

hypertriglyceridemia (see WARNINGS: Lipids), alterations in blood sugar levels (see PRECAUTIONS: Laboratory Tests)

Gastrointestinal

inflammatory bowel disease (see WARNINGS: Inflammatory Bowel Disease), hepatitis (see WARNINGS: Hepatotoxicity), pancreatitis (see WARNINGS: Lipids), bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, nausea, other nonspecific gastrointestinal symptoms

Hematologic

allergic reactions (see PRECAUTIONS: Hypersensitivity), anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis (see PATIENT INFORMATION). See PRECAUTIONS: Laboratory Tests for other hematological parameters.

Musculoskeletal

skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, decreases in bone mineral density (see WARNINGS: Skeletal), musculoskeletal symptoms (sometimes severe) including back pain, myalgia, and arthralgia (see PATIENT INFORMATION), transient pain in the chest (see PATIENT INFORMATION ), arthritis, tendonitis, other types of bone abnormalities, elevations of CPK/rare reports of rhabdomyolysis (see PRECAUTIONS: Laboratory Tests).

Neurological

pseudotumor cerebri (see WARNINGS: Pseudotumor Cerebri), dizziness, drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness

Psychiatric

suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression, violent behaviors (see WARNINGS: Psychiatric Disorders), emotional instability

Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy.

Reproductive System

abnormal menses

Respiratory

bronchospasms (with or without a history of asthma), respiratory infection, voice alteration

Skin and Appendages

acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry mouth, dry nose, dry skin, epistaxis, eruptive xanthomas,⁷ erythema multiforme, flushing, fragility of skin, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, infections (including disseminated herpes simplex), nail dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), Stevens-Johnson syndrome, sunburn susceptibility increased, sweating, toxic epidermal necrolysis, urticaria, vasculitis (including Wegener's granulomatosis; see PRECAUTIONS: Hypersensitivity), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting; see PATIENT INFORMATION)

Special Senses

Hearing - hearing impairment (see WARNINGS: Hearing Impairment), tinnitus.

Vision- corneal opacities (see WARNINGS: Corneal Opacities), decreased night vision which may persist (see WARNINGS: Decreased Night Vision), cataracts, color vision disorder, conjunctivitis, dry eyes, eyelid inflammation, keratitis, optic neuritis, photophobia, visual disturbances

Urinary System

glomerulonephritis (see PRECAUTIONS: Hypersensitivity), nonspecific urogenital findings (see PRECAUTIONS: Laboratory Tests for other urological parameters)

Laboratory

Elevation of plasma triglycerides (see WARNINGS: Lipids), decrease in serum high-density lipoprotein (HDL) levels, elevations of serum cholesterol during treatment

Increased alkaline phosphatase, SGOT (AST), SGPT (ALT), GGTP or LDH (see WARNINGS: Hepatotoxicity)

Elevation of fasting blood sugar, elevations of CPK (see PRECAUTIONS: Laboratory Tests), hyperuricemia

Decreases in red blood cell parameters, decreases in white blood cell counts (including severe neutropenia and rare reports of agranulocytosis; see PATIENT INFORMATION), elevated sedimentation rates, elevated platelet counts, thrombocytopenia

White cells in the urine, proteinuria, microscopic or gross hematuria

DRUG INTERACTIONS

• Vitamin A: Because of the relationship of %medicine_name% (isotretinoin) to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects.
• Tetracyclines: Concomitant treatment with %medicine_name% (isotretinoin) and tetracyclines should be avoided because %medicine_name% (isotretinoin) use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines.
• Micro-dosed Progesterone Preparations: Micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) may be an inadequate method of contraception during %medicine_name% (isotretinoin) therapy. Although other hormonal contraceptives are highly effective, there have been reports of pregnancy from female patients who have used combined oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products. These reports are more frequent for female patients who use only a single method of contraception. It is not known if hormonal contraceptives differ in their effectiveness when used with %medicine_name% (isotretinoin). Therefore, it is critically important for female patients of childbearing potential to select and commit to use 2 forms of effective contraception simultaneously, at least 1 of which must be a primary form (see PRECAUTIONS).
• Norethindrone/ethinyl estradiol: In a study of 31 premenopausal female patients with severe recalcitrant nodular acne receiving OrthoNovum® 7/7/7 Tablets as an oral contraceptive agent, %medicine_name% (isotretinoin) at the recommended dose of 1 mg/kg/day, did not induce clinically relevant changes in the pharmacokinetics of ethinyl estradiol and norethindrone and in the serum levels of progesterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Prescribers are advised to consult the package insert of medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products.
• St. John's Wort: %medicine_name% (isotretinoin) use is associated with depression in some patients (see WARNINGS: Psychiatric Disorders and ADVERSE REACTIONS: Psychiatric). Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John's Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John's Wort.
• Phenytoin: %medicine_name% (isotretinoin) has not been shown to alter the pharmacokinetics of phenytoin in a study in seven healthy volunteers. These results are consistent with the in vitro finding that neither isotretinoin nor its metabolites induce or inhibit the activity of the CYP 2C9 human hepatic P450 enzyme. Phenytoin is known to cause osteomalacia. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between phenytoin and %medicine_name% (isotretinoin). Therefore, caution should be exercised when using these drugs together.
• Systemic Corticosteroids: Systemic corticosteroids are known to cause osteoporosis. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between systemic corticosteroids and %medicine_name% (isotretinoin). Therefore, caution should be exercised when using these drugs together.

Laboratory Tests

• Pregnancy Test
  • Female patients of childbearing potential must have had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial %medicine_name% (isotretinoin) prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for %medicine_name% (isotretinoin). The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the two tests must be at least 19 days.
  • For patients with regular menstrual cycles, the second pregnancy test must be done during the first 5 days of the menstrual period immediately preceding the beginning of %medicine_name% (isotretinoin) therapy and after the patient has used 2 forms of contraception for 1 month.
  • For patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding, the second pregnancy test must be done immediately preceding the beginning of %medicine_name% (isotretinoin) therapy and after the patient has used 2 forms of contraception for 1 month.
  • Each month of therapy, patients must have a negative result from a urine or serum pregnancy test. A pregnancy test must be repeated each month, in a CLIA-certified laboratory, prior to the female patient receiving each prescription.
• Lipids: Pretreatment and follow-up blood lipids should be obtained under fasting conditions. After consumption of alcohol, at least 36 hours should elapse before these determinations are made. It is recommended that these tests be performed at weekly or biweekly intervals until the lipid response to %medicine_name% (isotretinoin) is established. The incidence of hypertriglyceridemia is 1 patient in 4 on %medicine_name% therapy (see WARNINGS: Lipids).
• Liver Function Tests: Since elevations of liver enzymes have been observed during clinical trials, and hepatitis has been reported, pretreatment and follow-up liver function tests should be performed at weekly or biweekly intervals until the response to %medicine_name% has been established (see WARNINGS: Hepatotoxicity).
• Glucose: Some patients receiving %medicine_name% (isotretinoin) have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during %medicine_name% (isotretinoin) therapy, although no causal relationship has been established.
• CPK: Some patients undergoing vigorous physical activity while on %medicine_name% (isotretinoin) therapy have experienced elevated CPK levels; however, the clinical significance is unknown. There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity. In a clinical trial of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, transient elevations in CPK were observed in 12% of patients, including those undergoing strenuous physical activity in association with reported musculoskeletal adverse events such as back pain, arthralgia, limb injury, or muscle sprain. In these patients, approximately half of the CPK elevations returned to normal within 2 weeks and half returned to normal within 4 weeks. No cases of rhabdomyolysis were reported in this trial.

REFERENCES

7. Dicken CH, Connolly SM. Eruptive xanthomas associated with isotretinoin (13-cis-retinoic acid). Arch Dermatol 116:951-952, 1980.

Category X. See Boxed CONTRAINDICATIONS AND WARNINGS.

Clinical Trials and Postmarketing Surveillance

The adverse reactions listed below reflect the experience from investigational studies of %medicine_name% (isotretinoin) , and the postmarketing experience. The relationship of some of these events to %medicine_name% (isotretinoin) therapy is unknown. Many of the side effects and adverse reactions seen in patients receiving %medicine_name% (isotretinoin) are similar to those described in patients taking very high doses of vitamin A (dryness of the skin and mucous membranes, eg, of the lips, nasal passage, and eyes).

Dose Relationship

Cheilitis and hypertriglyceridemia are usually dose related. Most adverse reactions reported in clinical trials were reversible when therapy was discontinued; however, some persisted after cessation of therapy (see WARNINGS and ADVERSE REACTIONS).

Body as a Whole

allergic reactions, including vasculitis, systemic hypersensitivity (see PRECAUTIONS: Hypersensitivity), edema, fatigue, lymphadenopathy, weight loss

Cardiovascular

palpitation, tachycardia, vascular thrombotic disease, stroke

Endocrine/Metabolic

hypertriglyceridemia (see WARNINGS: Lipids), alterations in blood sugar levels (see PRECAUTIONS: Laboratory Tests)

Gastrointestinal

inflammatory bowel disease (see WARNINGS: Inflammatory Bowel Disease), hepatitis (see WARNINGS: Hepatotoxicity), pancreatitis (see WARNINGS: Lipids), bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, nausea, other nonspecific gastrointestinal symptoms

Hematologic

allergic reactions (see PRECAUTIONS: Hypersensitivity), anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis (see PATIENT INFORMATION). See PRECAUTIONS: Laboratory Tests for other hematological parameters.

Musculoskeletal

skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, decreases in bone mineral density (see WARNINGS: Skeletal), musculoskeletal symptoms (sometimes severe) including back pain, myalgia, and arthralgia (see PATIENT INFORMATION), transient pain in the chest (see PATIENT INFORMATION ), arthritis, tendonitis, other types of bone abnormalities, elevations of CPK/rare reports of rhabdomyolysis (see PRECAUTIONS: Laboratory Tests).

Neurological

pseudotumor cerebri (see WARNINGS: Pseudotumor Cerebri), dizziness, drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness

Psychiatric

suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression, violent behaviors (see WARNINGS: Psychiatric Disorders), emotional instability

Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy.

Reproductive System

abnormal menses

Respiratory

bronchospasms (with or without a history of asthma), respiratory infection, voice alteration

Skin and Appendages

acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry mouth, dry nose, dry skin, epistaxis, eruptive xanthomas,⁷ erythema multiforme, flushing, fragility of skin, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, infections (including disseminated herpes simplex), nail dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), Stevens-Johnson syndrome, sunburn susceptibility increased, sweating, toxic epidermal necrolysis, urticaria, vasculitis (including Wegener's granulomatosis; see PRECAUTIONS: Hypersensitivity), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting; see PATIENT INFORMATION)

Special Senses

Hearing - hearing impairment (see WARNINGS: Hearing Impairment), tinnitus.

Vision- corneal opacities (see WARNINGS: Corneal Opacities), decreased night vision which may persist (see WARNINGS: Decreased Night Vision), cataracts, color vision disorder, conjunctivitis, dry eyes, eyelid inflammation, keratitis, optic neuritis, photophobia, visual disturbances

Urinary System

glomerulonephritis (see PRECAUTIONS: Hypersensitivity), nonspecific urogenital findings (see PRECAUTIONS: Laboratory Tests for other urological parameters)

Laboratory

Elevation of plasma triglycerides (see WARNINGS: Lipids), decrease in serum high-density lipoprotein (HDL) levels, elevations of serum cholesterol during treatment

Increased alkaline phosphatase, SGOT (AST), SGPT (ALT), GGTP or LDH (see WARNINGS: Hepatotoxicity)

Elevation of fasting blood sugar, elevations of CPK (see PRECAUTIONS: Laboratory Tests), hyperuricemia

Decreases in red blood cell parameters, decreases in white blood cell counts (including severe neutropenia and rare reports of agranulocytosis; see PATIENT INFORMATION), elevated sedimentation rates, elevated platelet counts, thrombocytopenia

White cells in the urine, proteinuria, microscopic or gross hematuria

The oral LD₅₀ of isotretinoin is greater than 4000 mg/kg in rats and mice ( > 600 times the recommended clinical dose of 1.0 mg/kg/day after normalization of the rat dose for total body surface area and > 300 times the recommended clinical dose of 1.0 mg/kg/day after normalization of the mouse dose for total body surface area) and is approximately 1960 mg/kg in rabbits (653 times the recommended clinical dose of 1.0 mg/kg/day after normalization for total body surface area). In humans, overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. These symptoms quickly resolve without apparent residual effects.

%medicine_name% (isotretinoin) causes serious birth defects at any dosage (see Boxed