Isotretinoin, a retinoid, is available as Accutane (Isotretinoin) in 10-mg, 20-mg and 40-mg soft gelatin capsules for oral administration. Each capsule contains beeswax, butylated hydroxyanisole, edetate disodium, hydrogenated soybean oil flakes, hydrogenated vegetable oil, and soybean oil. Gelatin capsules contain glycerin and parabens (methyl and propyl), with the following dye systems: 10 mg — iron oxide (red) and titanium dioxide; 20 mg — FD&C Red No. 3, FD&C Blue No. 1, and titanium dioxide; 40 mg — FD&C Yellow No. 6, D&C Yellow No. 10, and titanium dioxide.

Chemically, isotretinoin is 13--retinoic acid and is related to both retinoic acid and retinol (vitamin A). It is a yellow to orange crystalline powder with a molecular weight of 300.44. The structural formula is:

Isotretinoin is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1.0 mg/kg/day (see ), inhibits sebaceous gland function and keratinization. The exact mechanism of action of isotretinoin is unknown.

Pregnancy: Category X. See

Accutane (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 ). Prescribers should read the brochure, 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 Accutane (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 Accutane (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 Accutane (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 Accutane (Isotretinoin) therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of Accutane (Isotretinoin) therapy.

Accutane (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 Accutane (Isotretinoin) immediately and be referred to a neurologist for further diagnosis and care (see ).

Acute pancreatitis
In rare instances, fatal hemorrhagic pancreatitis has been reported.
Elevations of serum triglycerides in excess of 800 mg/dL have been reported in patients treated with Accutane (Isotretinoin) . Marked elevations of serum triglycerides were reported in approximately 25% of patients receiving Accutane (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 Accutane (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 Accutane (Isotretinoin) .

Blood lipid determinations should be performed before Accutane (Isotretinoin) is given and then at intervals until the lipid response to Accutane (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 Accutane (Isotretinoin) therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If Accutane (Isotretinoin) therapy is instituted, more frequent checks of serum values for lipids and/or blood sugar are recommended (see ).

The cardiovascular consequences of hypertriglyceridemia associated with Accutane (Isotretinoin) are unknown. : 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).

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

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

The oral LD 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.

Accutane (Isotretinoin) causes serious birth defects at any dosage (see ). Female patients of childbearing potential who present with isotretinoin overdose must be evaluated for pregnancy. Patients who are pregnant should receive counseling about the risks to the fetus, as described in the . Non-pregnant patients must be warned to avoid pregnancy for at least one month and receive contraceptive counseling as described in . Educational materials for such patients can be obtained by calling the manufacturer. Because an overdose would be expected to result in higher levels of isotretinoin in semen than found during a normal treatment course, male patients should use a condom, or avoid reproductive sexual activity with a female patient who is or might become pregnant, for 1 month after the overdose. All patients with isotretinoin overdose should not donate blood for at least 1 month.

Accutane (Isotretinoin) should be administered with a meal (see ).

The recommended dosage range for Accutane (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, 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 Accutane (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 Accutane (Isotretinoin) has not been established. Once daily dosing is 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 Accutane (Isotretinoin) , even in low doses, has not been studied, and is not recommended. It is important that Accutane (Isotretinoin) be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of Accutane (Isotretinoin) on bone loss is unknown (see , , and ).

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

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

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

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

OrthoNovum 7/7/7 is a registered trademark of Ortho-McNeil Pharmaceutical, Inc.

To be completed by the patient (and her parent or guardian if patient is under age 18) and signed by her doctor.

Read each item below and initial in the space provided to show that you understand each item and agree to follow your doctor's instructions.

______________________________________________________________                                              (Patient's Name)

Patient Signature:_______________________________________ Date: ______

Parent/Guardian Signature (if under age 18):___________________ Date:______

Please print: Patient Name and Address_________________________________

________________________________ Telephone _______________________

I have fully explained to the patient, __________________, the nature and purpose of the treatment described above and the risks to female patients of childbearing potential. I have asked the patient if she has any questions regarding her treatment with isotretinoin and have answered those questions to the best of my ability.

Doctor Signature: ______________________________________ Date: ______

To be completed by patient (and parent or guardian if patient is under age 18) and signed by the doctor.

Read each item below and initial in the space provided if you understand each item and agree to follow your doctor's instructions. A parent or guardian of a patient under age 18 must also read and understand each item before signing the agreement.

I now allow my doctor ___________________________ to begin my treatment with isotretinoin.

Patient Signature: ____________________________________ Date: ______

Parent/Guardian Signature (if under age 18): ________________ Date: ______

Patient Name (print) ___________________________________

Patient Address ___________________________ Telephone (___.___.___)

                         ____________________________________

I have:

Doctor Signature: _________________________________ Date: ______

Read the Medication Guide that comes with Accutane (Isotretinoin) before you start taking it and each time you get a prescription. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.

After stopping Accutane (Isotretinoin) , you may also need follow-up mental health care if you had any of these symptoms.

Accutane (Isotretinoin) is a medicine taken by mouth to treat the most severe form of acne (nodular acne) that cannot be cleared up by any other acne treatments, including antibiotics. Accutane (Isotretinoin) can cause serious side effects (see ). Accutane (Isotretinoin) can only be:

Severe nodular acne is when many red, swollen, tender lumps form in the skin. These can be the size of pencil erasers or larger. If untreated, nodular acne can lead to permanent scars.

Know the medicines you take. Keep a list of them to show to your doctor and pharmacist. Do not take any new medicine without talking with your doctor.

These are not all of the possible side effects with Accutane (Isotretinoin) . Your doctor or pharmacist can give you more detailed information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or Roche at 1-800-526-6367.

Medicines are sometimes prescribed for conditions that are not mentioned in Medication Guides. Do not use Accutane (Isotretinoin) for a condition for which it was not prescribed. Do not give Accutane (Isotretinoin) to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Accutane (Isotretinoin) . If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Accutane (Isotretinoin) that is written for health care professionals. You can also call iPLEDGE program at 1-866-495-0654 or visit www.ipledgeprogram.com.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Dilantin is a registered trademark of Warner-Lambert Company LLC.

NDC 0004-0169-49

Each capsule contains20 mg isotretinoin.