Sotret

Description

Isotret (isotret (isotretinoin capsules) inoin capsules) inoin, a retinoid, is available as Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) in 10 mg, 20 mg, 30 mg, and 40 mg soft gelatin capsules for oral administration. Each capsule contains butylated hydroxyanisole, edetate disodium, hydrogenated soybean oil, hydrogenated vegetable oil, iron oxide black, soybean oil and white wax. 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; 30 mg – FD&C Yellow No. 6, and titanium dioxide; 40 mg – FD&C Yellow No. 6, D&C Yellow No. 10, and titanium dioxide. Chemically, isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin is 13-cis-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:

 

 

Severe Recalcitrant Nodular Acne

Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) 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. Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition, Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) is indicated only for those female patients who are not pregnant, because Sotret 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules. 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)

Dosage And Admintisration

Sotret should be administered with a meal (see PATIENT INFORMATION).

The recommended dosage range for Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) 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 mg/kg/day⁸, 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 Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) 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 Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) 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 Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) , even in low doses, has not been studied, and is not recommended. It is important that Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of Sotret 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 3: Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) Dosing by Body Weight (Based on Administration With Food)

Body Weight		Total mg/day
kilograms	pounds	0.5 mg/kg	1 mg/kg	2 mg/kg*
40	88	20	40	80
50	110	25	50	100
60	132	30	60	120
70	154	35	70	140
80	176	40	80	160
90	198	45	90	180
100	220	50	100	200
*See DOSAGE AND ADMINISTRATION: the recommended dosage range is 0.5 to 1.0 mg/kg/ day.

 

Information For Pharmacists

Access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) to obtain an authorization and the “do not dispense to patient after” date. Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) 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.

A Sotret Medication Guide must be given to the patient each time Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) is dispensed, as required by law. This Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) Medication Guide is an important part of the risk management program for the patient.

How Supplied

Soft gelatin capsules, 10 mg (light pink), imprinted “5R”.

Boxes of 30 containing 3 Prescription Packs of 10 capsules (NDC 10631-584-31)

Boxes of 100 containing 10 Prescription Packs of 10 capsules (NDC 10631-584-77)

Soft gelatin capsules, 20 mg (maroon), imprinted “6R”.

Boxes of 30 containing 3 Prescription Packs of 10 capsules (NDC 10631-585-31)

Boxes of 100 containing 10 Prescription Packs of 10 capsules (NDC 10631-585-77)

Soft gelatin capsules, 30 mg (golden yellow), imprinted “8R”.

Boxes of 30 containing 3 Prescription Packs of 10 capsules (NDC 10631-447-31)

Boxes of 100 containing 10 Prescription Packs of 10 capsules (NDC 10631-447-77)

Soft gelatin capsules, 40 mg (yellow), imprinted “7R”.

Boxes of 30 containing 3 Prescription Packs of 10 capsules (NDC 10631-586-31)

Boxes of 100 containing 10 Prescription Packs of 10 capsules (NDC 10631-586-77)

Store at 20 – 25° C (68 – 77° F). (See USP Controlled Room Temperature). 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-cis-retinoic acid and acne. Lancet 2:1048-1049, 1980.

8. Strauss JS, Rapini RP, Shalita AR, et al. Isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin therapy for acne: results of a multicenter dose-response study. J Am Acad Dermatol 10:490-496, 1984.

Manufactured for: Ranbaxy Laboratories Inc. Jacksonville, FL 32257 USA. Manufactured by: Ranbaxy Laboratories Limited New Delhi -110 019, India. Distributed by: Ranbaxy Laboratories Inc.

Clinical Trials and Postmarketing Surveillance

The adverse reactions listed below reflect the experience from investigational studies of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules, and the postmarketing experience. The relationship of some of these events to isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules therapy is unknown. Many of the side effects and adverse reactions seen in patients receiving isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules are similar to those described in patients taking very high doses of vitamin A (dryness of the skin and mucous membranes, e.g., 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 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), sunburn susceptibility increased, sweating, 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

• Vitamin A: Because of the relationship of Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects.
• Tetracyclines: Concomitant treatment with Sotret (isotretinoin capsules) and tetracyclines should be avoided because isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsule 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 Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin. 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, isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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: Isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules 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: Isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules have 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin. 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 Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) . 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 mlU/mL before receiving the initial Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) . 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 and within 7 days following the office visit, immediately preceding the beginning of Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) 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 within 7 days following the office visit, immediately preceding the beginning of Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) 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 Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) is established. The incidence of hypertriglyceridemia is 1 patient in 4 on isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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 Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) has been established (see WARNINGS: Hepatotoxicity).
• Glucose: Some patients receiving isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsule therapy, although no causal relationship has been established.
• CPK: Some patients undergoing vigorous physical activity while on isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules 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 isotret (isotretinoin capsules) inoin (13-cis-retinoic acid). Arch Dermatol 116:951-952, 1980.

Psychiatric Disorders

Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) 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 lsotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin. 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 Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) 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 maybe 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 Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) 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 Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) 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 Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin therapy.

Pseudotumor Cerebri

Isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsule 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 Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) immediately and be referred to a neurologist for further diagnosis and care (see ADVERSE REACTIONS: Neurological).

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. Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules. Marked elevations of serum triglycerides were reported in approximately 25% of patients receiving isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules.⁵

Blood lipid determinations should be performed before Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) is given and then at intervals until the lipid response to Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) 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 Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) 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 Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) are unknown.

Animal Studies: In rats given 8 or 32 mg/kg/day of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin (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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules; 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 Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules 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 Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) , the drug should be discontinued and the etiology further investigated.

Inflammatory Bowel Disease

Isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules have 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules treatment has been stopped. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue Sotret immediately (see ADVERSE REACTIONS: Gastrointestinal).

Skeletal

Bone Mineral Density

Effects of multiple courses of Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) on the developing musculoskeletal system are unknown. There is some evidence that long-term, high-dose, or multiple courses of therapy with isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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 to 18 years, who started a second course of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin population. While causality to Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) has not been established, an effect cannot be ruled out. Longer term effects have not been studied. It is important that Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) 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 Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules.

The effect of multiple courses of Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) on epiphyseal closure is unknown.

Vision Impairment

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

Corneal Opacities

Corneal opacities have occurred in patients receiving isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules 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.

Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) must only be prescribed by prescribers who are registered and activated with the iPLEDGE program. Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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 Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) , wholesalers must be registered with iPLEDGE, and agree to meet all iPLEDGE requirements for wholesale distribution of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin. These include:

• Registering prior to distributing isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin and reregistering annually thereafter
• Distributing only FDA approved isotretinoin product
• Only shipping isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin to
• wholesalers registered in the iPLEDGE program with prior written consent from the manufacturer
• pharmacies licensed in the US and registered and activated in the iPLEDGE program
• Notifying the isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin manufacturer (or delegate) of any non-registered and/or non-activated pharmacy or unregistered wholesaler that attempts to order isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin
• Complying with inspection of wholesaler records for verification of compliance with the iPLEDGE program by the isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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 reregister annually
• Providing product flow data to manufacturer (or delegate) as detailed in the wholesalers agreement

Prescribers

To prescribe isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin, 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 how to diagnose and treat the various presentations of acne.
• I know the risk and severity of fetal injury/birth defects from isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin.
• 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 iPLEDGE Program Guide to Best Practices for Isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin and The iPLEDGE Program Prescriber Contraception Counseling Guide.
• Before beginning treatment of female patients of childbearing potential with isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin therapy, unless the patient commits to continuous abstinence.
• I will not prescribe isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin and another pregnancy test 1 month later.
• I will report any pregnancy case that I become aware of while the female patient is on isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin or 1 month after the last dose to the pregnancy registry.

To prescribe isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin, 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.

Isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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.

Isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin. 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 mlU/mL before receiving the initial isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin. 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 and within 7 days of the office visit, immediately preceding the beginning of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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 within 7 days following the office visit, immediately preceding the beginning of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin. 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 isotret (isotret (isotretinoin capsules) inoin capsules) inoin therapy, and for 1 month after discontinuing isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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:

 

Primary forms	Secondary forms
	Barrier forms (always used with spermicide):
•tubal sterilization	•male latex condom
•partner’s vasectomy	•diaphragm
•intrauterine device	•cervical cap
•hormonal (combination oral contraceptives, transdermal patch, injectables, implantables, or vaginal ring)	Others:•vaginal sponge (contains spermicide)

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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules. 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 Sotret (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, isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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

Isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin is contraindicated in female patients who are pregnant. To receive isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin
• Must fill the prescription within 7 days of the office visit
• Must not donate blood while on isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin and for 1 month after treatment has ended
• Must not share isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin with anyone, even someone who has similar symptoms

Female Patients of Childbearing Potential

Isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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 be capable of complying with the mandatory contraceptive measures required for isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin therapy
• Must have signed an additional Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form, before starting isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin, that contains warnings about the risk of potential birth defects if the fetus is exposed to isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin
• Must access the iPLEDGE program via the internet (www.ipledgeprogram.com) or telephone (1-866- 495-0654), before starting isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin, 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin or within 1 month of the last dose

Pharmacists

To dispense isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin, 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin.
• I will train all pharmacists, who participate in the filling and dispensing of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin prescriptions, on the iPLEDGE program requirements.
• I will comply and seek to ensure all pharmacists who participate in the filling and dispensing of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin prescriptions comply with the iPLEDGE program requirements described in the booklet entitled. The iPLEDGE Program Pharmacist Guide for Isotretinoin.
• I will obtain isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin product only from iPLEDGE registered wholesalers.
• I will not sell, buy, borrow, loan or otherwise transfer isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin for any party other than a qualified patient.

To dispense isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin, 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin prescription. Authorization signifies that the patient has met all program requirements and is qualified to receive isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin.
3. write the Risk Management Authorization (RMA) number on the prescription.

Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) must only be dispensed:

• in no more than a 30-day supply
• with a Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) Medication Guide
• after authorization from the iPLEDGE program
• prior to the “do not dispense to patient after” date provided by the iPLEDGE system (within 7 days of the office visit)
• with a new prescription for refills and another authorization from the iPLEDGE program (No automatic refills are allowed)

A Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) Medication Guide must be given to the patient each time Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) is dispensed, as required by law. This Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) Medication Guide is an important part of the risk management program for the patients.

Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) must not be prescribed, dispensed or otherwise obtained through the internet or any other means outside of the iPLEDGE program. Only FDA-approved Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) products must be distributed, prescribed, dispensed, and used. Patients must fill Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) 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 iPLEDGEProgram Guide to Best Practices for Isotretinoin includes: isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin teratogenic potential, information on pregnancy testing, and the method to complete a qualified isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin prescription.
2. The iPLEDGEProgram 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 iPLEDGEProgram Pharmacist Guide for Isotretinoin includes: isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin teratogenic potential and the method to obtain authorization to dispense an isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin which is linked to the Medication Guide dispensed by pharmacists with each isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin therapy including precautions and warnings, a Patient Information/Informed Consent (for all patients) form, and a toll-free line which provides isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin information in 2 languages.
6. The booklet for female patients not of childbearing potential and male patients, The iPLEDGE Program Guide to Isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin for Male Patients and Female Patients Who Cannot Get Pregnant, also includes information about male reproduction and a warning not to share isotret (isotretinoin capsules) inoin with others or to donate blood during isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin therapy and for 1 month following discontinuation of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin.
7. The booklet for female patients of childbearing potential, The iPLEDGE Program Guide to Isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin for Female Patients Who Can Get Pregnant, includes a referral program that offers female patients free contraception counseling, reimbursed by the manufacturer, by a reproductive specialist; and a second Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form concerning birth defects.
8. The booklet, The iPLEDGE Program Birth Control Workbook includes information on the types of contraceptive methods, the selection and use of appropriate, effective contraception, the rates of possible contraceptive failure and a toll-free contraception counseling line.
9. In addition, there is a patient educational DVD with the following videos —”Be Prepared, Be Protected” and “Be Aware: The Risk of Pregnancy While on Isotretinoin” (see PATIENT INFORMATION).

General

Although an effect of Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) on bone loss is not established, physicians should use caution when prescribing Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) to patients with a genetic predisposition for age-related osteoporosis, a history of childhood osteoporosis conditions, osteomalacia, or other disorders of bone metabolism. This would include patients diagnosed with anorexia nervosa and those who are on chronic drug therapy that causes drug induced osteoporosis/osteomalacia and/or affects vitamin D metabolism, such as systemic corticosteroids and any anticonvulsant. Patients may be at increased risk when participating 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. There are spontaneous reports of fractures and/or delayed healing in patients while on therapy with isotret (isotretinoin capsules) inoin or following cessation of therapy with isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin while involved in these activities. While causality to Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) has not been established, an effect must not be ruled out.

Information for Patients

See PRECAUTIONS and Boxed CONTRAINDICATIONS AND WARNINGS.

• • Patients must be instructed to read the Medication Guide supplied as required by law when Sotret is dispensed. The complete text of the Medication Guide is reprinted at the end of this document. For additional information, patients must also be instructed to read the iPLEDGE program patient educational materials. All patients must sign the Patient Information/Informed Consent (for all patients) form.
  • Female patients of childbearing potential must be instructed that they must not be pregnant when Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) therapy is initiated, and that they should use 2 forms of effective contraception simultaneously for 1 month before starting Sotret (isotretinoin capsules) , while taking Sotret (isotretinoin capsules) , and for 1 month after Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) has been stopped, unless they commit to continuous abstinence from heterosexual intercourse. They should also sign second Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form prior to beginning Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) therapy. They should be given an opportunity to view the patient DVD provided by the manufacturer to the prescriber. The DVD includes information about contraception, the most common reasons that contraception fails, and the importance of using 2 forms of effective contraception when taking teratogenic drugs and comprehensive information about types of potential birth defects which could occur if a female patient who is pregnant takes Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) at any time during pregnancy. Female patients should be seen by their prescribers monthly and have a urine or serum pregnancy test, in a CLIA-certified laboratory, performed each month during treatment to confirm negative pregnancy status before another Sotret prescription is written (see Boxed CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS).
  • Isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin is found in the semen of male patients taking Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) , but the amount delivered to a female partner would be about 1 million times lower than an oral dose of 40 mg. While the no-effect limit for isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin induced embryopathy is unknown, 20 years of postmarketing reports include 4 with isolated defects compatible with features of retinoid exposed fetuses; however 2 of these reports were incomplete, and 2 had other possible explanations for the defects observed.
  • 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 Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) treatment, patients and family members should be asked about any history of psychiatric disorder, and at each visit during treatment 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 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 Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) 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 Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) treatment 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 Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin therapy.
  • Patients must be informed that some patients, while taking isotretinoin or soon after stopping isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin, have become depressed or developed other serious mental problems. Symptoms of depression include sad, “anxious” or empty mood, irritability, acting on dangerous impulses, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down, or trouble concentrating. Some patients taking isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own lives. And some people have ended their own lives. There were reports that some of these people did not appear depressed. There have been reports of patients on isotret (isotret (isotretinoin capsules) inoin capsules) inoin becoming aggressive or violent. No one knows if isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin caused these behaviors or if they would have happened even if the person did not take isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin. Some people have had other signs of depression while taking isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin.
  • Patients must be informed that they must not share Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) with anyone else because of the risk of birth defects and other serious adverse events.
  • Patients must be informed not to donate blood during therapy and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) .
  • Patients should be reminded to take Sotret with a meal (see DOSAGE AND ADMINISTRATION). To decrease the risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid.
  • Patients should be informed that transient exacerbation (flare) of acne has been seen, generally during the initial period of therapy.
  • Wax epilation and skin resurfacing procedures (such as dermabrasion, laser) should be avoided during Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) therapy and for at least 6 months thereafter due to the possibility of scarring (see ADVERSE REACTIONS: Skin and Appendages).
  • Patients should be advised to avoid prolonged exposure to UV rays or sunlight.
  • Patients should be informed that they may experience decreased tolerance to contact lenses during and after therapy.
  • Patients should be informed that approximately 16% of patients treated with isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules in a clinical trial developed musculoskeletal symptoms (including arthralgia) during treatment. In general, these symptoms were mild to moderate, but occasionally required discontinuation of the drug. Transient pain in the chest has been reported less frequently. In the clinical trial, these symptoms generally cleared rapidly after discontinuation of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules, but in some cases persisted (see ADVERSE REACTIONS: Musculoskeletal). There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity (see Laboratory Tests: CPK).

• Pediatric patients and their caregivers should be informed that approximately 29% (104/358) of pediatric patients treated with isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules developed back pain. Back pain was severe in 13.5% (14/104) of the cases and occurred at a higher frequency in female patients than male patients. Arthralgias were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in 7.6% (6/79) of patients. Appropriate evaluation of the musculoskeletal system should be done in patients who present with these symptoms during or after a course of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules. Consideration should be given to discontinuation of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules if any significant abnormality is found.
• Neutropenia and rare cases of agranulocytosis have been reported. Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) should be discontinued if clinically significant decreases in white cell counts occur.

Hypersensitivity

Anaphylactic reactions and other allergic reactions have been reported. 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. Severe allergic reaction necessitates discontinuation of therapy and appropriate medical management.

Carcinogenesis and Mutagenesis and Impairment of Fertility

In male and female Fischer 344 rats given oral isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin at dosages of 8 or 32 mg/kg/day (1.3 to 5.3 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area) for greater than 18 months, there was a dose-related increased incidence of pheochromocytoma relative to controls. The incidence of adrenal medullary hyperplasia was also increased at the higher dosage in both sexes. The relatively high level of spontaneous pheochromocytomas occurring in the male Fischer 344 rat makes it an equivocal model for study of this tumor; therefore, the relevance of this tumor to the human population is uncertain. The Ames test was conducted with isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin in two laboratories. The results of the tests in one laboratory were negative while in the second laboratory a weakly positive response (less than 1.6 x background) was noted in S. typhimurium TA100 when the assay was conducted with metabolic activation. No dose-response effect was seen and all other strains were negative. Additionally, other tests designed to assess genotoxicity (Chinese hamster cell assay, mouse micronucleus test, S. cerevisiae D7 assay, in vitro clastogenesis assay with human-derived lymphocytes, and unscheduled DNA synthesis assay) were all negative.

In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were observed at oral dosages of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin of 2, 8, or 32 mg/kg/day (0.3, 1.3, or 5.3 times the recommended clinical dose of 1.0 mg/kg/day, respectively, after normalization for total body surface area).

In dogs, testicular atrophy was noted after treatment with oral isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin for approximately 30 weeks at dosages of 20 or 60 mg/kg/ day (10 or 30 times the recommended clinical dose of 1.0 mg/kg/day, respectively, after normalization for total body surface area). In general, there was microscopic evidence for appreciable depression of spermatogenesis but some sperm were observed in all testes examined and in no instance were completely atrophic tubules seen. In studies of 66 men, 30 of whom were patients with nodular acne under treatment with oral isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin, no significant changes were noted in the count or motility of spermatozoa in the ejaculate. In a study of 50 men (ages 17 to 32 years) receiving Sotret (isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin) therapy for nodular acne, no significant effects were seen on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose.

Pregnancy: Category X.

See Boxed CONTRAINDICATIONS AND WARNINGS.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because of the potential for adverse effects, nursing mothers should not receive Sotret (isotretinoin capsules) .

Pediatric Use

The use of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules in pediatric patients less than 12 years of age has not been studied. The use of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules for the treatment of severe recalcitrant nodular acne in pediatric patients ages 12 to 17 years should be given careful consideration, especially for those patients where a known metabolic or structural bone disease exists (see PRECAUTIONS: General). Use of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules in this age group for severe recalcitrant nodular acne is supported by evidence from a clinical study comparing 103 pediatric patients (13 to 17 years) to 197 adult patients ( > 18 years). Results from this study demonstrated that isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin, at a dose of 1 mg/kg/day given in two divided doses, was equally effective in treating severe recalcitrant nodular acne in both pediatric and adult patients.

In studies with isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules, adverse reactions reported in pediatric patients were similar to those described in adults except for the increased incidence of back pain and arthralgia (both of which were sometimes severe) and myalgia in pediatric patients (see ADVERSE REACTIONS).

In an open-label clinical trial (N=217) of a single course of therapy with isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules 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 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 to 18 years, who started a second course of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules 4 months after the first course, two patients showed a decrease in mean lumbar spine bone mineral density up to 3.25% (see WARNINGS: Skeletal: Bone Mineral Density).

Geriatric Use

Clinical studies of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Although reported clinical experience has not identified differences in responses between elderly and younger patients, effects of aging might be expected to increase some risks associated with isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin therapy (see WARNINGS and PRECAUTIONS).

REFERENCES

5. Katz RA, Jorgensen H, Nigra TP. Elevation of serum triglyceride levels from oral isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin in disorders of keratinization. Arch Dermatol 116:1369-1372, 1980.

6. Ellis CN, Madison KC, Pennes DR, Martel W, Voorhees JJ. Isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin therapy is associated with early skeletal radiographic changes. J Am Acad Dermatol 10:1024-1029, 1984.

The oral LD₅₀ of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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 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.

Isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin causes serious birth defects at any dosage (see Boxed CONTRAINDICATIONS AND WARNINGS). Female patients of childbearing potential who present with isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin overdose must be evaluated for pregnancy. Patients who are pregnant should receive counseling about the risks to the fetus, as described in the boxed CONTRAINDICATIONS AND WARNINGS. Non-pregnant patients must be warned to avoid pregnancy for at least one month and receive contraceptive counseling as described in PRECAUTIONS. Educational materials for such patients can be obtained by calling the manufacturer. Because an overdose would be expected to result in higher levels of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin overdose should not donate blood for at least 1 month.

Contraindications

Pregnancy: Category X.

See Boxed CONTRAINDICATIONS AND WARNINGS.

Allergic Reactions

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

Isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1 mg/kg/day (see DOSAGE AND ADMINISTRATION), inhibits sebaceous gland function and keratinization. The exact mechanism of action of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin is unknown.

Nodular Acne

Clinical improvement in nodular acne patients occurs in association with a reduction in sebum secretion. The decrease in sebum secretion is temporary and is related to the dose and duration of treatment with Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) , and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation.¹

Pharmacokinetics

Absorption

Due to its high lipophilicity, oral absorption of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin is enhanced when given with a high-fat meal. In a crossover study, 74 healthy adult subjects received a single 80 mg oral dose (2 x 40 mg capsules) of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules under fasted and fed conditions. Both peak plasma concentration (Cmax) and the total exposure (AUC) of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin were more than doubled following a standardized high-fat meal when compared with isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules given under fasted conditions (see Table 2). The observed elimination half-life was unchanged. This lack of change in half-life suggests that food increases the bioavailability of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin without altering its disposition. The time to peak concentration (Tmax) was also increased with food and may be related to a longer absorption phase. Therefore, Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) capsules should always be taken with food (see DOSAGE AND ADMINISTRATION). Clinical studies have shown that there is no difference in the pharmacokinetics of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin between patients with nodular acne and healthy subjects with normal skin.

Table 2: Pharmacokinetic Parameters of Isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin Mean (%CV), N=74

Isotretinoin Capsules 2 x 40 mg Capsules	AUC0-∞ (ng•hr/mL)	Cmax (ng/mL)	Tmax (hr)	t1/2(hr)
Fed*	10,004 (22%)	862 (22%)	5.3 (77%)	21 (39%)
Fasted	3,703 (46%)	301 (63%)	3.2 (56%)	21 (30%)
*Eating a standardized high-fat meal

Distribution

Isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin is more than 99.9% bound to plasma proteins, primarily albumin.

Metabolism

Following oral administration of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin, at least three metabolites have been identified in human plasma: 4-oxo-isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin). Retinoic acid and 13-cis-retinoic acid are geometric isomers and show reversible interconversion. The administration of one isomer will give rise to the other. Isotret (isotret (isotretinoin capsules) inoin capsules) inoin is also irreversibly oxidized to 4-oxo-isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin, which forms its geometric isomer 4-oxo-tretinoin.

After a single 80 mg oral dose of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules to 74 healthy adult subjects, concurrent administration of food increased the extent of formation of all metabolites in plasma when compared to the extent of formation under fasted conditions.

All of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin. However, the clinical significance of these models is unknown. After multiple oral dose administration of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin to adult cystic acne patients ( ≥ 18 years), the exposure of patients to 4-ojco-isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin at steady-state under fasted and fed conditions was approximately 3.4 times higher than that of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin.

In vitro studies indicate that the primary P450 isoforms involved in isotret (isotretinoin capsules) inoin metabolism are 2C8, 2C9, 3A4, and 2B6. Isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces.

Elimination

Following oral administration of an 80 mg dose of ¹⁴C-isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin as a liquid suspension, ¹⁴C-activity in blood declined with a half-life of 90 hours. The metabolites of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin and any conjugates are ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%). After a single 80 mg oral dose of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin to 74 healthy adult subjects under fed conditions, the mean + SD elimination half-lives (t_1/2) of isotretinoin and 4-ojco-isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin were 21.0 + 8.2 hours and 24.0 + 5.3 hours, respectively. After both single and multiple doses, the observed accumulation ratios of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin ranged from 0.90 to 5.43 in patients with cystic acne.

Special Patient Populations

Pediatric Patients

The pharmacokinetics of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin were evaluated after single and multiple doses in 38 pediatric patients (12 to 15 years) and 19 adult patients ( ≥ 18 years) who received isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules for the treatment of severe recalcitrant nodular acne. In both age groups, 4-oxo-isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin was the major metabolite; tretinoin and 4-oxo-tretinoin were also observed. The dose-normalized pharmacokinetic parameters for isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin following single and multiple doses are summarized in Table 3 for pediatric patients. There were no statistically significant differences in the pharmacokinetics of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin between pediatric and adult patients.

Table 3. Pharmacokinetic Parameters of Isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin Following Single and Multiple Dose Administration in Pediatric Patients, 12 to 15 Years of Age Mean (± SD), N = 38*

Parameter	Isotretinoin (Single Dose)	Isotretinoin (Steady-State)
Cmax (ng/mL)	573.25 (278.79)	731.98(361.86)
AUC(0-12) (ng•hr/mL)	3033.37(1394.17)	5082 (2184.23)
AUC(0-24) (ng•hr/mL)	6003.81 (2885.67)	–
Tmax (hr)†	6.00 (1.00 to 24.60)	4.00 (0 to 12)
Cssmin (ng/mL)	–	352.32 (184.44)
T1/2 (hr)	–	15.69 (5.12)
CL/F (L/hr)	–	17.96 (6.27)
* The single and multiple dose data in this table were obtained following a non-standardized meal that is not comparable to the high-fat meal that was used in the study in Table 2. † Median (range)

In pediatric patients (12 to 15 years), the mean + SD elimination half-lives (ti/i) of isotretinoin and 4- oxo-isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin were 15.7 + 5.1 hours and 23.1 + 5.7 hours, respectively. The accumulation ratios of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin ranged from 0.46 to 3.65 for pediatric patients.

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.