( 13-cis-Retinoic Acid )

Pronunciation: EYE-soe-TRET-i-noin
Class: First generation retinoid

Trade Names

Amnesteem
- Capsules 10 mg
- Capsules 20 mg
- Capsules 40 mg

Claravis
- Capsules 10 mg
- Capsules 20 mg
- Capsules 30 mg
- Capsules 40 mg

Sotret
- Capsules, softgel 10 mg
- Capsules, softgel 20 mg
- Capsules, softgel 30 mg
- Capsules, softgel 40 mg

Accutane Roche (Canada)
Clarus (Canada)

Pharmacology

Reduces sebum secretion and sebaceous gland size, and inhibits sebaceous gland differentiation.

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Pharmacokinetics

Absorption

The T _max is approximately 3 h (fasted); 5 h (fed). The mean C _max is 301 ng/mL (fasted); 862 ng/mL (fed). Absorption increases with food or milk.

Distribution

More than 99.9% bound to protein, primarily albumin.

Metabolism

The major metabolite is 4-oxo-isotretinoin. CYP2C8, CYP2C9, CYP3A4, and CYP2B6 involved in isotretinoin metabolism.

Elimination

The mean t _½ is 21 h (isotretinoin) and 24 h (4-oxo-isotretinoin). 65% to 83% is excreted equally via the urine and feces.

Special Populations

Children

No differences in the pharmacokinetics between children and adult patients.

Indications and Usage

Treatment of severe recalcitrant nodular acne.

Unlabeled Uses

Treatment of pityriasis rubra pilaris, psoriasis, rosacea; prevention and treatment of basal cell carcinoma; adjunctive treatment of inoperable neoplasms (eg, squamous cell carcinoma of the lung); treatment of advanced squamous cell carcinoma of the skin; keratoacanthomas; cutaneous T-cell lymphomas.

Contraindications

Hypersensitivity to parabens; pregnancy.

Dosage and Administration

Adults

PO 0.5 to 1 mg/kg/day divided into 2 doses with food for 15 to 20 wk. For severe cases, dose adjustments up to 2 mg/kg/day may be needed. If the total nodule count decreases more than 70% prior to completing 15 to 20 wk of treatment, the drug may be discontinued. After a period of 2 mo or more off therapy, and if warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated.

General Advice

• Instruct patient to swallow capsules whole. Do not open or crush capsules.
• Give medication with meals.
• Once-daily dosing is not recommended.

Storage/Stability

Amnesteem : Store at 59° to 86°F. Protect from light. Claravis , Sotret : Store at 68° to 77°F. Protect from light.

Drug Interactions

Carbamazepine

Coadministration has resulted in reduced carbamazepine plasma level.

Food

When taken with food, the absorption of isotretinoin has increased.

Tetracycline/Minocycline

Have been associated with pseudotumor cerebri or papilledema in isotretinoin patients.

Vitamin A

May increase toxic effects; do not take with isotretinoin.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Palpitation, stroke, syncope, tachycardia, vascular thrombosis, vasculitis.

CNS

Aggression, depression, dizziness, drowsiness, emotional instability, fatigue, headache, insomnia, lethargy, malaise, nervousness, paresthesias, pseudotumor cerebri, psychosis, seizures, stroke, suicidal ideation, suicide, suicide attempts, violent behaviors, weakness.

Dermatologic

Abnormal wound healing; acne fulminans; alopecia; bruising; dry lips, mouth, nose, and skin; epistaxis; eruptive xanthomas; flushing; fragility of skin; hair abnormalities; hirsutism; hyper- and hypopigmentation; increased sunburn susceptibility; infections; nail dystrophy; paronychia; peeling of palms and soles; photoallergic and photosensitizing reactions; pruritus; pyogenic granuloma; rash; sweating; urticaria.

EENT

Cataracts, color vision disorder, conjunctivitis, corneal opacities, decreased night vision, dry eyes, eyelid inflammation, hearing impairment, keratitis, optic neuritis, photophobia, tinnitus, visual disturbances.

GI

Bleeding and inflammation of the gums, colitis, esophageal ulceration, esophagitis, hepatitis, ileitis, inflammatory bowel disease, nausea, nonspecific GI symptoms, pancreatitis.

Genitourinary

Abnormal menses, glomerulonephritis, microscopic or gross hematuria, nonspecific urogenital findings, proteinuria, WBC in urine.

Hematologic-Lymphatic

Anemia, lymphadenopathy.

Lab Tests

Decreased HDL, RBC parameters, and WBC counts; elevated CPK, fasting blood sugar, platelet counts, sedimentation rates, serum cholesterol, and triglycerides; increased alkaline phosphatase, ALT, AST, gamma-glutamyl transpeptidase, or LDH; hyperuricemia; thrombocytopenia.

Metabolic-Nutritional

Alterations in blood glucose levels, edema, hypertriglyceridemia, weight loss.

Musculoskeletal

Arthralgia, arthritis, back pain, bone abnormalities, calcification of tendons and ligaments, decreased bone mineral density, musculoskeletal symptoms, myalgia, premature epiphyseal closure, rhabdomyolysis, skeletal hyperostosis, tendonitis.

Respiratory

Bronchospasm, respiratory tract infection, voice alteration.

Miscellaneous

Allergic reactions, including systemic hypersensitivity and vasculitis; transient chest pain.

Precautions

Warnings Pregnancy Isotretinoin must not be used by females who are or may become pregnant. Major human fetal abnormalities related to isotretinoin administration in pregnant females have been documented. There is an increased risk of spontaneous abortion and premature births. Documented external abnormalities include skull abnormality, ear abnormalities, eye abnormalities, facial dysmorphia, and cleft palate. Documented internal abnormalities include CNS abnormalities, CV abnormalities, thymus gland abnormality, and parathyroid hormone deficiency. Cases of intelligent quotient scores less than 85 with or without obvious CNS abnormalities also have been reported. If pregnancy occurs during treatment, isotretinoin must be discontinued and the patient should be referred to an obstetrician-gynecologist experienced in reproductive toxicity for evaluation and counseling. Special prescribing requirements Because of isotretinoin's teratogenicity, and to minimize fetal exposure, isotretinoin is approved for marketing only under a restricted distribution program, called iPLEDGE, approved by the FDA. Isotretinoin must be prescribed by prescribers and dispensed by pharmacies registered and activated with the iPLEDGE program, and must only be dispensed to patients who are registered and meet all the requirements of iPLEDGE.

Monitor Obtain 2 negative urine or serum pregnancy tests prior to receiving initial isotretinoin prescription and negative result for urine or serum pregnancy test each month; obtain pretreatment and follow-up lipids during fasting conditions; monitor liver function weekly or biweekly until isotretinoin response has been established; periodically determine blood glucose.

Pregnancy

Category X .

Isotretinoin must be prescribed and dispensed by prescribers and pharmacies registered with and activated by the FDA-restricted distribution program, iPLEDGE. Patients must be registered and meet all requirements of iPLEDGE. Consult the package insert for details.

Lactation

Undetermined.

Children

Safety and efficacy not established in children younger than 12 yr of age. Use with caution in children 12 to 17 yr of age, especially in those with known metabolic or structural bone disease.

Elderly

Clinical studies did not include sufficient numbers of subjects aged 65 yr and older to determine whether they respond differently from younger subjects.

Hypersensitivity

Anaphylactic reactions and other allergic reactions have been reported. Cutaneous allergic reactions and serious cases of allergic vasculitis, often with purpura, of the extremities and extracutaneous involvement (including renal) have been reported.

Hepatic Function

Clinical hepatitis possibly related to isotretinoin therapy has been reported. Mild to moderate elevations of liver enzymes have been seen.

Photosensitivity

May occur; avoid excessive sunlight and ultraviolet light.

Acne

Transient exacerbation of acne may occur, generally during initial therapy period.

Blood donation

Because of isotretinoin's teratogenic potential, patients receiving the drug should not donate blood for transfusion during treatment and for 1 mo after discontinuing therapy.

Diabetes

Certain patients have experienced problems in the control of their blood sugar. New cases of diabetes have been diagnosed during therapy.

Hearing impairment

Impaired hearing has been reported in patients taking isotretinoin.

Hypertriglyceridemia

Hypertriglyceridemia in excess of 800 mg/dL occurred in approximately 25% of patients; approximately 15% developed a decrease in HDL and approximately 7% showed an increase in cholesterol levels. Perform blood lipid determinations before isotretinoin is given, and then at regular intervals.

Inflammatory bowel disease

Inflammatory bowel disease, including regional ileitis, has been temporally associated with isotretinoin use.

Musculoskeletal effects

Decreases in lumbar spine and total hip bone mineral density have been observed. Bone fracture, delayed healing of bone fractures, hyperostosis, osteopenia, osteoporosis, and premature epiphyseal closure have been seen in patients receiving isotretinoin.

Neutropenia/Agranulocytosis

Neutropenia and rare cases of agranulocytosis have been reported. Discontinue if clinically significant.

Pancreatitis

Acute pancreatitis has been reported with elevated or normal serum triglyceride levels. In rare cases, fatal hemorrhagic pancreatitis has been reported.

Pseudotumor cerebri (benign intracranial hypertension)

Isotretinoin use has been associated with a number of cases of pseudotumor cerebri, some of which involved concomitant use of tetracyclines. Early signs and symptoms include headache, nausea, papilledema, visual disturbances, and vomiting.

Psychiatric disorders

May cause depression, psychosis, and, rarely, suicidal ideation, suicide attempts, and suicide.

St. John's wort

Avoid St. John's wort because of possible interference with hormonal contraceptive efficacy.

Visual impairment

Carefully monitor visual problems. If visual difficulties occur, discontinue the drug and have an ophthalmological examination. Corneal opacities have appeared in patients receiving isotretinoin for acne and more frequently in patients on higher dosages for keratinization disorders. Decreased night vision has occurred during therapy, and in some cases persisted after therapy was discontinued.

Overdosage

Symptoms

Abdominal pain, ataxia, cheilosis, dizziness, facial flushing, headache, vomiting.

Patient Information

• Because of teratogenic effects, instruct patient to practice abstinence or use 2 reliable methods of birth control during therapy and for 1 mo before and after therapy.
• Advise patient to be seen by health care provider monthly and have a urine or serum pregnancy test performed each month to confirm negative pregnancy status.
• Instruct patient to notify health care provider immediately if pregnancy is suspected.
• Advise patient to take medication with meals.
• Instruct patient to discontinue any other acne medications (including OTC topical preparations) before starting therapy.
• Advise patient to control weight, decrease dietary fat, and restrict alcohol intake 36 h before lipid determinations to avoid elevation in serum triglycerides.
• Caution patient against use of vitamin A, even in multivitamins, to avoid additive toxicity.
• Inform patient that contact lens tolerance may decrease.
• Suggest use of lubricant (eg, petroleum jelly) on lips to prevent cheilitis.
• Advise patient not to donate blood for at least 30 days after discontinuing therapy.
• Inform patient that transient exacerbations of acne may be experienced during first few weeks of therapy. Advise patient to continue drug therapy.
• Caution patient that decreased night vision can occur and onset can be sudden. Advise patient to be cautious when driving or operating any vehicle at night.
• Advise patient to take sips of water frequently, suck on ice chips or sugarless hard candy, or chew sugarless gum if dry mouth occurs.
• Caution patient to avoid exposure to sunlight and to use sunscreen or wear protective clothing to avoid photosensitivity reactions.
• Caution patient that problems could arise in the control of blood sugar.
• Inform patient of availability of patient information leaflet, emphasizing the need to carefully review pregnancy warnings and fetal risks.
• Prior to use, have patient complete a consent form included with package insert.
• Instruct patient to immediately notify health care provider if any of the following symptoms occur: abdominal pain, decreased tolerance to contact lens, depression, difficulty in controlling blood sugar, rectal bleeding, severe diarrhea, visual disturbances.
• Inform patient to avoid wax epilation and skin resurfacing procedures (eg, dermabrasion, laser) during therapy and for at least 6 mo thereafter because of possible scarring.

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