Isotretinoin 20 mg · Softgel capsules

The exact mechanism of action of Isotretinoin Capsules in the treatment of severe recalcitrant nodular acne in non-pregnant patients 12 years of age and older with multiple inflammatory nodules with a diameter of 5 mm or greater who are unresponsive to conventional therapy, including systemic antibiotics is unknown. Isotretinoin, a retinoid, inhibits sebaceous gland function and keratinization. Clinical improvement in nodular acne patients occurs in association with a reduction in sebum secretion. The decrease in sebum secretion is temporary and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation.

The following parameters are presented as mean [coefficient of variation (CV%)] following a single oral dose of 80 mg of Isotretinoin Capsules in healthy adult subjects unless otherwise stated.

Isotretinoin Cmax is 862 (22%) ng/mL and AUC0-inf is 10,004 (22%) ng*h/mL when Isotretinoin Capsules was administered with food in healthy adults. Isotretinoin accumulation ratio ranged from 0.90 to 5.43 in patients with cystic acne after multiple doses. No clinically significant differences in the pharmacokinetics of isotretinoin were observed between patients with nodular acne and healthy subjects without acne.

Absorption — Isotretinoin time to maximum concentration (Tmax) is 5.3 hours (77%) when administered with food.

Effect on Food: Isotretinoin AUC0-inf increased 2.7-fold and Cmax increased 2.9-fold relative to the fasted state following a high-fat meal. In addition, the extent of formation of all metabolites was higher, Tmax increased to 5.3 hours (77%), and the elimination half-life was unchanged under fed conditions [see Dosage and Administration (2.1)].

Distribution — Isotretinoin is more than 99.9% bound to plasma proteins, primarily to albumin.

Elimination — The mean ± SD elimination half-life of isotretinoin is 21± 8.2 hours and 24 ± 5.3 hours for its 4-oxo-isotretinoin metabolite.

Metabolism: Isotretinoin is primarily metabolized by CYP2C8, 2C9, 3A4, and 2B6 in vitro. Isotretinoin and its

metabolites are further metabolized into conjugates.

Isotretinoin is metabolized into at least three metabolites (4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin)) which are detected in human plasma. 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. Isotretinoin is also irreversibly oxidized to 4-oxo-isotretinoin, which forms its geometric isomer 4-oxo-tretinoin. The exposure of adult cystic acne patients to 4-oxo-isotretinoin at steady state under fasted and fed conditions was approximately 3.4 times higher than that of isotretinoin. All of these metabolites possess retinoid activity in vitro, however the clinical significance is unknown.

Excretion: Following administration of 80 mg of radiolabeled isotretinoin as a liquid suspension, the metabolites of isotretinoin were excreted in feces and urine in relatively equal amounts (total of 65% to 83%).

Specific Populations — Pediatric Patients: No clinically statistically significant differences in isotretinoin pharmacokinetics were observed based on age (12 to 15 years, and ≥18 years) in patients who received single and multiple doses of Isotretinoin Capsules. In both age groups, 4-oxo-isotretinoin was the major metabolite compared to tretinoin and 4-oxo-tretinoin.