Amnesteem (Isotretinoin) - Description and Clinical Pharmacology

DESCRIPTION

Isotretinoin, a retinoid, is available as Amnesteem in 10 mg, 20 mg and 40 mg soft gelatin capsules for oral administration. Each capsule contains yellow wax, butylated hydroxyanisole, edetate disodium, hydrogenated vegetable oil, and soybean oil. Gelatin capsules contain glycerin, with the following dye systems: 10 mg - red iron oxide paste and black ink; 20 mg - red iron oxide paste, yellow iron oxide paste, titanium dioxide and black ink; 40 mg - red iron oxide paste, yellow iron oxide paste, titanium dioxide, and black ink.

Chemically, isotretinoin 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:

CLINICAL PHARMACOLOGY

Isotretinoin is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1.0 mg/kg/day (see DOSAGE AND ADMINISTRATION), inhibits sebaceous gland function and keratinization. The exact mechanism of action of isotretinoin 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 isotretinoin 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 isotretinoin 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 × 40 mg capsules) of isotretinoin under fasted and fed conditions. Both peak plasma concentration (C_max) and the total exposure (AUC) of isotretinoin were more than doubled following a standardized high-fat meal when compared with isotretinoin given under fasted conditions (see Table 2 below). The observed elimination half-life was unchanged. This lack of change in half-life suggests that food increases the bioavailability of isotretinoin without altering its disposition. The time to peak concentration (T_max) was also increased with food and may be related to a longer absorption phase. Therefore, isotretinoin capsules should always be taken with food (see DOSAGE AND ADMINISTRATION). Clinical studies have shown that there is no difference in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects with normal skin.

Distribution

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

Metabolism

Following oral administration of isotretinoin, at least three metabolites have been identified in human plasma: 4- oxo -isotretinoin, 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. Isotretinoin is also irreversibly oxidized to 4- oxo -isotretinoin, which forms its geometric isomer 4- oxo -tretinoin.

After a single 80 mg oral dose of isotretinoin 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 isotretinoin. However, the clinical significance of these models is unknown. After multiple oral dose administration of isotretinoin to adult cystic acne patients (>/= 18 years), the exposure of patients to 4- oxo -isotretinoin at steady-state under fasted and fed conditions was approximately 3.4 times higher than that of isotretinoin.

In vitro studies indicate that the primary P450 isoforms involved in isotretinoin metabolism are 2C8, 2C9, 3A4, and 2B6. Isotretinoin 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 of¹⁴ C-isotretinoin as a liquid suspension,¹⁴ C-activity in blood declined with a half-life of 90 hours. The metabolites of isotretinoin 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 isotretinoin to 74 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (t_1/2) of isotretinoin and 4- oxo -isotretinoin were 21.0 ± 8.2 hours and 24.0 ± 5.3 hours, respectively. After both single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.90 to 5.43 in patients with cystic acne.

SPECIAL PATIENT POPULATIONS

Pediatric Patients

Pediatric pharmacokinetic information related to the use of isotretinoin after single and multiple doses is approved for Hoffman La-Roche's isotretinoin capsules. However, due to Hoffman La-Roche's marketing exclusivity rights, this drug product is not labeled for pediatric use.