Sotret (Page 2 of 11)

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 of 14 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 (t1/2 ) 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

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

Table 3. Pharmacokinetic Parameters of Isotretinoin 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)

* 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)

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)

In pediatric patients (12 to 15 years), the mean ± SD elimination half-lives (t1/2 ) of isotretinoin and 4- oxo -isotretinoin were 15.7 ± 5.1 hours and 23.1 ± 5.7 hours, respectively. The accumulation ratios of isotretinoin ranged from 0.46 to 3.65 for pediatric patients.

INDICATIONS AND USAGE

Severe Recalcitrant Nodular Acne

Sotret 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 should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition, Sotret 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 isotretinoin 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).

CONTRAINDICATIONS

Pregnancy: Category X.

See Boxed CONTRAINDICATIONS AND WARNINGS.

Allergic Reactions

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

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