Sotret

SOTRET- isotretinoin capsule, gelatin coated
SOTRET- isotretinoin capsule, liquid filled
Ranbaxy Laboratories Inc.

CAUSES BIRTH DEFECTS

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DO NOT GET PREGNANT

CONTRAINDICATIONS AND WARNINGS

Sotret must not be used by female patients who are or may become pregnant. There is an extremely high risk that severe birth defects will result if pregnancy occurs while taking isotretinoin capsules in any amount, even for short periods of time. Potentially any fetus exposed during pregnancy can be affected. There are no accurate means of determining whether an exposed fetus has been affected.

Birth defects which have been documented following isotretinoin exposure include abnormalities of the face, eyes, ears, skull, central nervous system, cardiovascular system, and thymus and parathyroid glands. Cases of IQ scores less than 85 with or without other abnormalities have been reported. There is an increased risk of spontaneous abortion, and premature births have been reported.

Documented external abnormalities include: skull abnormality; ear abnormalities (including anotia, micropinna, small or absent external auditory canals); eye abnormalities (including microphthalmia); facial dysmorphia; cleft palate. Documented internal abnormalities include: CNS abnormalities (including cerebral abnormalities, cerebellar malformation, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular abnormalities; thymus gland abnormality; parathyroid hormone deficiency. In some cases death has occurred with certain of the abnormalities previously noted.

If pregnancy does occur during treatment of a female patient who is taking isotretinoin capsules, isotretinoin capsules must be discontinued immediately and she should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling.

Special Prescribing Requirements

Because of isotretinoin’s teratogenicity and to minimize fetal exposure, Sotret is approved for marketing only under a special restricted distribution program approved by the Food and Drug Administration. This program is called iPLEDGE™. Sotret must only be prescribed by prescribers who are registered and activated with the iPLEDGE program. Sotret 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 (see PRECAUTIONS).

Table 1 Monthly Required iPLEDGE Interactions

Female Patients of Childbearing Potential Male Patients, And Female Patients Not of Childbearing Potential
PRESCRIBER
Confirms patient counseling X X
Enters the 2 contraception methods chosen by the patient X
Enters pregnancy test results X
PATIENT
Answers educational questions before every prescription X
Enters 2 forms of contraception X
PHARMACIST
Calls system to get an authorization X X

DESCRIPTION

Isotretinoin, a retinoid, is available as Sotret 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, 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:

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CLINICAL PHARMACOLOGY

Isotretinoin 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 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 Sotret, 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 x 40 mg capsules) of isotretinoin capsules under fasted and fed conditions. Both peak plasma concentration (Cmax ) and the total exposure (AUC) of isotretinoin were more than doubled following a standardized high-fat meal when compared with isotretinoin 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 isotretinoin 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 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.

Table 2 Pharmacokinetic Parameters of Isotretinoin Mean (%CV), N=74

Isotretinoin Capsules 2 x 40 mg Capsules AUC 0- ∞ (ng•hr/mL) C max (ng/mL) T max (hr) t 1/2 (hr)

*Eating a standardized high-fat meal

Fed* 10,004 (22%) 862 (22%) 5.3 (77%) 21 (39%)
Fasted 3,703 (46%) 301 (63%) 3.2 (56%) 21 (30%)

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