Clinical studies of isotretinoin did not include sufficient numbers of geriatric subjects (subjects aged 65 years of age and older) to determine whether they respond differently from younger adults. Although reported clinical experience has not identified differences in responses between geriatric and younger adults, effects of aging may increase some risks associated with isotretinoin therapy.
In humans, isotretinoin overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. These symptoms quickly resolved without apparent residual effects.
Patients who can become pregnant who present with an isotretinoin overdosage should be evaluated for pregnancy. Because an overdosage would be expected to result in higher levels of isotretinoin in semen than found during a normal treatment course, male patients treated with isotretinoin should use a condom, or avoid reproductive sexual activity with a patient who is or might become pregnant, for 1 month after the overdose.
All patients with isotretinoin overdose should not donate blood for at least 1 month.
Isotretinoin capsules, USP contain 10 mg, 20 mg, 25 mg, 30 mg, 35 mg or 40 mg of isotretinoin, USP (a retinoid) in hard gelatin capsules for oral administration. In addition to the active ingredient, isotretinoin USP, each capsule contains the following inactive ingredients: sorbitan monooleate, soybean oil, stearoyl polyoxyglycerides, and vitamin E.
The capsule shells contain the following:
- 10 mg — FD&C Blue No. 1, gelatin, and titanium dioxide
- 20 mg — FD&C Blue No. 1, gelatin, iron oxide yellow, and titanium dioxide
- 25 mg — D&C Yellow No. 10, FD&C Blue No. 1, FD&C Green No. 3, gelatin, and titanium dioxide
- 30 mg — FD&C Blue No. 1, FD&C Yellow No. 6, gelatin, sodium lauryl sulfate, and titanium dioxide
- 35 mg — FD&C Blue No. 1, FD&C Red No. 40, gelatin, and titanium dioxide
- 40 mg — FD&C Blue No. 1, FD&C Yellow No. 6, gelatin, sodium lauryl sulfate, and titanium dioxide
The black imprinting ink of the 10 mg and 20 mg capsules contain the following ingredients: ammonium hydroxide, iron oxide black, propylene glycol, and shellac.
The black imprinting ink of the 25 mg and 35 mg capsules contain the following ingredients: D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, iron oxide black, shellac and may contain propylene glycol.
The black imprinting ink of the 30 mg and 40 mg capsules contain the following ingredients: iron oxide black, propylene glycol, shellac, and may contain ammonium hydroxide or potassium hydroxide and strong ammonia solution.
Chemically, isotretinoin, USP 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. It is practically insoluble in water, soluble in chloroform and sparingly soluble in alcohol and in isopropyl alcohol. The structural formula is:
FDA approved dissolution test specifications differ from USP.
Isotretinoin is a retinoid, which when administered at the recommended dosage [see Dosage and Administration (2.1)] , 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 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. The exact mechanism of action of isotretinoin in the treatment of severe recalcitrant nodular acne is unknown.
The pharmacodynamics of isotretinoin are unknown.
No clinically significant differences in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects without acne were reported in published literature.
Absorption Following Isotretinoin Administration
The isotretinoin mean Tmax was 6.4 hours under fed conditions and 2.9 hours under fasting conditions following administration of a single 40 mg dose.
Effect on Food
No clinically significant differences in isotretinoin pharmacokinetics were observed following administration with a modified high-fat, high-calorie meal (123.2 calories from protein, 265.6 calories from carbohydrates, and 468 calories from fat; total calories 857 calories) with reduced vitamin A content. The mean AUC0-t and Cmax of isotretinoin were 6095 ng*hr/mL and 369 ng/mL, respectively, following administration of a single 40 mg isotretinoin dose under fed conditions; which were approximately 50% and 26% higher, respectively, compared to fasting conditions. However, isotretinoin may be given with or without meals [see Dosage and Administration (2.1)].
Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.
The mean elimination half-lives of isotretinoin and its 4-oxo-isotretinoin metabolite were 18 hours and 38 hours, respectively, after a single oral isotretinoin 40 mg dose.
Metabolism: Isotretinoin is primarily metabolized by CYP2C8, 2C9, 3A4, and 2B6 in vitro. Isotretinoin and its metabolites are further metabolized into conjugates.
Following oral administration of isotretinoin capsules, at least three metabolites (4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin)) have been identified in human plasma. The extent of formation of all metabolites was higher under fed conditions. All of these metabolites possess retinoid activity in vitro. The clinical significance is unknown.
Excretion: Following oral administration of an 80 mg dose 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%).
Pediatric Patients: No clinically significant differences in the pharmacokinetics of isotretinoin were observed based on age (12 to 15 years (n=38), and ≥18 years (n=19)). In both age groups, 4-oxo-isotretinoin was the major metabolite; tretinoin and 4-oxo-tretinoin were also observed [see Use in Specific Populations (8.4)].
Drug Interaction Studies
No clinically significant differences in the pharmacokinetics of phenytoin (CYP2C9 substrate) were observed when used concomitantly with isotretinoin.
In male and female Fischer 344 rats given oral isotretinoin at dosages of 8 or 32 mg/kg/day (1.3 or 5.3 times the recommended clinical isotretinoin dosage of 1 mg/kg/day, respectively, after normalization for total body surface area) for greater than 18 months, there was a dose-related increased incidence of pheochromocytoma relative to controls. The incidence of adrenal medullary hyperplasia was also increased at the higher dosage in both sexes. The relatively high level of spontaneous pheochromocytomas occurring in the male Fischer 344 rat makes it an equivocal model for study of this tumor; therefore, the relevance of this tumor to humans is uncertain.
The Ames test was conducted with isotretinoin in two laboratories. The results of the tests in one laboratory were negative, while in the second laboratory, a weakly positive response (less than 1.6 times background) was noted in S. typhimurium TA100 when the assay was conducted with metabolic activation. No dose response effect was seen, and all other strains were negative. Additionally, other tests designed to assess genotoxicity (Chinese hamster cell assay, mouse micronucleus test, S. cerevisiae D7 assay, in vitro clastogenesis assay with human-derived lymphocytes, and unscheduled DNA synthesis assay) were all negative.
In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were observed at oral dosages of isotretinoin of 2, 8, or 32 mg/kg/day (0.3, 1.3, or 5.3 times the recommended clinical isotretinoin dosage of 1 mg/kg/day, respectively, after normalization for total body surface area).
In dogs, testicular atrophy was noted after treatment with oral isotretinoin for approximately 30 weeks at dosages of 20 or 60 mg/kg/day (10 or 30 times the recommended clinical isotretinoin dosage of 1 mg/kg/day, respectively, after normalization for total body surface area). In general, there was microscopic evidence for appreciable depression of spermatogenesis, but some sperm were observed in all testes examined, and in no instance were completely atrophic tubules seen.
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