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1 Unit = 1 Package (60 Capsules)
Roaccutane 20 mg soft capsules
Each soft capsule contains 20 mg of isotretinoin.
Excipients with known effect: Contains soya bean oil (refined, hydrogenated and partially hydrogenated) and sorbitol.
Capsules, soft 20 mg capsules: Oval, opaque, brown-red and
white capsules imprinted with ROA 20 in black ink.
Pharmacotherapeutic group: Retinoid for treatment of acne.
ATC code: D10B A01
Mechanism of action
Isotretinoin is a stereoisomer of all-trans retinoic acid (tretinoin). The exact mechanism of action of isotretinoin has not yet been elucidated in detail, but it has been established that the improvement observed in the clinical picture of severe acne is associated with suppression of sebaceous gland activity and a histologically demonstrated reduction in the size of the sebaceous glands. Furthermore, a dermal anti-inflammatory effect of isotretinoin has been established.
Clinical efficacy and safety of Roaccutane 20mg
Hypercornification of the epithelial lining of the pilosebaceous unit leads to shedding of corneocytes into the duct and blockage by keratin and excess sebum. This is followed by formation of a comedone and, eventually, inflammatory lesions. Isotretinoin inhibits proliferation of sebocytes and also appears to act in acne by re-setting the orderly program of differentiation. Sebum is a major substrate for the growth of Propionibacterium acnes so that reduce sebum production inhibits bacterial colonisation of the duct.
The absorption of isotretinoin from the gastrointestinal tract is variable and dose-linear over the therapeutic range. The absolute bioavailability of isotretinoin has not been determined, since the compound is not available as an intravenous preparation for human use, but extrapolation from dog studies would suggest a fairly low and variable systemic bioavailability. When isotretinoin is taken with food, the bioavailability is doubled relative to fasting conditions.
Distribution of Roaccutane 20 mg
Isotretinoin is extensively bound to plasma proteins, mainly albumin (99.9 %). The volume of distribution of isotretinoin in man has not been determined since isotretinoin is not available as an intravenous preparation for human use. In humans, little information is available on the distribution of isotretinoin into the tissue. Concentrations of isotretinoin in the epidermis are only half of those in serum. Plasma concentrations of isotretinoin are about 1.7 times those of whole blood due to poor penetration of isotretinoin into red blood cells.
After oral administration of isotretinoin, three major metabolites have been identified in plasma: 4-oxo-isotretinoin, tretinoin, (all-trans retinoic acid), and 4-oxo-tretinoin. These metabolites have shown biological activity in several in vitro tests. 4-oxo-isotretinoin has been shown in a clinical study to be a significant contributor to the activity of isotretinoin (reduction in sebum excretion rate despite no effect on plasma levels of isotretinoin and tretinoin). Other minor metabolites includes glucuronide conjugates. The major metabolite is 4-oxo-isotretinoin with plasma concentrations at steady state, that are 2.5 times higher than those of the parent compound.
Isotretinoin and tretinoin (all-trans retinoic acid) are reversibly metabolised (interconverted), and the metabolism of tretinoin is therefore linked with that of isotretinoin. It has been estimated that 20-30 % of an isotretinoin dose is metabolised by isomerisation.
Enterohepatic circulation may play a significant role in the pharmacokinetics of isotretinoin in man. In vitro metabolism studies have demonstrated that several CYP enzymes are involved in the metabolism of isotretinoin to 4-oxo-isotretinoin and tretinoin. No single isoform appears to have a predominant role. Isotretinoin and its metabolites do not significantly affect CYP activity.
After oral administration of radiolabelled isotretinoin approximately equal fractions of the dose were recovered in urine and faeces. Following oral administration of isotretinoin, the terminal elimination half-life of unchanged drug in patients with acne has a mean value of 19 hours. The terminal elimination half-life of 4-oxo-isotretinoin is longer, with a mean value of 29 hours.
Isotretinoin is a physiological retinoid and endogenous retinoid concentrations are reached within approximately two weeks following the end of isotretinoin therapy.
Since isotretinoin is contraindicated in patients with hepatic impairment, limited information on the kinetics of isotretinoin is available in this patient population.
Renal failure does not significantly reduce the plasma clearance of isotretinoin or 4-oxo-isotretinoin.
The acute oral toxicity of isotretinoin was determined in various animal species. LD50 is approximately 2000 mg/kg in rabbits, approximately 3000 mg/kg in mice, and also over 4000 mg/kg in rats.
A long-term study in rats over 2 years (isotretinoin dosage 2, 8 and 32 mg/kg/d) produced evidence of partial hair loss and elevated plasma triglycerides in the higher dose groups. The side effect spectrum of isotretinoin in the rodent thus closely resembles that of vitamin A, but does not include the massive tissue and organ calcifications observed with vitamin A in the rat. The liver cell changes observed with vitamin A did not occur with isotretinoin.
All observed side effects of hypervitaminosis A syndrome were spontaneously reversible after withdrawal of isotretinoin. Even experimental animals in a poor general state had largely recovered within 1-2 weeks.
Like other vitamin A derivatives, isotretinoin has been shown in animal experiments to be teratogenic and embryotoxic.
Due to the teratogenic potential of isotretinoin there are therapeutic consequences for the administration to women of a childbearing age
Isotretinoin has not been shown to be mutagenic in vitro or in vivo animal tests.