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«Data Sheet ORATANE Isotretinoin 5 mg, 10 mg, 20 mg, 30 mg and 40 mg Capsules Name of the Medicine ORATANE Isotretinoin (BP/Ph.Eur) 5 mg, 10 mg, 20 ...»

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Data Sheet


Isotretinoin 5 mg, 10 mg, 20 mg, 30 mg and 40 mg Capsules

Name of the Medicine


Isotretinoin (BP/Ph.Eur) 5 mg, 10 mg, 20 mg, 30 mg and 40 mg Capsules


Isotretinoin is a retinoid with a specific antiseborrheic action for oral treatment of

severe cystic acne and conglobate acne resistant to other forms of treatment.

Isotretinoin, the active ingredient of ORATANE, is a synthetic stereoisomer of alltrans retinoic acid (tretinoin), an active substance that has proved effective in topical treatment of acne vulgaris. Isotretinoin is chemically identified as 13-cis retinoic acid: (2Z, 4E, 6E, 8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1yl)nona-2,4,6,8-tetraenoic acid, molecular weight 300.42 and molecular formula is C20H28O2.

The structural formula is:

The 5 mg, 10 mg, 20 mg, 30 mg and 40 mg capsules contain the following excipients: sodium edetate, soya oil (refined), beeswax (yellow), butylated hydroxyanisole, dl-α-tocopherol, soya bean oil hydrogenated, partly hydrogenated soya oil, gelatin, glycerol, sorbitol, and titanium dioxide. In addition the 10 mg capsules contain Ponceau Red (CI 16255) and ferric oxide (black).

The 20 mg capsules contain Ponceau Red (CI 16255) and indigo carmine (CI730150. The 30 mg capsules contain ferric oxide (red). The 40 mg capsules contain Sunset yellow (CI 15985).

Pharmacology Mechanism of Action Administered orally, isotretinoin has a marked effect in severe forms of acne, which have proved insufficiently responsive to previous treatment. The 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 dose-related 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.

Pharmacokinetics Time-related blood concentrations can be predicted on the basis of linear pharmacokinetics.

Absorption Peak plasma concentrations (Cmax) of approximately 200-300 ng/ml have been achieved in healthy volunteers three to four hours (tmax) after administration of 40 mg isotretinoin.

Taking isotretinoin with food increases bioavailability up to twofold relative to fasting conditions, probably as a result of easier absorption of this highly lipophilic medication. Furthermore, there is an overall decrease in fluctuations in systemic availability when isotretinoin is ingested with food.

Distribution Isotretinoin is extensively bound to plasma proteins (99.9 %) with the result that the free active fraction of the substance is less than 0.1 % of the total over a wide range of therapeutic concentrations. Albumin appears to be the major binding protein.

The volume of distribution of isotretinoin is notknown in humans since it is not available as an intravenous preparation.

Metabolism Three major metabolites have been identified in plasma: 4-oxo-isotretinoin, tretinoin (all-trans retinoic acid), and 4-oxo-tretinoin. The major blood metabolite of isotretinoin is 4-oxo-isotretinoin, which is rapidly formed following oral administration achieving peak concentrations of 100 - 140 ng/ml at about two hours after administration of 40 mg isotretinoin. Other minor metabolites have been detected but are not completely identified, which also includes glucuronide conjugates.

Isotretinoin metabolites have shown biological activity in several in-vitro tests.

Thus the observed clinical profile in patients could be the result of the pharmacological activity of isotretinoin and its metabolites.

Since isotretinoin and tretinoin (all-trans retinoic acid) are reversibly metabolised (= interconverted), the metabolism of tretinoin is linked with that of isotretinoin. It has been estimated that 20-30% of an isotretinoin dose is metabolised by isomerization.

Isotretinoin also isomerises in vivo via an alternative metabolic pathway to tretinoin (all-trans retinoic acid). Glucuronidation of the metabolites has not been conclusively demonstrated in humans but is strongly suggested by animal studies. Investigations in humans and dogs point to an enterohepatic recirculation of isotretinoin, which would contribute to the observed interindividual variability in plasma concentrations.

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. CYP2C8, CYP2C9, CYP2B6, and possibly CYP3A4 appear to have the greatest contributions in the metabolism of isotretinoin to 4-oxo-isotretinoin. CYP2C9, CYP2B6, and possibly CYP2C8, CYP3A4, CYP2A6, and CYP2E1 contribute to the metabolism of isotretinoin. CYP 26 is also known to metabolize retinoids Elimination Isotretinoin appears to be eliminated almost exclusively by hepatic metabolism and biliary excretion.

Following oral administration of isotretinoin, the elimination half-life of unchanged substance has ranged from 7 to 39 hours (mean approximately 20 hours) in both healthy volunteers and patients with cystic acne.

The mean elimination half-life of the 4-oxo metabolite in patients with cystic acne is slightly longer (25 hours, range: 17-50 hours) than that of the parent substance.

Isotretinoin is a physiological retinoid and endogenous retinoid concentrations are reached within approximately two weeks following the end of isotretinoin therapy.

Special Populations Since isotretinoin is contraindicated in patient’s hepatic impairment, there is no information on the pharmacokinetics of the substance in this population.

Patients with Renal Impairment In patients with severe renal insufficiency treatment should be started at a lower dose (e.g. 10 mg/day) and afterwards individually adjusted according to tolerability.

Indications Severe forms of nodulo-cystic acne which are resistant to therapy, particularly cystic acne and acne conglobata, especially when the lesions involve the trunk.

ORATANE should only be prescribed by physicians who are experienced in the use of systemic retinoids, preferably dermatologists, and understand the risk of teratogenicity if ORATANE is used during pregnancy.

Contraindications Pregnancy (Category X) Isotretinoin is highly teratogenic. It is, therefore, contraindicated not only in women who are pregnant or who may become pregnant while undergoing treatment but also in all women of childbearing potential. There is an extremely high risk that a deformed infant will result if pregnancy occurs while taking ORATANE in any amount even for short periods. Potentially all exposed foetuses can be affected.

Isotretinoin is contraindicated in women of childbearing potential unless the

female patient meets all of the following conditions:

 She has severe disfiguring cystic acne resistant to standard therapies.

 She must be reliable in understanding and carrying out instructions.

 She is capable of complying with the mandatory contraceptive measures.

 She is informed by the physicians of the hazards of becoming pregnant during and 1 month after treatment with isotretinoin and she is warned of the possibility of contraceptive failure.

 She confirms that she has understood the warnings.

 She has a negative pregnancy test within two weeks prior to beginning therapy. Monthly repetition of pregnancy testing is recommended.

 She must use effective contraception without any interruption for 1 month before beginning isotretinoin therapy, during therapy and for 1 month following discontinuation of therapy. Use of two complementary forms of contraception including a barrier method should be used. Microdosed progesterone only preparations (minipills) are an inadequate method of contraception during isotretinoin therapy.

 She starts isotretinoin therapy only on the second or third day of the next menstrual period.

 In the event of relapse treatments she must also use the same uninterrupted and effective contraceptive measures 1 month prior to, during and for 1 month after isotretinoin therapy.

 She must fully understand the precautions and confirm her understanding and her willingness to comply with reliable contraceptive measures as explained to her.

Even female patients, who normally do not employ contraception because of a history of infertility, should be advised to do so while taking isotretinoin, following the above guidelines.

Should pregnancy occur in spite of these precautions during treatment with isotretinoin or in the month following, there is a great risk of very severe malformation of the foetus (involving in particular the central nervous system, the heart and the large blood vessels). If pregnancy does occur, the doctor and patient should discuss the advisability of continuing the pregnancy.

Major human foetal abnormalities related to isotretinoin administration have been documented, including hydrocephalus, microcephalus, abnormalities of the external ear (micropinna, small or absent external auditory canals), microphthalmia, cardiovascular abnormalities, facial dysmorphia, thymus gland abnormalities, parathyroid hormone deficiency and cerebellar malformation.

There is also an increased risk of spontaneous abortion.

Isotretinoin is also contraindicated in hepatic and renal insufficiency;

hypervitaminosis A; patients with excessively elevated blood lipid values;

hypersensitivity to the medicine or any of the excipients.

Precautions General Prescribers should inform the individual patient of the risks associated with the use of isotretinoin.

Isotretinoin should only be prescribed by doctors who are experienced in the use of systemic retinoids and understand the risk of teratogenicity associated with isotretinoin therapy Hypersensitivity reactions may occur in susceptible individuals.

Liver function should be checked before and one month after the start of treatment and subsequently at three-monthly intervals.

Serum lipids (fasting value) should also be checked (before and one month after the start of therapy, and also at the end of the three-to-four-month treatment period). In high risk patients (with diabetes, obesity, alcoholism or disturbances of the lipid metabolism) undergoing treatment with isotretinoin, more frequent checks may be necessary. Isotretinoin should not be used together with any medicine known to enhance liver metabolism or interfere with enterohepatic circulation.

The serum lipid values usually return to normal on reduction of the dose or discontinuation of treatment. The changes in serum lipids may also resolve in response to dietary measures.

In known or suspected diabetic patients, frequent determination of blood glucose levels is recommended. Although no causal relationship has been established, elevated fasting blood sugars have been reported and new cases of diabetes have been diagnosed during isotretinoin therapy.

It is recommended that clinically significant serum triglyceride elevations be controlled, since levels in excess of 800 mg/dL are sometimes associated with acute pancreatitis, which is known to be potentially fatal. Hence, isotretinoin should be discontinued if uncontrolled hypertriglyceridaemia or symptoms of pancreatitis occur.

Patients, particularly those with dry eyes, should be monitored for the development of keratitis.

Decreased night vision has occurred during isotretinoin therapy and in rare instances has persisted after discontinuation of therapy (see Adverse effects).

Because the onset in some patients was sudden, patients should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at night. Visual problems should be carefully monitored.

Depression, (see Adverse effects) psychotic symptoms and rarely suicide attempts and suicide have been reported in patients treated with isotretinoin.

Although a causal relationship has not been established particular care needs to be taken in patients with a history of depression and all patients should be monitored for signs of depression and referred for appropriate treatment if necessary.

Rare cases of benign intracranial hypertension have been reported after isotretinoin and after tetracyclines. Supplementary treatment with tetracyclines is, therefore, contraindicated.

Myalgia and arthralgia may occur and may be associated with reduced tolerance to vigorous exercise (see Adverse effects). Isolated instances of raised serum CPK values have been reported in patients receiving isotretinoin, particularly those undertaking vigorous physical activity.

Hyperostosis has been seen in some patients suffering from keratinising dermatoses on treatment with higher doses ( 2 mg/kg) and long-term administration ( 1 year). Blood donation to women of childbearing age by patients being treated or recently treated (one to two weeks) with isotretinoin is contraindicated.

Aggressive dermabrasion should be avoided in patients on isotretinoin and for a period of 5-6 months after treatment because of the risk of hypertrophic scarring in atypical areas. Wax epilation should be avoided during therapy and at least for a period of 6 months thereafter due to the possibility of scarring or dermatitis.

Isotretinoin has been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. Patients experiencing severe (haemorrhagic) diarrhoea should discontinue isotretinoin immediately.

Use in Pregnancy Pregnancy (Category X) Isotretinoin is highly teratogenic and must not be given to women who are pregnant. Isotretinoin crosses the placental barrier in amounts that lead to congenital deformities. There is an extremely high risk that a deformed infant will result if pregnancy occurs while taking ORATANE in any amount even for short periods. Potentially all exposed foetuses can be affected.

Use in Lactation Owing to its lipophilicity, there is a high probability that isotretinoin is secreted into the breast milk. Isotretinoin must not be given to nursing mothers.

Use in Children Long term use in children under 13 years should be avoided because of a risk of premature epiphyseal closure.

Effects on Ability to Drive or Operate Machinery Isotretinoin is presumed to be safe or unlikely to produce an effect on the ability to drive or use machinery.

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