Oratane

Isotretinoin.

Isotretinoin (BP.Ph.Eur) 5 mg, 10 mg and 20 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 all-trans 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-1-yl)nona-2,4,6,8-tetraenoic acid, molecular weight 300.42 and molecular formula is C₂₀H₂₈O₂.
Excipients/Inactive Ingredients: The 5 mg, 10 mg and 20 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).

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 (C_max) of approximately 200-300 ng/ml have been achieved in healthy volunteers three to four hours (t_max) 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 not known 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.

Oratane is indicated for the treatment of severe forms of acne (nodulo-cystic forms) and acne, which has failed to respond to other therapies.
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.

The therapeutic response to Oratane and its adverse events are dose-related and varies between patients. This necessitates individual dosage adjustment during therapy. Oratane therapy should be started at a dose of 0.5 mg/kg daily. For most patients the dose ranges from 0.5-1.0 mg/kg per day. Patients with very severe disease or with truncal acne may require higher daily doses up to 2.0 mg/kg.
A cumulative dose of 120 mg/kg per treatment has been documented to increase remission rates and prevent relapse. The therapy duration in individual patients therefore varies as a function of the daily dose. Complete remission of the acne is often achieved by a therapy course of 16-24 weeks. In patients who show severe intolerance to the recommended dose, treatment may be continued at a lower dose with the consequence of a longer therapy duration.
In the majority of patients complete clearing of the acne is obtained with a single treatment course. In case of a definite relapse, a renewed course of Oratane therapy should be given with the same daily dose and cumulative treatment dose as previously. Since further improvement of the acne can be observed up to 8 weeks after discontinuation of treatment, retreatment should not be initiated until after this period.
The capsules should be taken with food once or twice daily.

Although the acute toxicity of overdosage is low, signs of hypervitaminosis A could appear in cases of accidental overdose. Such symptoms are reversible. Nevertheless, evacuation of the stomach may be indicated in the first few hours after overdosage.

Isotretinoin is contraindicated in hepatic and renal insufficiency; hypervitaminosis A; patients with excessively elevated blood lipid values; hypersensitivity to the medicine or any of the excipients.
Use in 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: The patient has severe disfiguring cystic acne resistant to standard therapies.
The patient must be reliable in understanding and carrying out instructions.
The patient is capable of complying with the mandatory contraceptive measures.
The patient is informed by the physicians of the hazards of becoming pregnant during and 1 month after treatment with isotretinoin and the patient is warned of the possibility of contraceptive failure.
The patient confirms that she has understood the warnings.
The patient has a negative pregnancy test within two weeks prior to beginning therapy. Monthly repetition of pregnancy testing is recommended.
The patient must use effective contraception without any interruption for 1 month before beginning isotretinoin therapy, during therapy and for 1 month following discontinuation of therapy. At least one and preferably two complementary forms of contraception including a barrier method should be used. Microdosed progesterone preparations (minipills) may be an inadequate method of contraceptive during isotretinoin therapy.
The patient starts isotretinoin therapy only on the second or third day of the next menstrual period.
In the event of relapse treatments the patient must also use the same uninterrupted and effective contraceptive measures 1 month prior to, during and for 1 month after isotretinoin therapy.
The patient 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 guidelines as previously mentioned.
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.

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 Reactions). 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.
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 Reactions). 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.
Psychiatric disorders: Depression, depression aggravated, anxiety, aggressive tendencies, mood alterations, psychotic symptoms, and very rarely, suicidal ideation, suicide attempts and suicide have been reported in patients treated with isotretinoin. 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. However, discontinuation of isotretinoin may be insufficient to alleviate symptoms and therefore further psychiatric or psychological evaluation may be necessary. Awareness by family or friends may be useful to detect mental health deterioration.
Male Patients: The available data suggest that the level of maternal exposure from the semen of patients receiving isotretinoin, is not of sufficient magnitude to be associated with the teratogenic effect of isotretinoin.
Male patients should be reminded that they must not share their medication with anyone, particularly not females.
Use in 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: The use of Oratane in pediatric patients less than 12 years of age has not been studied. The use of Oratane for the treatment of severe recalcitrant nodular acne in pediatric patients age 12 to 17 years should be given careful consideration, especially for those patients where a known metabolic or structural bone disease exists. Clinical study has shown that isotretinoin, at a dose of 1mg/kg/day given in two divided doses, was effective in treating recalcitrant nodular acne in patients age 13 to 17 years.

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.
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: The patient has severe disfiguring cystic acne resistant to standard therapies.
The patient must be reliable in understanding and carrying out instructions.
The patient is capable of complying with the mandatory contraceptive measures.
The patient is informed by the physicians of the hazards of becoming pregnant during and 1 month after treatment with isotretinoin and the patient is warned of the possibility of contraceptive failure.
The patient confirms that she has understood the warnings.
The patient has a negative pregnancy test within two weeks prior to beginning therapy. Monthly repetition of pregnancy testing is recommended.
The patient must use effective contraception without any interruption for 1 month before beginning isotretinoin therapy, during therapy and for 1 month following discontinuation of therapy. At least one and preferably two complementary forms of contraception including a barrier method should be used. Microdosed progesterone preparations (minipills) may be an inadequate method of contraceptive during isotretinoin therapy.
The patient starts isotretinoin therapy only on the second or third day of the next menstrual period.
In the event of relapse treatments the patient must also use the same uninterrupted and effective contraceptive measures 1 month prior to, during and for 1 month after isotretinoin therapy.
The patient 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 guidelines as previously mentioned. 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.
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.

Most of the adverse effects of isotretinoin are dose related. In the proper dosage, tolerability is generally acceptable in view of the severity of the disease. Every patient should be warned about the possible occurrence of adverse effects.
Hypervitaminosis A: The most frequently observed symptoms are those associated with hypervitaminosis A, i.e. dryness of the mucosa, which on the lips can be relieved by the application of a fatty ointment, dryness of the nasal mucosa which can lead to epistaxis, dryness of the pharyngeal mucosa and hoarseness and dryness of the vaginal and/or anal mucosa.
Eyes: Dryness of the eyes can cause conjunctivitis and reversible corneal opacities.
Conjunctivitis can be improved by a mild eye ointment. Intolerance to contact lenses may force the patient to wear glasses during treatment. Isolated cases of photophobia, dark adaptation disturbances (decreased night vision) and lenticular cataracts have been reported. Keratitis in association with isotretinoin treatment is a rare event and possibly related to the dry eye syndrome. Therefore patients, particularly those with dry eye syndrome, should be monitored for the development of keratitis.
Skin: Exanthema, pruritus, dermatitis facialis, sweating, pyogenic granuloma, paronychia, nail dystrophy and increased formation of granulation tissue may occur. Rare cases of persistent hair thinning have been reported. Reversible alopecia has been observed. Hirsutism, acne fulminans and hyperpigmentation (facial) have been reported rarely. Rarely, patients may experience photosensitivity reactions.
Bone: Bone changes and hyperostosis have occurred in children (including premature epiphyseal closure) and adults treated over long periods with high doses of isotretinoin generally for indications other than cystic acne. In one patient, spinal hyperostoses and calcification of the spinal ligaments with subsequent compression of the spinal cord were observed following long-term treatment over several years with another retinoid, etretinate. Isotretinoin is not intended for long-term therapeutic use, and the possibility of this adverse effect occurring if it is used improperly for long-term treatment should be borne in mind.
Minimal hyperostosis has been observed in cystic acne patients treated with a single course of isotretinoin. Due to the possible occurrence of these bone changes, a careful evaluation of the risk/benefit ratio should be carried out in every patient and isotretinoin administration should be restricted to severe cases.
Haematology: There have been cases of allergic vasculitis including Wegener's granulomatosis, decreases in white and red blood cell counts including anaemia and neutropenia, increases and decreases in platelet count, elevated sedimentation rate.
Respiratory System Disorders: Bronchospasm has been rarely reported; sometimes in patients with a pre-history of asthma.
Psychiatric and Central Nervous System Disorders: Behavioural disorders, depression (see Precautions), headache, increased intracranial pressure (pseudotumor cerebri) and seizures.
Rare (may affect up to 1 in 1,000 people): Depression, depression aggravated, aggressive tendencies, anxiety, mood alterations.
Very rare (may affect up to 1 in 10,000 people): Suicide, suicide attempt, suicidal ideation, psychotic disorder, abnormal behaviour.
Laboratory Data: Transitory and reversible increases in transaminases as well as some cases of hepatitis related to isotretinoin have been observed. In many such cases the changes have been within the normal range and values have returned to baseline levels during treatment. In other cases, however, it has been necessary to reduce the dosage or discontinue treatment with isotretinoin.
Increases in serum triglyceride and cholesterol levels as well as a decrease of HDL have also been observed, particularly at high dosages and in predisposed patients (with a family history of lipid metabolism disorders, diabetes, obesity or alcoholism). These changes too are dose-related, and values return to normal on reduction of the dosage or withdrawal of the medicine.
Other effects: Isolated cases of benign intracranial hypertension and visual disturbances, and occasionally nausea and headache have been observed. Pancreatitis and haematuria/proteinurea occur rarely.
Impaired hearing in certain frequencies and local or systemic infections due to Gram-positive microorganisms (Staphylococcus aureus) have been reported.
Muscle and joint pain and, more rarely, overdosage, inflammatory bowel disease (eg. Colitis, ileitis haemorrhage), and hyperuricaemia have been reported.
Lymphadenopathy has occasionally been noted.
Post Marketing: Sexual dysfunction including erectile dysfunction and decreased libido have also been reported.

Concurrent therapy with ORATANE and vitamin A must be avoided, as symptoms of hypervitaminosis A may be intensified. As tetracyclines can also cause an increase in intracranial pressure, their combination with isotretinoin is contraindicated. No further interactions between isotretinoin and other medicines (eg. Oral contraceptives) have been observed to date.
Concurrent topical therapy: Concurrent administration of other keratolytic or exfoliative antiacne agents is not indicated, nor is concurrent radiation therapy with ultraviolet light indicated. Patients should avoid exposure to the sun. Adjuvant therapy with mild topical medicines may be given, as required.

Protect from light and moisture.
5 mg: Store below 30°C.
10 mg and 20 mg: Store below 25°C.
Shelf life: The shelf life of Oratane 5 mg, 10 mg and 20 mg capsules in their original blister packaging when stored according to the instructions on the carton is 3 years.

Acne Treatment Preparations

D10BA01 - isotretinoin ; Belongs to the class of systemic retinoid preparations used in the treatment of acne.

POM

Cap 5 mg (soft gelatin, oval faint pinkish/cream to cream coloured, approximately 8 mm in length and 5 mm in diameter) x 60's. 10 mg (soft gelatin, oval opaque violet, approximately 10 mm in length and 7 mm in diameter) x 60's. 20 mg (soft gelatin, oval opaque maroon, approximately 13 mm in length and 8 mm in diameter) x 60's.