ORATANE® (Isotretinoin) soft gelatin capsule

ORATANE® (Isotretinoin) soft gelatin capsule

ORATANE® (Isotretinoin) soft gelatin capsule

Pharmacotherapeutic group: Retinoids for treatment of acne; ATC code: D10B A01

Each ORATANE 5 mg soft gelatin capsule contains 5 mg of isotretinoin. Each ORATANE 10 mg soft gelatin capsule contains 10 mg of isotretinoin. Each ORATANE 20 mg soft gelatin capsule contains 20 mg of isotretinoin. Each ORATANE 30 mg soft gelatin capsule contains 30 mg of isotretinoin. Each ORATANE 40 mg soft gelatin capsule contains 40 mg of isotretinoin.

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.

Therapeutic 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.

Dose and method of administration

Dose

Patient response to isotretinoin is dose-related and varies from case to case. This necessitates adapting the dosage to individual needs according to severity of the clinical picture and side effects. With a dosage of between 0.1 and 1.0 mg/kg daily over 12-16 weeks, it is generally possible to achieve a considerable improvement or complete healing. The daily dose is taken with meals; low doses once daily and higher amounts as a single dose or in several doses spread over the day.

Initial treatment

As a rule, therapy is started with 0.5 mg/kg daily and maintained for 2 to 4 weeks until the patient’s response is clear. Initially, the acne may be aggravated for a short period.

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 longer therapy duration.

Follow-up Treatment (Maintenance Dose)

In patients who respond well to isotretinoin, treatment should be continued with a dosage of 0.5 mg/kg daily. With patients who show signs of intolerance during the initial therapy, the daily dosage should be reduced to 0.1-0.2 mg/kg. Where response to the initial dosage is slight, and in particularly severe cases, the daily dosage may be increased to 1 mg/kg provided the medicine is well tolerated. The maintenance dose is administered for a period of 12 weeks after which the first stage of therapy is generally terminated. After discontinuation of treatment, often a further improvement is observed which may last from a few weeks to several months. There should, therefore, be an interval of at least eight weeks before restarting treatment. In the event of recurrence of the acne, treatment should be resumed on the above lines, bearing in mind that recurrences may respond to a lower dosage.

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Concurrent Adjuvant Treatment

As a rule this is not indicated. It is advisable to discontinue antimicrobials before beginning treatment with isotretinoin. Concomitant radiation (ultraviolet) therapy and exposure to sunlight should also be avoided. Concomitant topical therapy of a mild nature may, however, be carried out.

Special populations

Patients with renal impairment: If appropriate, treatment should be started at a lower dose (e.g. 10 mg/day) and afterwards individually adjusted according to tolerability.

Paediatric population: Long term use in children under 13 years should be avoided because of a risk of prematureepiphyseal closure

Method of Administration

The daily dose is taken with meals.

Contraindications

  • Isotretinoin is contraindicated in women who are pregnant, or who may become pregnant while undergoing treatment.
  • Isotretinoin is also contraindicated in patients with hypersensitivity to isotretinoin or to any of the excipients.
  • Isotretinoin is also contraindicated in patients with hepatic and renal insufficiency
  • Hypervitaminosis A.
  • Excessively elevated blood lipid values.

Special warnings and precautions for use

Pregnancy Prevention

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.

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.

Women of childbearing potential: 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. Micro-dosed 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.

Male Patients: The available data suggest that the level of maternal exposure from the semen of patientsreceiving isotretinoin, is not of sufficient magnitude to be associated with the teratogenic effectof isotretinoin.

Male patients should be reminded that they must not share their medication with anyone, particularly not females.

Hypersensitivity reactions: Hypersensitivity reactions may occur in susceptible individuals.

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

Lipid metabolism and high-risk patients: Serum lipids (fasting value) should also be checked (before and one month after the start oftherapy, 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) undergoingtreatment with isotretinoin, more frequent checks may be necessary. Isotretinoin should not beused together with any medicine known to enhance liver metabolism or interfere withenterohepatic circulation.

Eye disorders: Patients, particularly those with dry eyes, should be monitored for the development ofkeratitis.Decreased night vision has occurred during isotretinoin therapy and in rare instances haspersisted after discontinuation of therapy, see Section 4.8. Because the onset in some patientswas sudden, patients should be advised of this potential problem and warned to be cautiouswhen driving or operating any vehicle at night. Visual problems should be carefullymonitored.

Psychiatric disorders: Depression, psychotic symptoms and rarely suicide attempts and suicide havebeen reported in patients treated with isotretinoin. Although a causal relationship has not beenestablished particular care needs to be taken in patients with a history of depression and allpatients should be monitored for signs of depression and referred for appropriate treatment ifnecessary.

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

Musculo-skeletal and connective tissue disorders: Myalgia and arthralgia may occur and may be associated with reduced tolerance to vigorousexercise. Isolated instances of raised serum CPK values have been reported inpatients receiving isotretinoin, particularly those undertaking vigorous physical activity.Hyperostosis has been seen in some patients suffering from keratinising dermatoses ontreatment with higher doses (> 2 mg/kg) and long-term administration (> 1 year).

Blood donation: Blood donation to women of childbearing age by patients being treated or recently treated (oneto two weeks) with isotretinoin is contraindicated.

Skin and subcutaneous tissues disorder: Aggressive dermabrasion should be avoided in patients on isotretinoin and for a period of 5-6months after treatment because of the risk of hypertrophic scarring in atypical areas. Waxepilation should be avoided during therapy and at least for a period of 6 months thereafter dueto the possibility of scarring or dermatitis.

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

Interaction with other medicines and other forms of interaction

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 including combined oral contraceptives as recommended for pregnancy prevention have been observed to date.

Concurrent administration of other topical 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.

Fertility, pregnancy and lactation 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.

Breast-feeding: Owing to its lipophilicity, there is a high probability that isotretinoin is secreted into the breastmilk. Isotretinoin must not be given to nursing mothers.

Fertility: No data available.

Effects on ability to drive and use machines

Changes in vision, including decreased night vision, have been reported during isotretinoin therapy. Patients should be warned about the potential changes in vision, and advised not to drive or operate machinery if these symptoms occur or until their individual susceptibility is known.

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Undesirable effects

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 fattyointment, dryness of the nasal mucosa which can lead to epistaxis, dryness of the pharyngealmucosa and hoarseness and dryness of the vaginal and/or anal mucosa.Eye disorders Dryness of the eyes can cause conjunctivitis and reversible corneal opacities.

Vascular disorders: There have been cases of allergic vasculitis including Wegener’s granulomatosis,

Blood and lymphatic system disorders: There have been cases of reduction in white and red blood cell counts including anaemia andneutropenia, increases and decreases in platelet count, elevated sedimentation rate.

Respiratory, thoracic and mediastinal disorders: Bronchospasm has been rarely reported; sometimes in patients with a pre-history of asthma.

Psychiatric disorders and Nervous system disorders: Behavioural disorders, depression, headache, increased intracranial pressure(pseudotumor cerebri) and seizures.

Investigations: Transitory and reversible increases in transaminases as well as some cases of hepatitis relatedto isotretinoin have been observed. In many such cases the changes have been within thenormal 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 withisotretinoin.

Reproductive system and breast disorders: Sexual dysfunction including erectile dysfunction and decreased libido has been reportedwith unknown frequency, i.e. cannot be estimated from the available data.

Paediatric population: Bone changes and hyperostosis have occurred in children (including premature epiphysealclosure.

Overdose

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.

For advice on the management of overdose please contact the National Poisons Centre on 0800 POISON (0800 764766).

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