Roaccutane 10 mg & 20 mg Capsules

Severe recalcitrant nodular acne: Roaccutane is indicated for the treatment of severe recalcitrant nodular acne. Nodules are inflamed lesions with a diameter of 5 mm or greater. The nodules may become suppurative or haemorrhagic. u201cSevereu201d, by definition, means u201cmanyu201d as opposed to u201cfew or severalu201d nodules. Because of significant adverse effects associated with its use, Roaccutane should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. A single course of therapy has been shown to result in complete and prolonged remission of disease in many patients. If a second course of therapy is needed, it should not be initiated until at least 8 weeks after completion of the first course, because experience has shown that patients may continue to improve while off Roaccutane.

The initial diagnosis and prescription of Roaccutane should be performed by a dermatologist with expertise in the use of systemic retinoids for the treatment of severe acne and a full understanding of the risks of isotretinoin therapy and monitoring requirements.

The therapeutic response to Roaccutane and its adverse events are dose-related, and vary between patients. This necessitates individual dosage adjustment during therapy.

Posology

Standard dosage 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 treatment dose of 120 - 150 mg/kg 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 a severe intolerance to the recommended dose, treatment may be continued at a lower dose, with consequent increase in therapy duration. In the majority of patients, complete clearing of the acne is obtained with a single treatment course. In the case of a definite relapse, a renewed course of Roaccutane therapy should be given with the same daily dose as previously. Since further improvement of the acne can be observed up to 8 weeks after discontinuation of treatment, re-treatment should not be initiated until after this period.

Method of administration

The capsules should be taken with food, once or twice daily.

Concurrent topical therapy

Concurrent administration of other keratolytic or exfoliative anti-acne 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.

Pregnancy and lactation: Roaccutane may not be given to breastfeeding mothers. Roaccutane causes foetal malformations. These foetal malformations have been documented and include hydrocephalus, microcephalus, abnormalities of the external ear (micropinna, small or absent external auditory canals), microphthalmia, cardiovascular abnormalities, facial dysmorphia, thymus gland abnormalities, parathyroid gland abnormalities with parathyroid hormone deficiency and cerebellar malformations. There is also an increased risk of spontaneous abortion. Its use 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, unless an effective contraceptive is used, without any interruption, for one month prior to therapy, the duration of therapy and for at least one month after discontinuation of therapy. Even female patients who normally do not employ contraception because of a history of infertility (except in the case of hysterectomy) or who claim absence of sexual activity, must be advised to use effective contraceptive measures while taking Roaccutane, following the guidelines.

It is recommended that two reliable forms of contraception be used simultaneously. Roaccutane is contraindicated in women of child-bearing potential unless the female patient meets all the following conditions: The patient must have severe nodular acne, resistant to standard therapies. She must be reliable in understanding and carrying out instructions. She must be informed by her doctor of the hazards of becoming pregnant during, and one month after, treatment with Roaccutane. She must be warned of the possibility of contraception failure. She must confirm that she has understood the precautions. She must be capable of complying with the mandatory effective contraceptive measures. She must use effective contraception, without any interruption, for 1 month before starting Roaccutane therapy, during therapy and for 1 month following discontinuation of therapy. Careful consideration must be given in each individual case to the efficacy of the contraceptive methods chosen, particularly in the first cycle of hormonal contraception when additional methods are advised. She must have a negative result from a reliable pregnancy test within 11 days prior to the start of therapy. Monthly pregnancy testing during treatment is strongly recommended. She must start Roaccutane therapy only on the 2nd or 3rd day of the next normal menstrual period. In the event of relapse treatment, she must also use the same uninterrupted and effective contraceptive measures, 1 month prior to, during, and for 1 month after Roaccutane therapy, and the same reliable pregnancy evaluations should be followed.

She must fully understand the precautions and confirm her understanding and her willingness to comply with reliable contraceptive measures as explained to her. Should pregnancy occur, in spite of these precautions, during treatment with Roaccutane, or during the first month after discontinuation, there is an extremely high risk of severe malformation of the foetus (involving in particular, the central nervous system, the heart and the large blood vessels), even after exposure for short periods only. Every possible precaution must be taken to ensure that the patient is not pregnant at the time of commencement of, during the course of, and for one month after discontinuation of therapy. In order to assist prescribing physicians and patients in avoiding foetal exposure to isotretinoin, the manufacturer provides a Pregnancy Prevention Programme consisting of the following material to reinforce the warnings about the medicineu2019s teratogenicity and emphasise the mandatory need for reliable contraception in female patients of childbearing potential: Patient Information Brochure, Brochure on Birth Control, Female Patient Information and Consent Form, Physicianu2019s Guide to Prescription, Physicianu2019s Checklist for Prescription to Females. The pregnancy prevention information should be given to patients both orally and in writing. The Patient Information Brochure must be provided to all patients. In addition, all female patients must receive the Brochure on Birth Control and the Female Patient Information and Consent Form.

Roaccutane is also contraindicated in:

• Hypersensitivity to Roaccutane or any of its components. Roaccutane contains soya oil, partially hydrogenated soya oil, and hydrogenated soya oil. Therefore Roaccutane is contraindicated in patients allergic to soya.
• Pre-existing hypervitaminosis A.
• Hepatic insufficiency.
• Patients with excessively elevated blood lipid values.
• Supplementary treatment with tetracyclines is contraindicated, (see section 4.5).

You are reminded that Roaccutane is a scheduled medicine and not a cosmetic agent and that it is a criminal act to transfer it to, or share it with, any person not in possession of a valid prescription. Roaccutane should only be prescribed by physicians who are experienced in the use of systemic retinoids and understand the risk of teratogenicity associated with isotretinoin therapy. Both female and male patients should be given a copy of the Patient Information Brochure.

Hepatotoxicity

Several cases of clinical hepatitis have been noted which are considered to be possibly or probably related to Roaccutane therapy. Liver function should be checked before and 1 month after the start of treatment, and subsequently, at 3 month intervals. Transitory increases in liver transaminases have been reported. In many cases these changes have been within the normal range and values have returned to baseline levels during treatment. However, when transaminase levels exceed the normal levels, and do not return to normal values during treatment or if hepatitis is suspected, reduction of the dose or discontinuation of treatment should be considered.

Psychiatric disorders

Depression, aggravated depression, anxiety, aggressive tendencies, mood alterations, psychotic symptoms, and rarely, suicidal ideation, suicide attempts and suicide have been reported in patients treated with Roaccutane (see section 4.8). 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 Roaccutane may be insufficient to alleviate symptoms and therefore further psychiatric or psychological evaluation may be necessary.

Pseudotumor cerebri

Cases of benign intracranial hypertension (pseudotumor cerebri) have been reported, some of which involved concomitant use of tetracyclines. (See section 4.5). Early signs and symptoms of pseudotumor cerebri include papilloedema, headache, nausea and vomiting and visual disturbances. Patients with these symptoms should be screened for papilloedema and, if present, they should be told to discontinue Roaccutane therapy immediately and be referred to a neurologist for further diagnosis and care. Supplementary treatment with tetracyclines is contraindicated, (see section 4.3).

Visual impairment

Corneal Opacities: Dry eyes, corneal opacities, decreased night vision and keratitis usually resolve after discontinuation of therapy. Due to the possible occurrence of keratitis, patients with dry eyes should be monitored. Dry eyes can be helped by the application of a lubricating eye ointment or by the application of tear replacement therapy. Intolerance to contact lenses may occur which may necessitate the patient to wear glasses during treatment. Patients experiencing visual difficulties should be referred for an expert ophthalmological examination and withdrawal of Roaccutane considered.

Decreased night vision: Decreased night vision may occur during Roaccutane therapy, and may persist after discontinuation of therapy, (see section 4.8). 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.

Lipids

Serum lipids (fasting values) should also be checked, before, and one month after, the start of therapy, and also at the end of treatment. 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. Approximately 25 % of patients receiving Roaccutane experience an elevation in plasma triglycerides. Approximately 15 % developed a decrease in high-density lipoproteins and about 7 % showed an increase in cholesterol levels. These effects on triglycerides, HDL and cholesterol were reversible upon cessation of Roaccutane therapy. Roaccutane should be discontinued if hypertriglyceridaemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur. Levels in excess of 800 mg/dL or 9 mmol/L are sometimes associated with acute pancreatitis, which may be fatal (see section 4.8).

Special patient groups:

In high risk patients (with diabetes, obesity, alcoholism or lipid metabolism disorder) undergoing treatment with Roaccutane, more frequent checks of serum values for lipids and/or blood glucose may be necessary. In diabetic patients, frequent determination of blood glucose levels is recommended. New cases of diabetes mellitus have been diagnosed during Roaccutane therapy.

Musculo-skeletal and connective tissue disorders

Myalgia, arthralgia and increased serum creatine phosphokinase values have been reported in patients receiving Roaccutane, particularly in those undertaking vigorous physical activity. Hyperostosis: In clinical trials for disorders of keratinisation with a mean dose of 2,24 mg/kg/day, a high prevalence of skeletal hyperostosis was noted. Additionally, skeletal hyperostosis was noted in 6 of 8 patients in a prospective study of disorders of keratinisation. Skeletal hyperostosis has also been observed by X-rays in prospective studies of nodular acne patients treated with a single course of therapy at recommended doses.

Premature epiphyseal closure:

Bone changes including premature epiphyseal closure and calcification of tendons and ligaments have occurred after several years of administration at very high doses for treating disorders of keratinisation. The dose levels, duration of treatment and total cumulative dose in these patients generally far exceeded those recommended for the treatment of acne. Therefore, a careful evaluation of the risk/benefit ratio should be carried out in every patient.

Gastrointestinal disorders

Roaccutane 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 Roaccutane immediately.

Concurrent therapy with Roaccutane and vitamin A must be avoided, as symptoms of hypervitaminosis A may be intensified. Cases of benign intracranial hypertension (pseudotumor cerebri) have been reported, some of which involved concomitant use of tetracyclines. Therefore, concomitant treatment with tetracyclines must be avoided. (See section 4.3). No interactions between Roaccutane and other medicines have been observed to date.

Pregnancy is an absolute contraindication to treatment with Roaccutane. If pregnancy does occur in spite of the detailed precautions during treatment with Roaccutane or in the month following therapy, there is a great risk of very severe and serious malformation of the foetus. (See section 4.3).

A number of cases of decreased night vision have occurred during Roaccutane therapy and in rare instances have persisted after therapy. 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 machines.

a. Summary of the safety profile

Every patient should be warned about the possible occurrence of side effects. Most of the side effects of Roaccutane are dose-related.

b. Tabulated list of adverse reactions

Infections Very Rare (u2264 1/10 000) Gram positive (mucocutaneous) bacterial infection Blood and lymphatic system disorders: Very common (u2265 1/10) Common (u2265 1/100, < 1/10) Very Rare (u2264 1/10 000) Anaemia, increased red blood cell sedimentation rate, thrombocytopenia, thrombocytosis Neutropenia Lymphadenopathy Immune system disorders: Rare (u2265 1/10 000, < 1/1 000) Allergic skin reaction, anaphylactic reactions, hypersensitivity Metabolism and nutrition disorders: Very Rare (u2264 1/10 000) Diabetes mellitus, hyperuricaemia Psychiatric disorders: Rare (u2265 1/10 000, < 1/1 000) Very Rare (u2264 1/10 000) Depression, aggravated depression, aggressive tendencies, anxiety, mood alterations Abnormal behaviour, psychotic disorder, suicidal ideation, suicide attempt, suicide Nervous system disorders: Common (u2265 1/100,< 1/10) Very Rare (u2264 1/10 000) Headache Benign intracranial hypertension, convulsions, drowsiness Eye disorders: Very common (u2265 1/10) Very Rare (u2264 1/10 000) Blepharitis, conjunctivitis, dry eye, eye irritation Blurred vision, cataract, colour blindness (colour vision deficiencies), contact lens intolerance, corneal opacity, decreased night vision, keratitis, papilloedema (as sign of benign intracranial hypertension), photophobia Ear and labyrinth disorders: Very Rare (u2264 1/10 000) Impaired hearing Vascular disorders: Very Rare (u2264 1/10 000) Vasculitis (e.g. Wegeneru2019s (eosinophilic) granulomatosis, allergic vasculitis) Respiratory, thoracic and mediastinal disorders: Common (u22651/100, < 1/10) Very Rare (u2264 1/10 000) Epistaxis, nasal dryness, nasopharyngitis Bronchospasm (particularly in patients with asthma), hoarseness Gastrointestinal disorders: Very Rare (u2264 1/10 000) Colitis, ileitis, dry throat, gastrointestinal haemorrhage, haemorrhagic diarrhoea and inflammatory bowel disease, nausea, pancreatitis (see section 4.4: Gastrointestinal disorders) Hepatobiliary disorders: Very common (u2265 1/10) Very Rare (u2264 1/10 000) Increased transaminase (see section 4.4: Lipids) Hepatitis Skin and subcutaneous tissues disorders: Very common (u2265 1/10) Cheilitis, dermatitis, dry skin, localised exfoliation, Rare (u2265 1/10 000, <1/1 000) Very Rare (u2264 1/10 000) pruritus, erythematous rash, skin fragility (risk of frictional trauma) Alopecia Acne fulminans, aggravated acne (acne flare), erythema (facial), exanthema, hair disorders, hirsutism, nail dystrophy, paronychia, photosensitivity reaction, pyogenic granuloma, skin hyperpigmentation, increased sweating Musculo-skeletal and connective tissue disorders: Very common (u2265 1/10) Very Rare (u2264 1/10 000) Arthralgia, myalgia, back pain (particularly adolescent patients) Arthritis, calcinosis (calcification of ligaments and tendons), epiphyses premature fusion, exostosis, (hyperostotis), reduced bone density, tendonitis Renal and urinary disorders: Very Rare (u2264 1/10 000) Glomerulonephritis General disorders and administration site conditions: Very Rare (u2264 1/10 000) Increased formation of granulation tissue, malaise Investigations: Very common (u2265 1/10) Common (u22651/100, < 1/10) Very Rare (u2264 1/10 000) Increased blood triglycerides, decreased high density lipoprotein Increased blood cholesterol, increased blood glucose, haematuria, proteinuria Increased blood creatine phosphokinase The incidence of the adverse events was calculated from pooled clinical trial data involving 824 patients.

Post Marketing During the post-marketing period, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported with Roaccutane, (see section 4.4). Serious cases of rhabdomyolysis, often leading to hospitalisation and some with fatal outcome, have been reported, particularly in those undertaking vigorous physical activity.

Although the acute toxicity of Roaccutane is low, signs of hypervitaminosis A could appear in cases of accidental overdose. Evacuation of the stomach may be indicated in the first few hours after overdose. Further treatment is supportive and symptomatic.