Haemocarb Adco . Solution

Severe recalcitrant nodular acne : Oratane 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, ORATANE 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 Oratane.

The initial diagnosis and prescription of Oratane 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 Oratane and its adverse events are dose-related, and vary between patients. This necessitates individual dosage adjustment during therapy.

Standard dosage

Paediatric population

Oratane should not be used for treatment of prepubertal acne and is not recommended in children less than 12 years of age due to lack of data on efficacy and safety.

Adults including adolescents and the elderly

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. The 5 mg capsule may be used if necessary, to adjust the reduced dosage appropriately. Note that the 5 mg capsule alone should not be used to initiate therapy as the starting dose cannot be achieved with a single 5 mg capsule daily. 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 Oratane 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 medicines 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:

ORATANE should not be given to breastfeeding women. ORATANE causes foetal malformations. These foetal malformations have been documented and include hydrocephalus, microcephalus, abnormalities of the external ear (micropinna, small or absent auditory canals), microphthalmia, cardiovascular abnormalities, facial dysmorphia, thymus gland abnormalities, parathyroid hormone deficiency and cerebellar malformations. There is also an increased risk of spontaneous abortion. ORATANE 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 ORATANE, following the guidelines. It is recommended that two reliable forms of contraception be used simultaneously.

ORATANE is contraindicated in women of childbearing potential unless the patient meets all the following conditions:

• The patient must have severe nodular acne, resistant to standard therapies.
• She must be informed by her medical practitioner of the hazards of becoming pregnant during, and one month after, treatment with ORATANE.
• She must be warned of the possibility of contraception failure.
• She must confirm that she has understood the precautions.
• She must be reliable in understanding and carrying out instructions.
• She must be capable of complying with the mandatory effective contraceptive measures.
• She must use effective contraception, without interruption, for one month prior to therapy, the duration of therapy and for one month after discontinuation of therapy. Careful consideration must be given in each individual case to the efficacy of the contraceptive methods chosen, additional methods of contraception may be advised, particularly in the first cycle of hormonal contraception.
• She must have a negative result from a reliable pregnancy test within eleven days prior to the start of therapy.
• Monthly repetition of pregnancy testing strongly is recommended during therapy.
• She must start ORATANE therapy only on the 2nd or 3rd day of the next normal menstrual period.
• In the event of relapse treatment, she must use the same uninterrupted and effective contraceptive measures, one month prior to, during, and for one month after ORATANE 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 ORATANE 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 ORATANE therapy.

In order to assist prescribing medical practitioners and patients in avoiding foetal exposure to isotretinoin, the manufacturer provides a Pregnancy Prevention Program 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
• Medical practitioneru2019s guide to prescription
• Medical practitioneru2019s checklist for prescription to females

The pregnancy prevention information should be given to patients both verbally 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.

Oratane is also contraindicated in:

• Hypersensitivity to isotretinoin or to any of the ingredients of Oratane (see section 6.1).
• Oratane contains soya-bean oil. Therefore, Oratane is contraindicated in patients allergic to peanut or soya.
• Pre-existing hypervitaminosis A.
• Hepatic insufficiency.
• Patients with excessively elevated blood lipid values.
• Concurrent therapy with tetracyclines (see section 4.5).

Oratane is a scheduled medicine, not a cosmetic medicine. It is a criminal offence to transfer it to or share it with any person not in possession of a valid prescription. Oratane should only be prescribed by medical practitioners experienced in the use of systemic retinoids and who understand the risk of teratogenicity associated with isotretinoin therapy. All patients should be given a copy of the Patient Information Brochure.

Hepatitis, which may be fatal, may occur with Oratane therapy. Liver Function should be evaluated before and one month after the start of therapy with Oratane and thereafter at three-monthly intervals. Elevations of liver enzymes have been reported with isotretinoin as in Oratane therapy, some of which normalised with dosage reduction or with continued administration. If normalisation does not occur or if hepatitis is suspected during treatment, reduction of dose or discontinuation of Oratane therapy should be considered and the aetiology further evaluated.

Oratane should be used with caution in:

• Patients with a history of depression - 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 Oratane (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 Oratane may be insufficient to alleviate symptoms and therefore further psychiatric or psychological evaluation may be necessary.
• Hypercholesterolaemia and patients with a tendency to develop hypertriglyceridaemia (e.g. those with diabetes mellitus, obesity, alcoholism or a family history of hypertriglyceridaemia) u2013 Blood lipid determinations should be performed before therapy with Oratane and at regular intervals until the lipid response to Oratane is established, usually within one month 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 resolve in response to dietary measures. Approximately 25 % of patients receiving isotretinoin as in Oratane experience an elevation in plasma triglycerides, 15 % a decrease in high-density lipoproteins ( HDL) cholesterol and 7 % an increase in total cholesterol. These effects on triglycerides, HDL and cholesterol were reversible upon cessation of isotretinoin as in Oratane therapy.
• Diabetes mellitus u2013 Frequent determinations of blood glucose levels are recommended. New cases of diabetes mellitus have been diagnosed during isotretinoin as in Oratane therapy.

Oratane therapy has been associated with:

• Pseudotumour cerebri (benign intracranial hypertension) u2013 Early signs and symptoms include papilloedema, headache, nausea, vomiting and visual disturbances. Patients presenting with these symptoms should be screened for papilloedema and, if present, discontinue therapy with Oratane. The patient should be referred to a neurologist. 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 Oratane considered.
• Decreased night vision: Decreased night vision may occur during Oratane 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. Patients experiencing visual difficulties should be referred for an expert ophthalmological opinion. Withdrawal of Oratane may be necessary.
• Acute pancreatitis - Oratane 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).
• Musculoskeletal and connective tissue disorders - Myalgia, arthralgia and increased serum creatine phosphokinase values have been reported in patients receiving isotretinoin as in Oratane, 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 u2013 Isotretinoin as in Oratane 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 Oratane immediately.

Concurrent use of Oratane with vitamin A should be avoided. Patients should be advised against taking supplements containing vitamin A to avoid additive toxic effects from hypervitaminosis A. Concurrent use of Oratane with tetracyclines is contraindicated. Cases of benign intracranial hypertension (pseudotumor cerebri) have been reported with concomitant use (see section 4.3). Concomitant therapy of Oratane and keratolytic or exfoliative anti-acne medicines is not indicated. Adjuvant therapy with mild topical preparations may be given, if required. Radiation therapy or ultraviolet therapy should not be undertaken during therapy with Oratane. No interactions between isotretinoin as in Oratane and oral contraceptives have been reported.

Pregnancy

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

Breastfeeding

The passage of isotretinoin into human milk is very likely. Due to the potential of adverse effects in the child exposed via motheru2019s milk, Oratane is contraindicated during breastfeeding (see section 4.3).

Fertility

Isotretinoin in therapeutic dosages does not affect the number, motility and morphology of sperm and does not jeopardise the formation and development of the embryo on the part of the men taking isotretinoin as in Oratane.

Isotretinoin as in ORATANE may cause drowsiness, dizziness and visual disturbances which may have influence on the ability to drive and use machines. A number of cases of decreased night vision have occurred during Oratane therapy and in some 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. Therefore, they should not drive or operate machines until they know how treatment with Oratane affects them.

Summary of the reported safety profile

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

Tabulated list of adverse events

System Organ Class Incidence Adverse events

• Infections and Infestations: Less frequent Gram positive (mucocutaneous) Bacterial infection
• Blood and lymphatic system disorders: Frequent Anaemia, increased red blood cell sedimentation rate, thrombocytopenia, thrombocytosis, neutropenia; Less frequent Lymphadenopathy
• Immune system disorders: Less frequent Allergic skin reaction, anaphylactic reactions, hypersensitivity
• Metabolism and nutrition disorders: Less frequent Diabetes mellitus, hyperuricaemia
• Psychiatric disorders: Less frequent Depression, aggravated depression, aggressive tendencies, anxiety, mood alterations, abnormal behaviour, psychotic disorder, suicidal ideation, suicide, suicide attempt
• Nervous system: Frequent Headache; Less frequent Benign intracranial hypertension (pseudotumour cerebri), convulsions , drowsiness, dizziness
• Eye disorders: Frequent Blepharitis, conjunctivitis, dry eyes, eye irritation; Less frequent 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, visual disturbances.
• Ear and labyrinth disorders: Less frequent Impaired hearing
• Vascular disorders: Less frequent Vasculitis (e.g. Wegeneru2019s (eosinophilic) granulomatosis, allergic vasculitis)
• Respiratory, thoracic and mediastinal disorders: Frequent Nasopharyngitis, epistaxis, nasal dryness; Less frequent Bronchospasm (particularly in patients with asthma), hoarseness
• Gastrointestinal disorders: Less frequent Colitis, ileitis, dry throat, gastrointestinal haemorrhage, haemorrhagic diarrhoea and inflammatory bowel disease, nausea, pancreatitis (see section 4.4)
• Hepatobiliary disorders: Frequent Increased transaminase; Less frequent Hepatitis
• Skin and Subcutaneous tissue disorders: Frequent Cheilitis, dermatitis, dry skin, localised exfoliation, pruritus, erythematous rash, skin fragility (risk of frictional trauma); Less frequent Alopecia, Acne fulminans, aggravated acne (acne flare), erythema (facial), exanthema, hair disorders, hirsutism, nail dystrophy, paronychia, photosensitivity reaction, pyogenic granuloma, skin hyperpigmentation, increased sweating
• Frequency unknown: Erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis
• Musculoskeletal and connective tissue disorders: Frequent Arthralgia, myalgia, back pain (particularly adolescent patients); Less frequent Arthritis, calcinosis (calcification of ligaments and tendons), epiphyses premature fusion, exostosis, (hyperostotis), reduced bone density, tendonitis; Frequency unknown Rhabdomyolysis: often leading to hospitalisation and some fatal outcome, have been reported, particularly in those undertaking vigorous physical activity.
• Reproductive system and breast disorders: Frequency unknown Sexual dysfunction including erectile dysfunction and decreased libido, gynaecomastia, vulvovaginal dryness.
• Renal and urinary disorders: Less frequent Glomerulonephritis
• General disorders and administration site conditions: Less frequent Increased formation of granulation tissue, malaise
• Investigations: Frequent Increased blood triglicerides, decreased high density lipoprotein, increased blood cholesterol, increased blood glucose, haematuria, proteinuria; Less frequent Increased blood creatine phosphokinase

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c 6.04 Adverse Drug Reactions Reporting Form u201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

See section 4.8 and section 4.4. Symptoms of overdose: Isotretinoin is a derivative of vitamin A. Signs of hypervitaminosis A may occur in case of overdose. Manifestations of acute vitamin A toxicity include severe headache, nausea or vomiting, drowsiness, irritability, and pruritus. Signs and symptoms of accidental overdosage with Oratane would probably be similar.

Treatment of overdose: Treatment is symptomatic and supportive.