INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo ORATANE 10 MG (Soft Gelatine Capsules)
ORATANE 20 MG (Soft Gelatine Capsules)

SCHEDULING STATUS
S5

PROPRIETARY NAME
(and dosage form)

ORATANE 10 MG (Soft Gelatine Capsules)
ORATANE 20 MG (Soft Gelatine Capsules)

This product is teratogenic. It should not be taken by pregnant women.

COMPOSITION
Each soft gelatine capsule contains 10 mg or 20 mg
isotretinoin and DL- alpha-tocopherol 1,56% w/w and butylated hydroxyanisole 0,06% w/w as antioxidants.
Chemical name: 3,7-dimethyl-9-(2,6, 6-trimethyl-1-yl)-2,4,6,8-nonatetraenoic acid (13-cis retinoic acid).

PHARMACOLOGICAL CLASSIFICATION
A.13.4.2. Dermatological preparations. Other.

PHARMACOLOGICAL ACTION
Pharmacodynamics
Isotretinoin is a retinoid. It is the cis configuration of tretinoin, which is the acid form of vitamin A.
The exact mechanism of action for isotretinoin is not known. However, isotretinoin reduces sebaceous gland size and inhibits sebaceous gland activity, thereby decreasing sebum secretion. This action is probably responsible for the rapid initial clinical improvement in nodular acne. Isotretinoin has also been shown to decrease the number of Propionibacterium acnes organisms within the follicle. However, since isotretinoin has no effect on P. acnes in vitro,this action is probably a secondary effect due to decreased sebum secretion. In addition isotretinoin has been shown to have anti-keratinizing and anti-inflammatory actions.
Pharmacokinetics
Absorption
Isotretinoin is rapidly absorbed from the gastrointestinal tract and reaches peak plasma concentrations (Cmax) of approximately 200-300 ng/mL in healthy volunteers three to four hours (tmax) after administration of 40 mg isotretinoin.
Taking isotretinoin with food increases bioavailability.
Distribution
Isotretinoin is highly bound to plasma proteins, approximately 99,9%. Albumin appears to be the major binding protein.
Isotretinoin crosses the placental barrier in amounts that lead to congenital deformities.
Owing to its lipophilicity, there is a high probability that isotretinoin is secreted into the breast milk.
Metabolism
Isotretinoin is metabolised in the liver and possibly the gut wall, the major metabolite being 4-oxo-isotretinoin.
Elimination
Isotretinoin appears to be eliminated almost exclusively by hepatic metabolism and biliary excretion.
The terminal half-life of isotretinoin and 4-oxo-isotretinoin is between 10 and 20 hours and 17 to 50 hours respectively.

INDICATIONS
ORATANE
is indicated in:
- the treatment of severe, recalcitrant nodular acne, where severe is defined as numerous lesions of at least 5 millimetres in diameter that may be suppurative or haemorrhagic.
- severe, inflammatory acne and acne conglobata.
Taking into consideration its potential adverse effects, ORATANE may be considered in patients with moderately severe acne who are prone to scarring or dyspigmentation.
Because of the potential adverse effects, isotretinoin should be reserved for patientswith severe nodular acne who are unresponsive to or intolerant of conventional therapy, including systemic antibiotics.

CONTRA-INDICATIONS
ORATANE
is contra-indicated in:
- pregnancy and lactation (see separate section);
- hypersensitivity to any of the ingredients in the formulation as well as acitretin, tretinoin or vitamin A derivatives;
- patients with liver and kidney impairment, hypervitaminosis A and patients with hyperlipidaemias;
- simultaneous intake of vitamin A or other retinoids and simultaneous administration of tetracyclines.

WARNINGS
ORATANE
is a medicine only available on prescription for a specific patient. Under no circumstances may it be given to another person as it is a criminal offence.
Serum Liver Profile
It is recommended that liver function be measured prior to therapy, after one month of treatment and thereafter as appropriate to establish the hepatic function response.
Jaundice or hepatitis and transient alterations to liver enzyme levels have been reported with isotretinoin therapy.
Serum Lipid Profile
Transient elevations in plasma triglycerides and, to a lesser extent, total cholesterol and lowering of high density lipoproteins (HDL) can be associated with the use of ORATANE. The lipid profile should be determined prior to therapy and thereafter monthly to ensure that the treatment does not cause deterioration in these laboratory values.
For all patients, especially those with an increased risk of a lipometabolic disorder (e.g. familial predisposition to diabetes, alcohol abuse with fatty generation of the liver, slimming treatments, heavy smoking, already existing or familial lipometabolic disorder), treatment with ORATANE should only be continued if the laboratory values do not deteriorate during the therapy.
Isotretinoin-treated patients with high serum triglycerides are at risk to develop pancreatitis.
Depression and Suicidal Behaviour
Treatment with ORATANE may lead to depression, psychotic symptoms and suicidal behaviour (See SIDE-EFFECTS). Should this occur, ORATANE should be discontinued and patients should be further monitored if necessary.
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.
Benign Intracranial Hypertension
Rare cases of benign intracranial hypertension (pseudotumour cerebri) have been reported. Symptoms include blurred vision or other changes in vision including corneal opacities and papilloedema, severe or continuing headache, nausea and vomiting. In the event of visual changes, ORATANE therapy should be discontinued. Opthalmological examinations are advised.
Diabetes Mellitus or Family History thereof
Possible alteration of blood glucose concentrations may occur. 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.
Dark Adaptation Visual Disturbance
Temporary corneal clouding and an impairment of night vision have been found in a few patients. Patients should be warned as to the effect that it could have on the ability to drive in the night.
Skeletal Hyperostosis
Incidences of skeletal hyperostosis have occurred. Symptoms include back pain, bone or joint pain, difficulty in moving and stiff painful muscles.
Inflammatory Bowel Disease or Regional Ileitis
ORATANE
therapy should be discontinued if symptoms e.g. rectal bleeding, severe abdominal or stomach pain, severe diarrhoea occur.
Pregnancy and Lactation
All females of childbearing potential should be warned about the teratogenic effects of isotretinoin.
See separate boxed section on PREGNANCY AND LACTATION.
The patient’s skin condition may worsen within the first several weeks of treatment.
Patients who wear contact lenses should be advised to wear glasses during the treatment period due to the dryness and sensitivity of the eyes experienced with ORATANE treatment.
Patients receiving ORATANE should not donate blood during, or for at least 1 month after cessation of therapy.
Skin reactions
Patients should be monitored closely for severe skin reactions and the use of ORATANE should be discontinued if these events occur (see Special Precautions).

INTERACTIONS
Concomitant use of isotretinoin and vitamin A (including dietary supplements) should be avoided because of additive toxic effects.
Tetracyclines should be avoided as their use with isotretinoin has been associated with the development of benign intracranial hypertension.
There have been no reports of clinical significant interactions with the concomitant use of oral contraceptives and isotretinoin.

PREGNANCY AND LACTATION
Pregnancy
The use of ORATANE is contraindicated in women who are pregnant or who may become pregnant while on therapy. It is also contraindicated in all women of childbearing potential unless an effective contraceptive has been used for one month prior without any interruption. In the event of a pregnancy, severe deformities in the unborn child will be caused. Major deformities, which occur in a high percentage, even if ORATANE has only been taken for short periods of time during pregnancy, include:
- Central nervous system (CNS) abnormalities, including hydrocephalus, microcephaly and cranial nerve deficit;
- Eye abnormalities, including microphtalmia;
- Heart defects;
- Parathyroid deficiency;
- Skeletal or connective tissue abnormalities, including absence of terminal phalages, alterations of the skull and cervical vertebra, and malformations of the hip, ankle and forearm, facial dysmorphia, cleft or high palate, low-set ears, micropinna and small or absent external auditory canals;
- Meningomyelocele, multiple synostoses and syndactyly;
- Thymus gland abnormality.
It is advisable for female patients to commence using contraceptive measures one month The following precautionary measures must be strictly observed in order to be certain of ruling out the possibility of pregnancy before, during and one month after completion of therapy:
1. Before the treatment with ORATANE begins, the doctor must give the patient specific and detailed advice on the teratogenic risk of the drug, the need for effective and continuous contraception and the possible consequences of a pregnancy, should this occur during the treatment with ORATANE or within 1 month of its completion. It is particularly important here to ensure that the patient is capable of understanding the verbal clarification and can be relied upon to take the necessary steps to prevent conception.
2. The possibility of an already existing pregnancy must be ruled out with certainty by means of a laboratory pregnancy test and, if necessary, a gynaecological examination, before therapy with ORATANE begins. The doctor or an appropriate laboratory should carry out the pregnancy test. It is recommended to start the treatment with ORATANE on the 2nd or 3rd day of menstruation.
3. It is absolutely essential that every women of childbearing age who is treated with ORATANE should practice effective and continuous contraception for 1 month before the treatment, during the treatment and for 1 month after withdrawal of the drug. The efficacy of the chosen method of contraception is to be considered carefully in each individual case, especially in the 1st cycle of hormonal contraception.
4. To guarantee the efficacy of the contraception, a laboratory pregnancy test is to be carried out every month by the doctor.
5. If the treatment is repeated, this kind of continuous and effective contraception must again be practised and prolonged for 1 month after withdrawal of the drug.
6. If, despite these measures, a pregnancy occurs during treatment with ORATANE or during the month following treatment, there is a high risk of very severe deformities in the unborn child. The risk of spontaneous abortion is also increased.
Even women who take no contraceptive measures because of supposed infertility should be urged to observe the above-described precautionary measures for as long as ORATANE is being taken.
The following supportive publications are provided:
- Patient Information Leaflet
- Female Patient Information Leaflet
- Female Patient Consent Form
- Information Guide for Prescriber
Lactation
ORATANE must not be administered to breast-feeding women.

DOSAGE AND DIRECTIONS FOR USE
General dosing information
The initial diagnosis and prescription of ORATANE should be performed by a dermatologist.
Generally, the initial dose of ORATANE should be individualised according to the patient's weight and the severity and location of the disease.
ORATANE capsules should be swallowed whole with liquid during meals.
Low doses should be given once daily, higher levels as a single dose or 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 response of the patient has been established. Worsening of the acne may occur initially.
Follow-up treatment (Maintenance dose)
If patients respond well to the initial dosing of 0,5 mg/kg/day, this dosage may be continued. 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 inadequate, and in particularly severe cases, the dosage may be increased to 1,0 mg/kg/day provided that the medicine is well tolerated. The maintenance dose is administered for a period of 12 weeks after which the first stage of therapy is usually terminated.
In most patients a single course of therapy may result in complete and prolonged remission of severe nodular acne. However, if a second course of therapy is necessary, it should not be initiated for at least 8 weeks (possibly 16 to 20 weeks, depending on individual response) after completion of the first course.
Improvement in the condition may continue following discontinuation of isotretinoin use.
Concurrent Adjuvant Therapy
As a rule this is not indicated. It is advisable to discontinue antimicrobials before beginning treatment with ORATANE.
Patients should also be advised not to use other anti-acne agents or cosmetic agents with exfoliative or keratolytic actions simultaneously.
Concomitant radiation therapy (ultraviolet) and exposure to the sun should also be avoided during treatment with ORATANE.
Supporting therapy with topical preparations of a mild nature may be used, if deemed necessary.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Most of the side-effects of ORATANE are dose related. In the proper dosage, tolerability is generally accepted in view of the severity of the disease.
Every patient should be warned about the possible occurrence of side-effects.
The following side-effects have been reported:
Hypervitaminosis
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 (nose bleeds) and dryness of the pharyncheal mucosa and hoarseness.
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.
There have been post-marketing reports of severe skin reactions (e.g. erythema multiforme (EM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), associated with the use of ORATANE. These events may be serious and result in hospitalisation, disability, life threatening events or death. Patients should be monitored closely for severe skin reactions and the use of ORATANE should be discontinued if these events occur.
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, even after therapy has stopped.
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 hyperostosis 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 in platelet count, elevated sedimentation rate.
Psychiatric and Central Nervous System Disorders
Behavioural disorders, depression (see WARNINGS), psychosis, headache, increased intracranial pressure (pseudotumor cerebri), seizures, malaise and drowsiness.
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. There is a risk to develop pancreatitis in isotretinoin treated patients with high serum triglycerides (>800 mg%). (See WARNINGS).
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. (See WARNINGS).
Other Effects
Isolated cases of benign intracranial hypertension and visual disturbances, and occasionally nausea and headache have been observed.
Haematuria/proteinurea occurs rarely.
Impaired hearing in certain frequencies and local or systemic infections due to Gram-positive micro-organisms (Staphylococcus aureus) have been reported.
Muscle and joint pain and, more rarely, overdosage, inflammatory bowel disease (e.g. colitis, ileitis, haemorrhage) and hyperuricaemia have been reported.
Lymphadenopathy has occasionally been noted.
Bronchospasm has been reported less frequently, mostly in patients with a history of asthma.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
See SIDE-EFFECTS AND SPECIAL PRECAUTIONS. Hypervitaminosis A could appear in cases of accidental overdose. Gastric lavage may be indicated in the first few hours after ingestion. Further treatment is generally supportive and symptomatic.

IDENTIFICATION
10 mg: Light violet coloured oblong soft gelatine capsule, containing a yellow/orange opaque viscous suspension.
20 mg: Maroon coloured oblong soft gelatine capsule, containing a yellow/orange opaque viscous suspension.

PRESENTATION
PVC/PVDC Aluminium blister packs of 60 capsules.

STORAGE INSTRUCTIONS
Store below 25ºC. Protect from light. Keep blister in outer carton until required for use. Do not refrigerate or freeze the product.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER
ORATANE
10 MG (Capsules): 35/13.4.2/0375
ORATANE 20 MG (Capsules): 35/13.4.2/0376

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE
Pharmaplan (Pty) Ltd
106 16th Road
MIDRAND

DATE OF PUBLICATION OF THIS PACKAGE INSERT
26 October 2010

Under licence from Douglas Pharmaceuticals, New Zealand.

New addition to this site: May 2014
Source: Pharmaceutical Industry

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