ISOSKIN Capsule

Indications:

• the treatment of severe, recalcitrant nodular acne, where severe is defined as numerous lesions of at least 5 millimeters in diameter that may be suppurative or haemorrhagic.

• severe, inflammatory acne and acne conglobata.

Dosage and direction for use:

General dosing Information

The initial diagnosis and prescription of ISOSKIN should be performed by a dermatologist.

Generally, the initial dose of ISOSKIN should be individualized according to the patient's weight and the severity and location of the disease.

ISOSKIN capsules should be swallow 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 ISOSKIN.

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 ISOSKIN.

Supporting therapy with topical preparations of a mild nature may be used, if deemed necessary.

ISOSKIN is contra-indicated in:

- pregnancy and lactation

- 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 hyperlipidemias

- simultaneous intake of vitamin A or other retinoids and simultaneous administration of tetracyclines.

Most of the side-effects of ISOSKIN 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 ISOSKIN. These events may be serious and result in hospitalization, disability, life threatening events or death. Patients should be monitored closely for severe skin reactions and the use of ISOSKIN 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, decrease 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, 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%).

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.

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.

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:

The use of ISOSKIN 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 ISOSKIN 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 microphthalmia

- 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 ISOSKIN 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 ISOSKIN 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 ISOSKIN begins. The doctor or an appropriate laboratory should carry out the pregnancy test. It is recommended to start the treatment with ISOSKIN on the 2nd or 3rd day of menstruation.

3. It is absolutely essential that every women of childbearing age who is treated with ISOSKIN 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 ISOSKIN 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 ISOSKIN 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:

ISOSKIN must not be administered to breast-feeding women.

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.