ACNOTIN Capsule

Isotretinoin is a retinoid for systemic treatment of acne. It is indicated for severe forms of nodulo-cystic acne which are resistant to previous therapy, particularly cystic acne and acne conglobata, especially when the lesions involve the trunk.

Acnotin 10/20 should only be prescribed by physicians who are experienced in the use of systemic retinoids, preferably dermatologists, and understand the risk of teratogenicity if Acnotin 10/20 is used during pregnancy.

Dosage and Administration

The therapeutic response to Isotretinoin and side effects vary according to the individual patient, needing individual dose adjustments during therapy.

Therapy should be started with 0.5mg/kg daily. During the initial period of Isotretinoin therapy, transient exacerbation of acne can occur. After about 4 weeks, dosage for maintenance treatment should be adjusted to recommended maintenance dose range of 0.1-1.0mg/kg/day to meet individual needs. Treatment usually lasts a total of 16 weeks. Patients with very severe disease or with truncal acne may require higher daily doses up to 2.0mg/kg.

When assessing the results of the therapy, it should be borne in mind that there is often a further improvement after discontinuation of treatment. There should therefore be an interval of at least 8 weeks before re-starting treatment, which should be resumed in accordance with the previously mentioned dosage guidelines.

The capsules should be taken with meals, low doss once daily and higher amounts as a single dose or in several doses spread over the day. Concurrent administration of other keratolytic or exfoliative antiacne agents is not indicated, nor is concurrent radiotherapy with ultraviolet light indicated. Patients should avoid exposure to the sun.

Patient with severe renal insufficiency should be started at a lower dose (e.g. 10mg/day) and afterwards individually adjusted according to tolerance.

1. Hepatic and renal insufficiency; hypervitaminosis A; patients with excessively elevated blood lipid values; hypersensitivity to Isotretinoin.

2. Blood donation by patients during and within 1 month of cessation of Isotretinoin should be avoided to prevent accidental exposure of the developed fetus of a pregnant patient who may receive such blood.

Most of the adverse reactions of Isotretinoin are dose-related. With the recommended dosage, the risk/benefit ratio is generally acceptable considering the severity of the disease.

Incidence more frequent: chelitis (scaling, redness, burning, pain and other signs of inflammation of lips), epistaxis (nosebleeds) and skin infection.

Symptoms Associated with Hypervitaminosis A: The following symptoms are the most frequently reported: Dryness of the skin, dryness of the mucosae, eg of the lips, the nasal mucosa (epistaxis), the eyes (conjunctivitis, reversible corneal opacities and intolerance to contact lenses).

Skin and Appendages Disorders: Exanthema, pruritus, dermatitis facialis, sweating, pyogenic granuloma, paronychia, nail dystrophy, increased formation of granulation tissue, persistent hair thinning, reversible alopecia, acne fulminans, hirsutism, hyperpigmentation, photosensitivity, photoallergic reactions, skin fragility.

Musculoskeletal System Disorder: Muscle pain, joint pain, hyperostosis and other bone changes, tendinitis.

Psychiatric and Central Nervous System Disorders: Behavioral disorders, depression, headache, increased intracranial pressure, seizures.

Sensory Disorders: Isolated cases of visual disturbances impaired hearing at certain frequencies, photophobia, dark adaptation disturbances (decreased night vision), lenticular cataract, keratitis.

Gastrointestinal System Disorders: Nausea, inflammatory bowel disease, e.g. colitis, ileitis and hemorrhage have been reported to occur.

Liver and Biliary System Disorders: Transitory and reversible increases in transaminases, some cases of hepatitis. 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 dose or discontinue treatment with Isotretinoin.

Respiratory System Disorders: Bronchospasm.

Disorders of the Blood: Decrease in white cell count, red blood cell parameters, increase or decrease in platelet count, elevated sedimentation rate.

Laboratory Findings: Increase in serum triglyceride and cholesterol levels, hyperuricemia. Decreases in 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 drug. Every patient should be warned about the possible occurrence of adverse effects.

Resistance Mechanism Disorders: Local or systemic infections due to gram-positive microorganisms (Staphylococcus aureus).

Miscellaneous Reactions:

- Lymphadenopathy, hematuria, and proteinuria, pancreatitis (especially patients with high serum triglyceride levels (>800mg) treated with Isotretinoin are at risk of developing pancreatitis), vasculitis (e.g. Wegener’s granulomatosis).

- Bleeding or inflammation of gums; cataract or corneal opacities.

Concurrent therapy with Isotretinoin and vitamin A must be avoided as symptoms of hypervitaminosis A may be intensified.

Rare cases of benign intracranial hypertension ‘pseudo tumor cerebri’ have been reported after Isotretinoin and after tetracyclines. Supplementary treatment with tetracyclines should therefore be avoided.

The effect of micro dosed progesterone preparations or “minipills” may be diminished and thus such preparations should not be used during Acnotin 10/20 therapy.

Isotretinoin is highly teratogenic. It is therefore contraindicated not only in women who are pregnant or who may become pregnant while undergoing treatment but in all women of childbearing potential. There is an extremely high risk that a deformed infant will result if pregnancy occurs while taking Isotretinoin in any amount even for short periods. Potentially all exposed fetuses can be affected.

Acnotin 10/20 is contraindicated in women of childbearing potential unless the female patient meets all the following conditions:

- She has severe acne resistant to standard therapies.

- She is reliable in understanding and carrying out instructions.

- She is capable of complying with mandatory effective contraceptive measures.

- She is informed by her physician of the hazards of becoming pregnant during and 1 month after treatment with Acnotin 10/20. She is warned of the possibility of contraceptive failure. Monthly pregnancy testing is recommended.

- She uses effective contraception without any interruption for 1 month before beginning Acnotin 10/20 therapy, during therapy and for 1 month following discontinuation of therapy. It is recommended to use two forms of effective contraception to prevent pregnancy.

- She starts Acnotin 10/20 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 Acnotin 10/20 therapy and the same reliable pregnancy evaluations should be followed.

- Even female patients who normally do not apply 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 contraception while taking Acnotin 10/20 following the above guidelines.

- Should pregnancy occur in spite of these precautions during treatment with Acnotin 10/20 or in the month following, there is a great risk of very severe malformations of the fetus (involving i particular the central nervous system, the heart and the large blood vessels). Major human fetal 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 gland abnormalities and cerebellar malformation. There is also an increased risk of spontaneous abortion. If pregnancy does occur, the physician and patient should discuss the advisability of continuing the pregnancy.

- She confirms that she has understood the precautions.

- As Isotretinoin is highly lipophilic, the passage of the drug in human milk is very likely. Because of the potential for adverse effects, the use of Isotretinoin should be avoided during pregnancy.

1. Isotretinoin should only be prescribed by physicians who are experienced in the use of systemic retinoids, preferably dermatologists, and understand the risk of teratogenicily if Isotretinoin is used during pregnancy. Both female and male patients should be given a copy of the Patient Information Brochure.

2. Liver function should be checked before and 1 month after the start of treatment, and subsequently at 3-monthly intervals. Serum lipids (fasting value) should also be checked (before and 1 month after start of therapy, and also at end of the 3- to 4-month treatment period). Blood glucose levels should be monitored in diabetic patients.

3. Depression, psychotic symptoms and rarely, suicide attempts and suicide have been reported in patients treated with Isotretinoin. 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 of necessary.

4. Patients experiencing visual problems should be referred for an expert ophthalmological examination and withdrawal of Acnotin 10/20 should be considered. Visual problem should be carefully monitored. Vision problems that can occur include photophobia, blurred vision or dryness of the eyes. In some patients onset of decreased night vision may be sudden, and patients should be advised of this potential problem and warned to be cautious with driving or operating any machinery at night. Due to the possible occurrence of keratitis, patients with dry eyes should be monitored. Wearing contact lenses may be uncomfortable.

5. A careful evaluation of the risk/benefit ration should be carried out in every patient and Isotretinoin administration should be restricted to severe cases.

6. Since acne is an androgen-dependent disease, contraceptives containing an androgen progestational substance, such as one derived form 19-nortestosterone (norsteroid), particularly in the presence of gyneco-endocrinological problems should be avoided.

7. Dermabrasion should be avoided in patients on Isotretinoin and for a period of 5-6 months after treatment because of the risk of hypertrophic scarring in atypical areas.

8. Wax epilation should be avoided in patients on Isotretinoin and for a period of 6months after treatment because of the risk of dermatitis or possibility of scarring.

9. Avoid prolonged exposure to sunlight.

10. Special patient groups: In high-risk patients (with diabetes, obesity, alcoholism or disorders of lipid metabolism) undergoing treatment with Isotretinoin, more frequent checks of serum lipids and/or blood glucose will be necessary.

In known or suspected diabetes, frequent determination of blood glucose levels in 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.

Dental problems can occur resulting from dryness of mouth and may increase dental disease, including tooth decay, gun disease, and fungus infections; regular dental appointments are needed and use of sugarless candy or saliva substitute or melting ice in month may be necessary to lessen dental problems. Avoid prolonged exposure to sunlight.

The exact mechanism of action of Isotretinoin is not known in detail. However, the pharmacological profile of Isotretinoin suggest that it acts by reducing sebaceous gland size and inhibits sebaceous gland activity, thereby decreasing sebum secretion. Furthermore a dermal antiinflammatory effect of Isotretinoin has been established.