Neotigason

Acitretin.

Each capsule contains 10mg or 25mg acitretin.

Pharmacology: Properties and effects: Retinol (Vitamin A) is known to be essential for normal epithelial growth and differentiation, though the mode of this effect is not yet established. Both retinol and retinoic acid are capable of reversing hyperkeratotic and metaplastic skin changes. However, these effects are generally only obtained at dosages associated with considerable local or systemic toxicity. Acitretin, a synthetic aromatic derivative of retinoic acid, has a favourable therapeutic ratio, with a greater and more specific inhibitory effect on psoriasis and disorders of epithelial keratinization. The usual therapeutic response to acitretin consists of desquamation (with or without erythema) followed by more normal re-epithelialisation.
Acitretin is the main active metabolite of etretinate.
Pharmacokinetics: Absorption: Acitretin reaches peak plasma concentration 1-4 hours after ingestion of the drug. Bioavailability of orally administered acitretin is best when the drug is taken together with food. Bioavailability of a single dose is approximately 60%, but this may vary considerably from one patient to another (36-95%).
Distribution: Acitretin is highly lipophilic and penetrates readily into body tissues. Protein binding of acitretin exceeds 99%. In animal studies, acitretin passed the placental barrier in quantities sufficient to produce fetal malformations. Due to its lipophilic nature, it can be assumed that acitretin passes into breast milk in considerable quantities.
Metabolism: Acitretin is metabolized by isomerization into its 13-cis isomer (cis acitretin), by glucuronidation and cleavage of the side chain.
Elimination: Multiple-dose studies in patients aged 21-70 years showed an elimination half-life of approximately 50 hours for acitretin and 60 hours for its main metabolite in plasma, cis acitretin, which is also a teratogen. From the longest elimination half-life observed in these patients for acitretin (96 hours)and cis acitretin (123 hours), and assuming linear kinetics, it can be predicted that more than 99% of the drug is eliminated within 36 days after cessation of long-term therapy. Furthermore, plasma concentrations of acitretin and cis acitretin dropped below the sensitivity limit of the assay (<6 ng/ml) within 36 days following cessation of treatment. Acitretin is excreted entirely in the form of its metabolites, in approximately equal parts via the kidneys and the bile.

Severe forms of psoriasis including: erythrodermic psoriasis; local or generalized pustular psoriasis.
Severe disorders of keratinization, such as: congenital ichthyosis; pityriasis rubra pilaris; Darier's disease; other disorders of keratinization which may be resistant to other therapies.

Because there are differences in the absorption and rate of metabolism of acitretin, the dosage must be individually adjusted. The capsules should preferably be taken once daily with a meal, or with milk. The following will serve as guidelines.
Adults: The initial daily dosage, 25mg (i.e. 1 capsule 25mg) or 30mg (i.e. 3 capsules 10mg) for about 2-4 weeks may give satisfactory therapeutic results.
The maintenance dose must be based on clinical efficacy and tolerability. In general, a daily dosage of 25-50mg taken for a further 6-8 weeks achieves optimal therapeutic results.
It may be necessary in some cases to increase the dose up to a maximum of 75mg/day (i.e. 3 capsules 25mg).
In patients with Darier's disease starting dose of 10mg may be appropriate. The dose should be increased cautiously as isomorphic reactions may occur.
Therapy can be terminated in patients with psoriasis whose lesions have resolved sufficiently. Relapses should be treated as described previously.
Patients with severe congenital ichthyosis and severe Darier's disease may require therapy beyond 3 months. The lowest effective dosage, not exceeding 50mg/day should be given.
Continuous use beyond 6 months is contraindicated as only limited clinical data are available on patients treated beyond this length of time.
Elderly: Dosage recommendations are the same as for other adults.
Children: In view of possible severe side effects associated with long-term treatment, the risk should be carefully weighed against the therapeutic benefit. Acitretin should be used only when all alternative therapies have proved inadequate.
The dosage should be established according to bodyweight. The daily dosage is about 0.5mg/kg.
Higher doses (up to 1mg/kg daily) may be necessary in some cases for limited periods, but only up to a maximum of 35mg/day. The maintenance dose should be kept as low as possible in view of possible long-term side effects.
Combination treatment: Other dermatological therapy, particularly with keratolytics, should normally be stopped before administration of Neotigason. However, the use of topical corticosteroids or bland emollient ointment may be continued if indicated.
When Neotigason is used in combination with other types of therapy, it may be possible depending on the individual patient's response, to reduce the dosage of Neotigason.

Manifestations of acute Vitamin A toxicity include severe headache, vertigo, nausea or vomiting, drowsiness. irritability and pruritus. Signs and symptoms of accidental of deliberate overdosage with Neotigason will probably be similar. Specific treatment is unnecessary because of the low acute toxicity of the preparation.
Because of the variable absorption of the drug, gastric lavage may be worthwhile within the first few hours after ingestion.

Neotigason is highly teratogenic and must not be used by women who are pregnant. The same applies to women of childbearing potential unless strict contraception is practised 4 weeks before, during and for 3 years after treatment (see Warnings).
The use of Neotigason is contraindicated in woman who are breastfeeding.
Neotigason is contraindicated in patients with severe hepatic or renal impairment and in patients with chronic abnormally elevated blood lipid values.
Since both Neotigason and tetracyclines can cause increased intracranial pressure, their combined use is contraindicated. Supplementary treatment with antibiotics such as tetracyclines is therefore contraindicated (see Interactions).
An increased risk of hepatitis has been reported to result from combined use of methotrexate and etretinate. Consequently, the combination of methotrexate with Neotigason is also contraindicated (see Interactions).
Concomitant administration of Neotigason and vitamin A or other retinoids is contraindicated due to the risk of hypervitaminosis A.
Neotigason is contraindicated in cases of hypersensitivity to the preparation (acitretin or excipients) or to other retinoids.
Owing to the presence of glucose, patients with rare glucose-galactose malabsorption should not take this medicine.

Neotigason is contraindicated in every woman of childbearing potential unless each of the following conditions is met: 1. The patient is suffering from a severe disorder of keratinization which is resistant to standard therapies.
2. She can be relied on to understand and follow the physician's instructions.
3. She is capable of taking the stipulated contraceptive measures reliably and without fail.
4. It is absolutely essential that every woman of childbearing potential who is to undergo treatment with Neotigason uses an effective contraceptive without interruption for 4 weeks before, during and for 3 years after the discontinuation of treatment with Neotigason.
Even female patients who normally do not practice contraception because of a history of infertility should be advised to do so, while taking Neotigason.
5. Therapy should not begin until the second or third day of the next normal menstrual period.
6. At the start of therapy, a negative pregnancy test result (minimum sensitivity of 25mIU/mL) must be obtained up to three days before the first dose is given. During therapy, pregnancy tests should be arranged at 28-day intervals. A negative pregnancy test not older than 3 days is mandatory before prescription is made at these visits. After stopping therapy, pregnancy tests should be performed at 1-3 monthly intervals for a period of 3 years after the last dose is given.
7. Before therapy with Neotigason is instituted, the physician must give patients of childbearing potential detailed verbal and written information about the precautions to be taken, the risk of very severe fetal malformation, and the possible consequences if pregnancy occurs during the course of treatment with Neotigason or within 3 years of discontinuing therapy.
8. The same effective and uninterrupted contraceptive measures must be taken every time therapy is repeated, however long the intervening period may have been, and must be continued for 3 years afterwards.
9. Should pregnancy occur, in spite of these precautions, there is a high risk of severe malformation of the fetus (e.g. craniofacial defects, cardiac and vascular or CNS malformations, skeletal and thymic defects) and the incidence of spontaneous abortion is increased. The risk applies especially during treatment with Neotigason and 2 months after treatment. For up to 3 years after Neotigason discontinuation, the risk is lower (particularly in woman who have not consumed alcohol) but cannot be entirely excluded due to possible formation of etretinate.
10. Women of childbearing age must not consume alcohol (in drinks, food or medicines) during treatment with Neotigason and for 2 months after Neotigason cessation of therapy (see Precautions, Interactions and Pharmacology: Pharmacokinetics under Actions).

Full patient information about the teratogenic risk and the strict pregnancy prevention measures should be given by the physician to all patients, both male and female.
Clinical evidence has shown that etretinate can be formed with concurrent ingestion of Neotigason and alcohol. Etretinate is highly teratogenic and has a longer half-life (approximately 120 days) than acitretin. Women of childbearing age must not consume alcohol (in drinks, food or medicines) during treatment with Neotigason and for 2 months after cessation of Neotigason therapy. Contraceptive measures and pregnancy tests must also be taken for 3 years after completion of Neotigason treatment (see Warnings and Pharmacology: Pharmacokinetics under Actions).
Woman of childbearing potential must not receive blood from patient being treated with Neotigason. Therefore donation of blood by a patient being treated with Neotigason is prohibited during and for three years after completion of treatment with Neotigason.
Due to the risk of foetal malformations, the medicine must not be passed on the other people.
Hepatic function should be checked before starting treatment with Neotigason, every 1-2 weeks for the first 2 months after commencement and then every 3 months during treatment. If abnormal results are obtained, weekly checks should be instituted. If hepatic function fails to return to normal or deteriorates further, Neotigason must be withdrawn. In such cases it is advisable to continue monitoring hepatic function for at least 3 months (see Adverse Reactions).
Serum cholesterol and serum triglycerides (fasting values) must be monitored, one month after the commencement and then every 3 months during treatment.
Decreased night vision has been reported with Neotigason therapy. 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 (see Adverse Reactions).
There has been rare reports of benign intracranial hypertension. Patients with severe headache, nausea, vomiting, and visual disturbances should discontinue Neotigson immediately and be referred for neurologic evaluation and care.
In adults receiving long-term treatment with Neotigason, appropriate examinations should be periodically performed in view of possible ossification abnormalities (see Adverse Reactions). If such disorders arise, the continuation of therapy should be discussed with the patient on the basis of a careful risk/benefit analysis. In children, growth parameters and bone development must be closely monitored.
It should be emphasized that, at the present time, not all the consequences of life-long administration of Neotigason are known.
The effect of UV light are enhanced by retinoid therapy, therefore patients should avoid excess exposure to sunlight and the unsupervised use of sun lamps. Where necessary a sun-protection product with a high protection factor of at least SPF 15 should be used.
Effects on ability to drive and use machines: Decreased night vision has been report with Neotigason therapy. Patient should be advised of this potential problem and warned to be cautions when driving or operating any vehicle at night. Visual problems should be carefully monitored (see Adverse Reactions).
Use in Children: Since there have been occasional reports of bone changes in children, including premature epiphyseal closure, skeletal hyperostosis and extraosseous calcification after long-term treatment with etretinate, these effects may be expected with Neotigason. Neotigason therapy in children is not therefore recommended. If, in exceptional circumstances, such therapy is undertaken the child should be carefully monitored for any abnormalities of musculo-skeletal development and growth parameters and bone development must be closely monitored.

Women of childbearing potential / Contraception in males and females: See Warnings.
Neotigason is highly teratogenic. Its use is contraindicated not only in pregnant women and women who might become pregnant during or within 3 years of the cessation of treatment, but in all women of childbearing potential. The risk of giving birth to a deformed child is exceptionally high if Neotigason is taken before or during pregnancy, no matter for how long or at what dosage.
Primary contraceptive method can be a combination hormonal contraceptive product or an intrauterine device and it is recommended that a condom or diaphragm (cap) is also used. Low dose progesterone-only products (minipills) are not recommended due to indications of possible interference with their contraceptive effect.
For male patients treated with Neotigason, available data, based on the level of maternal exposure from the semen and seminal fluid indicate a minimal, if any, risk of teratogenic effects.
Pregnancy: Neotigason is contraindicated in pregnant women (see Contraindications).
Breastfeeding: Neotigason must not be given to nursing mothers (see Contraindications).

Undesirable effects are seen in most patients receiving Neotigason. However, they usually disappear when the dosage is reduced or the drug withdrawn. An initial worsening of psoriasis symptoms is sometimes seen at the beginning of the treatment period. The most frequent side effects observed are symptoms of hypervitaminosis A, e.g. dryness of the lips, which can be alleviated by application of a fatty ointment. Mucous membranes and transitional epithelia become dried out or exhibit inflammatory lesions. This has occasionally led to nosebleeds and rhinitis, to ocular disturbances (xerophthalmia, conjunctivitis) and may lead to intolerance of contact lenses.
Corneal ulcerations have been observed rarely. Cheilitis, rhagades of the corner of the mouth, dry mouth and thirst may also occur. Occasionally, stomatitis, gingivitis and taste disturbances have been reported. Increased incidence of vulvo-vaginitis due to Candida albicans has been noted during treatment with Neotigason.
Thinning of the skin and scaling may occur all over the body, particularly on the palms and soles.
Sticky skin, dermatitis, erythema and pruritus have been frequently reported. Increased hair loss, nail fragility and paronychia are frequently observed. Occasionally, bullous eruption and abnormal hair texture have been reported. Rarely, patients may experience photosensitivity reactions.
These side effects are in general reversible after discontinuation of Neotigason treatment. Headache is occasionally reported although intracranial hypertension (Pseudotumor cerebri) is rare. Patients with severe headache, nausea, vomiting, and visual disturbances should discontinue Neotigason immediately and be referred for neurologic evaluation and care. Occasionally, blurred vision and impaired night vision have been noted (see Precautions).
Muscle, joint and bone pain have also been occasionally reported. Maintenance treatment may result in progression of existing spinal hyperostosis, in appearance of new hyperostotic lesions and in extraskeletal calcification, as has been observed in long-term systemic treatment with retinoids.
Occasionally, peripheral edema and flushing have been reported. Gastro-intestinal disorders, hepatitis and icterus have been observed rarely.
Transient, usually reversible elevation of transaminases and alkaline phosphatases has been observed.
During treatment with high doses of Neotigason, reversible elevation of serum triglycerides and serum cholesterol has occurred, especially in high-risk patients (disturbances of lipid metabolism, diabetes mellitus, obesity, alcoholism). An associated risk of atherogenesis cannot be ruled out if these conditions persist.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Concomitant administration of vitamin A and other retinoids must be avoided because of the risk of hypervitaminosis A.
Low dose progesterone-only products (minipills) may be an inadequate method of contraception during Neotigason, see Use in Pregnancy & Lactation. Interactions with combined estrogen/progestogen oral contraceptives have not been observed.
Investigations into the effect of Neotigason on the protein binding of anticoagulants of the coumarin type (warfarin) revealed no interaction.
If Neotigason is given concurrently with phenytoin, it must be remembered that Neotigason partially reduces phenytoin's protein binding.
Methotrexate, tetracyclines: see Contraindications.
Further interactions between Neotigason and other substances (e.g. digoxin, cimetidine, combined estrogen/progestogen oral contraceptives) have not been observed so far.

Psoriasis, Seborrhea & Ichthyosis Preparations

D05BB02 - acitretin ; Belongs to the class of systemic retinoids used in the treatment of psoriasis.

P₁S₁S₃