Producer: F. Hoffmann-La Roche Ltd., (Hoffman-la Roche Ltd) Switzerland
Code of automatic telephone exchange: D05BB02
Release form: Firm dosage forms. Capsules.
General characteristics. Structure:
1 capsule of 10 mg contains:
Active agent: ацитретин 10 mg (in a look, the dry spray containing 25% of active agent);
Excipient: microcrystallic cellulose of 50 mg.
1 capsule of 25 mg contains:
Active agent: ацитретин 25 mg (in the form of the dry spray containing 25% of active agent);
Excipient: microcrystallic cellulose of 125 mg.
Composition of dry spray (on 1 g):
ацитретин 250 mg, gelatin of 270 mg, maltodextrin of 410 mg, sodium ascorbate of 70 mg.
Pharmacodynamics. System retinoid.
Atsitretin, active ingredient of the drug Neotigazon®, - a synthetic aromatic analog of retinoic acid. In preclinical trials on portability of an atsitretin of mutagen or cancerogenic action it was revealed not; there were no instructions on its direct hepatotoxic also. Atsitretin had the expressed teratogenic effect on animals.
Clinical trials confirmed what at psoriasis and disturbances of keratinization ацитретин normalizes processes of proliferation, a differentiation and keratinization of cells of epidermis, and its side effects, in general, are quite postponed. Effect of drug is purely symptomatic; its mechanism remains, generally to unknown.
Pharmacokinetics. Absorption. The maximum concentration of an atsitretin in plasma are observed in 1-4 hours after reception. The best bioavailability of an atsitretin is reached at administration of drug during food. Bioavailability of a single dose makes about 60%, however it is subject to considerable individual fluctuations (36-95%).
Distribution. Atsitretin has the expressed lipophilicity and easily gets into fabrics. Its linkng with proteins exceeds 99%. In researches on animals ацитретин passed through a placental barrier in the quantities capable to cause malformations in a fruit. Lipophilic properties of an atsitretin force to assume that it in significant amounts gets to breast milk.
Metabolism. Atsitretin is metabolized by an isomerization in 13 - cis-isomer (cis-atsitretin), and also by formation of glucuronides and eliminating of a side chain.
Removal. Researches with multiple dose of drug by patients aged from 21 up to 70 years showed that the elimination half-life (T1/2) of an atsitretin makes about 50 hours, and its main metabolite in plasma, cis-atsitretina, which is teratogenic, - 60 hours. Considering the largest duration of an elimination half-life of an atsitretin (96 hours) and cis-atsitretina (123 hours) at these patients, and also proceeding from their linear kinetics, it is possible to predict that more than 99% of drug will be removed from an organism within 36 days after the termination of prolonged treatment. Moreover, within 36 days after the termination of treatment of concentration of an atsitretin and cis-atsitretina in plasma decreased below a test-sensitivity limit (<6 ng/ml). Atsitretin is brought only in the form of metabolites, approximately in equal quantities through kidneys and bilious ways.
Indications to use:
Severe forms of psoriasis, including, a psoriasis erythrosis, the localized or generalized pustular psoriasis.
Heavy dyskeratoses, such as inborn ichthyosis; red hair deprive; disease to Darya; other heavy disturbances of keratinization, resistant to traditional types of therapy.
Route of administration and doses:
Because of individual distinctions in absorption and speed of metabolism of an atsitretin the dose needs to be selected individually. It is better to accept capsules during food or with milk once a day. Further indicative recommendations are provided.
The initial daily dose of 25 mg (i.e. 1 capsule on 25 mg) or 30 mg a day (i.e. 3 capsules on 10 mg) within 2-4 weeks can render sufficient therapeutic effect.
The maintenance dose depends on clinical performance and portability of drug. As a rule, the optimum therapeutic effect is reached at the daily dose of 25-50 mg accepted within 6-8 weeks. In certain cases happens it is necessary to increase a dose to the maximum, equal 75 mg/days (i.e. 3 capsules on 25 mg).
After sufficient regress of psoriasis defeats treatment of patients with psoriasis can be stopped. A recurrence treats as it is stated above.
At dyskeratoses the maintenance therapy which is carried out usually is required as it is possible smaller doses. They can be lower than 20 mg a day and should not exceed 50 mg a day.
Considering a possibility of heavy by-effects, at prolonged treatment it is necessary to compare possible risk with the expected therapeutic effect carefully. Atsitretin it is necessary to appoint only at inefficiency of all other methods of treatment. The daily dose depends on body weight and makes about 0,5 mg/kg. In certain cases for limited time higher doses, to 1 mg/kg a day (no more than 35 mg/days) can be required. The maintenance dose has to be as it is possible smaller, considering possible side reactions at prolonged treatment.
If Neotigazon is applied in a combination with other types of treatment, then it is possible to reduce its dose depending on individual reaction of the patient.
At treatment by Neotigazon it is possible to continue to apply usual outside treatment; it does not influence Neotigazon's action.
Features of use:
Neotigazon can be appointed only the doctors having experience of use of system retinoids and understanding risk of teratogenic action of an atsitretin.
Women of childbearing age during treatment by Neotigazon should not take alcohol and also alkogolsoderzhashchy drinks, products and medicines as there are clinical data on what at a concomitant use of an atsitretin and alcohol in an organism can be formed этретинат. The mechanism - this metabolic transformation is not installed therefore it is not clear whether also other substances can participate in it. Etretinat highly тератогенен also has longer T1/2 in comparison with atsitretiny. Reception of ethanol should be avoided for 2 months after the therapy termination atsitretiny.
Women of childbearing age cannot transfuse blood from the patients receiving Neotigazon. Therefore, during treatment by Neotigazon and within a year after its end donorship of blood is forbidden.
It is necessary to control function of a liver prior to treatment by Neotigazon, each 1-2 weeks within the first month after an initiation of treatment, and then - every 3 month. If results of analyses indicate pathology, control should be carried out weekly. If function of a liver is not normalized or will worsen further, Neotigazon it is necessary to cancel. In this case it is recommended to continue to control function of a liver for, at least, 3 more months.
It is necessary to control the level of cholesterol and triglycerides of serum on an empty stomach, especially patients have risk groups (disturbances of lipidic exchange, a diabetes mellitus, obesity, alcoholism) and at prolonged treatment.
At patients with a diabetes mellitus retinoids can improve or worsen tolerance to glucose therefore at early stages of treatment it is necessary to check concentration of glucose in blood more often than usual.
The adults receiving long therapy by Neotigazon should conduct regularly the corresponding examinations, considering a possibility of anomalies of ossification (see. "Side effects"). At emergence of such disturbances it is necessary to discuss a question of treatment continuation with the patient, having carefully correlated possible risk and advantage of drug use.
At children it is necessary to watch closely parameters of growth and development of bones.
Because of a possibility of disturbance of a scotopia of patients it is necessary to warn about need of manifestation of care during the driving of the car or work with cars and mechanisms at night. It is necessary to carry out careful monitoring of a vision disorder.
Now not all effects of use of Neotigazon which can arise throughout life are known.
On the basis of available data on extent of influence on the frequency of inborn defects at fertilization of women sperm and semen of the male patients accepting ацитретин it is possible to draw a conclusion on the minimum risk of development of teratogenic effects.
Side reactions are noted at most of the patients accepting Neotigazon. However they usually disappear after reduction of a dose or drug withdrawal. Sometimes in an initiation of treatment the aggravation of symptoms of a disease is observed.
The most frequent side effects are symptoms of a hypervitaminosis And, for example, dryness of lips which can be eliminated with use of fat cream; a cheilitis and cracks in mouth corners, dryness and an inflammation of mucous membranes and a transitional epithelium; sometimes - nasal bleeding, rhinitis and ophthalmologic disturbances (a xerophthalmia, conjunctivitis), and also intolerance of contact lenses; seldom - helcomas. Also cases of thirst and dryness in a mouth, sometimes - stomatitis, an ulitis and disturbance of flavoring feelings, increase in frequency of the vulvovaginitis caused by Candida albicans were observed.
There can be a thinning and a peeling of skin on all body, especially on palms and soles. Frequent cases of "glutinosity" of skin, dermatitis, eczema and itch, hair loss, fragility of nails and a paronychia are described. There are separate messages on developing of violent rashes and change of structure of hair; seldom reactions of a photosensitization develop. After Neotigazon's cancellation these side effects are, as a rule, reversible.
There are separate messages on headaches though increase in intracranial pressure is noted seldom. At emergence of severe headaches, nausea vomitings and a vision disorder Neotigazon it is necessary to cancel immediately, and to direct the patient to the neuropathologist. Disturbance of dark adaptation was sometimes noted.
There can be muscle, bones and joints pains. The maintenance therapy can lead to increase in already being available backbone hyperostoses, emergence of new hyperostoses and calcification of soft tissues as it is observed at prolonged system use and other retinoids.
Cases of emergence of peripheral hypostases and inflows are described, gastrointestinal frustration, hepatitis, jaundice, temporary and, as a rule, reversible increase in activity of aminotransferases and an alkaline phosphatase seldom develop.
At treatment reversible increase in triglycerides and cholesterol of serum arose high doses of Neotigazon, especially patients have groups of high risk (with disturbances of lipidic exchange, a diabetes mellitus, obesity, alcoholism). If these disturbances persistirut, it is impossible to exclude the increased risk of an atherogenesis.
At treatment atsitretiny in rare instances there can be peripheral neuropathy.
Interaction with other medicines:
Because of risk of a hypervitaminosis And it is necessary to avoid simultaneous use of vitamin A and other retinoids.
As both Neotigazon, and tetracyclines can cause increase in intracranial pressure, their simultaneous use is contraindicated.
There are messages on the increased risk of development of hepatitis at the combined use of a methotrexate and Tigason (etretinat) therefore purpose of a methotrexate along with Neotigazon is also contraindicated.
Neotigazon does not influence linkng of anticoagulants of a coumarinic row (warfarin) with proteins.
If Neotigazon appoint along with Phenytoinum, it is necessary to consider that Neotigazon partially lowers extent of linkng of Phenytoinum with proteins.
The low-dosed monodrugs of progesterone (minipilla) can be not a well-tried remedy of contraception during therapy atsitretiny.
Other interactions between Neotigazon and other medicines (for example, the digoxin, Cimetidinum combined estrogen / прогестогенными by peroral contraceptives) are not revealed so far.
In a research at healthy volunteers the single dose of an atsitretin together with alcohol led to formation of an etretinat (earlier it was revealed in vitro). In recently conducted researches formation of an etretinat was also found in some patients accepting Neotigazon. Until this phenomenon does not receive a full explanation, it is necessary to consider pharmacokinetic features of an etretinat: as the period of its semi-removal makes about 120 days, within two years after completion of treatment it is necessary to use contraceptives.
Hypersensitivity to active or to excipients of drug, hypersensitivity to other retinoids;
heavy liver and renal failure;
the expressed chronic lipidemia.
concomitant use with tetracyclines, a methotrexate, vitamin A and other retinoids.
Neotigazon possesses strong teratogenic action and should not be appointed pregnant. Same treats also all women capable to a child-bearing if only they do not apply reliable contraceptives in four weeks prior to treatment, during treatment and within two years after its end (see further).
Pregnancy and lactation
Neotigazon высокотератогенен. It is contraindicated not only to pregnant women and women who can become pregnant during treatment or within 2 years after the termination of its reception, but also to all women potentially capable to a child-bearing. The risk of the birth of the child with defects of the birth is especially high if Neotigazon accept to or during pregnancy, regardless of a dose and duration of therapy. Neotigazon's action on a fruit is always accompanied by risk of inborn malformations. Neotigazon is contraindicated to any woman capable to a child-bearing if one of the following conditions is not satisfied at least:
1. The patient suffers from heavy disturbance of keratinization, resistant to standard types of treatment.
2. It is possible to be sure that the patient accepts and follows instructions of the doctor.
3. The patient is able to apply accurately and continuously provided contraceptives.
4. It is absolutely necessary that each woman capable to a child-bearing, applied effective contraceptives (preferably 2 methods a target="_blank" href="">of contraception at the same time) without breaks within 4 weeks prior to treatment, in the course of treatment and within two years after completion of treatment by Neotigazon. The main method a target="_blank" href="">of contraception is a reception of the combined oral contraceptive or intrauterine contraceptives, use of condom or a diaphragm (cap) is also recommended. Use of the low-dosed monodrugs of progesterone (minipilla) in a type of possible easing of their contraceptive effect is not recommended.
5. Treatment should not begin before the 2nd or 3rd following normal menstrual cycle.
6. At least, in a week prior to treatment the negative take of inspection on pregnancy has to be received. During treatment it is recommended to conduct additional examinations on pregnancy at least 1 time a month and through intervals of 1-3 months after drug withdrawal.
7. Prior to treatment by Neotigazon the doctor has to in detail, orally and in writing, to inform the women capable to a child-bearing, on necessary precautionary measures, danger of very heavy malformations of a fruit and possible effects of approach of pregnancy during treatment by Neotigazon or within 2 years after his termination.
8. The same effective and continuous birth control has to be applied every time at repetition of a course of treatment, irrespective of its duration and be observed within two years after the termination of a course.
9. If, despite all precautionary measures, during treatment by Neotigazon or within two years after his termination there occurs pregnancy, there is a big risk of heavy malformations of a fruit (for example, brain hernias).
10. The woman has to avoid alcohol intake during treatment and within two months after the end of administration of drug.
Feeding by a breast
Neotigazon nursing mothers cannot appoint.
In case of acute overdose Neotigazon it is necessary to cancel immediately. It is not required to accept other special measures as acute toxicity of drug is small. Symptoms of overdose are identical to that at an acute hypervitaminosis And (a headache, dizziness).
At a temperature not above 25 °C, in the place protected from light and moisture. To store in the place, unavailable to children!
According to the recipe
Capsules of 10 mg or 25 mg.
On 5 or 10 capsules in the PVC blister / PVDH Is scarlet/. On 6, 10 or 20 blisters on 5 capsules or on 3, 5 or 10 blisters on 10 capsules with the application instruction in a cardboard pack.