Instruction for use: Otezla

Dosage form: film coated tablets

Active substance: Apremilast

ATX

L04AA32 Apremilast

Pharmacological group:

Immunosuppressants, selective immunosuppressants [Immunosuppressants]

The nosological classification (ICD-10)

L40 Psoriasis: Chronic plaque psoriasis with diffuse; generalized psoriasis; Psoriasis of the scalp; hairy parts of the skin; A generalized form of psoriasis; Psoriazoformny dermatitis; Psoriasis complicated with erythroderma; disabling psoriasis; Isolated psoriatic plaque; Eksfolliativny psoriasis; psoriatic erythroderma; Psoriasis with eczematization; Hyperkeratosis in psoriasis; Inverse psoriasis; Psoriasis ekzemopodobnye; dermatoses psoriazoformny; Psoriasis genitals; Psoriasis lesions with hairy areas of the skin; erythrodermic psoriasis; Chronic psoriasis of the scalp; Chronic psoriasis; ordinary psoriasis; refractory psoriasis; Koebner phenomenon; psoriasis

L40.0 Psoriasis vulgaris: Psoriatic plaque; Vulgar psoriasis; Psoriasis vulgaris; Chronic vulgar plaque psoriasis

L40.5 Arthropathy psoriasis (M07.0-M07.3 *, M09.0 *): Psoriatic arthritis; Arthropathic form of psoriasis

M07.3 Other psoriatic arthropathies (L40.5 +): Psoriatic arthritis; Generalized form of psoriatic arthritis; Psoriatic arthritis

Composition

Film coated tablets - 1 tab.

active substance: Aprimilast 10/20/30 mg

Auxiliary substances: MCC - 26.25 / 52.5 / 78.75 mg; Lactose monohydrate - 60/120/180 mg; Sodium croscarmellose - 3/6/9 mg; Magnesium stearate - 0.75 (1.5 / 2.25 mg

(Table 10 mg): Opadrai II pink (polyvinyl alcohol - 40%, titanium dioxide - 24.6%, macrogol - 20.2%, talc - 14.8%, iron dye red oxide (E172) - 0 , 4%) - 4 mg

The film membrane (Table 20 mg): Opadrai II brown (polyvinyl alcohol 40%, titanium dioxide 12.13%, macrogol 20.2%, talc 14.8%, iron dye red oxide (E172) -1 , 22%, iron dye oxide yellow (E172) - 11.65) - 8 mg

(Table 30 mg): Opaprai II beige (40% polyvinyl alcohol, 22.99% titanium dioxide, 20.2% macrogol, 14.8% talc, iron oxide red dye (E172) -1 , 18%, iron oxide dye yellow (E 172) 0.43% iron dye oxide black (E172) 0.4) 12 mg

Description of dosage form

Tablets, 10 mg: pink, diamond-shaped, film-coated, with engravings "10" on one side and "APR" on the other side.

Tablets, 20 mg: brown, diamond-shaped, coated, with engravings "20" on one side and "APR" on the other side.

Tablets, 30 mg: beige, diamond-shaped, coated, with engraved "30" on one side and "APR" on the other side.

Pharmachologic effect

Mode of action - Immunosuppressive.

Pharmacodynamics

Mechanism of action

Apremilast, is a small molecule - the inhibitor of PDE-4, which acts inside the cell, modulating the inflammatory and anti-inflammatory mediators. PDE-4 is the specific PDE of cAMP, the dominant PDE in inflammatory cells. With the inhibition of PDE-4, the amount of cAMP increases, which in turn leads to suppression of the inflammatory response by modulating the expression of TNF-α, IL-23, IL-17 and other inflammatory cytokines. CAMP also modulates levels of some anti-inflammatory cytokines, for example IL-10. These pro- and anti-inflammatory mediators are involved in the pathogenesis of psoriasis and psoriatic arthritis (PsA).

Pharmacodynamic effects

In clinical trials in patients with PcA, apreamilast significantly modulated, but did not completely inhibit blood plasma proteins: IL-1α, IL-6, IL-8, monocyte chemoattract protein-1 (MXE-1), inflammatory-1β macrophage protein (MBB-1β ), Matrix metalloproteinase-3 (MMP-3) and TNF-α. After 40 weeks of treatment, there was a decrease in the concentration of IL-17 and IL-23 and an increase in the concentration of IL-10 in blood plasma. In patients with psoriasis, aprimilast reduced focal epidermal thickenings of affected skin areas, infiltration by inflammation cells, and expression of proinflammatory genes, including the genes of inducible nitric oxide synthase (iNOS), IL-12 / IL-23p40, IL-17A, IL-22 and IL-8.

The apremilast, when administered at doses up to 50 mg twice a day, does not extend the QT interval in healthy subjects.

1493 patients with active PsA (≥3 swollen joints and ≥3 painful joints), despite previous therapy with low molecular weight or biological disease-modifying drugs (BMLS) for at least 6 months, received inward placebo, Aprilmilast 20 mg or apromilast 30 mg 2 times in a day. Apremilast was used in the form of monotherapy (34.8%) or in combination with stable doses of low molecular weight BMLS (65.2%). 76.4% of patients had previously received only low molecular weight BMLS, and 22.4% of patients had previously been treated with biological BMLS, of which 7.8% were ineffective. The average duration of PsA is 5 years.

The therapy with apoilmastomas resulted in a significant improvement in the symptoms of PsA in comparison with placebo.

The efficacy of treatment with aprelymastomas did not differ in patients who received or did not receive BMLS, including methotrexate. In patients who took BMLS or biological BMLS before the treatment with apoililast, the therapeutic effects of apremilast were more pronounced than those who took placebo. On the background of therapy with apoilmastomas, a significant, statistically significant improvement in functional activity was noted.

In total, 1,257 patients with moderate to severe plaque psoriasis who were scheduled to undergo phototherapy or systemic therapy were randomized to placebo or to the group of uremilast (inside, 30 mg twice daily). Approximately 30% of patients have not previously received phototherapy, standard systemic or biological drugs.

On the background of therapy with apomorphil in patients with moderate to severe psoriasis, there was a significant improvement in comparison with placebo. The efficacy of aphrodilast was manifested in a complex of clinical manifestations of psoriasis, including itching, nail and scalp damage, and quality of life.

The clinical efficacy of apimilast has been confirmed in various subgroups of patients formed from the initial demographic and clinical characteristics (including the duration of psoriasis and the presence of PsA in the anamnesis). The positive clinical effect of the drug did not depend on the previous drug therapy of psoriasis and its results. Response to treatment with aphrolylast was rapid and was expressed in a significant decrease in psoriasis symptoms by the 2nd week of treatment, compared with placebo.

Pharmacokinetics

Suction. Aprremilast is well absorbed, and its absolute bioavailability after oral administration is approximately 73%. The median Tmax in blood plasma is approximately 2.5 hours. The pharmacokinetics of apreylast is linear, with an increase in the degree of exposure, in proportion to the dose (within 10-100 mg / day). After taking apromilast 1 time a day, cumulation is minimal, and after application 2 times a day it is approximately 53% in healthy people and 68% in psoriasis patients. Bioavailability of aphomilast is not disrupted when applied to food, so it can be taken regardless of the time of ingestion.

Distribution. Apremilast binds to human blood plasma proteins by approximately 68%. The average apparent Vd is 87 liters, indicating an extravascular distribution.

Biotransformation. Apremilast is extensively metabolized, both with the participation of cytochrome 450 (CYP) isoenzymes and non-CYP pathways, including oxidation, hydrolysis and conjugation. Therefore, inhibition of any one of these pathways should not substantially induce significant drug interaction. In the oxidative metabolism of apremilast, the isoenzyme CYP3A4 and, to a lesser extent, the isoenzymes CYP1A2 and CYP2A6 are involved.

After ingestion, the main component in the blood is aprimilast. The compound is largely metabolized, and only 3 and 7% of the accepted amount of the drug is excreted unchanged by the kidneys and intestines, respectively. In the blood, the basic inactive metabolite is the glucuronide conjugate of the o-demethylated apomorphite (M12). Since aprimilast is a substrate for the isoenzyme CYP3A4, its effect is reduced when used simultaneously with rifampicin, a strong inducer of the isoenzyme CYP3A4.

In vitro, apreamilast is not an inhibitor or inducer of CYP450 isoenzymes.

Therefore, when combined with the substrates of CYP450 isoenzymes, aprimilast will not disrupt the clearance or exposure to active substances that are metabolized by the CYP450 isoenzymes.

In vitro, apreamilast is a substrate and a weak inhibitor of P-gp (IC50> 50μM), however clinically significant interactions involving P-gp are unlikely.

In vitro, aprimilast slightly inhibits or does not influence (IC50> 10μM) on carriers of organic anatomies OAT1 and OAT3, the carrier of organic cations OCT2, the transport organic anion (OATP) 1B1 and OATP1B3 transport polypeptide or BCRP and is not a substrate for these compounds. In this regard, clinically significant drug interactions are unlikely with the joint application of apreblast with substrates or inhibitors of these transporters.

Excretion. In healthy people, the clearance of apremilast averages about 10 liters / h and the final T1 / 2 is about 9 hours. After ingestion of the labeled compound with kidneys and intestines, approximately 58 and 39% of radioactivity, respectively, are released, with approximately 3 and 7% Radioactive apomilast.

Elderly patients. Apremilast was studied in young and elderly healthy volunteers. Exposure of apoglilast in the elderly (65-85 years) is approximately 13% higher in AUC and 6% higher in Cmax compared with volunteers aged 18-55 years. Data on the use of the drug in clinical trials in patients older than 75 years are limited. In elderly patients there is no need for dose adjustment.

Renal insufficiency. In patients with mild and moderate renal insufficiency and healthy volunteers, there were no significant differences in the pharmacokinetics of aprimilast. Therefore, with renal failure of mild to moderate severity, a dose change is not required. In severe renal failure (GFR less than 30 mL / min / 1.73 m2 or Cl creatinine <30 mL / min), the dose is reduced to 30 mg once daily. In 8 patients with severe renal insufficiency, with a single dose of apremilast in a dose of 30 mg, the values of AUC and Cmax increased by approximately 89 and 42%, respectively.

Liver failure. The pharmacokinetics of apreylmast and its main metabolite M12 is not impaired in patients with moderate or severe hepatic impairment. With hepatic failure, dose adjustment is not required.

Pre-clinical safety study results

The results of the preclinical study of the pharmacology of safety and toxicity with repeated administration of apreylast have not revealed specific risks to humans. Aprremilast did not possess immunotoxicity, phototoxicity or irritant effect on the skin.

Fertility and early embryonic development. Apremilast did not affect fertility in male mice. Doses in which no apparent adverse effect (NOAEL) on fertility did not occur were more than 50 mg / kg / day (3 times the clinical exposure).

In a combined study of the effect on fertility in female mice and evaluation of embryo-fetal toxicity, prolongation of estrogenic cycles and an increase in the mating period were observed with doses of apologilast 20 mg / kg / day and higher. However, the frequency of pregnancies was not violated. The dose at which there was no visible effect (NOEL) on the fertility of females was 10 mg / kg / day (corresponding to clinical exposure).

Embryophyte development. The NOEL value for embryo-fetal development was 10 mg / kg / day (1.3 of the clinical exposure value). In apes, aprimilast increased prenatal losses (abortions) in proportion to the dose when administered orally at doses of 50 mg / kg / day or more. At a dose of 20 mg / kg / day, there was no effect on embryo-fetal development (1.4 of the magnitude of clinical exposure).

Pre- and postnatal development. In mice, an increase in the pre- and postnatal death of suckling young and a decrease in their body weight was detected at the first week of lactation at doses ≥80 mg / kg / day (≥4 above the level of clinical exposure). The effect of apremilast on pregnancy, the number of pregnant mice at the end of the gestation period, the number of mice born or the development of suckling babies after the 7th postnatal day have not been revealed. All the undesirable effects on postnatal development were observed during the first week and did not appear in subsequent periods. Sexual maturation, behavior, mating, fertility and parameters of the uterus were not violated. The NOEL value for female mice and F1 generation was 10 mg / kg / day (1.3 of the clinical exposure value for AUC).

Carcinogenicity studies. Apreemilast showed no signs of endogenicity in studies in mice and rats.

Genotoxicity studies. Aprremilast is not genotoxic. The apremilast did not cause mutations according to the results of the Ames test or chromosome aberrations in the culture of peripheral blood lymphocytes in the presence or absence of metabolic activation. Apremilast did not exhibit clastogenic activity on micronuclei of mice in vivo in doses up to 2000 mg / kg / day.

Indication of the drug Otezla

Psoriatic arthritis (treatment of active PsA in adults in monotherapy or combination with anti-rheumatic BMLS with insufficient response or intolerance to previous therapy);

Psoriasis (treatment of plaque psoriasis of moderate to severe severity in adults with insufficient response, the presence of contraindications or intolerance to other basic anti-inflammatory therapy, including cyclosporine, methotrexate or drugs used together with UVA irradiation (PUVA therapy).

Contraindications

Hypersensitivity to aprelymalitis or other components that make up the drug;

pregnancy;

Children under 18 years of age (not enough clinical experience).

With caution: patients with rare hereditary disorders in the form of intolerance to galactose, congenital insufficiency of lactase or impaired absorption of glucose-galactose (the drug contains lactose); Patients with severe renal insufficiency (see "Pharmacokinetics", "Method of administration and dose", "Special instructions"); Patients with insufficient body weight (see "Special instructions").

Application in pregnancy and breastfeeding

Before starting treatment, pregnancy should be excluded. Women who are capable of giving birth should use an effective method of contraception during therapy.

Data on the use of apremilast in pregnant women are limited. Aprmilast is contraindicated in pregnancy. In mice and monkeys, its effects are embryo-fetal loss, reduced fetal weight and delayed ossification in mice at doses higher than the maximum doses for humans. If the exposure is 1.3 of the level of clinical exposure, then the negative effect does not develop (see "Pharmacokinetics").

The apremilast was found in the milk of mice (see "Pharmacokinetics"). It is not known whether apimonilast or its metabolites are fed into human milk. Since it is impossible to exclude the risk of undesirable effects on the baby during breastfeeding, aphumilast should not be used during breastfeeding.

Fertility. Data on the impact on human fertility are not available. In experiments on mice, the undesirable effect on the fertility of males with the exposure of aphylmast is 3 times higher than in the clinical one, and in females - at an exposure comparable with the clinical one. Data on the non-clinical study of fertility are presented in the section "Pharmacokinetics".

Side effects

The most frequent undesirable drug reactions (NLR) in clinical phase III trials were gastrointestinal disturbances - diarrhea (15.7%) and nausea (13.9%). Basically, these disorders were mild or moderate and only 0.3% of each of these NLRs were regarded as severe. These NLRs occurred mainly in the first 2 weeks of treatment and usually disappeared after 4 weeks. Other frequent NLR were upper respiratory tract infections (8.4%), headache (7.9%) and tension headache (7.2%). Overall, most NLDs were mild or moderate.

The most frequent NLDs that caused the cessation of treatment in the first 16 weeks were diarrhea (1.7%) and nausea (1.5%). The overall frequency of severe NLR was low, and these reactions were not specific for any organ system.

Hypersensitivity reactions were rarely recorded during clinical trials of aprethmast.

The NLR observed in patients treated with apomorphite therapy is classified according to the lesion of organs and organ systems (MedDRA).

These NLRs are documented in the clinical trials of apremilast with PsA (1945 patients) and psoriasis (1,184 patients). The frequency of NLR was determined according to the following gradation: very often (≥1 / 10); Often (≥1 / 100, <1/10); Infrequently (≥1 / 1000, <1/100), rarely (≥1 / 10000, <1/1000).

Infectious and parasitic diseases: often - bronchitis, upper respiratory tract infection, nasopharyngitis *.

From the immune system: infrequently - hypersensitivity reactions.

From the side of metabolism and nutrition: often - a decrease in appetite *.

Mental disorders: often - insomnia.

From the nervous system: often - migraine *, tension headache *, headache *.

From the respiratory system, chest and mediastinum: often - cough.

From the digestive tract: very often - diarrhea *, nausea *; Often - vomiting *, dyspepsia, frequent stool, pain in the upper abdomen *, GERD.

From the skin and subcutaneous tissues: infrequent - rash.

From the musculoskeletal and connective tissue: often - pain in the back *.

General disorders and disorders at the injection site: often - fatigue.

Laboratory and instrumental data: infrequent - weight loss.

* At least one of these NLRs is regarded as serious.

Description of selected NLRs

Decreased body weight. The body mass of patients was regularly evaluated in clinical trials. The average decrease in body weight against the background of taking apremilast for 52 weeks was 1.99 kg. Overall, in 14.3% of patients receiving aprethilast, weight loss was 5-10%, and in 5.7% - more than 10%. None of the patients had a weight loss associated with clinically significant consequences. In total, only 0.1% of patients discontinued taking aprethilast because of a decrease in body weight as an undesirable phenomenon.

At the beginning of treatment for patients with reduced body weight, additional precautions should be taken in the sections "With caution" and "Special instructions".

Depression. During clinical trials, depression developed in 1.2% (14 of 1184) of patients with psoriasis who received apo-mymilad compared with 0.5% (2 of 418) in the placebo group. In none of the cases the depression was serious and did not require discontinuation of treatment.

In clinical studies of psoriatic arthritis in 0.9% (18/1945) of patients on the background of treatment with aphilastomas, depression / depressive state was noted. In the placebo group, it was recorded in 0.7% (5/671). In 0.1% (2/1945) patients taking aprethilast, depression / depressive status was regarded as serious. In the placebo group, there were no serious cases of depression. 3 patients (3/1945, 0.2%) taking aprethilast discontinued treatment due to depression / depressive condition.

Special patient groups

Elderly patients. In clinical trials, there was no difference in the profile of safety of apremilast in elderly patients (≥65 years) and in patients under the age of 65 years.

Patients with impaired liver function. The safety of apremilast was not assessed in patients with PsA or psoriasis and impaired liver function.

Patients with impaired renal function. In clinical trials with PsA and psoriasis, the safety characteristics of the drug were not different in patients with normal renal function and mild renal insufficiency. The safety of apremilast has not been studied in patients with PsA or psoriasis and moderate to severe renal insufficiency.

Interaction

The combined use of the cytochrome P450 3A4 (CYP3A4) isoenzyme with powerful inducer, rifampicin, leads to a weakening of the systemic effect of apremilast and a decrease in its effectiveness. Therefore, the combined use of powerful inductors of the CYP3A4 isoenzyme (for example, rifampicin, phenobarbital, carbamazepine, phenytoin and St. John's wort preparations) with aphro-mild is not recommended. With simultaneous re-application of apreamilast and rifampicin, AUC and Cmax of apremilast declined by 72 and 43%, respectively. In conditions of combined use of apreamilast with powerful inductors of CYP3A4 isoenzyme (eg rifampicin), the clinical response may be reduced. During clinical trials, apoglilast was combined with local therapies (corticosteroids, tar shampoo, salicylic acid preparations for the treatment of the scalp), and UV-B phototherapy.

There was no clinically significant drug interaction between ketoconazole and aprelimal. The apremilast can be combined with strong inhibitors of the CYP3A4 isoenzyme, such as ketoconazole.

There was no pharmacokinetic drug interaction between aprimilast and methotrexate in patients with PsA. Aprremilast can be combined with methotrexate.

There was no pharmacokinetic drug interaction between apreurast and oral contraceptives containing ethinylestradiol and norgestimate. Aprremilast can be combined with oral contraceptives.

Dosing and Administration

Inside, regardless of the time of food intake. Covered tablets should be swallowed whole, preferably washed down with water.

Treatment with OAT can only be prescribed by a specialist with sufficient experience in the diagnosis and treatment of psoriasis and PsA.

The recommended dose of Otesla is 30 mg orally 2 times a day, in the morning and in the evening, with an interval of approximately 12 hours. An initial dose titration is required, as shown in the table. After the initial titration, repeated titration is not required.

Table

Scheme dose titration

If the patient misses the drug, the next dose should be taken as soon as possible. If the dose is missed immediately before the time of the next dose, the missed dose is not taken and proceeds to the next dose of the drug at the appropriate time. The patient should not take two doses of the drug at the same time.

The maximum therapeutic effect was noted in the first 24 weeks of treatment. If after 24 weeks the effect is not achieved, treatment should be reviewed.

It is recommended to regularly evaluate the patient's response to treatment. There are no clinical data on the use of the drug for more than 52 weeks (see Pharmacodynamics).

Special Populations

Children and teenagers. The efficacy and safety of apremilast in children aged 0-18 years has not been studied.

Elderly patients. There is no need to change the dose in elderly patients (see "Side effects" and "Pharmacokinetics").

Impaired renal function. In patients with mild or moderate renal insufficiency, there is no need to change the dose. The dose of apoimilast should be reduced to 30 mg once a day in patients with severe renal insufficiency (Cl creatinine <30 mL / min when evaluated by Cockcroft-Gault formula). At the initial titration it is recommended to take only the morning dose, as indicated in the table, and the evening dose - to skip.

Dysfunction of the liver. There is no need to change the dose in patients with hepatic impairment (see "Pharmacokinetics").

Overdose

Symptoms: Aprilmalast was studied in healthy volunteers at a maximum daily dose of 100 mg (50 mg twice daily) for 4.5 days without signs of dose-limiting toxicity.

Treatment: In case of overdose, it is recommended to observe symptoms and signs of NLR. If necessary, prescribe symptomatic and supportive treatment.

Special instructions

In patients with severe renal insufficiency, the dose of Otetal should be reduced to 30 mg once a day (see "Pharmacokinetics" and "Method of administration and dose").

In patients with insufficient body weight at the beginning of the course of therapy, it is necessary to regularly monitor body weight during treatment. In the case of unexplained or clinically significant weight loss, a thorough medical examination of the patient should be made and consideration should be given to discontinuing treatment.

Effect on the ability to drive and work with machinery. The apremilast does not affect the ability to drive or operate machinery.

Release form

film-coated tablets 10, 20 and 30 mg.

Packaging to start treatment: 4 tablets. 10 mg, 4 tablets. 20 mg and 5 tablets. For 30 mg in a blister of PVC / aluminum foil; 14 tab. 30 mg in another blister of PVC / aluminum foil. 2 blisters are placed in a cardboard envelope.

Packaging for continuing treatment: 14 tablets. 30 mg in a PVC / aluminum foil blister. 4 blisters are placed in a cardboard box sealed with two transparent stickers.

Manufacturer

All stages: Selden International Sarl., Switzerland / Celgene International Sarl., Switzerland. Ruth de Perrot, 1, 2017 Bodry, Switzerland / Route de Perreux, 1, 2017 Boudry, Switzerland.

When the drug is packaged at OJSC Pharmstandard-Leksredstva:

Manufacturer Seldzhen International Sarl., Switzerland / Celgene International Sarl., Switzerland. Ruth de Perrot, 1, 2017 Bodry, Switzerland / Route de Perreux, 1, 2017 Boudry, Switzerland.

Packer. OJSC Pharmstandard-Leksredstva

The organization that accepts claims. Representative office of Seldzhen International Holdings Corporation Corporation

Conditions of supply of pharmacies

On prescription.

Storage conditions of the drug Otezla

At a temperature of not higher than 30 ° C.

Keep out of the reach of children.

Shelf life of the drug Otezla

2 years.

Do not use after the expiry date printed on the package.