OF THE HOTEL (Otezla)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceApremilastApremilast
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  • OF THE HOTEL
    pills inwards 
    Selden International Sarl     Switzerland
    • Dosage form: & nbspfilm-coated tablets
    Composition:

    1 tablet of 10 mg contains:

    active substance: aprimilast 10 mg; Excipients: cellulose microcrystalline 26.25 mg, lactose monohydrate 60.0 mg, croscarmellose sodium 3.0 mg, magnesium stearate 0.75 mg, film coat (Opadrai II pink) 4.0 mg *.

    1 tablet of 20 mg contains:

    active substance: aprimilast 20 mg; Excipients: cellulose microcrystalline 52.5 mg, lactose monohydrate 120.0 mg, croscarmellose sodium, 6.0 mg, magnesium stearate 1.5 mg, film coat (Opadrai II brown) 8.0 mg *.

    1 tablet of 30 mg contains:

    active substance: aprimilast 30 mg; Excipients: cellulose microcrystalline 78.75 mg, lactose monohydrate 180.0 mg. sodium croscarmellose 9.0 mg, magnesium stearate 2.25 mg. Film shell (Opadrai II beige) 12.0 mg *.

    * Film coating composition in% (m / m):

    Opadrai II pink: polyvinyl alcohol 40, titanium dioxide 24.60, macrogol 20.20, talc 14.80, iron dye red oxide (E 172) 0.40;

    Opaprai II brown: polyvinyl alcohol 40, titanium dioxide 12.13, macrogol 20.20, talc 14.80, iron dye red oxide (E 172) 1.22, iron dye oxide yellow (E 172) 11.65;

    Bead defecation II: polyvinyl alcohol 40, titanium dioxide 22.99, macrogol 20.20, talc 14.80, iron dye red oxide (E 172) 1.18, iron dye oxide yellow (E 172) 0.43, iron dye oxide black (E 172) 0.40.

    Description:

    Tablets 10 mg: pink, diamond-shaped tablet covered with a film sheath, with engraved "10" on one side and "APR" on the other side;

    Tablets of 20 mg: brown, diamond-shaped tablet coated with a film sheath, with engraved "20" on one side and "APR" on the other side;

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

    Pharmacotherapeutic group:Immunosuppressants, selective immunosuppressants
    ATX: & nbsp

    L.04.A.A.32   Apremilast

    Pharmacodynamics:

    Mechanism of action

    Apremilast, an oral preparation, is a small molecule, a phosphodiesterase 4 (PDE4) inhibitor that acts inside the cell, modulating the proinflammatory and anti-inflammatory mediators. PDE4 is the specific phosphodiesterase (PDE) of cyclic adenosine monophosphate (cAMP) and the dominant PDE in inflammatory cells. When PDE4 is suppressed, the amount of cAMP increases, which in turn leads to the suppression of the inflammatory response by modulating the expression of tumor necrosis factor alpha (TNFα), interleukin (IL) -23, IL-17 and other inflammatory cytokines.cAMP also modulates the 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 studies in patients with psoriatic arthritis (PsA) aprimilast significantly modulated, but did not completely inhibit blood plasma proteins: IL-1α, IL-6, IL-8, monocyte chemoattract protein-1 (MXB-1), macrophage inflammation-1β (MBB-1β), matrix metalloproteinase-3 MMP-3) and TNF-α. After 40 weeks of treatment with apologilast, 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 thickening affected areas, infiltration of inflammatory cells and the expression of proinflammatory genes, genes including inducible nitric oxide synthase (iNOS), IL-12 / IL-23r40, IL-17A, IL-22 and IL-8.

    The apremilast, when administered in doses up to 50 mg 2 times a day, does not extend the QT interval in healthy subjects.

    1493 patients with active PsA (≥ 3 ≥3 swollen joints and tender joints), despite previous therapy low molecular or biological disease-modifying drugs (BMLS) lasting at least 6 monthsreceived inside the placebo, aprimilast 20 mg or aprimilast 30 mg 2 times a day. Apremilast were used as 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 BMLS, and 22.4% of patients had previously been treated with biological BMLS, of which 7.8% were ineffective. The average duration of PsA was 5 years.

    The therapy with apoimilastom led to a significant improvement in the symptoms of PsA in comparison with placebo.

    The efficacy of treatment with aphrolylast was not different in patients who received or did not receive BMS, 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, there was a significant, statistically significant improvement in functional activity.

    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 (oral, 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 aphrodlast was manifested in a complex of clinical manifestations of psoriasis, including itching, nail and scalp damage, and quality of life. The clinical efficacy of aprelimal 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. The response to treatment with aphrolylast was rapid and was expressed in a significant reduction in the symptoms of psoriasis by the second week of treatment, compared with placebo.

    Pharmacokinetics:

    Suction

    Aprremilast is well absorbed and its absolute bioavailability after ingestion is approximately 73%. Median time to reach (tmax) the maximum concentration in the blood plasma (Cmax) 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 per day). After taking apromilast 1 time a day, cumulation is minimal, and after applying 2 times a day it is approximately 53% in healthy people and 68% in psoriasis patients. Bioavailability of aphomilast is not disturbed when it is applied to food, so it can be taken regardless of the time of ingestion.

    Distribution

    Apremilast binds to human plasma proteins by approximately 68%. The average apparent volume of distribution (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 a 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 O-demethylated apomorphite (Ml2). As 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 aprimilast 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 CYP450 isoenzymes.

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

    In vitro aprimilast slightly inhibits or does not affect (IC50> 10 μM) on the carriers of organic anatoms OAT1 and OAT3, the carrier of organic cations OCT2, the transport polypeptide of organic anions (OATP) 1B1 and OATP1B3 or the breast cancer resistance protein (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 / hour and the final half-life is approximately 9 hours. After ingestion of the labeled compound with kidneys and intestines, approximately 58% and 39% of radioactivity, respectively, are excreted, with approximately 3% and 7% of the dose in the form of a radioactive aprimilast.

    Elderly patients

    The apremilast was studied in young and elderly healthy volunteers. Exposure of ergilavast in the elderly (65 to 85 years) is approximately 13% higher in terms of the area under the concentration / time curve (AUC) and 6% higher in Cmax in comparison with volunteers aged 18-55 years. Data on the use of the drug in clinical studies in patients older than 75 years are limited. In elderly patients there is no need for dose adjustment.

    Renal insufficiency

    In patients with mild to moderate renal insufficiency and healthy volunteers, there were no significant differences in the pharmacokinetics of aprimilast. Therefore, with renal failure of mild or moderate severity, a dose change is not required. In severe renal failure (glomerular filtration rate less than 30 ml / min / 1.73 m2 or creatinine clearance <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 apremilast 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. Apremilast 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 there was no apparent side effect (NOAEL) on fertility 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 at doses of apremilast 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).

    Embryo-fetal development

    The NOEL value for embryo-fetal development was 10 mg / kg / day (1.3 of the clinical exposure value). In the monkeys 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 in the first week of lactation at doses ≥ 80 mg / kg / day (≥ 4.0 above the clinical exposure level). There was no effect on the pregnancy rate, 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.

    All the undesirable effects on postnatal development were noted during the first week and did not appear in subsequent periods.Sexual maturation, behavior, mating, fertility and uterine parameters 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 when studied in mice and rats.

    Genotoxicity studies

    Aprremilast is not genotoxic. Apremilast did not cause mutations according to the results of the Ames test or chromosomal 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.

    Indications:

    Psoriatic arthritis

    Treatment of active psoriatic arthritis (PsA) in adults in monotherapy or in combination with antirheumatic disease-modifying agents (BMLS) with insufficient response or with intolerance of previous therapy of BMLS.

    Psoriasis

    Treatment of plaque psoriasis of moderate to severe severity in adults with insufficient response, contraindications or intolerance to other basic anti-inflammatory therapy, including ciclosporin, methotrexate or medicines used together with ultraviolet-A irradiation (PUVA).

    Contraindications:

    - Hypersensitivity to apreylmast or other components that make up the drug;

    - Pregnancy;

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

    Carefully:

    - In patients with rare hereditary disorders in the form of intolerance to galactose, with congenital insufficiency of lactase or with impaired absorption of glucose-galactose (the preparation contains lactose);

    - In patients with severe renal insufficiency (see section "Pharmacokinetics", "Method of administration and dose", "Special instructions");

    - In patients with insufficient body weight (see section "Special instructions").

    Pregnancy and lactation:

    Women capable of childbearing

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

    Pregnancy

    Data on the use of aphomilast 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 the section "Pharmacological properties").

    Breastfeeding period

    Aprremilast was found in milk of mice (see section "Pharmacological properties"). It is not known whether aprimilast or its metabolites into human milk. Since it is impossible to exclude the risk of undesirable effects on the baby during breastfeeding, aprimilast should not be used during breastfeeding.

    Fertility

    There are no data on the effect on fertility in humans. In experiments on mice, there was no undesirable effect on male fertility with the exposure of aphylamastes 3-fold higher than clinical, and in females - with exposure comparable to clinical. Data on non-clinical study of fertility are presented in the section "Pharmacological properties".

    Dosing and Administration:

    For oral administration.

    Treatment with Othella can be prescribed only by a specialist with sufficient experience in the diagnosis and treatment of psoriasis and psoriatic arthritis.

    Covered tablets should be swallowed whole, preferably by washing them with water.Take regardless of the time you eat.

    Doses

    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. Initial titration of the dose is required, as shown in Table I. After the initial titration, no re-titration is required.

    Table 1: Diagram of titration dose

    Day 1

    Day 2

    Day 3

    Day 4


    Day 5

    Day 6 onwards

    morning

    morning

    evening

    morning

    evening

    morning

    evening

    morning

    evening

    morning

    evening

    10 mg

    10 mg

    10 mg

    10 mg

    20 mg

    20 mg

    20 mg

    20 mg

    30 mg

    30 mg

    30 mg

    If the patient misses the drug, the next dose should be taken as soon as possible. If a dose is missed immediately before the time of taking the next dose, then the missed dose is not taken and proceed to the next drug intake at the appropriate time. The patient MUST NOT take two doses of the drug at the same time.

    The maximum therapeutic effect was observed 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 the section "Pharmacodynamics").

    Special Populations

    Children and teens

    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 the section "Side effect" and "Pharmacokinetics").

    Renal impairment

    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 (creatinine clearance less than 30 ml / min when evaluated by the Cockcroft-Gault formula). At the initial titration it is recommended to take only the morning dose, as indicated in Table 1, and the evening dose - to skip.

    Dysfunction of the liver

    There is no need to change the dose in patients with hepatic insufficiency (see the section "Pharmacokinetics").

    Side effects:

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

    The most frequent NLRs that caused the discontinuation 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 responses were not specific for any organ system.

    Hypersensitivity reactions were rarely recorded during clinical trials of aprethmast.

    The NLR observed in patients treated with apreylastomas is classified according to the damage to organs and organ systems (MEDDRA medical dictionary for regulatory activities).

    These NLRs are documented in the clinical trials of apo-milastar in psoriatic arthritis (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 *.

    Impaired immune system

    Infrequent: hypersensitivity reactions.

    Disorders from the metabolism and nutrition

    Often: decreased appetite *.

    Disorders of the psyche

    Often: insomnia.

    Disturbances from the nervous system

    Often: migraine *, tension headache *, headache *.

    Disturbances from the respiratory system, chest and mediastinal organs

    Often: cough.

    Disorders from the gastrointestinal tract

    Very often: diarrhea *, nausea *;

    Often: vomiting *, dyspepsia, frequent stools, pain in the upper abdomen *, gastroesophageal reflux disease.

    Disturbances from the skin and subcutaneous tissues

    Infrequent: rash.

    Disturbances from musculoskeletal and connective tissue

    Often: back pain.

    General disorders and disorders at the site of administration

    Often: fatigue.

    Laboratory and instrumental data

    Infrequent: weight loss.

    * - at least one of these NLRs is regarded as serious.

    Description of selected NLRs

    Weight loss

    The body mass of the patients was regularly evaluated during clinical trials. The average decrease in body weight against the background of taking apremilast for 52 weeks was 1.99 kg. In all, 14.3% of patients who received aprimilast, 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.

    See additional precautions when initiating treatment for patients with reduced body weight in the sections "With caution" and "Special instructions."

    Depression

    During clinical trials, 1.2% (in 14 of 1184) of patients with psoriasis who received aprimilast, depression developed 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 apoilmastomas, depression / depressive state was noted. In the placebo group, it was recorded in 0.7% (5/671). In 0.1% (2/1945) of the patients taking aprimilast, depression / depressive condition was regarded as serious. In the placebo group, there were no serious cases of depression. 3 patients (3/1945, 0.2%) who received aprimilast, 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 hepatic function

    The safety of apremilast has not been evaluated in patients with PsA or psoriasis and impaired liver function.

    Patients with impaired renal function

    In clinical trials with PsA and psoriasis, the safety profile of the drug was not different in patients with normal renal function and with mild renal insufficiency. The safety of apremilast has not been studied in patients with PsA or psoriasis and renal insufficiency of moderate and severe severity.

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

    Joint application with a powerful inducer of cytochrome P450 isoenzyme Z4 (CYP3A4), rifampicin,leads to a weakening of the systemic effect of apremilast and a decrease in its effectiveness. Therefore, combined use of powerful inductors of the CYP3A4 isoenzyme is not recommended (for example, rifampicin, phenobarbital, carbamazepine, phenytoin and preparations of St. John's wort perfumed) with aprelymastom. With the simultaneous re-application of aurililast and rifampicin AUC and Cmax aprimilast decline, respectively, by 72% and 43%. In conditions of combined use of apreamilast with powerful inducers of the isoenzyme CYP3A4 (for example, rifampicin) the clinical response may be reduced.

    During clinical trials aprimilast combined with local therapies (corticosteroids, tar shampoo, salicylic acid preparations for scalp treatment) and with UV-B phototherapy.

    There was no clinically significant drug interaction between ketoconazole and aprelimal. 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. Apremilast can be combined with methotrexate.

    There was no pharmacokinetic drug interaction between apreurast and oral contraceptives containing ethinyl estradiol and norgestimate. Apremilast can be combined with oral contraceptives.

    Special instructions:

    Patients with severe renal insufficiency gravity Otesla drug dose should be reduced to 1 to 30 mg once a day (cm. To "Pharmacokinetics" and "Dosage and administration").

    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 transp. cf. and fur:Apremilast does not affect the ability to drive or operate machinery.
    Form release / dosage:Tablets, film-coated, 10, 20 and 30 mg.
    Packaging:

    1. 4 tablets 10 mg, 4 tablets 20 mg and 5 tablets 30 mg in one blister of PVC / aluminum foil; 14 tablets 30 mg in another blister of PVC / aluminum foil.2 blisters with instructions for use in packaging-cardboard envelope.

    2. 14 tablets of 30 mg in a blister of PVC / aluminum foil. 4 blisters with instructions for use in a pack of cardboard. A pack of cardboard is sealed with two transparent stickers.

    Storage conditions:Store at a temperature not exceeding 30 ° C.
    Shelf life:2 years.
    Terms of leave from pharmacies:On prescription
    Registration number:LP-003829
    Date of registration:08.09.2016
    Expiration Date:08.09.2021
    The owner of the registration certificate:Selden International SarlSelden International Sarl Switzerland
    Manufacturer: & nbsp
    Representation: & nbspSeldzhen International Holdings Corporation Seldzhen International Holdings Corporation USA
    Information update date: & nbsp15.06.2017
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