Mechanism of action
APREMILAST is a small molecule – PDE4 inhibitor which acts intracellularly, modulating proinflammatory and anti-inflammatory mediators. PDE4 – specific PDE cAMP predominant PDE in inflammatory cells. When PDE4 inhibition increased amount of cAMP, which in turn leads to the suppression of the inflammatory response by modulating expression of TNF-α, IL-23, IL-17 and other inflammatory cytokines. cAMP modulates the levels of certain inflammatory cytokines, such as IL-10. These pro- and anti-inflammatory mediators involved in the pathogenesis of psoriasis and psoriatic arthritis (PsA).
In clinical studies of patients PsA APREMILAST significantly modulate, but not completely inhibited plasma proteins: IL-1α, IL-6, IL-8, monocyte hemoattraktny protein-1 (MXE-1), macrophage protein-1β inflammation (MBB-1β ), matrix metalloproteinase-3 (MMP-3) and TNF-α. After 40 weeks of treatment APREMILAST decreased concentrations of IL-17 and IL-23 and increasing IL-10 concentration in blood plasma. Patients with psoriasis APREMILAST reduced focal epidermal thickening of the affected areas, infiltration by inflammatory cells and the expression of proinflammatory genes including genes inducible nitric oxide synthase (iNOS), IL-12 / IL-23p40, IL-17A, IL-22 and IL-8.
APREMILAST when administered at 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 months, prepared into a placebo, 20 mg or APREMILAST APREMILAST 30 mg 2 times in a day. APREMILAST 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 were treated before biological BMLS, including 7.8% of this therapy was ineffective. The average duration of PsA -. 5 years
APREMILAST therapy led to a significant improvement in symptoms of PsA as compared with placebo.
APREMILAST effectiveness of treatment did not differ in patients simultaneously treated or not treated with BMLS, including methotrexate. Patients taking BMLS or biological BMLS to APREMILAST therapy, therapeutic effects APREMILAST were more pronounced than those who took a placebo. The therapy APREMILAST showed a significant, statistically significant improvement in functional activity.
A total of 1257 patients with plaque psoriasis moderate and severe, which planned a phototherapy or systemic therapy, were randomized to the placebo group or APREMILAST group (oral, 30 mg 2 times a day). Approximately 30% of patients have not previously received phototherapy standard system or biological preparations.
The therapy APREMILAST in patients with psoriasis moderate to severe, there was significant improvement compared with placebo. APREMILAST effectively exhibit on a set of clinical manifestations of psoriasis, including itching, loss of nails and scalp, as well as quality of life.
Clinical efficacy APREMILAST confirmed in various subgroups of patients, formed by the initial demographic and clinical characteristics (including the presence and length of psoriasis PsA history). Positive clinical effect of the drug is independent of previous medication therapy of psoriasis and its results. Response to treatment was rapid and APREMILAST expressed in a significant reduction of the symptoms of psoriasis already by the 2nd week of treatment, compared with placebo.
Selja International Sarl Switzerland
The active ingredient is:
APREMILAST – 30 mg
Treatment of the active psoriatic arthritis (PsA) in adults in monotherapy or in combination with the basic anti-inflammatory drugs (DMARDs) when there is insufficient response or intolerance prior DMARD therapy.
Treatment plaque psoriasis secondary to severe in adults with inadequate response contraindications or intolerance of antiinflammatory therapy, including cyclosporin, methotrexate or medicines used together with UV-A radiation (PUVA).
Hypersensitivity to APREMILAST or other components forming part of the formulation;
Children up to age 18 years (insufficient clinical experience).
The most common adverse drug reactions (ADRs) in phase III clinical trials were gastrointestinal disorders – diarrhea (15.7%) and nausea (13.9%). In general, these disorders were mild or moderate, and only 0.3% of each of these ADRs were considered to be severe. These ADRs arise primarily during the first 2 weeks of treatment and is typically resolved within 4 weeks. Other common ADRs were upper respiratory tract infection (8.4%), headache (7.9%) and tension headache (7.2%). In general, the majority of ADRs were mild to moderate in severity.
Hypersensitivity reactions are rarely recorded in clinical studies APREMILAST. NLR reported in clinical studies APREMILAST in psoriatic arthritis (1945 patients) and psoriasis (1184 patients). Infectious and parasitic diseases of: bronchitis, upper respiratory tract infection, nasopharyngitis.
Disorders of immune system: hypersensitivity reactions.
Violations by the Metabolism and nutrition: loss of appetite.
Mental disorders: insomnia, depression.
Disorders of the nervous system: migraine, tension headache, headache.
Violations of the respiratory system, thorax and mediastinum: cough.
Disorders of the gastrointestinal tract: diarrhea, nausea, vomiting, indigestion, frequent stools, pain in the upper abdomen, gastroesophageal reflux disease, gastrointestinal bleeding.
Violations of the skin and subcutaneous tissue: skin rash.
Violations by musculoskeletal and connective tissue disorders: pain in the back.
General disorders and at the injection site: fatigue.
Laboratory and instrumental data: weight loss.
How to accept, acceptance rate and dosage
For oral administration.
Treatment with Otesla may assign only a specialist with adequate experience in the diagnosis and treatment of psoriasis and psoriatic arthritis.
The coated tablets should be swallowed whole, preferably with a glass of water. Taken without regard to mealtime.
APREMILAST recommended dose – 30 mg orally two times a day, morning and evening at an interval of about 12 hours. It requires initial dose titration. After the initial titration re-titration is not required.
Store at a temperature not higher than 30 ° C.
Keep out of the reach of children.
The combined use of a potent inducer of cytochrome P450 3A4 (CYP3A4), rifampicin, weakens the systemic exposure APREMILAST and reduce its effectiveness. Therefore, the combined use is not recommended potent inducers isoenzyme CYP3A4 (e.g. rifampin, phenobarbital, carbamazepine, phenytoin and preparations Hypericum perforatum) with APREMILAST.
With the simultaneous application of repeated APREMILAST and rifampicin Cmaxapremilasta and AUC are reduced respectively by 72 and 43%. The conditions combined use with potent inducers APREMILAST isoenzyme CYP3A4 (e.g. rifampicin) can decrease clinical response. During clinical studies APREMILAST combined with the means of local therapy (corticosteroids, tar shampoo, salicylic acid, drugs for the treatment of the scalp) and UV-B phototherapy.
No clinically significant drug interaction between ketoconazole and APREMILAST. APREMILAST can be combined with potent inhibitors isoenzyme CYP3A4, such as ketoconazole.
Not detected pharmacokinetic drug interaction between APREMILAST and methotrexate in patients with PsA. APREMILAST can be combined with methotrexate.
There was no pharmacokinetic interaction between the drug and APREMILAST oral contraceptives containing ethinylestradiol and norgestimate. APREMILAST can be combined with oral contraceptives.
Patients with a rare hereditary disorders of galactose intolerance, congenital lactase deficiency or impaired absorption of glucose-galactose should not take the drug.
Mental disorders: application APREMILAST associated with an increased risk of developing mental disorders, such as insomnia and depression. The incidence of suicidal ideation and behavior, including suicide, have been observed in patients with both an indication of depression in history, and without it (see. Section “Side effects”).
The risks and benefits of the beginning and continuation of therapy APREMILAST should be carefully evaluated in patients who report their existing mental disorders or the presence of such a history, or in the case of the planned patient receiving other concomitant medications that can cause mental disorders.
The patient and the person caring for the patient should inform the doctor to prescribe, of any changes to the patient’s mood or behavior, as well as the appearance of his suicidal thoughts. Severe renal impairment: Patients with severe renal insufficiency gravity Otesla dose should be reduced up to 30 mg 1 time per day (see “Pharmacokinetics” section and “Dosage and Administration”.).
Patients who are underweight: in patients who are underweight at the start of therapy is necessary to regularly control body weight during treatment. In the event of unexplained or clinically significant weight loss is necessary to conduct a thorough physical examination of the patient and consider discontinuing treatment.
Effect on ability to drive and use machines: APREMILAST not affected or influenced to a small extent on the ability to drive or operate machinery
APREMILAST studied in healthy volunteers in the maximum daily dose of 100 mg (50 mg 2 times a day) for 4.5 days without evidence of dose-limiting toxicity.
In overdose recommended for symptoms and signs monitoring ADRs.
If necessary, appoint symptomatic and supportive treatment.