Dilaxa, 200 mg capsules 10 pcs

Painful menstruation (algodysmenorrhea), Back pain, Arthritis, Radiculitis, Osteochondrosis, Neck pain, Sciatica, Pain after injuries and operations, Rheumatoid arthritis, Joint pain (arthralgia), Lumbago, Arthrosis, Pain, Osteoarthritis

• Symptomatic treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis.
• Pain syndrome (back pain, musculoskeletal, postoperative and other types of pain).
• Treatment of primary dysmenorrhea.

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Active ingredient

Composition

1 capsule 100 mg/200 mg contains:

Active substance:

Celecoxib 100.00 mg/200.00 mg

Auxiliary substances: lactose monohydrate, sodium lauryl sulfate, povidone-K30, croscarmellose sodium, magnesium stearate

Solid gelatin capsules #3

Corpus: titanium dioxide (E171), gelatin

Cap:titanium dioxide (E171), gelatin

Solid gelatin capsules #1

Corpus: titanium dioxide (E171), iron oxide yellow dye (E172), gelatin

Cap:titanium dioxide (E171), iron oxide yellow dye (E172), gelatin

How to take, the dosage

Orally, without chewing, with water, regardless of meals.

Because the risk of cardiovascular complications may increase with increasing dose and duration of Dilax®, the lowest effective dose of the drug should be taken for the shortest possible course. The maximum recommended daily dose for long-term use is 400 mg.

Simptomatic treatment of osteoarthritis: The recommended dose is 200 mg daily in 1 or 2 doses.

Symptomatic treatment of rheumatoid arthritis:the recommended dose is 100 mg or 200 mg 2 times daily.

Simptomatic treatment of ankylosing spondylitis:the recommended dose is 200 mg daily in 1 or 2 doses. In some patients, the efficacy of 400 mg daily has been observed.

Treatment of pain syndrome and primary dysmenorrhea:The recommended initial dose is 400 mg, followed by an additional dose of 200 mg on day 1 if necessary. On subsequent days, the recommended dose is 200 mg twice daily, as needed.

Elderly Patients:Dose adjustment is usually not necessary. However, in patients with body weight less than 50 kg, it is better to start treatment with the minimum recommended dose.

Hepatic impairment: in patients with mild hepatic impairment (Child-Pugh class A) no dose adjustment is required. In patients with moderate hepatic insufficiency (class B according to Child-Pugh classification) the initial recommended dose of the drug should be reduced by half. There is no experience of Dilax® use in patients with severe hepatic insufficiency (Child-Pugh class C) (see section “Contraindications”).

Kidney function impairment: In patients with mild to moderately severe renal failure, no dose adjustment is required. There is no experience of using the drug Dilaxa® in patients with severe renal failure (see sections “Special Precautions” and “Contraindications”).

Simultaneous use with fluconazole:In concomitant use of fluconazole (CYP2C9 isoenzyme inhibitor) and the drug Dilax® the initial recommended dose of the drug should be reduced by half. Caution should be exercised when concomitant use with other CYP2C9 isoenzyme inhibitors.

Slow metabolism of substrates isoenzyme CYP2C9: In patients who are slow metabolizers or are suspected of having this condition, Dilaxa® should be used with caution as it may lead to the accumulation of celecoxib in high plasma concentrations. In such patients, the initial recommended dose should be reduced by half.

Interaction

Studies in vitro have shown that celecoxib, although not a substrate of the CYP2D6 isoenzyme, inhibits its activity. Therefore, there is a possibility of drug interaction under in vivo conditions with drugs whose metabolism is bound to the CYP2D6 isoenzyme.

Varfarin and other anticoagulants: concomitant use may prolong prothrombin time.

Fluconazole, ketoconazole: console administration of fluconazole 200 mg once daily leads to increase of celecoxib concentration in blood plasma by 2 times. This effect is associated with inhibition of celecoxib metabolism by fluconazole through CYP2C9 isoenzyme. Patients taking fluconazole (CYP2C9 isoenzyme inhibitor) should reduce the recommended dose of celecoxib by half (see section “Dosage and administration”). Ketoconazole (CYP3A4 isoenzyme inhibitor) has no clinically significant effect on the metabolism of celecoxib.

Dextromethorphan and metoprolol: Current use of celecoxib at a dose of 200 mg per day was found to increase concentrations of dextromethorphan and metoprolol (substrates of the CYP2D6 isoenzyme) by 2.6 and 1.5-fold, respectively. This increase in concentrations is associated with the inhibition of CYP2D6 isoenzyme substrates metabolism by celecoxib by inhibiting the activity of CYP2D6 isoenzyme itself.

Methotrexate: no pharmacokinetic clinically significant interactions between celecoxib and methotrexate were noted.

Hypotensive drugs, including angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor antagonists II (ARAs II), diuretics, and beta-adrenoblockers: Inhibition of Pg synthesis may reduce the effects of hypotensive drugs, including ACE and/or ARA II inhibitors, diuretics, and beta-adrenoblockers. This interaction should be taken into account when using celecoxib concomitantly with ACE and/or ARA II inhibitors, diuretics and beta-adrenoblockers. However, no significant pharmacodynamic interaction with lisinopril regarding the effect on BP has been observed.

In elderly patients, in patients who are dehydrated (including patients receiving diuretic therapy) or in patients with impaired renal function, concomitant use of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, ARA II and diuretics may result in impaired renal function, including possible acute renal failure. Usually these effects are reversible. Therefore, caution should be exercised when concomitant use of these drugs. In such cases it is reasonable to carry out rehydration first and then start the therapy with Dilaxa®. Besides, it is necessary to consider the possibility of kidney function monitoring in the beginning of therapy and periodically during concomitant use of the drugs.

Cyclosporine: Because NSAIDs affect renal Pg synthesis, may increase the risk of nephrotoxicity when used concurrently with cyclosporine.

Diuretics:NSAIDs in some patients may decrease the natriuretic effect of furosemide and thiazides by reducing renal Pg synthesis. This should be considered when using celecoxib.

On oral contraceptives: celecoxib has no clinically significant effect on the pharmacokinetics of the combined contraceptive drug (1 mg norethisterone/35 µg ethinylestradiol).

Lithium: Concomitant use of lithium salts at a dose of 450 mg twice daily and celecoxib at a dose of 200 mg twice daily resulted in an increase in blood plasma lithium concentration of approximately 17 %. Patients taking lithium medications should be closely monitored when using or discontinuing celecoxib. Other NSAIDs:The simultaneous use of celecoxib and other NSAIDs (not containing acetylsalicylic acid) should be avoided (increased risk of side effects).

Other drugs: no clinically significant interactions between celecoxib and antacids (magnesium/aluminum hydroxide), omeprazole, glibenclamide, phenytoin, or tolbutamide were noted.

Celecoxib does not affect the antiaggregant effect of acetylsalicylic acid at low doses. Celecoxib has no antiplatelet effect on platelets, therefore it should not replace acetylsalicylic acid for the prevention of cardiovascular diseases.

In healthy volunteers NSAIDs have no effect on digoxin pharmacokinetics. However, when concomitant use of digoxin and indomethacin, ibuprofen in patients increased concentrations of digoxin in blood plasma were observed. This should be taken into account when concomitant use with other drugs that increase plasma concentrations of digoxin. There is no information about the interaction of celecoxib and digoxin. Given the other effects of celecoxib on the cardiovascular system, caution should be exercised when taking it concomitantly with digoxin. In this case, it is recommended that adverse reactions be closely monitored. Celecoxib is predominantly metabolized in the liver by CYP2C9 isoenzyme. As barbiturates are inducers of CYP2C9 isoenzyme, when used concomitantly with celecoxib, a decrease in the plasma concentration of celecoxib may be observed.

Children: Interaction studies have been performed only with adult patients.

Special Instructions

Gastrointestinal diseases (gastric and duodenal ulcer, ulcerative colitis, Crohn’s disease, bleeding history), presence of infection Helicobacter pylori, concomitant use with digoxin, anticoagulants (e.g., warfarin), antiplatelet agents (e.g., acetylsalicylic acid, clopidogrel), oral glucocorticosteroids (GCS) (e.g., prednisolone), diuretics, selective serotonin reuptake inhibitors (e.g, citalopram, fluoxetine, paroxetine, sertraline), CYP2C9 isoenzyme inhibitors, in patients who are slow metabolizers or are suspected of this condition, fluid retention and edema, moderate liver function impairment (see hepatic disorders, history of liver disease, hepatic porphyria, impaired renal function (CK 30-60 ml/min), significant reduction in circulating blood volume (including after surgery), cardiovascular disease, arterial hypertension (see section “Indications”).

Particular indications>, cerebrovascular diseases, dyslipidemia/hyperlipidemia, diabetes mellitus, peripheral artery disease, long-term use of NSAIDs, severe somatic diseases, in elderly patients (including those receiving diuretics, weakened patients with low body weight), smoking, tuberculosis, alcoholism.

It is contraindicated in patients under 18 years of age.

Elderly patients:dose adjustment is usually not necessary. However, in patients with body weight less than 50 kg, it is better to start treatment with the minimum recommended dose.

Hepatic impairment: in patients with mild hepatic impairment (Child-Pugh class A) no dose adjustment is required. In patients with moderate hepatic insufficiency (class B according to Child-Pugh classification) the initial recommended dose of the drug should be reduced by half. There is no experience of Dilax® use in patients with severe hepatic insufficiency (Child-Pugh class C).

Kidney function impairment: In patients with mild to moderately severe renal failure no dose adjustment is required. There is no experience of using the drug Dilaxa® in patients with severe renal failure.

The drug Dilaxa®, which has antipyretic effects, may decrease the diagnostic value of fever, making the diagnosis of infection difficult.

Effects on the cardiovascular system

Celecoxib, like all coxibs, can increase the risk of serious cardiovascular complications, such as thrombosis, myocardial infarction, and stroke, which can be fatal. The risk of these reactions increases with increasing dose, duration of drug administration, and in patients with cardiovascular disease or with cardiovascular risk factors. In order to reduce the risk of these reactions, the drug Dilaxa® should be used in the lowest effective dose and the shortest possible course (at the discretion of the attending physician). The treating physician and the patient should take into account the possibility of developing such complications even in the absence of previously known symptoms of cardiovascular dysfunction. Patients should be informed about the symptoms of serious adverse cardiovascular events and the steps that should be taken if they occur.

The use of NSAIDs (selective COX-2 inhibitors) in patients after coronary artery bypass surgery to treat pain in the first 10-14 days may increase the rate of myocardial infarctions and cerebrovascular events.

celecoxib has no antiplatelet antiplatelet effect, therefore it should not replace acetylsalicylic acid to prevent thromboembolism. Also in this regard, antiplatelet therapy (e.g., acetylsalicylic acid) should not be abolished in patients at risk of thromboembolic complications.

Like all NSAIDs, celecoxib may increase BP, which may cause cardiovascular complications. Like other NSAIDs, celecoxib should be used with caution in patients with arterial hypertension. BP should be monitored at the beginning and during therapy with celecoxib.

Effects on the digestive system

Very rare cases of perforations, ulceration and bleeding from the GI tract have been observed in patients receiving celecoxib. The risk of developing these complications when using NSAIDs is highest in elderly patients, patients with cardiovascular diseases, patients receiving acetylsalicylic acid simultaneously, and patients with such GI diseases as ulcers, bleeding, inflammatory processes in the acute stage and in the anamnesis. Other risk factors for gastrointestinal bleeding are concomitant use of oral GCS or anticoagulants, long-term treatment with NSAIDs, smoking, taking ethanol. Most spontaneous reports of serious adverse reactions with fatal outcome have been reported in elderly and debilitated patients.

Simultaneous use with warfarin and other anticoagulants

The simultaneous use of NSAIDs with oral anticoagulants increases the risk of bleeding. Caution should be exercised when concomitant use of these drugs. Oral anticoagulants include warfarin, coumarin-type anticoagulants and direct-acting oral anticoagulants (such as apixaban, dabigatran and rivaroxaban). Serious (some of them were fatal) bleeding has been reported in patients who used warfarin or similar agents concomitantly with celecoxib. Taking into account the presence of reports about prolongation of prothrombin time, blood clotting parameters should be monitored after the beginning of treatment with the drug Dilaxa® or when changing its dose.

Fluid retention and edema

As with other drugs that inhibit Pg synthesis, fluid retention and edema may be noted in some patients taking Dilaxa®, so caution should be exercised when using the drug in patients with conditions predisposed to or worsened by fluid retention. Patients with a history of heart failure or arterial hypertension should be closely monitored.

Impact on renal function

NSAIDs, including celecoxib, may have toxic effects on renal function. Celecoxib has not been found to be more toxic than other NSAIDs.

Dilaxa® should be used with caution in patients with impaired renal function, heart failure, impaired liver function, in patients taking diuretics, ACE inhibitors, ARA II, and in elderly patients. Renal function should be carefully monitored in such patients. Caution should be exercised when using Dilax® in patients with dehydration. In such cases it is reasonable to carry out rehydration and then initiate therapy with Dilaxa®.

Influence on liver function

The drug Dilaxa® should not be used in patients with severe hepatic dysfunction (Child-Pugh Class C). In patients with moderate hepatic impairment (B class according to Child-Pugh classification) Dilaxa® should be used with caution and in the lowest effective dose. Severe liver dysfunction, including fulminant hepatitis (sometimes fatal), liver necrosis and liver failure (sometimes fatal or requiring liver transplantation) have rarely been observed. Most of these reactions developed 1 month after starting celecoxib.

Patients with symptoms and/or signs of liver dysfunction or those patients in whom liver dysfunction has been detected by laboratory methods should be closely monitored for the development of more severe liver reactions during treatment with Dilax®.

Anaphylactic reactions

Cases of anaphylactic reactions have been reported while taking Dilax®.

Serious skin reactions

Extremely rare serious skin reactions, such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, some of which have been fatal, have been reported while taking celecoxib. The risk of developing such reactions is higher at the beginning of therapy, in most cases noted, they occurred in the first month of therapy. In case of skin rash, changes of mucous membranes or other signs of hypersensitivity it is necessary to stop the use of Dilax®.

GCS therapy

Dilaxa® should not be substituted for GCS therapy when treating glucocorticosteroid deficiency.

Inhibition of isoenzyme function CYP2D6

Celecoxib was found to be a moderate inhibitor of the CYP2D6 isoenzyme. During the therapy with celecoxib the dose of drugs metabolized by CYP2D6 isoenzyme should be decreased, and after the treatment with celecoxib the dose of these drugs should be increased (see section “Interaction with other medicinal products”).

Special information about excipients

Dilaxa® contains lactose, so the drug is contraindicated in patients with lactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.

We should use caution when driving vehicles and engaging in other potentially dangerous activities requiring high concentration and quick psychomotor reactions, since the drug Dilaxa® may cause dizziness and other side effects which may affect the above mentioned abilities.

Synopsis

Capsules 100 mg. Solid gelatin capsules № 3 of white color (body and cap). The content of the capsules is granulated powder of white or almost white color.

Capsules 200 mg. Solid gelatin capsules № 1 brownish-yellow (body and cap). The contents of the capsules is a granulated powder of white or almost white color.

Contraindications

Side effects

Adverse reactions (ARs) are presented by class of organ systems and by frequency of occurrence according to the data obtained:

HDs are grouped according to MedDRA terminology and by frequency of occurrence: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); infrequent (≥ 1/1000 to < 1/100); rare (≥ 1/10 000 to < 1/1000); very rare (< 1/10 000); frequency unknown (cannot be estimated from available data).

Unwanted drug reactions noted in clinical trials of celecoxib and observational experience (MedDRA terminology)1,2

Infectious and parasitic diseases:

often: sinusitis, upper respiratory tract infections, pharyngitis, urinary tract infections.

Blood and lymphatic system disorders:

infrequent: Anemia;

rare: leukopenia, thrombocytopenia;

very rare: pancytopenia4.

Immune system disorders:

often: hypersensitivity;

very rarely: anaphylactic shock4, anaphylactic reactions4.

Disorders of metabolism and nutrition:

infrequent: hyperkalemia.

Mental disorders:

often: insomnia;

infrequently: anxiety, depression, fatigue;

rarely: confusion, hallucinations4.

Nervous system disorders:

often: dizziness, hypertonicity, headache4;

infrequently: cerebral infarction1, paresthesia, somnolence;

rare: ataxia, dysgeusia;

very rarely: Intracranial hemorrhage (including fatal)4, aseptic meningitis4, epilepsy (including exacerbation of epilepsy)4, aguesia4, anosmia4.

Visual organ disorders:

infrequent: blurred vision, conjunctivitis4;

infrequent: blurred vision, conjunctivitis4;

very rarely: retinal artery occlusion4, retinal vein occlusion4.

Hearing organ and labyrinth disorders:

infrequent:Tinnitus, decreased hearing1.

Cardiac disorders:

often: myocardial infarction1;

infrequent: heart failure, palpitations, tachycardia;

rarely:arrhythmia4.

vascular disorders:

very often: arterial hypertension1 (including worsening the course of arterial hypertension);

rarely: pulmonary embolism4, “flushes”4;

very rare: vasculitis4.

Disorders of the respiratory system, thoracic and mediastinal organs:

often: Rhinitis, cough, shortness of breath1;

infrequently: bronchospasm4;

rarely: pneumonitis4.

Gastrointestinal tract disorders:

often: nausea4, abdominal pain, diarrhea, dyspepsia, flatulence, vomiting1, dysphagia1;

infrequent: constipation, gastritis, stomatitis, gastrointestinal (GI) inflammation (including aggravation of existing inflammation), belching;

rarely: gastrointestinal bleeding4, 12 duodenal ulcer, stomach ulcer, esophageal ulcer, intestinal ulcer, large intestinal ulcer, intestinal perforation, esophagitis, melena, pancreatitis, colitis4.

Liver and biliary tract disorders:

infrequent: impairment of liver function, increased activity of “liver” enzymes (including alanine aminotransferase and aspartate aminotransferase);

seldom: hepatitis4;

very rarely: Liver failure4 (sometimes fatal or requiring liver transplantation), fulminant hepatitis4 (sometimes fatal), liver necrosis4, cholestasis4, cholestatic hepatitis4, jaundice4.

Skin and subcutaneous tissue disorders:

often: skin rash, skin itching (including generalized);

infrequently: urticaria, ecchymosis4;

rarely: Quincke’s edema4, alopecia, photosensitivity;

very rarely: exfoliative dermatitis4, erythema multiforme4, Stevens-Johnson syndrome4, toxic epidermal necrolysis4, drug reaction with eosinophilia and systemic symptoms (DRESS or hypersensitivity syndrome)4, acute generalized exanthematous pustulosis (OGEP)4, bullous dermatitis4.

Musculoskeletal and connective tissue disorders:

often: Arthralgia4;

infrequent: muscle spasms (calf muscle spasms);

very rare: myositis4.

Renal and urinary tract disorders:

infrequent: increased concentration of creatinine, plasma urea;

rarely: acute renal failure4, hyponatremia4;

very rarely: tubulointerstitial nephritis4, nephrotic syndrome4, minimal change disease4.

Disorders of the genitals and mammary gland:

Rarely: menstrual disorders4;

frequency unknown: infertility in women (decreased fertility in women)3.

General disorders and disorders at the site of administration:

often: Flu-like condition, peripheral edema/fluid retention;

infrequent: facial edema, chest pain4.

Injuries, intoxications, and complications of manipulation:

often:injuries (accidental injury).

1 NRs developed in 2 clinical trials of polyp prevention (ARS and PreSAP lasting up to 3 years), when using celecoxib at a dose of 400 mg/day. Above are only NRs that were previously reported in the post-registration period or developed with greater frequency than in studies of the drug in arthritis patient populations.

2 Previously unknown HPs developed in 2 clinical trials of polyp prevention (ARS and PreSAP lasting up to 3 years), when using celecoxib at a dose of 400 mg/day:

frequently: angina pectoris, irritable bowel syndrome, nephrolithiasis, increased plasma creatinine concentration, benign prostatic hyperplasia, increased body weight;

infrequent:. Helicobacteriosis, shingles, rye, bronchopneumonia, labyrinthitis, gum infection, lipoma, floating opacities in the vitreous, conjunctival hemorrhage, deep vein thrombosis, dysphonia, hemorrhoidal hemorrhage, frequent defecation, ulcerative stomatitis, allergic dermatitis, ganglion, nycturia, vaginal bleeding, mammary gland soreness, lower extremity fracture, increased plasma sodium content.

3 Referring to the database to find out the frequency was not informative because women planning to become pregnant were excluded from all studies.

4 Frequency values are based on data from a meta-analysis of studies in which 38102 patients took the drug.

In the final (confirmed) data from the APC and PreSAP studies (combined data from both studies), patients receiving celecoxib 400 mg/day for up to 3 years had an increased incidence of myocardial infarction relative to placebo of 7.6 cases per 1,000 patients (infrequent). There was no increase in the incidence of stroke (not differentiated by type) relative to placebo.

Overdose

Clinical data on overdose are limited. Single administration at a dose of up to 1200 mg and multiple administration at a dose of up to 1200 mg 2 times a day were not accompanied by clinically significant side effects. Supportive therapy should be given if overdose is suspected. Dialysis is presumably ineffective, since the binding of celecoxib to plasma proteins is high (97%).

Pregnancy use

Pregnancy

Animal studies (rats and rabbits) have shown reproductive toxicity, including birth defects. The use of Pg synthesis inhibitors can adversely affect pregnancy. Epidemiological studies suggest an increased risk of miscarriage after the use of Pg synthesis inhibitors in early pregnancy. There are insufficient data on the use of celecoxib in pregnant women, but the potential risk of use cannot be excluded. Celecoxib, as well as other drugs that inhibit Pg synthesis, can cause labor weakness and premature closure of the arterial duct in the third trimester of pregnancy.

When used in the second and third trimesters of pregnancy, NSAIDs, including celecoxib, can cause impaired renal function in the fetus, which can lead to decreased amniotic fluid volume or in severe cases to oligocarbia. These effects may develop soon after the start of treatment and are usually reversible.

Use of Dilax® is contraindicated in pregnancy and women planning a pregnancy. If pregnancy occurs during treatment, celecoxib should be discontinued.

Breastfeeding period

Celecoxib is excreted in milk in lactating rats at concentrations similar to those in plasma. Studies have shown that celecoxib is excreted into the breast milk of women at very low concentrations. Breast-feeding should be stopped when using Dilaxa®.

Fertility

According to the mechanism of action, the use of NSAIDs, including celecoxib, may cause delayed follicle maturation or lack of follicle wall rupture in the ovaries, which may be associated with reversible infertility.

Similarities