Dilax Capsules 100mg №10

Tradename: Dilax^®

International non-proprietary name: celecoxib

Active ingredient

Celecoxib substance granules 132.975 mg

[The active substance of the substance granules:

Celecoxib 100.00 mg

Auxiliary substances of the substance-granules: lactose monohydrate 24.875 mg, sodium lauryl sulfate 4.05 mg, povidon-K30 3.375 mg, croscarmellose sodium 0.675 mg]

Excipients: croscarmellose sodium 0.675 mg, Magnesium stearate 1.35 mg

Hard gelatin capsules No. 3

Body: titanium dioxide (E171) 2%, gelatin up to 100%

Cap: titanium dioxide (E171) 2%, gelatin up to 100%

on 1 capsule of 200 mg:

Celecoxib substance granules 265.95 mg

[The active substance of the substance granules:

Celecoxib 200.00 mg

Auxiliary substances of the substance-granules: lactose monohydrate 49.75 mg, sodium lauryl sulfate 8.10 mg, povidon-K30 6.75 mg, croscarmellose sodium 1.35 mg]

Excipients: croscarmellose sodium 1.35 mg, magnesium stearate 2.70 mg

Hard gelatin capsules No. 1

Body: titanium dioxide (E171) 1%, iron dye yellow oxide (E172) 1%, gelatin up to 100%

Cap: titanium dioxide (E171) 1%, iron dye yellow oxide (E172) 1%, gelatin up to 100%

During production at JSC “KRKA, dd, Novo Mesto”, Slovenia

on 1 capsule of 100 mg:

Active substance:

Celecoxib 100.00 mg

Excipients: lactose monohydrate 24.875 mg, sodium lauryl sulfate 4.05 mg, povidon-K30 3.375 mg, croscarmellose sodium 1.35 mg, magnesium stearate 1.35 mg

Hard gelatin capsules No. 3

Body: titanium dioxide (E171) 2%, gelatin up to 100%

Cap: titanium dioxide (E171) 2%, gelatin up to 100%

on 1 capsule of 200 mg:

Active substance:

Celecoxib 200.00 mg

Excipients: lactose monohydrate 49.75 mg, sodium lauryl sulfate 8.10 mg, povidon-K30 6.75 mg, croscarmellose sodium 2.70 mg, magnesium stearate 2.70 mg

Hard gelatin capsules No. 1

Body: titanium dioxide (E171) 1%, iron dye yellow oxide (E172) 1%, gelatin up to 100%

Cap: titanium dioxide (E171) 1%, iron dye yellow oxide (E172) 1%, gelatin up to 100%

Dosage Form: capsules

Description

Capsules 100 mg. Hard gelatin capsules No. 3 are white (body and cap). The contents of the capsules are granulated powder of white or almost white color.

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

Pharmacotherapeutic group: nonsteroidal anti-inflammatory drug (NSAIDs)

Pharmacodynamics

Celecoxib has anti-inflammatory, analgesic and antipyretic effects, blocking the formation of inflammatory prostaglandins (Pg) mainly due to inhibition of cyclooxygenase-2 (COX-2). COX-2 induction occurs in response to inflammation and leads to the synthesis and accumulation of Pg, primarily PgE₂that causes increased inflammation (swelling and pain). In therapeutic doses in humans, celecoxib does not significantly inhibit cyclooxygenase-1 (COX-1) and does not affect the concentrations of Pg, which are synthesized as a result of activation of COX-1,as well as normal physiological processes associated with COX-1 and occurring in the tissues, primarily of the stomach, intestines and platelets.

Impact on kidney function

Celecoxib reduces kidney excretion of PgE₂ and 6-keto-PgF1 (prostacyclin metabolite), but does not affect the serum concentration of thromboxane B₂ (THB₂) and kidney excretion of 11-dehydro-thcB₂, a thromboxane metabolite (both are products of COX-1).

Celecoxib does not cause a decrease in glomerular filtration rate in elderly patients and patients with chronic renal failure (CRF), transiently reduces sodium excretion. In patients with arthritis, the incidence of peripheral edema, arterial hypertension and heart failure was comparable to that in patients receiving non-selective COX inhibitors, which have inhibitory activity against COX-1 and COX-2. This effect was most pronounced in patients receiving diuretic therapy. However, there was no increase in the incidence of high blood pressure and the development of heart failure, and the peripheral edema was mild and went away on its own.

Pharmacokinetics

Suction

When taken on an empty stomach, celecoxib is well absorbed, reaching a maximum concentration (C_max) in blood plasma after about 2-3 hours. C_max in blood plasma after administration of 200 mg of celecoxib is 705 ng / ml. The absolute bioavailability of celecoxib has not been studied. C_max and the area under the concentration-time curve (AUC) is approximately proportional to the dose taken in the range of therapeutic doses up to 200 mg 2 times a day, when using celecoxib at higher doses, the degree of increase in C_max and AUC occurs less proportionally.

Food effect

Taking celecoxib along with fatty foods increases the time to achieve C_max about 4 hours and increases absorption by about 20%.

Distribution

The degree of binding to plasma proteins does not depend on the plasma concentration of celecoxib and is about 97%. Celecoxib does not bind to red blood cells. Celecoxib penetrates the blood-brain barrier.

Metabolism

Celecoxib is metabolized mainly with the participation of the cytochrome P450 (CYP) CYP2C9 isoenzyme in the liver by hydroxylation, oxidation, and partially glucuronidation (see the section "Interaction with Other Drugs"). The resulting metabolites are not pharmacologically active against COX-1 and COX-2.

The activity of the CYP2C9 isoenzyme is reduced in patients with genetic polymorphism, such as the polymorphism homozygous for the isoenzyme CYP2C9 * 3, which leads to a decrease in the efficiency of enzymes.

Removal

Celecoxib is excreted through the intestines and by the kidneys as metabolites (57% and 27%, respectively), less than 1% of the dose taken - unchanged. With repeated use the half-life (T_1/2) is 8-12 hours, and clearance is about 500 ml / min. With repeated use, equilibrium plasma concentrations are reached by the 5th day of administration. Variability of the main pharmacokinetic parameters (AUC, C_maxT_1/2) is about 30%.The average volume of distribution in the equilibrium state is approximately 500 l / 70 kg in young healthy patients, which indicates a wide distribution of celecoxib in the tissues.

Pharmacokinetics in selected groups of patients

Elderly patients

In patients older than 65 years, an increase of 1.5-2 times the average values ​​of C_max and AUC, which is largely due to changes in body weight rather than age (older patients tend to have lower average body weight than younger people, which is why they, all other things being equal, have higher celecoxib concentrations). For the same reason, older women usually have a higher plasma concentration of celecoxib than older men. These pharmacokinetic features, as a rule, do not require dose adjustment. However, in elderly patients with a body weight of less than 50 kg, treatment should be initiated with the minimum recommended dose.

Race

The representatives of the Negroid race AUC celecoxib is about 40% higher than that of the Caucasians. The causes and clinical significance of this fact are unknown, therefore, treatment of people of the Negroid race is recommended to begin with the minimum recommended dose.

Liver dysfunction

Celecoxib plasma concentrations in patients with mild hepatic insufficiency (class A according to the Child-Pugh classification) do not change significantly.In patients with moderately severe liver failure (Child-Pugh class B), plasma concentration of celecoxib can be almost doubled.

Renal dysfunction

In elderly patients with glomerular filtration rate (GFR)> 65 ml / min / 1.73 m²associated with age-related changes and in patients with GFR of 35-60 ml / min / 1.73 m², the pharmacokinetics of celecoxib does not change. There is no significant correlation between serum creatinine concentration (or creatinine clearance (CK)) and celecoxib clearance. It is assumed that the presence of severe renal failure does not affect the clearance of celecoxib, since the main route of its elimination is the transformation in the liver into inactive metabolites.

Indications for use

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

Contraindications

• Hypersensitivity to celecoxib or any other component of the drug.

• Hypersensitivity to other sulfonamide derivatives.
• A complete or incomplete combination of asthma, recurrent nasal polyposis and paranasal sinuses and intolerance to Acetylsalicylic acid or other NSAIDs (including a history of).
• Condition after coronary artery bypass surgery.

• Active erosive and ulcerative lesions of the mucous membrane of the stomach or duodenum, peptic ulcer and duodenal ulcer in the acute stage or Gastrointestinal bleeding .
• Inflammatory bowel disease (Crohn's disease, ulcerative colitis) in the acute phase.
• Heart failure (II-IV functional class according to the NYHA classification).
• Clinically proven ischemic heart disease, peripheral arterial disease and cerebrovascular disease in the severe stage.
• Hemorrhagic stroke.
• Subarachnoid hemorrhage.

• Pregnancy and breastfeeding period (see section “Use during pregnancy and during breastfeeding”).

• Severe hepatic impairment (Child-Pugh class C) (no experience).

• Severe renal failure (CC less than 30 ml / min), progressive kidney disease, confirmed hyperkalemia (no experience with the application).
• Age up to 18 years (no experience of use).

• Lactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome (Dilax^® contains lactose).

Carefully: diseases of the gastrointestinal tract (peptic ulcer of the stomach or duodenum, ulcerative colitis, Crohn's disease, a history of bleeding), the presence of infection Helicobacter pylori, simultaneous use with Digoxin , anticoagulants (for example, warfarin), antiplatelet agents (for example, acetylsalicylic acid, clopidogrel), glucocorticosteroids (GCS) for oral administration (for example, prednisolone), diuretics, selective serotonin reuptake inhibitors (for example, citalopram, serotonin (for example, citalopram, serotonin reuptake inhibitors, selective serotonin reuptake inhibitors (for example, citalopram, serotonin), diuretics, selective serotonin reuptake inhibitors (for example, citalopram, serotonin, for example, citalopram, diuretics, selective serotonin reuptake inhibitors (for example, citalopram, serotonin, for example, citalopram, diuretics, selective inhibitors of serotonin reuptake inhibitors (eg citalopram, serotonin), diuretics, selective serotonin reuptake inhibitors (e.g.paroxetine, sertraline), inhibitors of CYP2C9 isoenzyme, in patients who are slow metabolisers or there is a suspicion of such a condition, fluid retention and edema, impaired liver function of moderate severity (see the section "Specific Instructions") porphyria, impaired renal function (CC 30-60 ml / min), a significant decrease in circulating blood volume (including after surgery), diseases of the cardiovascular system, including coronary heart disease, arteries flax hypertension (see section "Special Instructions"), cerebrovascular diseases, dyslipidemia / hyperlipidemia, diabetes mellitus, peripheral artery disease, long-term use of NSAIDs, severe somatic diseases in elderly patients (including those receiving diuretics, debilitated low-mass patients body), smoking, tuberculosis, alcoholism.

Use during pregnancy and during breastfeeding

Experience with celecoxib during pregnancy is insufficient. Potential risk of using the drug Dilax^® during pregnancy is not installed, but it can not be excluded.

When using NSAIDs, including celecoxib, due to inhibition of Pg synthesis, some women may develop changes in the ovaries, which can cause complications during pregnancy. When planning a pregnancy or conducting an examination for infertility, consider abolishing NSAIDs, including celecoxib.

Celecoxib, belonging to the group of inhibitors of the synthesis of Pg, when used during pregnancy, especially in the third trimester, can cause weakness of labor and premature closure of the arterial duct. The use of inhibitors of Pg synthesis in early pregnancy may adversely affect the course of pregnancy.

There are limited data on the excretion of celecoxib in breast milk. Given the potential risk of side effects in the child and the need for celecoxib for the mother, the appropriateness of breastfeeding should be evaluated.

Dosage and administration

Inside, without chewing, drinking water, regardless of the meal.

Since the risk of cardiovascular complications may increase with an increase in the dose and duration of administration of the drug Dilax^®, you should take the minimum effective dose of the drug the minimum possible short course. The maximum recommended daily dose for long-term use is 400 mg.

Symptomatic treatment of osteoarthritis: The recommended dose is 200 mg per day in 1 or 2 doses.

Symptomatic treatment of rheumatoid arthritis: The recommended dose is 100 mg or 200 mg 2 times a day.

Symptomatic treatment of ankylosing spondylitis: The recommended dose is 200 mg per day in 1 or 2 doses. In some patients, the effectiveness of the use of 400 mg 2 times a day.

Treatment of pain and primary dysmenorrhea: The recommended initial dose is 400 mg, followed, if necessary, by taking an additional dose of 200 mg on the first day. In the following days, the recommended dose is 200 mg 2 times a day, as needed.

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

Liver dysfunction: in patients with mild hepatic impairment (class A according to the Child-Pugh classification) dose adjustment is not required. In the case of moderate liver failure (Child-Pugh class B), treatment should begin with the minimum recommended dose. Experience of using the drug Dilax^® in patients with severe hepatic impairment (class C according to Child-Pugh classification) is not (see section “Contraindications”).

Renal impairment: in patients with mild to moderate severity of renal failure, dose adjustment is not required. Experience of using the drug Dilax^® in patients with severe severity of renal insufficiency is not (see sections "Special instructions", "Contraindications").

Simultaneous use with Fluconazole : patients taking fluconazole (CYP2C9 isoenzyme inhibitor), Dilax^® should be taken at the minimum recommended dose. Caution should be exercised when used with other inhibitors of the isoenzyme CYP2C9.

Slow metabolism of CYP2C9 isoenzyme substrates: in patients who are slow metabolizers or suspected of such a condition, Dilax should be used^® with caution, as this can lead to high concentrations of celecoxib in plasma. In such patients, the initial recommended dose should be reduced by 2 times.

Side effect

Classification of the incidence of side effects of the World Health Organization (WHO):

very often ≥ 1/10

often from ≥ 1/100 to <1/10

infrequently from ≥ 1/1000 to <1/100

rarely from ≥ 1/10000 to <1/1000

very rarely from <1/10000

Since the cardiovascular system:

often: peripheral edema, increased blood pressure, including weighting of the course of arterial hypertension;

infrequently: "flushes", a feeling of heartbeat;

seldom: chronic heart failure, arrhythmia, tachycardia, ischemic stroke and myocardial infarction.

From the digestive system:

often: abdominal pain, diarrhea, dyspepsia , flatulence, vomiting;

infrequently: dental diseases (post-extraction alveolar alveolitis);

rarely: gastric and duodenal ulcer, esophageal ulceration;

very rarely: intestinal perforation, pancreatitis.

From the nervous system:

often: dizziness, insomnia;

infrequently: anxiety, increased muscle tone, drowsiness;

rarely: confusion (psychosis).

From the urinary system:

often: urinary tract infection.

On the part of the respiratory system:

often: bronchitis, cough, sinusitis, upper respiratory tract infections;

infrequently: pharyngitis, rhinitis.

From the skin:

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

infrequently: urticaria, ecchymosis;

seldom: alopecia.

From the side of blood-forming organs:

infrequently: anemia;

rarely: thrombocytopenia.

From the senses:

infrequently: tinnitus, blurred vision.

Laboratory values:

infrequently: increased activity of “liver” enzymes (including alanine aminotransferase and aspartate aminotransferase).

Allergic reactions:

rarely: angioedema;

very rarely: bullous eruptions (bullous dermatitis).

Other:

infrequently: exacerbation of allergic diseases (hypersensitivity), flu-like syndrome, accidental injuries, swelling of the face.

According to post-marketing surveillance

Allergic reactions:

very rarely: anaphylaxis (anaphylactic reactions).

From the nervous system:

rarely: hallucinations;

very rare: hemorrhages in the brain, aseptic meningitis , loss of taste, loss of smell.

From the senses:

infrequently: conjunctivitis.

Since the cardiovascular system:

rarely: pulmonary thromboembolism;

very rarely: vasculitis.

From the digestive system:

rarely: gastrointestinal bleeding, hepatitis;

very rarely: liver failure, fulminant hepatitis, hepatic necrosis (seesection "Specific instructions", subsection "Impact on liver function"), cholestasis , cholestatic hepatitis, jaundice.

From the skin:

rarely: photosensitivity reactions;

very rarely: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, drug rash in combination with eosinophilia and systemic symptoms (DRESS or hypersensitivity syndrome), acute generalized exanthematic pustus, exfoliative dermatitis.

From the urinary system:

seldom: acute renal failure (see section "Special Instructions", subsection "Impact on renal function"), hyponatremia;

very rare: interstitial nephritis, nephrotic syndrome, minimal renal dysfunction.

From the reproductive system:

rarely: menstrual disorders:

frequency is unknown: a decrease in fertility in women * (see the section "Use during pregnancy and during breastfeeding").

Other:

infrequently: chest pain.

* Women planning pregnancy were excluded from the study, so they were not taken into account when calculating the frequency of occurrence.

Overdose

Clinical data on overdose is limited. A single dose of up to 1200 mg and repeated use of a dose of up to 1200 mg 2 times a day were not accompanied by clinically significant side effects. If overdose is suspected, supportive care should be performed.Dialysis is presumably not effective, since celecoxib has a high association with plasma proteins (97%).

Interaction with other drugs

Research in vitro showed that celecoxib, although not a substrate of the CYP2D6 isoenzyme, inhibits its activity. Therefore, there is the likelihood of drug interactions in conditions in vivo with drugs whose metabolism is associated with the CYP2D6 isoenzyme.

Warfarin and other anticoagulants: with simultaneous use may prolong the prothrombin time.

Fluconazole, Ketoconazole : with the simultaneous use of 200 mg of fluconazole 1 time per day, an increase in plasma celecoxib concentration in 2 times is observed, which is associated with inhibition of celecoxib metabolism by fluconazole through the CYP2C9 isoenzyme. Patients taking fluconazole (an inhibitor of the isoenzyme CYP2C9), celecoxib should be used in the minimum recommended dose (see the section "Dosage and administration"). Ketoconazole (an inhibitor of the CYP3A4 isoenzyme) has no clinically significant effect on celecoxib metabolism.

Angiotensin Converting Enzyme Inhibitors (ACE inhibitors) / receptor antagonists

Angiotensin II (APA II): inhibiting the synthesis of Pg can reduce the antihypertensive effect of an ACE inhibitor / ARA II. This interaction should be considered with simultaneous use of celecoxib with an ACE inhibitor / ARA II. However, no significant pharmacodynamic interaction with lisinopril was noted with respect to the effect on blood pressure.

In elderly patients, in patients with dehydration (including patients receiving diuretic therapy) or in patients with impaired renal function, simultaneous use of NSAIDs, including selective COX-2 inhibitors, with an ACE inhibitor can lead to a deterioration in renal function, including acute renal failure. Typically, these effects are reversible after the abolition of NSAIDs.

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

Contraceptives for oral administration: Celecoxib has no clinically significant effect on the pharmacokinetics of the combined contraceptive drug (1 mg norethisterone / 35 µg ethinyl estradiol).

Lithium: with simultaneous use of lithium salts in a dose of 450 mg 2 times a day and celecoxib in a dose of 200 mg 2 times a day, an increase in plasma lithium concentration was noted by about 17%. Patients taking lithium preparations should be closely monitored when celecoxib is used or withdrawn. Other NSAIDs: the simultaneous use of celecoxib and other NSAIDs (not containing acetylsalicylic acid) should be avoided (the risk of side effects increases).

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

Celecoxib does not affect the antiplatelet effect of acetylsalicylic acid in low doses.Celecoxib does not have an antiplatelet effect on platelets, so they should not replace acetylsalicylic acid in order to prevent cardiovascular diseases.

In healthy volunteers, NSAIDs do not affect the pharmacokinetics of digoxin. However, with simultaneous use of digoxin and Indomethacin and Ibuprofen , an increase in the concentration of digoxin in the blood plasma was observed in patients. This should be taken into account when used simultaneously with other drugs that increase the concentration of digoxin in the blood plasma. No information is available on the interaction of celecoxib and digoxin. Given the other effects of celecoxib on the cardiovascular system, it should be taken with caution at the same time as digoxin. In this case, it is recommended to carefully monitor adverse reactions. Celecoxib is predominantly metabolized in the liver by the CYP2C9 isoenzyme. Since barbiturates are inducers of the CYP2C9 isoenzyme, with simultaneous use with celecoxib, a decrease in plasma concentration of the latter can be noted.

special instructions

Dilax's preparation^®, which has antipyretic effect, can reduce the diagnostic value of fever, which complicates the diagnosis of infection.

Effect on the cardiovascular system

Celecoxib, like all coxibs, can increase the risk of serious complications of the cardiovascular system, such as thrombus formation, myocardial infarction and stroke, which can be fatal.The risk of these reactions increases with increasing dose, the duration of the drug, as well as in patients with diseases of the cardiovascular system or with risk factors for the development of cardiovascular diseases. In order to reduce the risk of these reactions, the drug Dilax^® should be used in the lowest effective dose and the shortest possible course (at the discretion of the attending physician). The attending physician and patient should consider the possibility of the development of such complications even in the absence of previously known symptoms of impaired function of the cardiovascular system. Patients should be informed about the symptoms of serious adverse effects on the cardiovascular system and the measures that should be taken if they occur.

When using NSAIDs (selective COX-2 inhibitors) in patients after coronary artery bypass surgery for the treatment of pain in the first 10-14 days, the incidence of myocardial infarction and cerebral circulation disorders may increase.

Celecoxib does not have an antiplatelet effect on platelets, so they should not be replaced. acetylsalicylic acid for the prevention of thromboembolism. Also in this regard, antiplatelet therapy (eg, acetylsalicylic acid) should not be canceled in patients at risk of developing thromboembolic complications.

Like all NSAIDs, celecoxib can lead to an increase in blood pressure, which can cause complications of the cardiovascular system. Like other NSAIDs, celecoxib should be used with caution in patients with arterial hypertension.Blood pressure should be monitored at the beginning and during celecoxib therapy.

Effect on the digestive system

Celecoxib patients had extremely rare cases of perforation, ulceration and bleeding from the gastrointestinal tract (GIT). The risk of developing these complications when using NSAIDs is highest in elderly patients, patients with cardiovascular diseases, patients receiving acetylsalicylic acid at the same time, and patients with gastrointestinal diseases such as ulcers, bleeding, inflammation in the acute stage and in history. Other risk factors for the development of bleeding from the gastrointestinal tract are the simultaneous use of corticosteroids for oral or anticoagulants, long-term NSAID therapy, smoking, and ethanol. Most spontaneous reports of serious fatal adverse reactions were observed in elderly and debilitated patients.

Simultaneous use with Warfarin and other anticoagulants

It was reported that serious (some of them were fatal) bleeding in patients who used warfarin or similar agents along with celecoxib. Given the presence of reports of prolongation of the prothrombin time, after the start of treatment with the drug Dilax^® or when changing its dose should be monitored indicators