Dynastat® [Parecoxib]

Pharmacological properties

dynastat (sodium parecoxib) is a pro-forma of valdecoxib. within the range of clinical doses, valdecoxib is a selective cog-2 inhibitor. cyclooxygenase is responsible for the synthesis of prostaglandins. distinguish two isoforms: cog-1 and cog-2. cog-2, an isoform of the enzyme induced by a pro-inflammatory stimulus, is primarily responsible for the synthesis of prostanoid mediators of pain, inflammation and fever. TSOG-2 also takes part in the processes of ovulation, implantation and closure of the ductus arteriosus, regulation of renal function and central nervous system function (fever induction, pain perception and cognitive function), and can also play a role in ulcer healing. cog-2 was determined in the tissues around a gastric ulcer in men, but its relationship to ulcer healing has not been proven.

The difference in antiplatelet activity between some NSAIDs that suppress COX-1 and selective COX-2 inhibitors may have clinical significance for patients at risk of thromboembolic complications. Selective COX-2 inhibitors reduce the formation of systemic (and therefore possibly endothelial) prostacyclin without affecting platelet thromboxane. The clinical significance of these observations has not yet been identified.

Studies have established the effectiveness of Dynastat in the treatment of postoperative pain after dental, gynecological (hysterectomy), orthopedic (knee and hip arthroplasty) interventions and coronary artery bypass grafting. The first tangible analgesic effect appears after 7–13 minutes, clinically significant anesthesia occurs after 23–39 minutes, and the maximum effect occurs within 2 hours after iv or intramuscular administration of 40 mg of Dynastat. The severity of the analgesic effect of a dose of 40 mg is comparable with the corresponding action of 60 mg of i.v. or 30 mg of i.v. ketorolac. The duration of analgesia after a single dose depends on the dose administered and the clinical type of pain, and ranges from 6 to more than 12 hours.

Ability to reduce the need for opioid analgesics

During a placebo-controlled study (n = 1050), patients after orthopedic and general surgery parenterally received Dynastat, first 40 mg iv, and then 20 mg 2 times a day for at least 72 hours as an addition to standard treatment, which included the administration of opioids as required by the patient. The decrease in the use of opioids in the treatment with Dynastat on the 2nd and 3rd day was 7.2 and 2.8 mg (37 and 28%), respectively. Such a decrease in opioid use was accompanied by a significantly lower number of patient complaints about opioid-related symptoms of distress. An additional decrease in the severity of pain was demonstrated compared with that observed with opioids alone. Additional studies with other types of surgical procedures have yielded similar results. There is no data that would show a decrease in the overall incidence of side effects when using parecoxib in combination with opioids compared with placebo.

Effect on the digestive tract

In short-term studies (7 days), the frequency of detection by endoscopy of gastroduodenal ulcers and erosion in healthy individuals of young and old age (≥65 years) who received Dynastat (5-21%) was higher than in the placebo group (5-12%) ), but statistically significantly lower than with NSAIDs (66–90%).

Safety study of the drug after coronary bypass surgery

In addition to the usual reports of side effects, predefined categories of events determined by an independent expert committee were studied in two placebo-controlled safety studies in which patients received parecoxib sodium for at least 3 days, after which they were transferred to oral valdecoxib for a total duration of 10-14 daysAll patients received standard anesthesia during treatment.

Patients received low doses of acetylsalicylic acid prior to randomization and throughout the period of both studies during coronary artery bypass grafting.

In the first study of coronary artery bypass surgery, patients who received 40 mg of parecoxib sodium iv twice a day for at least 3 days were evaluated, followed by switching to valdecoxib 40 mg 2 times a day (parecoxib sodium / valdecoxib group, n = 311) or placebo / placebo, n = 151 for 14 days; the study was double-blind and placebo-controlled. Nine deliberately defined categories of adverse events were evaluated (cardiovascular thromboembolic complications, pericarditis, the appearance or exacerbation of congestive heart failure, renal failure / impaired renal function, complications of an upper gastrointestinal ulcer, massive gastrointestinal bleeding, infections, non-infectious pulmonary complications and death) . The rate of cardiovascular / thromboembolic complications (myocardial infarction, ischemia, cerebrovascular disorders, deep vein thrombosis and pulmonary embolism) in the parecoxib / valdecoxib group was statistically significantly higher (p0.05) compared with the placebo / placebo group as during the period / in the introduction of the drug (2.2 and 0.0%, respectively), and throughout the study period (4.8 and 1.3%, respectively). Complications of postoperative wounds (mainly sternum wounds) in the treatment of parecoxib / valdecoxib were noted more often.

In the second study of coronary artery bypass surgery, four obviously defined categories of side effects (cardiovascular / thromboembolic complications, impaired renal function / renal failure, ulcers of the upper gastrointestinal tract / bleeding, complication of postoperative wounds) were evaluated. Patients were randomized 24 hours after coronary artery bypass grafting as follows: an initial dose of parecoxib 40 mg iv followed by iv 20 mg every 12 hours for 3 days and then transferred to oral valdecoxib (20 mg every 12 hours) for during the rest of the treatment period 10 days (n = 544); iv placebo followed by oral administration of valdecoxib (n = 544); iv placebo followed by oral placebo (n = 548). A significantly higher (p = 0.033) incidence of adverse events of the category “cardiovascular / thromboembolic complications” was noted in the group treated with parkecoxib / valdecoxib (2.0%) compared with the placebo / placebo group (0.5%). Placebo / valdecoxib treatment was also accompanied by a higher incidence of cardiovascular / thromboembolic complications compared with placebo therapy, but this difference was not statistically significant. In three of the six cases, cardiovascular thromboembolic complications in the placebo / valdecoxib group developed during the placebo treatment period; these patients did not receive valdecoxib. Obviously identified side effects that were observed with the greatest frequency in all three groups were the phenomena of the category of complications from the postoperative wound, including deep surgical infectious lesions and problems with healing of the sternum wound.

There was no statistically significant difference between the groups that received active drugs and placebo in any of the other previously defined categories of side effects (impaired renal function / renal failure, complications in the form of ulcers of the upper gastrointestinal tract or complications from a postoperative wound).

Research on general surgery

During a large-scale (n = 1050) study, patients after extensive orthopedic / general surgical interventions received an initial dose of parecoxib 40 mg iv, then 20 mg iv every 12 hours for at least 3 days, followed by transfer to oral administration of valdecoxib ( 20 mg every 12 hours) (n = 525) for the remaining 10 days of the treatment period, or iv placebo and then placebo orally (n = 525). There were no significant differences between the sodium / valdecoxib and placebo parecoxib groups relative to the general safety profile, including the four predefined categories of side effects described in the second study described above, during coronary artery bypass grafting.

Platelet effect

In the study of low multiple doses with the participation of healthy individuals of young and old age, there was no effect of Dynastat at doses of 20 or 40 mg per day on platelet aggregation or bleeding compared with placebo. In young patients, the administration of Dynastat at a dose of 40 mg 2 times a day did not affect the inhibition of platelet function caused by acetylsalicylic acid.

Pharmacokinetics

After iv or intramuscular administration, parecoxib is rapidly converted by enzymatic hydrolysis in the liver to valdecoxib, which is a pharmacologically active substance.

Absorption

Exposure to valdecoxib after administration of single doses of Dynastat, as measured by AUC and C_maxis approximately linear in the range of clinical doses. AUC and C_max after administration, 2 times a day, linearity is maintained for doses up to 50 mg iv and 20 mg iv. Equilibrium plasma concentrations of valdecoxib are achieved within 4 days with the introduction of the drug 2 times a day.

After intravenous and intramuscular administration of a single dose of 20 mg parecoxib sodium C_max valdecoxib is achieved over approximately 30 minutes and 1 hour, respectively. Valdecoxib exposure was the same for AUC and C_max after iv and v / m administration. The exposure of parecoxib to AUC was the same after i / v and i / m administration. The average value of C_max parecoxib after i / m administration was lower than after i / v bolus administration, due to slower extravascular absorption with i / m administration. This decrease was not clinically significant since C_max valdecoxib after i / v and i / m administration of parecoxib sodium were comparable.

Distribution

The volume of distribution of valdecoxib after iv administration is about 55 liters. Binding to plasma proteins reaches about 98% in the concentration range achieved with the maximum recommended doses of 80 mg / day. Valdecoxib (but not parecoxib) intensively penetrates red blood cells.

Metabolism

In vivo, parecoxib is rapidly and almost completely converted to valdecoxib and propionic acid with a half-life in plasma of about 22 minutes. Valdecoxib is excreted from the body through active hepatic metabolism, in which numerous metabolic pathways are involved, including isoenzymes of the cytochrome P450 (CYP) 3A4 and CYP 2C9 and the glucuronidation (about 20%) of the sulfonamide moiety. It was determined that the hydroxylated metabolite of valdecoxib (with the participation of the CYP metabolic pathway) in human plasma is active as a COX-2 inhibitor. It accounts for about 10% of the concentration of valdecoxib; it is believed that, due to its low concentration, this metabolite does not have a significant clinical effect after administration of therapeutic doses of parecoxib sodium.

Breeding

Valdecoxib is excreted by metabolism in the liver, while 5% of unchanged valdecoxib is detected in the urine. Unchanged parecoxib in the urine is not determined, and only in residual quantities - in the feces. About 70% of the dose is excreted in the urine as inactive metabolites. The plasma clearance of valdecoxib is approximately 6 l / h. After intravenous and intramuscular administration of parecoxib sodium, the elimination half-life (T_½) valdecoxib is about 8 hours.

Elderly patients: During pharmacokinetic and therapeutic studies, Dinastat was prescribed to 335 elderly patients (65–96 years old). In healthy elderly volunteers, the imaginary total clearance of valdecoxib was reduced, leading to an increase of approximately 40% in plasma exposure compared with healthy young people. When corrected according to body weight, the equilibrium plasma exposure of valdecoxib was 16% higher in elderly women compared with men of this age group.

Impaired renal function: in patients with varying degrees of renal failure after iv administration of 20 mg of Dynastat, parecoxib was rapidly excreted from blood plasma. Since renal excretion of valdecoxib is not important for its pharmacokinetics, changes in its clearance were not detected even in patients with severe renal impairment and in patients undergoing hemodialysis.

Impaired liver function: moderate impaired liver function does not lead to a decrease in the rate or magnitude of the conversion of parecoxib to valdecoxib. In patients with moderate liver dysfunction (7–9 points on the Child-Pugh scale), treatment should be started with half the usual recommended dose of Dynastat, and the maximum dose should be reduced to 40 mg, since the exposure of valdecoxib in such patients is more than doubled (130%) . Patients with severe hepatic impairment did not participate in the studies, so the use of Dynastat is not recommended for such patients.

Preclinical Safety Data

Extraclinical data obtained using a routine study of pharmacological safety or repeated dose toxicity with a twofold increase in the maximum exposure of parecoxib did not pose a particular danger to humans. However, when studying repeated dose toxicity in animals, the systemic exposure of valdecoxib (the active metabolite of parecoxib) amounted to about 80% of the systemic exposure in healthy elderly people with a maximum recommended therapeutic dose of 80 mg / day. The maximum dose was accompanied by an increase in skin infections and an extension of the healing time, probably due to inhibition of COX-2.

In the course of animal reproductive toxicity studies, cases of post-implantation loss, resorption, and delayed increase in fetal body weight with doses that did not cause toxicity in mothers were noted. Animal studies did not reveal the effects of parecoxib on female and male fertility.

The effect of parecoxib in late pregnancy or in the pre- and postnatal periods was not evaluated. With the on / in the introduction of a single dose of parecoxib sodium to rats during lactation, concentrations of parecoxib, valdecoxib and the active metabolite of valdecoxib in milk were found to be close to the concentration in the mothers plasma.

The carcinogenic potential of parecoxib sodium was not evaluated.

Indications

Short-term treatment of postoperative pain.

The decision regarding the administration of a selective COX-2 inhibitor should be based on an individual assessment of all patient risk factors.

Application

The standard recommended dose is a single or starting administration of 40 mg of the drug dynastat IV or IM, if necessary, in the future, the drug is used every 6-12 hours for 20 or 40 mg, but not more than 80 mg / day. an intravenous bolus injection must be performed quickly and directly into a vein or existing intravenous catheter. v / m injection is performed slowly and deep into the thickness of the muscle.

Elderly patients. No dose adjustment is required for elderly patients (≥65 years old). However, in elderly patients with a body weight of 50 kg, treatment should be started with half the standard recommended dose of Dynastat and reduce the maximum daily dose to 40 mg.

Impaired liver function. In patients with minor impairment of liver function (5-6 points on the Child-Pugh scale), dose adjustment is not required. In patients with moderate hepatic impairment (7–9 points on the Child-Pugh scale), Dynastat should be prescribed with caution in a dose equal to half the usual recommended dose, and the maximum daily dose should be reduced to 40 mg. Regarding patients with severe hepatic impairment (≥10 points on the Child-Pugh scale), there is no clinical experience with the use of Dynastat, therefore, it is not recommended to use the drug to treat these patients.

Impaired renal function. Based on the pharmacokinetics of the drug, there is no need to adjust the dosage of Dynastat when it is used in patients with mild to moderate renal impairment (creatinine clearance 30–80 ml / min). For the treatment of patients with severe (creatinine clearance 30 ml / min) impaired renal function or those with a tendency to fluid retention, Dynastat should be used in the minimum recommended dose and carefully monitor renal function.

Cooking solution

40 mg of Dynastat should be restored using 2 ml of 0.9% (9 mg / ml) sodium chloride solution. Other solvents suitable for reduction are only the following:

• 5% (50 g / l) glucose solution for infusion;
• 0.45% (4.5 mg / ml) sodium chloride solution;
• 5% (50 g / l) glucose solution for injection.

Remove the 40 mg parecoxib purple protective cap from the vial to access the center of the rubber stopper. Using a sterile needle and syringe, draw 2 ml of the appropriate solvent and insert the needle through the central part of the rubber stopper, moving the solvent inside the vial.

Using careful rotational movements, completely dissolve the powder and check the reconstituted preparation before use. All contents of a bottle are intended for single administration.

Before administration, it is necessary to inspect the reconstituted Dynastat for solid particles and discoloration. If the solution has changed color, is opaque or contains solid particles, it cannot be used. Dynastat must be administered within 24 hours after recovery or disposed of.

Contraindications

Known hypersensitivity to parecoxib or any ingredient in the drug. history of allergic reactions of any type, especially skin reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, or known hypersensitivity to sulfonamides.

History of bronchospasm, urticaria, acute rhinitis, nasal polyps, angioedema, or allergic reactions after taking acetylsalicylic acid or NSAIDs, including other specific COX-2 inhibitors.

Active peptic ulcer or gastrointestinal bleeding.

Severe hepatic impairment (plasma albumin 25 g / l or Child-Pugh score ≥10).

Inflammatory bowel disease.

Congestive heart failure (NYHA Class II – IV).

Confirmed coronary artery disease, peripheral artery disease and / or cerebrovascular disease.

The use of Dynastat is contraindicated for the treatment of pain in the postoperative period after coronary artery bypass grafting (CABG).

III trimester of pregnancy and lactation.

Children under 18 years old.

Side effects

The following are side effects, the incidence of which was higher than in the placebo group, during 12 placebo-controlled clinical trials involving 1543 patients regarding dental, gynecological, orthopedic surgeries, as well as coronary artery bypass grafting and preoperative dental and orthopedic surgeries practice.the dose of dynastat was 20 or 40 mg in single or multiple doses (up to 80 mg / day). the frequency of drug withdrawal due to the development of adverse reactions in these studies was 5.0% in the group that received dynastat and 4.3% in patients who received placebo.

Side effects are grouped by organs and systems and by frequency of occurrence: very often (≥1 / 10), often (≥1 / 100, 1/10), infrequently (≥1 / 1000, 1/100), rarely (≥1 / 10 000, 1/1000), very rarely (1/10 000), unknown (cannot be estimated based on available data, including isolated cases).

Infections and infestations. Infrequently - abnormal serous discharge from the sternum wound, wound infection.

On the part of the blood and lymphatic system. Often - postoperative anemia; infrequently - thrombocytopenia.

Trophic and metabolic disorders. Often - hypokalemia.

Mental disorders. Often - agitation, insomnia.

From the nervous system. Often - hypesthesia. Infrequently - cerebrovascular disorders.

From the side of the heart. Infrequently - bradycardia.

From the vascular system. Often - hypertension, hypotension. Infrequent exacerbation of hypertension.

Respiratory, mediastinal and thoracic disorders. Often - respiratory failure, pharyngitis.

From the gastrointestinal tract. Often - alveolar osteitis ("dry alveolus"), flatulence, dyspepsia. Infrequently - gastroduodenal ulcers.

On the part of the skin and subcutaneous tissues. Frequent - itching. Infrequently - ecchymoses.

From the musculoskeletal system and connective tissue. Often - back pain.

From the kidneys and urinary system. Often - oliguria.

General disorders and disorders at the injection site. Often - peripheral edema.

The results of other studies. Often - an increase in blood creatinine. Infrequently - an increase in AlAT, AsAT, urea nitrogen in the blood.

The following rarely reported serious adverse reactions are associated with the use of NSAIDs, which cannot be excluded with the use of the drug Dynastat: bronchospasm, hepatitis.

Patients using parecoxib after coronary artery bypass grafting have a higher risk of side effects such as cardiovascular / thromboembolic manifestations, surgical infections, or complications of wound healing after sternotomy. Cardiovascular / thromboembolic events include myocardial infarction, stroke / TIA, pulmonary embolism, and deep vein thrombosis.

During post-marketing surveillance, reports were received about the following reactions that arose in connection with the use of parecoxib.

Rarely: acute renal failure, impaired renal function, myocardial infarction, congestive heart failure, abdominal pain, nausea, vomiting, dyspnea, tachycardia, and Stevens-Johnson syndrome.

Very rare: erythema multiforme, exfoliative dermatitis and hypersensitivity reactions, including anaphylaxis and angioedema.

During post-marketing surveillance, reports were received about the following reactions, which were identified in connection with the administration of valdecoxib and cannot be excluded with respect to parecoxib: toxic epidermal necrolysis.

special instructions

The clinical experience of treatment with dynastat for longer than 3 days is limited.

Since there is significance of increasing the frequency of adverse reactions when using parecoxib at higher doses, other COX-2 inhibitors or NSAIDs, it is necessary to re-evaluate the general condition of the patient who is treated with parecoxib and, in the absence of an increase in effect, it is recommended to consider other treatment options.

Prolonged use of COX-2 inhibitors, including parecoxib, is accompanied by an increased risk of cardiovascular and thrombotic side effects. The exact magnitude of the risk increase after applying a single dose has not been established, nor has it been determined which duration of therapy is accompanied by an increase in risk.

Patients with significant risk factors for cardiovascular complications (hypertension, hyperlipidemia, diabetes mellitus, smoking) should be prescribed parecoxib only after careful consideration.

If specific symptoms worsen in these patients, appropriate measures should be taken or consideration should be given to discontinuing parecoxib therapy. Dynastat was not studied in other cardiovascular revascularization procedures other than coronary artery bypass grafting. A study in other areas of surgery, in addition to coronary artery bypass grafting, included patients only with ASA (American Society of Anesthesiology) physical status class I – III.

Due to the lack of antiplatelet efficacy, COX-2 inhibitors are not used to replace acetylsalicylic acid in the prevention of cardiovascular thromboembolic complications. Antiplatelet therapy should not be discontinued in such cases.

Patients who take parecoxib may experience perforations, ulcers, or bleeding from the upper gastrointestinal tract, in some cases with a fatal outcome. It is recommended to be careful during treatment of patients with a very high risk of developing gastrointestinal complications associated with NSAIDs; elderly patients who take other NSAIDs or acetylsalicylic acid, in case of active gastrointestinal diseases or in the presence of a history of gastrointestinal conditions such as peptic ulcer or bleeding. There is a risk of a further increase in the likelihood of side effects from the gastrointestinal tract (gastric ulcer, intestinal ulcer, or other complications) if sodium parecoxib is administered simultaneously with acetylsalicylic acid (even at low doses).

Dynastat was examined during dental, orthopedic, gynecological (mainly hysterectomy) surgical interventions and during coronary artery bypass grafting. There is little experience with the use of Dynastat in other types of surgical interventions, for example, in operations on the gastrointestinal tract and urinary tract.

During post-marketing observation, reports were received that patients taking parecoxib sometimes experienced serious skin reactions, including erythema multiforme, exfoliative dermatitis and Stevens-Johnson syndrome (sometimes with fatal consequences). In addition, during post-marketing monitoring, fatal cases of toxic epidermal necrolysis were reported in patients who received valdecoxib (the active metabolite of parecoxib), and therefore this phenomenon cannot be excluded with respect to parecoxib. The highest risk of developing such reactions is noted at the beginning of the course of therapy; the development of reactions in most cases is detected during 1 month of treatment.

During therapy, the doctor should take appropriate measures to timely identify serious skin reactions, for example, appoint additional consultations to the patient. Patients should be warned about the need to immediately inform their doctor about the appearance of any changes in skin condition.

Parecoxib should be discontinued at the first appearance of skin rashes, mucosal lesions, or any other signs of hypersensitivity. There are known cases of serious skin reactions with NSAIDs, including selective COX-2 inhibitors, and other drugs. It should be noted that the frequency of reports of serious skin reactions is higher for valdecoxib (an active metabolite of parecoxib) compared to other selective COX-2 inhibitors. Patients with a history of sulfonamide allergies may have an increased risk of skin reactions. The lack of a history of patients allergic to sulfonamides does not exclude the risk of serious skin reactions.

During post-marketing observation, when using valdecoxib and parecoxib, there were reports of the development of hypersensitivity reactions in the form of anaphylactic reactions and angioedema. Some of these reactions occurred in patients with a history of allergic reactions to sulfonylamides. At the first manifestations of hypersensitivity, parecoxib should be discontinued.

During post-marketing surveillance, reports of the development of acute renal failure in patients who received parecoxib were received. Since inhibition of prostaglandin synthesis can lead to impaired renal function and fluid retention in the body, it is necessary to carefully prescribe Dynastat to patients with impaired renal function, hypertension and with impaired heart, liver, or other conditions that are accompanied by fluid retention.

Caution is advised to initiate Dynastat therapy in dehydrated patients. In such cases, it is recommended to first rehydrate, and then start therapy with Dynastat.

Dynastat should be used with caution in patients with moderate impaired liver function (7-9 points on the Child-Pugh scale).

If during treatment the patient shows a deterioration in the function of any of the organ systems described above, it is necessary to take appropriate measures and stop taking parecoxib sodium.

Dynastat may mask fever symptoms and other signs of inflammation. In some cases, a deterioration in the course of soft tissue infections was revealed in connection with taking NSAIDs and during non-clinical studies of Dynastat. Care should be taken to monitor the state of the postoperative wound in patients after surgery who receive Dynastat.

Caution is needed while using Dynastat and warfarin or other oral anticoagulants.

The use of Dynastat, like any drug with a known ability to suppress the synthesis of cyclooxygenase / prostaglandins, is not recommended for women who are planning a pregnancy.

Incompatibility

When diluted or administered, Dynastat should not be mixed with other drugs due to the possibility of precipitation. After dilution in an appropriate solvent, Dynastat can be introduced into the IV infusion system with only 0.9% sodium chloride solution for injection, 5% glucose solution for injection, ringers lactate solution or 5% rum glucose and 0.45% solution of sodium chloride for injection. The introduction of a dissolved preparation into the system with 5% r-rum dextrose in ringers lactate r-r or with other iv solutions not listed in this list is not recommended, as this may cause precipitation from r-r.

Dynastat should not be entered in the system for iv administration, intended for the introduction of other drugs. Before and after the injection of the drug Dynastat, the system for iv administration must be thoroughly washed with a solution compatible with the drug.

Use during pregnancy and lactation. Dynastat is contraindicated in the III trimester of pregnancy.

There are suggestions that parecoxib sodium can cause serious developmental defects if prescribed in the third trimester of pregnancy. As with other drugs that can inhibit prostaglandin synthesis, it can cause premature closure of the ductus arteriosus or decrease the activity of uterine contractions.

Like other drugs that inhibit COX-2, Dynastat is not recommended for women who are planning a pregnancy.

There are no data on the use of Dynastat in pregnant women or during childbirth. Animal studies have demonstrated reproductive toxicity of the drug. The potential risk to humans is unknown. Dynastat should not be used during the I – II trimester of pregnancy unless the drug is absolutely necessary (that is, the potential benefit to the patient outweighs the potential risk to the fetus).

Parecoxib, valdecoxib (its active metabolite) and active metabolites of valdecoxib are excreted in breast milk in female rats. It is not known whether these substances are excreted in human milk. Dynastat should not be prescribed to women during lactation.

Children.Safety and efficacy of the drug in patients under the age of 18 have not been established. Therefore, the drug is not used in this category of patients.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. The effect of the drug Dynastat on driving and working with mechanisms was not investigated. Patients who feel dizzy or drowsy after using Dynastat should refrain from driving or working with other mechanisms.

Interactions

Interaction studies were performed only in adults.

Concomitant use with opioid analgesics: opioid analgesics can be used simultaneously with parecoxib, the dosage of which is described in the APPLICATION section. For clinical evaluation, parecoxib was administered at set intervals, while opioids were administered as needed.

Since the risk of the cardiovascular system when using specific COX-2 inhibitors can increase with increasing doses and duration of administration, these drugs should be prescribed in the smallest effective daily doses and for the shortest duration of treatment.

At a combination of solution of Dynastat with other medicines precipitation can occur