Pharmacological properties of the drug Dynastat
Parecoxib sodium is the pro form of valdecoxib and does not inhibit either COX-1 or COX-2 in vitro Following IV or IM administration, parecoxib is rapidly hydrolyzed to valdecoxib, which is active in animal models of prostaglandin-mediated pain, fever and inflammation. The mechanism of action of valdecoxib is the inhibition of COX-2-mediated prostaglandin synthesis. In therapeutic doses, valdecoxib is a specific inhibitor of COX-2 and does not inhibit COX-1 and, accordingly, COX-1-dependent physiological functions in tissues, especially the stomach, intestines and platelets. The concentration of valdecoxib after a single injection of Dynastat, determined by AUC parameters and maximum plasma concentration, is approximately linear in the range of therapeutic doses (or linear when Dynastat is administered up to 50 mg IV or 20 mg IM 2 times a day ). The equilibrium concentration of valdecoxib in blood plasma is achieved within 4 days when administered 2 times a day. With a single intravenous and intramuscular administration of parecoxib sodium at a dose of 20 mg, the maximum concentration of valdecoxib is achieved after approximately 30 minutes and 1 hour, respectively. Concentrations of valdecoxib, determined by AUC and maximum plasma concentration, were identical for IM and IV administration. The volume of distribution of valdecoxib after intravenous administration of Dynastat is 55 L (more than the total volume of water in the body). Plasma protein binding is 98% over the concentration range achieved with the maximum recommended dose of 80 mg per day. Valdecoxib (but not parecoxib) penetrates erythrocytes extensively. Parecoxib is rapidly and almost completely metabolized to valdecoxib in vivo with a plasma half-life of approximately 22 minutes. Elimination of valdecoxib is carried out by intensive metabolism in the liver with the participation of various enzyme systems, in particular cytochrome P450 isoforms CYP 3A4 and 2C9, as well as CYP-independent glucuronidation of sulfonamide. Valdecoxib is excreted from the body by metabolism in the liver, with less than 5% of this substance appearing unchanged in the urine. Unchanged parecoxib is not detected in urine, and only traces of it are detected in feces. Approximately 70% of the administered dose of the drug is excreted in the urine in the form of inactive metabolites. Plasma clearance of valdecoxib is approximately 6 L/h. After intramuscular or intravenous administration of parecoxib sodium, the half-life of valdecoxib is approximately 8 hours.
Use of the drug Dynastat
To dissolve the drug, you can use glucose solution for intravenous infusion; 0.45% sodium chloride solution or 5% glucose solution for injection. It is not recommended to dissolve Dynastat in sterile water for injection, since the resulting solution is not isotonic. The use of lactated Ringer's solutions or 5% glucose in lactated Ringer to dissolve Dynastat may cause precipitation of the drug from the solution and is therefore not recommended. After dissolving Dynastat, the solution should be carefully inspected visually for possible detection of foreign particles or color changes. The solution should not be used if there is a change in color, cloudiness or the presence of foreign particles. Treatment of acute pain syndrome The standard recommended dose is 40 mg IV or IM, then every 6–12 hours the drug is administered as needed in a dose of 20 or 40 mg, but not more than 80 mg per day. An IV bolus injection should be performed quickly and directly into a vein or existing IV line. The IM injection should be performed slowly and deep into the muscle. When used in recommended doses for the treatment of acute pain, the onset of the analgesic effect is observed after 7–14 minutes and reaches its maximum within 2 hours. The duration of analgesia depends on the dose of the drug, the clinical characteristics of the pain syndrome and ranges from 7 to 24 hours or longer. Use before surgery to prevent postoperative pain. The standard recommended dose is 40 mg IM or IV 45 minutes before surgery. Repeated administration of Dynastat after surgery is carried out in accordance with the recommendations for the treatment of acute pain syndrome (may be necessary to prolong the analgesic effect). Reduced need for opiates When used together with Dynastat, the daily need for opiates is significantly reduced. The optimal effect is achieved when using the drug before the introduction of opiates. Elderly and senile persons There is no need for dose adjustment. However, in elderly women weighing less than 50 kg, treatment should begin with half the standard recommended dose of Dynastat and reduce the maximum daily dose to 40 mg. Liver dysfunction: In patients with mild liver dysfunction (5–6 on the Child-Pugh scale), no dose adjustment is necessary. In patients with moderate liver dysfunction (7-9 on the Child-Pugh scale), Dynastat should be used with caution, at half the standard recommended dose, and a reduction in the maximum daily dose to 40 mg. In patients with severely impaired liver function (9 on the Child-Pugh scale), there is no clinical experience with the drug, so the use of Dynastat in these patients is not recommended. Renal impairment No dosage adjustment is necessary, but caution should be exercised when treating patients with severe renal impairment or those with a tendency to retain fluid in the body. Children The drug has not been studied in patients under 18 years of age, so it cannot be recommended for children.
Dynastat lyophilisate for the preparation of solution for injection, 40 mg, 10 pcs.
Dynastat has been studied for its use in dental, orthopedic, gynecological (mainly hysterectomy) interventions and coronary artery bypass surgery. There is limited experience with its use in other types of surgical procedures, such as gastrointestinal or urological (see section "Pharmacological").
Methods of administration other than intravenous and intramuscular (eg, intraarticular, intrathecal) have not been studied and should not be used.
Because the potential for adverse reactions increases with high doses of parecoxib, other COX-2 inhibitors, and NSAIDs, patients receiving parecoxib should be monitored after dose increases and, if efficacy does not improve, other treatment options should be considered (see Dosage). application and dose"). Clinical experience with Dynastat treatment for periods longer than 3 days is limited (see section "Pharmacological").
If patients experience deterioration in any of the organ systems described below during treatment, appropriate measures should be taken and discontinuation of parecoxib therapy should be considered.
Cardiovascular reactions.
Long-term use of COX-2 inhibitors was associated with an increased risk of cardiovascular and thrombotic adverse events. The exact risk associated with a single dose has not been established, and the duration of treatment associated with an increased risk has not been precisely determined.
Patients with significant risk factors for cardiovascular events (eg, hypertension, hyperlipidemia, diabetes mellitus, smoking) should receive treatment with parecoxib after careful consideration (see Pharmacological Section).
If these patients show clinical signs of deterioration in the form of specific symptoms, appropriate measures should be taken and discontinuation of parecoxib therapy should be considered. Dynastat has not been studied in revascularization operations for cardiovascular pathology, with the exception of coronary artery bypass surgery. Studies of the drug in surgical settings other than coronary artery bypass grafting included only patients with ASA (American Society of Anesthesiologists) physical status class I-III.
Acetylsalicylic acid and other non-steroidal anti-inflammatory drugs.
COX-2 inhibitors cannot replace acetylsalicylic acid in the prevention of cardiovascular thromboembolic diseases because they do not reduce platelet aggregation. Therefore, antiplatelet therapy should not be stopped (see Section “Pharmacological”). Dynastat should be used with caution along with warfarin and other oral anticoagulants (see Section “Interaction with other drugs and other types of interactions”). Concomitant use of parecoxib with other non-steroidal anti-inflammatory drugs other than acetylsalicylic acid should be avoided.
Dynastat may mask increased body temperature and other signs of inflammation (see section "Pharmacological"). In some cases, a worsening of soft tissue infections has been described in connection with the use of non-steroidal anti-inflammatory drugs and in preclinical studies of the drug Dynastat. In postoperative patients receiving Dynastat, the surgical site should be closely monitored for signs of infection.
Gastrointestinal reactions.
Upper gastrointestinal complications (perforation, ulceration, or bleeding), some of which were fatal, have occurred in patients treated with parecoxib. It is recommended to treat patients at high risk of developing gastrointestinal complications with caution when using non-steroidal anti-inflammatory drugs; elderly people or patients with a history of gastrointestinal disease, in particular ulcers and gastrointestinal bleeding, or patients concomitantly taking acetylsalicylic acid. The class of non-steroidal anti-inflammatory drugs may also be associated with an increased risk of gastrointestinal complications when used concomitantly with corticosteroids, selective serotonin reuptake inhibitors, antiplatelet drugs, or when used by patients who drink alcohol. There is a further increase in the risk of developing gastrointestinal side effects (gastrointestinal ulcers or other gastrointestinal complications) when parecoxib is used concomitantly with acetylsalicylic acid (even at low doses).
Skin reactions.
Skin reactions, including erythema multiforme, exfoliative dermatitis, and Stevens-Johnson syndrome (some fatal), have been reported in patients receiving parecoxib during post-marketing surveillance. In addition, fatal cases of toxic epidermal necrolysis have been reported in patients receiving valdecoxib (the active metabolite of parecoxib) during post-marketing surveillance; and the occurrence of this disease cannot be excluded when using parecoxib (see section "Adverse reactions"). Based on other severe skin reactions reported with celecoxib and valdecoxib, DRESS syndrome may occur during treatment with parecoxib. It is likely that patients are at high risk of experiencing these reactions at the very beginning of therapy; reactions predominantly occurred during the first month of treatment.
Appropriate measures, such as additional patient consultation, should be taken to monitor for any severe skin reactions. Patients should be advised to immediately report any skin changes they experience to their doctor.
Treatment with parecoxib should be discontinued at the first appearance of skin rashes, mucosal changes or any signs of hypersensitivity. Severe skin reactions are known to occur when using non-steroidal anti-inflammatory drugs, in particular selective COX-2 inhibitors, as well as other drugs. However, it is likely that the incidence of severe skin events is greater with valdecoxib (the active metabolite of parecoxib) compared with other selective COX-2 inhibitors. Patients with a history of sulfonamide allergy may be at higher risk of developing skin reactions (see Contraindications section). Patients without a history of sulfonamide allergy may also be at risk of developing severe skin reactions.
Hypersensitivity.
Hypersensitivity reactions (anaphylaxis and angioedema) have been reported since the marketing of valdecoxib and parecoxib (see Adverse Reactions section). Some of these reactions have been observed in patients with a history of allergic reactions to sulfonamides (see section "Contraindications"). Treatment with parecoxib should be discontinued at the first sign of hypersensitivity.
Since the marketing of parecoxib, cases of severe hypotension have been reported shortly after administration of parecoxib. Some of these cases were observed without signs of anaphylaxis. The physician should be prepared to treat severe hypotension.
Fluid retention, edema, renal reactions.
As with other medicinal products known to inhibit prostaglandin synthesis, fluid retention and edema have occurred in selected patients receiving parecoxib. Therefore, parecoxib should be used with caution in patients with cardiac dysfunction, existing edema, and other conditions that contribute to or are aggravated by fluid retention, particularly in patients receiving diuretic treatment or who have other risk factors for hypovolemia. If clinical signs of deterioration are observed in these patients, appropriate measures should be taken, including discontinuation of parecoxib treatment.
During post-marketing surveillance, cases of acute renal failure have been observed in patients receiving parecoxib (see Adverse Reactions section). Since inhibition of prostaglandin synthesis can lead to renal dysfunction and fluid retention, Dynastat should be used with caution in patients with impaired liver function (see Section "Dosage and Administration") or arterial hypertension or patients with impaired liver or cardiac function or other conditions. , promoting fluid retention.
At the beginning of treatment, patients with dehydration should use Dynastat with caution. In this case, it is recommended to first rehydrate and then begin therapy with Dynastat.
Arterial hypertension.
What about all non-steroidal anti-inflammatory drugs, the use of parecoxib can lead to the emergence or worsening of pre-existing hypertension, and may cause an increase in the incidence of cardiovascular events. Parecoxib should be used with caution in patients with arterial hypertension. Blood pressure should be closely monitored when initiating parecoxib therapy and throughout the course of treatment. If blood pressure rises significantly, other treatments should be considered.
Insufficiency of liver function.
In patients with moderate hepatic impairment (7-9 points on the Child-Pugh scale), Dynastat should be used with caution (see Section "Dosage and Administration").
Use of oral anticoagulants.
Concomitant use of non-steroidal anti-inflammatory drugs with oral anticoagulants increases the risk of bleeding. Oral anticoagulants include warfarin, other coumarin anticoagulants and new oral anticoagulants (for example, apixaban, dabigatran and rivaroxaban) (see Section “Interaction with other medicinal products and other types of interactions”).
Sodium content.
This medicinal product contains less than 1 mmol sodium (23 mg) per ml, i.e. practically free of sodium.
Special precautions for handling the drug and disposal of residues.
Before use, Dynastat must be reconstituted. Dynastat does not contain preservatives. To restore it, it is necessary to follow aseptic techniques.
Solvents for restoration.
Acceptable solvents for reconstituting Dynastat are:
- sodium chloride 9 mg/ml (0.9%), solution for injection/infusion;
- glucose 50 mg/ml (5%), solution for infusion;
- sodium chloride 4.5 mg/ml (0.45%) and glucose 50 mg/ml (5%), solution for injection/infusion.
Recovery process.
To reconstitute lyophilized parecoxib (as parecoxib), use aseptic technique.
From a vial containing 40 mg parecoxib, remove the removable cap to release the central part of the rubber stopper. With a sterile syringe needle, draw up 2 mL of the acceptable solvent and insert the needle into the center of the rubber stopper to transfer the solvent into the 40 mg vial. Dissolve the powder completely, stirring gently in a circular motion, and inspect the reconstituted product before use. The entire contents of the bottle are intended for single administration.
After reconstitution, the solution should be clear. Before administration, it is necessary to conduct a visual inspection of the drug Dynastat for the presence of mechanical particles and color changes. The solution can be used if its color has changed or if it is cloudy or contains mechanical particles. Dynastat must be administered within 24 hours of reconstitution or discarded.
The reconstituted drug is physiological.
Compatible with solution in the intravenous system.
After reconstitution with acceptable solvents, Dynastat can only be administered intravenously or intramuscularly or in an intravenous system containing solvents:
- sodium chloride 9 mg/ml (0.9%), solution for injection/infusion;
- glucose 50 mg/ml (5%), solution for infusion;
- sodium chloride 4.5 mg/ml (0.45%) and glucose 50 mg/ml (5%), solution for injection/infusion;
or
- Ringer lactate solution for injection.
For single use only. Any unused drug or waste must be discarded.
There is evidence that when used, the chemical and physical stability of the reconstituted solution cannot be stored in the refrigerator or frozen, and is stored for up to 24 hours at 25 °C. Therefore, it is considered that the maximum shelf life for a reconstituted product is 24 hours. However, due to the significant risk of microbiological contamination for injectables, reconstituted solutions must be used immediately, unless reconstituted under controlled and validated aseptic conditions. If such requirements have not been met, the time and conditions for storing the drug before use must be consistent with the person using it, and the storage time should generally not exceed 12 hours at 25 °C.
Contraindications to the use of the drug Dynastat
Hypersensitivity to the components of the drug. Patients with allergic reactions to sulfonamides. History of bronchospasm, acute rhinitis, nasal polyps, angioedema, urticaria, or allergic reactions that developed after taking acetylsalicylic acid or other NSAIDs, including selective COX-2 inhibitors. III trimester of pregnancy and lactation period; pain relief after coronary artery bypass surgery. There are no data on the use of Dynastat for the treatment of children under 18 years of age.
Side effects of the drug Dynastat
Frequent (1/100, ≤1/10) - back pain, peripheral edema, hypertension (arterial hypertension), hypotension, hypesthesia, alveolar osteitis, dyspepsia, flatulence, increased creatinine levels, hypokalemia, agitation, insomnia, postoperative anemia, pharyngitis , respiratory failure, itching, oliguria. Uncommon (1/1000, ≤1/100) - increased serous discharge from the wound after sternotomy, wound infection, increased hypertension (arterial hypertension), bradycardia, increased ALT and AST levels, increased blood urea nitrogen levels, ecchymosis, thrombocytopenia, cerebrovascular disorders. Patients with a history of cerebrovascular pathology have an increased risk of developing side effects when using Dynastat.
Special instructions for the use of the drug Dynastat
Dynastat should be prescribed with caution to patients with severe dehydration. It is advisable to first rehydrate such patients and only then begin treatment. Patients with a history of cerebrovascular pathology have an increased risk of developing side effects when treated with the drug. Dynastat injections can mask the manifestations of fever. There are no data regarding the use of Dynastat in pregnant women (including postpartum women). The use of prostaglandin synthetase inhibitors can lead to premature closure of the ductus arteriosus or a decrease in the activity of uterine contractions, therefore Dynastat should not be used in the third trimester of pregnancy. Dynastat should not be used during pregnancy at all, unless the potential benefit of the drug outweighs the possible risk to the fetus. The use of Dynastat during breastfeeding is not recommended (if breastfeeding is not stopped during treatment). Parecoxib, valdecoxib and its active metabolites are excreted in breast milk in female rats. It is not known whether these substances are excreted in human breast milk. The effect of Dynastat on the ability to drive a car and operate potentially dangerous machinery has not been studied.
Dynastat
During treatment with Dynastat, cases of ulcer formation (including perforated ones) and bleeding from the upper gastrointestinal tract were observed. In this regard, caution should be exercised when prescribing the drug to patients with gastric and duodenal ulcers, bleeding from the gastrointestinal tract in the anamnesis and inflammatory diseases of the gastrointestinal tract in active form and in the anamnesis, as well as elderly patients, patients with cardiovascular diseases and patients taking acetylsalicylic acid.
If the first signs of a skin rash or other signs of hypersensitivity appear, Dynastat should be discontinued.
During the use of valdecoxib, the development of hypersensitivity reactions (anaphylactoid reactions and angioedema) was noted in patients taking valdecoxib; they are also not excluded for parecoxib. These reactions have been observed in patients with known and not yet known allergic reactions to sulfonamides.
After administration of parecoxib, anticoagulant activity should be monitored particularly carefully during the first few days in patients taking warfarin or similar drugs, as such patients may be at greater risk of bleeding.
Due to the inhibition of prostaglandin synthesis, some patients taking parecoxib may experience fluid retention and edema, so caution should be exercised when prescribing Dynastat to patients with conditions arising or worsened by fluid retention. Patients with a history of heart failure or hypertension should be closely monitored.
Caution should be exercised when prescribing Dynastat to patients with severe dehydration. In such cases, it is advisable to first rehydrate and then begin therapy.
There is no experience with the use of the drug in patients with severe liver dysfunction. The use of Dynastat is not recommended for them. The drug should be used with caution when treating patients with moderate liver dysfunction and should be prescribed at the lowest recommended dose.
Patients with symptoms and/or signs of liver dysfunction or those in whom testing has revealed abnormal liver function should be closely monitored during treatment with Dynastat.
Due to its anti-inflammatory effect, Dynastat may reduce the importance of diagnostic signs (for example, fever) in determining infection.
Dynastat should be used with caution after coronary artery bypass surgery, since this category of patients has an increased risk of developing serious adverse reactions, especially in patients with a history of cerebrovascular diseases, as well as in those whose body mass index is >30 kg/m2.
For patients receiving fluconazole therapy, Dynastat should be prescribed at the lowest recommended dose. When co-administered with ketoconazole, no dose adjustment is required.
Serum lithium concentrations should be carefully monitored after initiation of Dynastat therapy or after changes in its dosage regimen in patients receiving lithium therapy.
Due to its insufficient effect on platelet function, parecoxib should not be considered a replacement for acetylsalicylic acid prescribed for the prevention of cardiovascular diseases.
Use in pediatrics
There is no experience using the drug in patients under 18 years of age
.
Impact on the ability to drive vehicles and operate machinery
During the treatment period, dizziness, drowsiness and anxiety may occur, so it is necessary to refrain from engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.
Drug interactions Dynastat
There was no significant inhibitory effect of the drug on CYP isoforms 3A4, 2D6, 2E1 and 1A2. Weak inhibitory activity was detected regarding isoforms 2C9 and 2C19. It has been established that in humans the metabolism of valdecoxib is carried out predominantly with the participation of cytochrome P450 isoforms CYP 3A4 and 2C9. The further pathway of metabolism is glucuronidation. The intensity of both CYP-dependent and CYP-independent metabolic pathways may be significantly reduced in some individuals with their genetic polymorphisms, which may result in significantly increased plasma concentrations of these substances. When fluconazole is co-administered, the AUC and maximum plasma concentrations for valdecoxib are increased (62 and 19%, respectively), indicating the need to reduce the dose of parecoxib sodium in patients receiving fluconazole. AUC and maximum plasma concentrations for valdecoxib are increased (by 38 and 24%, respectively) when used in combination with ketoconazole, which, however, does not require dose adjustment of Dynastat in patients receiving ketoconazole. Dynastat does not affect acetylsalicylic acid-induced inhibition of platelet aggregation or bleeding time and can be administered together with a low dose of acetylsalicylic acid (≤325 mg). Dynastat does not increase the cardioprotective effect of acetylsalicylic acid. Valdecoxib does not cause clinically significant inhibition of CYP 2D6-dependent metabolism of dextromethorphan. Anticoagulant therapy with warfarin or similar agents should be monitored, especially in the first days after the administration of Dynastat, since such patients have a higher risk of bleeding complications. Valdecoxib increases the mean plasma concentrations of R-warfarin, but not S-warfarin, or the mean prothrombin time when these drugs are used together. NSAIDs may reduce the effects of diuretics or antihypertensive drugs. As with other NSAIDs, the risk of developing acute renal failure may be increased when parecoxib sodium is co-administered with ACE inhibitors. The use of NSAIDs in combination with cyclosporine or tacrolimus may enhance the nephrotoxic effects of the latter. Monitor renal function when parecoxib sodium is coadministered with any of the above-mentioned drugs. The use of valdecoxib and glibenclamide (CYP 3A4 substrate) does not affect the pharmacokinetics (drug concentration) and pharmacodynamics (blood glucose and insulin levels) of glibenclamide. Valdecoxib does not have a clinically significant effect on the plasma concentration of methotrexate. Valdecoxib significantly reduces the plasma (by 25%) and renal (30%) clearance of lithium, while the concentration of lithium in the blood plasma increases by 34% compared with that when taking lithium itself. In patients receiving lithium treatment, lithium plasma concentrations should be closely monitored when initiating or switching to parecoxib sodium treatment. The use of parecoxib sodium intravenously at a dose of 40 mg with propofol (CYP 2C9 substrate) or midazolam (CYP 3A4) does not affect the pharmacokinetics (metabolism and plasma concentrations) or pharmacodynamics of propofol or midazolam when administered intravenously. In addition, intravenous administration of parecoxib sodium does not affect the pharmacokinetics of fentanyl or alfentanil administered intravenously (CYP 3A4 substrates). In patients undergoing orthopedic surgery in whom the drug was administered preoperatively, no interaction between parecoxib sodium and inhaled anesthetics (nitric oxide and isoflurane) was observed.
Dynastat
Pharmaceutically (in one syringe) incompatible with solutions of opioid analgesics.
Concomitant administration with opioid analgesics does not cause increased sedation and additional depression of the respiratory center.
When prescribed simultaneously with warfarin and other indirect anticoagulants, the risk of bleeding increases.
It can be used in combination with low doses (up to 325 mg) of ASA (does not affect the inhibition of platelet aggregation and bleeding time caused by ASA), in combination with heparin (the pharmacodynamics of heparin do not differ from those when heparin is administered as monotherapy).
When used simultaneously with ACE inhibitors or diuretics, the risk of developing acute renal failure may increase; with NSAIDs and cyclosporine, the nephrotoxic effect of the latter increases.
Co-administration with fluconazole (primarily an inhibitor of CYP2C9) AUC and Cmax of valdecoxib in plasma increases by 62 and 19%, respectively (requires dose reduction).
When co-administered with ketoconazole (CYP3A4 inhibitor), AUC and Cmax increase by 38 and 24%, respectively (clinically insignificant).
Inducers of microsomal oxidation in the liver (rifampicin, phenytoin, carbamazepine, dexamethasone) increase the metabolism of valdecoxib.
Increases plasma concentrations of dextromethorphan (CYP2D6 substrate) by 3 times.
Caution should be exercised when simultaneously prescribing drugs that are metabolized primarily by the CYP2D6 enzyme and that are characterized by a narrow therapeutic index (flecainide, propafenone, metoprolol).
Caution should be exercised when coadministered with drugs that are CYP2C19 substrates (phenytoin, diazepam, imipramine, omeprazole).
Does not have a clinically significant effect on plasma concentrations of methotrexate, but adequate monitoring should be carried out due to methotrexate-related toxicity.
Enhances the effect (by 34%) of Li+ drugs: reduces serum (by 25%) and renal (30%) clearance of Li+.
It does not affect the pharmacokinetics and pharmacodynamics of glibenclamide (CYP3A4 substrate), propofol (CYP2C9 substrate), midazolam (CYP3A4 substrate), fentanyl (CYP3A4 substrate), inhaled anesthetics (including dinitrogen oxide and isoflurane).
Myelotoxic drugs increase the manifestations of hematotoxicity of the drug.
