Dynastat (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Pharmacia, Ltd. (United Kingdom)

Manufactured By

Searle, Ltd. (Puerto Rico)

ATC Code

M01AH (Coxibs)

Active Substance

Parecoxib (Rec.INN registered by WHO)

Dosage Forms

	Dynastat	Lyophilisate for preparation of solution for injections 20 mg: vial 1, 3, 5 or 10 pcs. in a set with solvent
		Lyophilisate for preparation of solution for injections 40 mg: vial 1, 3, 5 or 10 pcs. in a set with solvent.

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for injections in the form of a porous mass or a white or almost white tablet; the attached solvent is a transparent colorless solution.

Excipients: sodium hydrogen phosphate heptahydrate, phosphoric acid and/or sodium hydroxide (to maintain pH level).

Solvent sodium chloride solution 0.9% – 1 ml.

Vials (1) in a set with solvent (amp. 1 pc.) – cardboard packs.
Vials (3) in a set with solvent (amp. 3 pcs.) – cardboard packs.
Vials (5) in a set with solvent (amp. 5 pcs.) – cardboard packs.
Vials (10) in a set with solvent (amp. 10 pcs.) – cardboard packs.

Lyophilisate for preparation of solution for injections in the form of a porous mass or a white or almost white tablet; the attached solvent is a transparent colorless solution.

Excipients: sodium hydrogen phosphate heptahydrate, phosphoric acid and/or sodium hydroxide (to maintain pH level).

Solvent sodium chloride solution 0.9% – 2 ml.

Vials (1) in a set with solvent (amp. 1 pc.) – cardboard packs.
Vials (3) in a set with solvent (amp. 3 pcs.) – cardboard packs.
Vials (5) in a set with solvent (amp. 5 pcs.) – cardboard packs.
Vials (10) in a set with solvent (amp. 10 pcs.) – cardboard packs.

Clinical-Pharmacological Group

NSAID. Selective COX-2 inhibitor

Pharmacotherapeutic Group

NSAID

Pharmacological Action

NSAID. Selective COX-2 inhibitor. After administration of Dynastat, its active substance Parecoxib is rapidly hydrolyzed to form valdecoxib.

The mechanism of action of valdecoxib is associated with inhibition of prostaglandin synthesis involving cyclooxygenase-2 (COX-2). Valdecoxib acts as a selective COX-2 inhibitor on both peripheral and central prostaglandins; it does not inhibit COX-1 and has virtually no effect on COX-1-dependent physiological processes in tissues, especially in the gastric and intestinal mucosa, and does not affect platelet aggregation and bleeding time. Due to the selective action on COX-2 and the absence of effect on COX-1, the frequency of endoscopically confirmed ulcers and erosions of the stomach and duodenum when using Dynastat is lower than against the background of non-selective NSAIDs.

Pharmacokinetics

After IV or IM administration, Parecoxib is rapidly metabolized in the liver by enzymatic hydrolysis to valdecoxib, which is the pharmacologically active component.

Absorption

After IV administration of Dynastat in the dose range of 20, 50 and 80 mg/day, changes in the pharmacokinetic parameters of valdecoxib such as AUC and C_max are linear. After a single IV or IM administration of parecoxib sodium at a dose of 20 mg, the C_max of valdecoxib is reached approximately after 30 min and 1 h, respectively. The AUC and C_max values of valdecoxib are similar after IV and IM administration.

Distribution

C_ss of valdecoxib in plasma when administered 2 times/day are achieved within 4 days. V_d of valdecoxib after IV administration is approximately 55 L.

Plasma protein binding is approximately 98% at concentrations achieved with the maximum dose (80 mg/day).

Valdecoxib, but not Parecoxib, predominantly accumulates in erythrocytes.

Metabolism

Parecoxib is rapidly and almost completely converted to valdecoxib and propionic acid, with the T_1/2 of parecoxib from plasma being approximately 22 min. It is intensively metabolized in the liver through many pathways, including metabolism involving CYP3A4 and CYP2C9 isoenzymes, as well as by CYP-independent glucuronidation (approximately 20%) of the sulfonamide moiety. A hydroxylated metabolite of valdecoxib is detected in plasma, which exhibits activity as a COX-2 inhibitor. It accounts for approximately 10% of the valdecoxib concentration; since the concentration of this metabolite is low, it can be considered that it does not have a significant clinical effect after administration of therapeutic doses of parecoxib sodium.

Excretion

Valdecoxib is eliminated by metabolic transformation in the liver, and less than 5% of valdecoxib is excreted unchanged in the urine. Unchanged parecoxib is not detected in urine, and is detected in feces only in trace amounts. Approximately 70% of the dose is excreted in the urine in the form of inactive metabolites. Plasma clearance for valdecoxib is about 6 L/h. After IV or IM administration of parecoxib sodium, the T_1/2 of valdecoxib is about 8 h. The drug is not removed by hemodialysis.

Pharmacokinetics in special clinical cases

It has been noted that in elderly patients the clearance of valdecoxib is reduced, so the plasma concentration of valdecoxib is approximately 40% higher than in young patients. C_ss of valdecoxib in plasma is 16% higher in elderly women than in elderly men.

In patients with varying degrees of renal impairment after IV administration of 20 mg of Dynastat, Parecoxib is rapidly eliminated from plasma. Since the kidneys do not play a significant role in the elimination of valdecoxib, and therefore their functional state does not have a significant effect on the pharmacokinetics of the drug, no change in the clearance of valdecoxib is detected even in patients with severe renal impairment, as well as in patients on hemodialysis.

In moderate liver damage, there is no decrease in the rate and extent of conversion of parecoxib to valdecoxib. Since the exposure to valdecoxib in such patients increases by more than 2 times (by 130%), a dose reduction is necessary.

Indications

• Acute pain;
• For the prevention or reduction of postoperative pain;
• To reduce the need for opioid analgesics.

ICD codes

Dosage Regimen

Dynastat can be administered IV or IM either as a single dose or as regular repeated injections or as needed. After starting therapy, the dose should be adjusted depending on the patient’s response. There is experience with the use of the drug for 7 days.

For acute pain, the recommended single initial dose is 40 mg for IV or IM administration. Then, if necessary, administration can be continued every 6-12 h at 20-40 mg; the daily dose should not exceed 80 mg.

IV bolus injection can be performed directly into a vein or into the tube of a pre-installed IV infusion system. IM administration should be performed slowly and deep into the muscle.

For prevention or reduction of postoperative pain, the drug is administered at a dose of 40 mg IV or IM (preferably IV) 45-30 minutes before surgery. To maintain analgesia, repeated postoperative administration of the drug according to the scheme described for the treatment of acute pain may be required.

To reduce the need for opioid analgesics, Dynastat can be used in combination with opioid analgesics according to the scheme described for the treatment of acute pain. The daily requirement for opioids is reduced by 20-40% when they are prescribed simultaneously. The optimal effect is achieved when Dynastat is administered before opioids.

For elderly patients, dose adjustment is generally not required. However, in elderly patients with a body weight of less than 50 kg, treatment should be started with half the recommended dose; the maximum daily dose should not exceed 40 mg.

For patients with mild hepatic impairment, dose adjustment is usually not required. For patients with moderate hepatic impairment, the drug should be prescribed with caution, administration should be started with half the recommended dose, and the maximum daily dose should be reduced to 40 mg. There is no experience with the use of Dynastat in patients with severe liver damage; therefore, the use of the drug in such patients is not recommended.

In case of severe renal failure (CC <30 ml/min) or conditions predisposing to fluid retention in the body, Parecoxib should be prescribed at the lowest recommended dose and renal function should be carefully monitored.

Rules for preparation of injection solution

To prepare the solution, 1 ml (for 20 mg vials) or 2 ml (for 40 mg vials) of 0.9% sodium chloride solution for injection is used.

The following solvents can also be used: 5% dextrose (glucose) solution for injection, 5% dextrose solution with 0.45% sodium chloride for injection (the solution prepared using these solvents is isotonic).

The use of Ringer’s lactate (Hartmann’s) solution for injection or Ringer’s lactate solution for injection with 5% dextrose for the preparation of Dynastat solution is not recommended, as this leads to precipitation.

The use of sterile water for injection as a solvent is also not recommended, since the resulting solution will not be isotonic.

The prepared solution should not be cooled or frozen.

After dissolution, Dynastat can be administered into an IV infusion system containing the following solvents: sodium chloride solution for injection (0.9%), dextrose solution for injection (5%), Ringer’s lactate solution for injection, 5% dextrose solution with 0.45% sodium chloride.

Administration of Dynastat solution into IV infusion systems containing 5% dextrose in Ringer’s lactate solution or other drugs not listed above is not recommended, as this may cause precipitation.

Dynastat should not be mixed with other drugs.

Adverse Reactions

From the cardiovascular system often (≥1% and <10%) – decrease or increase in blood pressure; sometimes (≥0.1% and <1%) – bradycardia, cerebrovascular disorders; rarely (<0.1%)- chronic heart failure.

From the central and peripheral nervous system often – dizziness, anxiety, insomnia, hypesthesia.

From the sensory organs sometimes – ear pain.

From the digestive system often – post-extraction alveolar osteitis, constipation, flatulence, dyspepsia; sometimes – dry mouth, ulcers and erosions of the stomach and duodenum, increased ALT and AST activity; rarely – hepatitis.

From the metabolism often – increased creatinine level, hypokalemia; sometimes – hyperglycemia, increased blood urea nitrogen level.

From the respiratory system often – respiratory failure; sometimes – pharyngitis.

Dermatological reactions often – increased sweating, itching; sometimes – rash, postoperative complications at the wound site (delayed wound healing);

From the musculoskeletal system sometimes – arthralgia.

From the hematopoietic system sometimes – thrombocytopenia.

From the urinary system sometimes – oliguria; rarely – acute renal failure.

Allergic reactions rarely – anaphylactic shock, bronchospasm; against the background of valdecoxib use, angioedema, anaphylactic reactions, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis have been noted (these reactions are also not excluded against the background of parecoxib use).

Other often – back pain, peripheral edema, postoperative anemia, ecchymosis; sometimes – asthenia.

Local reactions sometimes – pain at the injection site, pathological discharge from the drain installed after surgery accompanied by sternotomy, wound infection (including during coronary artery bypass graft surgery).

The indicated rare serious side effects were noted against the background of NSAID use and also cannot be completely excluded for Dynastat.

Contraindications

• Allergic reactions to sulfonamides;
• Allergic reactions (including bronchospasm, acute rhinitis, angioedema, urticaria) after taking acetylsalicylic acid or other NSAIDs, including other selective COX-2 inhibitors;
• Severe hepatic failure;
• Erosive and ulcerative lesions of the gastrointestinal tract in the acute phase (including acute peptic ulcer);
• Chronic heart failure (III-IV functional class according to NYHA classification);
• Third trimester of pregnancy;
• Lactation period;
• Children and adolescents under 18 years of age;
• Hypersensitivity to parecoxib, as well as to any of the components included in the drug.

With caution the drug should be prescribed for coronary artery bypass grafting, in case of fluid retention in the body (including conditions arising or worsening due to it, including chronic heart failure and arterial hypertension), with dehydration, history of erosive and ulcerative lesions of the gastrointestinal tract, inflammatory bowel diseases, during gastrointestinal surgeries, urological surgeries, with moderately severe hepatic failure, severe renal failure.

Use in Pregnancy and Lactation

There is no experience with the use of Dynastat during pregnancy.

Dynastat should be used during pregnancy only if the intended benefit to the mother outweighs the potential risk to the fetus.

The use of Dynastat is contraindicated in the third trimester of pregnancy, because due to inhibition of prostaglandin synthesis, it can cause a decrease in uterine contractility, as well as premature closure of the ductus arteriosus.

It is not known whether Parecoxib is excreted in breast milk, therefore, taking into account the potential risk of side effects from parecoxib in the breastfed child and considering the importance of the drug for the mother, it is worth assessing whether to continue breastfeeding or start therapy with Dynastat, interrupting feeding for the duration of treatment.

Use in Hepatic Impairment

For patients with mild hepatic impairment, dose adjustment is usually not required. For patients with moderate hepatic impairment, the drug should be prescribed with caution, administration should be started with half the recommended dose, and the maximum daily dose should be reduced to 40 mg. There is no experience with the use of Dynastat in patients with severe liver damage; therefore, the use of the drug in such patients is not recommended.

The condition of patients with symptoms and/or signs of impaired liver function or those who have been found to have abnormal liver function by testing should be carefully monitored during treatment with Dynastat.

Use in Renal Impairment

In case of severe renal failure (CC <30 ml/min) or conditions predisposing to fluid retention in the body, Parecoxib should be prescribed at the lowest recommended dose and renal function should be carefully monitored.

Pediatric Use

The drug is contraindicated in children and adolescents under 18 years of age.

Geriatric Use

For elderly patients, dose adjustment is generally not required. However, in elderly patients with a body weight of less than 50 kg, treatment should be started with half the recommended dose; the maximum daily dose should not exceed 40 mg.

Special Precautions

During treatment with Dynastat, cases of ulcer formation (including perforating) and bleeding from the upper gastrointestinal tract have been noted. In this regard, caution should be exercised when prescribing the drug to patients with gastric and duodenal ulcers, a history of gastrointestinal bleeding and active and history of inflammatory gastrointestinal diseases, as well as elderly patients, patients with cardiovascular diseases and patients taking acetylsalicylic acid.

If the first signs of skin rash or other signs of hypersensitivity appear, Dynastat should be discontinued.

Against the background of valdecoxib use, the development of hypersensitivity reactions (anaphylactoid reactions and angioedema) has been noted in patients taking valdecoxib; they are also not excluded for parecoxib. These reactions were noted in patients with both known and unknown allergic reactions to sulfonamides.

After prescribing parecoxib, anticoagulant activity should be especially carefully monitored during the first few days in patients taking warfarin or similar drugs, since such patients may be at greater risk of bleeding.

Due to 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 that arise or worsen due to fluid retention. Patients with a history of heart failure or arterial hypertension should be under careful observation.

Caution should be exercised when prescribing Dynastat to patients with severe dehydration. In such cases, it is advisable to first carry out rehydration and then start therapy.

There is no experience with the use of the drug in patients with severe hepatic impairment. The use of Dynastat in them is not recommended. The drug should be used with caution when treating patients with moderate hepatic impairment and prescribed at the lowest recommended dose.

The condition of patients with symptoms and/or signs of impaired liver function or those who have been found to have abnormal liver function by testing should be carefully monitored during treatment with Dynastat.

Due to its anti-inflammatory action, Dynastat may reduce the significance of diagnostic signs (such as fever) in identifying an infection.

Dynastat should be used with caution after coronary artery bypass graft surgery, as this category of patients has an increased risk of developing serious adverse reactions, especially in patients with a history of cerebrovascular disease, as well as in those whose body mass index >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.

Careful monitoring of serum lithium concentration should be performed after initiation of Dynastat therapy or after a change in its dosing regimen in patients receiving lithium therapy.

Due to its insufficient effect on platelet function, Parecoxib cannot be considered as a replacement for acetylsalicylic acid prescribed for the prevention of cardiovascular diseases.

Use in Pediatrics

There is no experience with the use of the drug in patients under 18 years of age.

Effect on the Ability to Drive Vehicles and Operate Machinery

During treatment, dizziness, drowsiness, and anxiety may occur, therefore it is necessary to refrain from engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Single doses of up to 200 mg of parecoxib were administered intravenously to healthy volunteers without the occurrence of clinically significant adverse effects. Parecoxib at a dose of 50 mg was administered intravenously twice a day (100 mg/day) for 7 days without revealing signs of toxicity.

Data on the clinical symptoms of overdose are not available.

In case of suspected overdose of Dynastat, symptomatic treatment is indicated. Dialysis is unlikely to be effective for removing the drug, as Parecoxib is characterized by a high degree of binding to plasma proteins.

Drug Interactions

Dynastat, when used concomitantly, may reduce the antihypertensive effect of ACE inhibitors.

Concomitant use of Dynastat with warfarin causes a slight increase in the AUC of warfarin, as well as prothrombin time.

When Dynastat is used concomitantly with fluconazole (a CYP2C9 inhibitor), the plasma AUC of parecoxib increases by 62%, with ketoconazole (a CYP3A4 inhibitor) – by 38%.

Valdecoxib (the active metabolite of parecoxib) causes a significant decrease in serum (25%) and renal (30%) clearance of lithium and, as a result, a 34% increase in the serum AUC of lithium.

The metabolism of valdecoxib may be increased when it is co-administered with inducers of hepatic microsomal enzymes (including rifampicin, phenytoin, carbamazepine, or dexamethasone).

When Dynastat is used concomitantly, the plasma concentration of dextromethorphan (a CYP2D6 substrate) increases 3-fold. Caution should be exercised when co-administering Dynastat and drugs whose metabolism is primarily mediated by the CYP2D6 isoenzyme and which have a narrow therapeutic index (flecainide, propafenone, metoprolol).

No clinically significant pharmacokinetic interactions were observed between parecoxib and intravenously or orally administered midazolam, heparin, propofol, fentanyl, or alfentanil.

No clinically significant interactions were observed between valdecoxib and glibenclamide (glyburide), methotrexate, or oral contraceptives (ethinyl estradiol/norethindrone).

There is no evidence of interaction between parecoxib and inhaled anesthetics such as nitrous oxide and isoflurane.

Parecoxib does not affect the antithrombotic effect of acetylsalicylic acid.

Concomitant administration with naloxone does not affect the severity of the analgesic effect of valdecoxib, therefore it is assumed that concomitant administration with opioid analgesics does not cause increased sedation and additional depression of the respiratory center.

NSAIDs may reduce the effectiveness of furosemide and thiazides by reducing renal prostaglandin synthesis.

When NSAIDs and cyclosporine or tacrolimus are used concomitantly, the nephrotoxic effect of the latter is enhanced.

Storage Conditions

List B. The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.