Dexofen solution for injection 50 mg/2 ml ampoule 2 ml No. 5

Instructions Dexofen solution for injection 50 mg/2 ml ampoule 2 ml No. 5

Composition

active ingredient: dexketoprofen;

1 ml of solution for injection contains 36.91 mg of dexketoprofen trometamol, equivalent to 25 mg of dexketoprofen (one 2 ml ampoule contains 73.8 mg of dexketoprofen trometamol, equivalent to 50 mg of dexketoprofen);

Excipients: sodium chloride; ethanol 96%; sodium hydroxide; water for injections.

Dosage form

Solution for injection.

Main physicochemical properties: transparent and colorless solution, free from mechanical inclusions.

Pharmacotherapeutic group

Nonsteroidal anti-inflammatory and antirheumatic drugs. Propionic acid derivatives. Dexketoprofen. ATX code M01A E17.

Pharmacological properties

Pharmacodynamics.

Dexketoprofen trometamol is the tromethamine salt of (S)-(+)-2-(3-benzoylphenyl)propionic acid, which has analgesic, anti-inflammatory and antipyretic effects and belongs to the class of nonsteroidal anti-inflammatory drugs (NSAIDs).

Mechanism of action

The mechanism of action of NSAIDs is based on a decrease in prostaglandin synthesis by inhibiting cyclooxygenase activity. In particular, the conversion of arachidonic acid to cyclic endoperoxides PGG2 and PGH2 is inhibited, from which prostaglandins PGE1, PGE2, PGF2, PGD2 are formed, as well as prostacyclin PGI2 and thromboxanes ThA2 and ThB2. In addition, inhibition of prostaglandin synthesis may affect other inflammatory mediators, such as kinins, which may also indirectly affect the main effect of the drug.

Pharmacodynamics

Dexketoprofen trometamol has been shown to inhibit cyclooxygenase-1 and cyclooxygenase-2 activity in laboratory animals and humans.

Clinical efficacy and safety

Clinical studies in various types of pain have demonstrated that dexketoprofen trometamol has a pronounced analgesic effect. The analgesic effect of dexketoprofen trometamol when administered intramuscularly and intravenously to patients with moderate to severe pain has been studied in various types of surgical pain (orthopedic and gynecological operations, abdominal operations), as well as in musculoskeletal pain (acute low back pain) and renal colic. During the studies, the analgesic effect of the drug began quickly and reached a maximum within 45 minutes.

The duration of analgesic effect after administration of 50 mg of dexketoprofen trometamol is usually 8 hours. Clinical studies have shown that the use of the drug allows for a significant reduction in the dose of opiates when used simultaneously for the purpose of relieving postoperative pain. When patients who were prescribed morphine for the purpose of relieving postoperative pain using a patient-controlled analgesia device were also prescribed dexketoprofen trometamol, they required significantly less morphine (by 30-45%) than patients who received placebo.

Pharmacokinetics.

Absorption

After intramuscular administration of dexketoprofen trometamol to humans, the maximum concentration (Cmax) is reached after approximately 20 minutes (10-45 minutes). It has been proven that with a single intramuscular or intravenous administration of 25-50 mg of the drug, the area under the "concentration-time" curve (AUC) is proportional to the dose.

Distribution

Similar to other drugs with a high degree of binding to plasma proteins (99%), the volume of distribution of dexketoprofen is on average 0.25 l/kg. The half-life is approximately 0.35 hours, and the half-life is 1–2.7 hours.

Pharmacokinetic studies of multiple administration of the drug have demonstrated that Cmax and AUC after the last intramuscular or intravenous administration do not differ from those after a single administration, indicating the absence of drug accumulation.

Biotransformation and excretion

Dexketoprofen is mainly metabolized by conjugation with glucuronic acid and subsequent renal excretion. After administration of dexketoprofen trometamol, only the S-(+) optical isomer is detected in the urine, indicating that there is no transformation of the drug into the R-(-) optical isomer in humans.

Elderly patients

After single and multiple doses, the extent of exposure to the drug in healthy elderly volunteers (aged 65 years and over) participating in the study was significantly higher (up to 55%) than in young volunteers, but there was no statistically significant difference in maximum concentration and time to reach it. The mean half-life increased (up to 48%) and the determined total clearance decreased.

Standard preclinical studies – safety pharmacology, genotoxicity and immunopharmacology – did not reveal any special hazard for humans. Chronic toxicity studies in animals have revealed a maximum dose of the drug that does not cause adverse reactions, which is 2 times higher than the dose recommended for humans. When higher doses of the drug were administered to monkeys, the main adverse reaction was blood in the stool, decreased body weight gain, and when the highest dose was administered, gastrointestinal pathology in the form of erosions. These reactions occurred at doses at which the exposure to the drug was 14-18 times higher than at the maximum dose recommended for humans. Carcinogenicity studies in animals have not been conducted.

Like all NSAIDs, dexketoprofen can cause embryo or fetal death in animals by directly affecting its development or indirectly by damaging the gastrointestinal tract of the mother.

Indication

Symptomatic treatment of acute pain of moderate to severe intensity in cases where oral administration of the drug is inappropriate, such as postoperative pain, renal colic and low back pain.

Contraindication

• Hypersensitivity to dexketoprofen, any other NSAID or to the excipients of the drug;
• if substances with a similar effect, such as acetylsalicylic acid or other NSAIDs, provoke the development of attacks of bronchial asthma, bronchospasm, acute rhinitis or cause the development of nasal polyps, the appearance of urticaria or angioedema;
• if photoallergic or phototoxic reactions occurred during treatment with ketoprofen or fibrates;
• with a history of gastrointestinal bleeding or perforation associated with previous NSAID therapy;
• patients with active peptic ulcer/gastrointestinal bleeding or a history of gastrointestinal bleeding, ulcers or perforations;
• patients with chronic dyspepsia;
• with other bleeding in the active phase or with increased bleeding;
• with Crohn's disease or nonspecific ulcerative colitis;
• with severe heart failure;
• with moderate or severe renal impairment (creatinine clearance ≤59 ml/min);
• with severe liver dysfunction (10-15 points on the Child-Pugh scale);
• with hemorrhagic diathesis and other blood clotting disorders;
• with severe dehydration (due to vomiting, diarrhea or insufficient fluid intake);
• in the third trimester of pregnancy and during breastfeeding.

Due to the ethanol content in the medicinal product, the drug is contraindicated for neuraxial (intrathecal or epidural) administration.

Interaction with other medicinal products and other types of interactions

The simultaneous use of the following drugs with NSAIDs is not recommended:

• other NSAIDs (including selective cyclooxygenase-2 inhibitors), including salicylates in high doses (≥ 3 g per day): the simultaneous use of several NSAIDs increases the risk of gastrointestinal ulcers and bleeding due to their mutually reinforcing effects.
• Anticoagulants: NSAIDs enhance the effect of anticoagulants, such as warfarin, due to the high degree of binding of dexketoprofen to blood plasma proteins, as well as inhibition of platelet function and damage to the gastric and duodenal mucosa. If concomitant use is necessary, it should be carried out under the close supervision of a physician who will monitor relevant laboratory parameters.
• Heparins: increased risk of bleeding (due to inhibition of platelet function and damage to the gastric and duodenal mucosa); if concomitant use is necessary, it should be carried out under the close supervision of a physician who will monitor relevant laboratory parameters.
• Corticosteroids: Increased risk of gastrointestinal ulcers or bleeding.
• Lithium (reported for several NSAIDs): NSAIDs increase the level of lithium in the blood, which can lead to intoxication (reduced renal excretion of lithium), therefore, at the beginning of dexketoprofen use, when adjusting the dose or discontinuing the drug, it is necessary to monitor the level of lithium in the blood.
• Methotrexate in high doses (at least 15 mg per week): due to the decrease in renal clearance of methotrexate against the background of the use of NSAIDs, its negative effect on the blood system is generally increased.
• Hydantoin derivatives and sulfonamides: possible increased toxicity of these substances.

The simultaneous use of the following drugs with NSAIDs requires caution:

Possible interactions should be considered when using the following medications:

• β-blockers: NSAIDs can weaken their antihypertensive effect by inhibiting prostaglandin synthesis.
• Cyclosporine and tacrolimus: possible increased nephrotoxicity due to the effect of NSAIDs on renal prostaglandins; renal function should be monitored during combination therapy.
• Thrombolytic agents: increased risk of bleeding.
• Antiplatelet agents and selective serotonin reuptake inhibitors: increased risk of gastrointestinal bleeding.
• Probenecid: an increase in dexketoprofen plasma concentrations is possible, which is likely due to inhibition of renal tubular secretion and conjugation of the drug with glucuronic acid and requires correction of the dexketoprofen dose.
• Cardiac glycosides: NSAIDs can increase the concentration of glycosides in the blood plasma.
• Mifepristone: There is a theoretical risk that the efficacy of mifepristone may be altered by prostaglandin synthetase inhibitors. Limited data suggest that co-administration of NSAIDs on the same day as a prostaglandin does not adversely affect the efficacy of mifepristone or prostaglandin in cervical ripening or contractility, nor does it reduce the clinical efficacy of drugs for medical termination of pregnancy.
• Quinolone antibiotics: Animal studies have shown that the use of high doses of quinolone derivatives in combination with NSAIDs increases the risk of seizures.
• Tenofovir: when used concomitantly with NSAIDs, the concentration of urea nitrogen and creatinine in the blood plasma may increase, therefore, renal function should be monitored to assess the possible effect of the concomitant use of these drugs.
• Deferasirox: Concomitant use with NSAIDs may increase the risk of gastrointestinal toxicity; careful patient monitoring is required when this medicinal product is used in combination with deferasirox.
• Pemetrexed: Concomitant use with NSAIDs may decrease the elimination of pemetrexed, therefore special caution is required when using NSAIDs at high doses. In patients with mild to moderate renal impairment (creatinine clearance 45 to 79 ml/min), the concomitant use of pemetrexed and NSAIDs should be avoided for two days before and two days after taking pemetrexed.

Application features

The drug should be used with caution in patients with a history of allergic conditions. Avoid using the drug in combination with other NSAIDs, including selective cyclooxygenase-2 inhibitors. Adverse reactions can be reduced by using the lowest effective dose for the shortest time necessary to improve the condition.

Digestive tract safety

Elderly patients. Elderly patients have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, sometimes fatal. Treatment of such patients should be started with the lowest possible dose. Before starting the use of dexketoprofen trometamol in patients with a history of esophagitis, gastritis and/or peptic ulcer disease, it should be ensured that these diseases are in remission. In patients with existing symptoms of gastrointestinal pathology and with a history of gastrointestinal diseases, the condition of the digestive tract should be monitored for possible disorders, especially gastrointestinal bleeding, during the use of the drug. NSAIDs should be prescribed with caution to patients with a history of gastrointestinal diseases (ulcerative colitis, Crohn's disease), as there is a risk of their exacerbation. The use of NSAIDs can lead to relapses of nonspecific ulcerative colitis, as well as Crohn's disease in patients who are in remission. For such patients and patients taking low-dose acetylsalicylic acid or other drugs that increase the risk of gastrointestinal adverse reactions, combination therapy with protective drugs, such as misoprostol or PPIs, should be considered.

Patients, especially the elderly, who have a history of adverse reactions from the digestive tract should inform their doctor about all unusual symptoms related to the digestive system, in particular gastrointestinal bleeding, especially in the initial stages of treatment.

Caution should be exercised when prescribing the drug to patients who are concomitantly taking medications that may increase the risk of ulceration or bleeding: oral corticosteroids, anticoagulants (e.g. warfarin), selective serotonin reuptake inhibitors or antiplatelet agents such as acetylsalicylic acid.

Kidney dysfunction

Patients with impaired renal function should be prescribed the drug with caution, since against the background of the use of NSAIDs, impaired renal function, fluid retention in the body and edema are possible. Due to the increased risk of nephrotoxicity, the drug should be prescribed with caution during treatment with diuretics, as well as in patients who may develop hypovolemia. During treatment, the body should receive a sufficient amount of fluid to avoid dehydration, which can lead to increased toxic effects on the kidneys. Like all NSAIDs, the drug may increase the concentration of urea nitrogen and creatinine in the blood plasma. Like other prostaglandin synthesis inhibitors, its use may be accompanied by adverse reactions from the kidneys, leading to glomerulonephritis, interstitial nephritis, papillary necrosis, nephrotic syndrome and acute renal failure. Most impaired renal function occurs in elderly patients.

Liver dysfunction

Patients with impaired liver function should be prescribed the drug with caution. As with other NSAIDs, the drug may cause a temporary and slight increase in the values of some liver parameters, as well as a pronounced increase in the activity of AST and ALT. If these parameters increase, therapy should be discontinued.

Most liver dysfunction occurs in elderly patients.

Cardiovascular and cerebrovascular safety

Non-selective NSAIDs can reduce platelet aggregation and increase bleeding time by inhibiting prostaglandin synthesis. The simultaneous use of dexketoprofen trometamol and low molecular weight heparin in prophylactic doses in the postoperative period was studied in clinical studies, no effect on coagulation parameters was found. However, patients who use dexketoprofen trometamol simultaneously with drugs that affect hemostasis, such as warfarin, other coumarin drugs or heparin, should be under close medical supervision. The greatest number of cardiovascular system dysfunctions occurs in elderly patients.

Skin reactions

Very rare cases of serious skin reactions (some fatal) have been reported with NSAIDs, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis. Patients appear to be at greatest risk at the start of treatment, with most patients experiencing these reactions within the first month of treatment. The drug should be discontinued if skin rash, signs of mucosal involvement or other signs of hypersensitivity occur.

Other information

Particular caution should be exercised when prescribing the drug to patients:

• with hereditary disorders of porphyrin metabolism (for example, in acute intermittent porphyria);
• with dehydration;
• immediately after major surgical interventions.

If the doctor considers that long-term use of dexketoprofen is necessary, liver and kidney function should be monitored regularly.

In very rare cases, severe acute hypersensitivity reactions (e.g. anaphylactic shock) have been observed. At the first signs of severe hypersensitivity reactions after taking the drug, treatment should be discontinued. Depending on the symptoms, any necessary treatment in such cases should be carried out under the supervision of a doctor.

Patients with asthma in combination with chronic rhinitis, chronic sinusitis and/or nasal polyps are at higher risk of allergy to acetylsalicylic acid and/or NSAIDs than other patients. The use of this drug may cause asthma attacks or bronchospasm, especially in patients with allergy to acetylsalicylic acid or NSAIDs.

Severe infectious complications of the skin and soft tissues may develop in the setting of chickenpox. To date, there is no data to rule out the role of NSAIDs in aggravating this infectious process. Therefore, the drug is not recommended for use in chickenpox.

The drug should be administered with caution to patients with hematopoietic disorders, systemic lupus erythematosus, and mixed connective tissue diseases.

Like other NSAIDs, dexketoprofen trometamol may mask the symptoms of infectious diseases during its use. In isolated cases, there have been reports of activation of infectious processes localized in soft tissues during the use of NSAIDs. Therefore, if symptoms of a bacterial infection appear or worsen during the use of the drug, patients are advised to consult a doctor immediately.

1 ampoule of the drug contains 200 mg of ethanol, which is equal to 5 ml of beer or 2.08 ml of wine per dose. The drug may have a negative effect on people suffering from alcoholism. The ethanol content should be taken into account when using the drug in pregnant and breastfeeding women, children and patients at risk, for example, with liver disease, as well as patients with epilepsy. The drug contains less than 1 mmol sodium (23 mg) per dose, therefore it is practically sodium-free.

Use during pregnancy or breastfeeding

Dexofen is contraindicated in the third trimester of pregnancy and during breastfeeding.

Pregnancy.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or fetal development. Epidemiological studies have shown that the use of drugs that inhibit prostaglandin synthesis in early pregnancy increases the risk of miscarriage, fetal heart defects and anterior abdominal wall non-union. Thus, the absolute risk of developing cardiovascular anomalies increased from < 1% to approximately 1.5%. It is believed that the risk of such phenomena increases with increasing dose and duration of therapy. The use of prostaglandin synthesis inhibitors in animals caused an increase in pre- and post-implantation losses and increased embryo-fetal mortality. In addition, in animals treated with prostaglandin synthesis inhibitors during organogenesis, the incidence of fetal malformations, including cardiovascular anomalies, increased. However, studies of dexketoprofen in animals did not reveal toxic effects on the reproductive organs. Dexketoprofen should be prescribed during the first and second trimesters of pregnancy only if clearly needed. When prescribing dexketoprofen to women planning a pregnancy or during the first and second trimesters of pregnancy, the lowest effective dose should be used for the shortest possible duration of treatment.

During the third trimester, all prostaglandin synthesis inhibitors cause:

Risks to the fetus:

• renal dysfunction, which can progress to renal failure with the development of oligohydramnios.

Risks for the woman at the end of pregnancy and for the newborn:

• increased bleeding time due to inhibition of platelet aggregation, even when using the drug in low doses;
• suppression of uterine contractile activity, which leads to prolongation and delay of labor.

Breastfeeding.

There is no data on the penetration of dexketoprofen into breast milk. Dexofen is contraindicated during breastfeeding.

Fertility.

As with all NSAIDs, dexketoprofen trometamol may impair female fertility and is therefore not recommended in women attempting to conceive. Women who have difficulty conceiving or are undergoing investigation of infertility should consider discontinuing the drug.

If dexketoprofen is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the lowest effective dose should be used for the shortest possible duration.

Ability to influence reaction speed when driving vehicles or other mechanisms

Dizziness, visual disturbances or drowsiness may occur while using the drug. In such cases, the ability to react quickly, navigate the road situation and drive vehicles or other mechanisms may be impaired.

Method of administration and doses

Adults. The recommended dose is 50 mg every 8–12 hours. If necessary, a second dose should be administered after 6 hours. The maximum daily dose should not exceed 150 mg. The drug is intended for short-term use, therefore it should be used only during acute pain (no longer than 2 days). Patients should be transferred to oral analgesics, if possible. Adverse reactions can be reduced by using the lowest effective dose for the shortest possible time necessary to improve the condition. For moderate to severe postoperative pain, the drug can be used according to indications in the same recommended doses in combination with opioid analgesics.

Elderly patients: Dose adjustment is usually not required. However, due to physiological decline in renal function, a lower dose is recommended, with a maximum daily dose of 50 mg in mild renal impairment.

Hepatic impairment. For patients with mild to moderate liver disease (Child-Pugh score 5-9), the maximum daily dose should be reduced to 50 mg and liver function should be closely monitored. The drug is contraindicated in severe liver disease (Child-Pugh score 10-15).

Renal impairment: For patients with mild renal impairment (creatinine clearance 60–89 mL/min), the maximum daily dose should be reduced to 50 mg. In patients with moderate or severe renal impairment (creatinine clearance < 59 mL/min), the drug is contraindicated.

Children and adolescents: The drug should not be used in children and adolescents due to lack of data on its efficacy and safety.

Method of application

Intramuscular injection

The injection solution should be injected slowly deep into the muscle.

Intravenous infusion

For intravenous infusion, the contents of the 2 ml ampoule should be diluted in 30-100 ml of 0.9% sodium chloride solution, glucose solution or Ringer-lactate solution. The infusion solution should be prepared under aseptic conditions, avoiding exposure to natural daylight. The prepared solution should be clear. The infusion should be carried out within 10-30 minutes. Avoid exposure to natural daylight on the prepared solution.

The drug, diluted in 100 ml of 0.9% sodium chloride solution or in glucose solution, can be mixed with dopamine, heparin, hydroxyzine, lidocaine, morphine, pethidine and theophylline.

The drug should not be mixed in an infusion solution with promethazine and pentazocine.

Intravenous injection (bolus administration)

If necessary, the contents of one ampoule (2 ml of solution for injection) should be administered intravenously over at least 15 seconds.

The drug can be mixed in small volumes (e.g. in a syringe) with injectable solutions of heparin, lidocaine, morphine and theophylline.

The drug should not be mixed in small volumes (e.g., in a syringe) with solutions of dopamine, promethazine, pentazocine, pethidine, and hydrocortisone because a white precipitate forms.

The drug can only be mixed with the medicines listed above.

For intramuscular or intravenous bolus administration, the drug should be administered immediately after it has been withdrawn from the ampoule.

When storing diluted drug solutions in polyethylene bags or in products made of ethyl vinyl acetate, cellulose propionate, low-density polyethylene, and polyvinyl chloride designed for administration, no changes in the content of the active substance due to sorption were observed.

The drug is intended for single use, therefore the remaining solution should be disposed of. Before administering the drug, it is necessary to make sure that the solution is clear and colorless. A solution containing solid particles should not be used.

Children.

The drug should not be used in children and adolescents due to the lack of data on its efficacy and safety.

Overdose

Symptoms of overdose are unknown. Similar drugs cause disorders of the digestive tract (vomiting, anorexia, abdominal pain) and the nervous system (drowsiness, dizziness, disorientation, headache). In case of accidental overdose, symptomatic treatment should be immediately initiated according to the patient's condition. Dexketoprofen trometamol is removed from the body by dialysis.

Adverse reactions

The table below lists the adverse reactions, classified by organ system and frequency, whose relationship to dexketoprofen trometamol, according to clinical studies, is considered at least possible, as well as adverse reactions reported after the drug was marketed.

Gastrointestinal disorders were observed most frequently.

Ulcers, perforations or gastrointestinal bleeding may develop, sometimes with fatal outcome, especially in elderly patients. According to available data, nausea, vomiting, diarrhea, flatulence, constipation, dyspeptic phenomena, abdominal pain, melena, vomiting with blood, ulcerative stomatitis, exacerbation of colitis and Crohn's disease may occur against the background of the drug. Gastritis is less common. Edema, arterial hypertension and heart failure, which may be caused by the use of NSAIDs, have also been noted. As with other NSAIDs, the following adverse reactions are possible: aseptic meningitis, which generally occurs in patients with systemic lupus erythematosus or patients with mixed connective tissue diseases, and blood reactions (purpura, aplastic and hemolytic anemia, rarely - agranulocytosis and bone marrow hypoplasia). Bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare), are possible.

According to clinical trial results and epidemiological data, the use of some NSAIDs, especially in high doses and for long periods, may be accompanied by some increase in