Dexpro solution for injection 2.5% ampoule 2 ml No. 5

Instructions for Dexpro injection solution 2.5% ampoule 2 ml No. 5

Composition

active ingredient: dexketoprofen;

1 ampoule of 2 ml of solution contains dexketoprofen trometamol 73.8 mg, which corresponds to dexketoprofen 50 mg;

Excipients: ethanol (96%), sodium chloride, sodium hydroxide, water for injections.

Dosage form

Solution for injection.

Main physicochemical properties: clear colorless liquid.

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, PGF2a, 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 pain during surgical interventions (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 the first 45 minutes. The duration of the analgesic effect after the use of 50 mg of dexketoprofen trometamol is usually 8 hours. Clinical studies have demonstrated that the use of the drug Dexpro allows for a significant reduction in the dose of opiates when they are used simultaneously for the purpose of relieving postoperative pain. When patients who were given morphine for postoperative pain relief using a patient-controlled analgesia device were also given dexketoprofen trometamol, they required significantly less morphine (by 30–45%) than patients who received placebo.

Pharmacokinetics.

Absorption

After intramuscular administration of dexketoprofen trometamol in humans, the maximum concentration 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 AUC curve (concentration – time) 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 (65 years and older) 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 at the highest dose – gastrointestinal pathologies 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, for example, in postoperative pain, renal colic and low back pain.

Contraindication

- Hypersensitivity to dexketoprofen, any other non-steroidal anti-inflammatory drug (NSAID) or to the excipients of the drug;

- patients in whom the use of substances with similar effects, such as acetylsalicylic acid or other NSAIDs, provokes the development of attacks of bronchial asthma, bronchospasm, acute rhinitis, nasal polyps, the appearance of urticaria or angioedema;

- if photoallergic or phototoxic reactions occurred during treatment with ketoprofen or fibrates;

- history of gastrointestinal bleeding or perforation associated with NSAID therapy;

- active peptic ulcer/gastrointestinal bleeding, or history of gastrointestinal bleeding, ulcers or perforations;

- chronic dyspepsia;

- bleeding in the active phase or increased bleeding;

- Crohn's disease or nonspecific ulcerative colitis;

- severe heart failure;

- moderate or severe renal impairment (creatinine clearance ≤59 ml/min);

- severe liver dysfunction (10–15 points on the Child-Pugh scale);

- hemorrhagic diathesis and other blood clotting disorders;

- with severe dehydration (due to vomiting, diarrhea or insufficient fluid intake);

- III trimester of pregnancy and breastfeeding period;

Due to the ethanol content of the medicinal product, Dexpro 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/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 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 supervision of a physician and with careful monitoring of 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 medical supervision and with careful monitoring of relevant laboratory parameters;

- corticosteroids: the risk of developing ulcers in the digestive tract or gastrointestinal bleeding increases;

- 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, when starting dexketoprofen, 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 increase in the toxicity of these substances.

- diuretics, angiotensin-converting enzyme (ACE) inhibitors, antibacterial aminoglycosides and angiotensin II receptor antagonists. Dexketoprofen reduces the effectiveness of diuretics and other antihypertensive agents. In some patients with impaired renal function (for example, in cases of dehydration or in the elderly), the use of cyclooxygenase inhibitors simultaneously with ACE inhibitors, angiotensin II receptor antagonists or antibacterial aminoglycosides may worsen renal function, which is usually reversible. When using dexketoprofen together with any diuretic, it is necessary to ensure that the patient is not dehydrated, and at the beginning of treatment it is necessary to monitor renal function;

- methotrexate in low doses (less than 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 in general is increased. In the first weeks of simultaneous use, it is necessary to conduct a blood test every week. Even with a slight impairment of renal function, as well as in elderly patients, treatment should be carried out under strict medical supervision;

- pentoxifylline: there is a risk of bleeding. It is necessary to increase monitoring and check the bleeding time more often;

- zidovudine: there is a risk of increased toxicity to erythrocytes due to the effect on reticulocytes, which leads to severe anemia after the 1st week of NSAID use. Within 1-2 weeks after starting NSAID use, a blood test should be performed and the reticulocyte count checked;

- sulfonylurea drugs: NSAIDs can enhance the hypoglycemic effect of these drugs by displacing sulfonylurea drugs in their binding to blood plasma proteins.

Possible interactions should be considered when using the following agents:

- beta-blockers: NSAIDs can weaken their antihypertensive effect by inhibiting prostaglandin synthesis;

- cyclosporine and tacrolimus: possible increase in nephrotoxicity due to the effect of NSAIDs on renal prostaglandins. In combination therapy, renal function should be monitored;

- thrombolytic agents: increased risk of bleeding;

- antiplatelet agents and selective serotonin reuptake inhibitors: increased risk of gastrointestinal bleeding;

- probenecid: an increase in the concentration of dexketoprofen in the blood plasma is possible, which is probably due to inhibition of renal tubular secretion and conjugation of the drug with glucuronic acid and requires correction of the dose of dexketoprofen;

- cardiac glycosides: NSAIDs can increase the concentration of glycosides in 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 medical abortion;

- quinoline antibiotics: results of animal studies have shown that the use of quinolone derivatives in high doses in combination with NSAIDs increases the risk of seizures;

- tenofovir: when used together with NSAIDs, the concentration of urea nitrogen and creatinine in the blood plasma may increase, therefore, to assess the possible effect of the combined use of these drugs, it is necessary to monitor renal function;

- deferasirox: when used together with NSAIDs, the risk of gastrointestinal toxicity may increase. When using this medicinal product together with deferasirox, careful patient monitoring is necessary;

- pemetrexed: Pemetrexed excretion may be reduced when used concomitantly with NSAIDs, therefore special caution should be exercised when using NSAIDs at high doses. Patients with mild to moderate renal impairment (creatinine clearance 45 to 79 ml/min) should avoid NSAIDs for two days before and two days after taking pemetrexed.

Application features

Use with caution in patients with a history of allergic conditions. Avoid using Dexpro 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.

Gastrointestinal 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 at the lowest possible dose. As with all NSAIDs, patients with a history of esophagitis, gastritis and/or peptic ulcer disease should be assured that these diseases are in remission. Patients with existing symptoms of gastrointestinal pathology and a history of gastrointestinal disease should be monitored for possible disturbances during treatment with the drug, especially gastrointestinal bleeding. 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. For such patients and patients taking low-dose acetylsalicylic acid or other agents that increase the risk of gastrointestinal adverse reactions, combination therapy with protective drugs, such as misoprostol or proton pump inhibitors, should be considered.

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

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

Kidney safety

Patients with impaired renal function should be prescribed the drug with caution, since against the background of the use of NSAIDs, deterioration of 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 in treatment with diuretics, as well as in those 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 other 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 safety

Patients with impaired liver function should be prescribed the drug with caution. Similar to other NSAIDs, Dexpro 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 and 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 heparins, should be under close medical supervision. The greatest number of cardiovascular system dysfunctions occurs in elderly patients.

Skin reactions

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

Masking the symptoms of underlying infections

Dexpro may mask the symptoms of infections, which may prevent diagnosis and timely treatment and, thereby, worsen the consequences of the infection. Such cases have been observed with bacterial pneumonia and bacterial complications of varicella. When Dexpro is administered for the relief of pain associated with an infectious process, monitoring of the infectious process is recommended. In outpatient settings, the patient should consult a doctor if symptoms persist or worsen.

Other information

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

- with hereditary disorders of porphyrin metabolism (for example, with 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 Dexpro, treatment should be discontinued. Depending on the symptoms, any necessary treatment in such cases should be carried out under medical supervision.

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 administration of this medicinal product may cause asthma attacks or bronchospasm, especially in patients with allergy to acetylsalicylic acid or NSAIDs.

Severe skin and soft tissue infections may develop in association with chickenpox. To date, there is no evidence to rule out the role of NSAIDs in exacerbating this infectious process. Therefore, Dexpro is not recommended for use in chickenpox.

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

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

This medicinal product contains up to 200 mg of alcohol (ethanol) in each 2 ml ampoule (3 mg/kg/dose (10% w/v)), equivalent to 5 ml of beer or 2 ml of wine. The small amount of alcohol contained in this medicinal product will not have a noticeable effect.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.

Use during pregnancy or breastfeeding

The use of the drug Dexpro is contraindicated in the third trimester of pregnancy and during breastfeeding.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or foetal development. Epidemiological studies have shown that the use of medicinal products that inhibit prostaglandin synthesis in early pregnancy increases the risk of miscarriage, foetal heart defects and anterior abdominal wall non-union. Thus, the absolute risk of cardiovascular malformations increased from < 1% to approximately 1.5%. It is believed that the risk of such events increases with increasing dose and duration of therapy. The use of prostaglandin synthesis inhibitors in animals has 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, an increased incidence of foetal malformations, including cardiovascular malformations, has been observed. However, animal studies of dexketoprofen trometamol have not revealed reproductive toxicity. The use of dexketoprofen from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This may occur shortly after the start of treatment and is usually reversible after discontinuation of the drug. In addition, cases of narrowing of the ductus arteriosus in the fetus have been reported after taking the drug in the second trimester of pregnancy, most of which resolved after discontinuation of treatment. Therefore, dexketoprofen trometamol should be prescribed in the first and second trimesters of pregnancy only if clearly needed. When dexketoprofen trometamol is prescribed to women planning a pregnancy or in the first and second trimesters of pregnancy, the lowest possible effective dose should be used for the shortest possible duration of treatment. Antenatal monitoring for oligohydramnios should be considered after exposure to dexketoprofen for several days, starting from the 20th week of pregnancy. Pregnant women should discontinue dexketoprofen if oligohydramnios is detected.

During the third trimester, all prostaglandin synthesis inhibitors cause:

risks to the fetus:

- cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);

- impaired kidney function (see above);

Risks for mother and baby at the end of pregnancy:

- prolongation of bleeding time (effect of inhibiting platelet aggregation), which is possible even when using low doses;

- delayed uterine contractions with corresponding delayed labor and prolonged labor.

Breast-feeding

There is no data on the penetration of dexketoprofen into breast milk. The drug Dexpro 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.

Ability to influence reaction speed when driving vehicles or other mechanisms

While using Dexpro, dizziness, visual disturbances or drowsiness may occur. 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

To minimize adverse reactions, the lowest effective dose should be used for the shortest period of time (see section "Special warnings and precautions for use").

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. Dexpro 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. 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 physiologically decreased renal function, a lower dose of the drug is recommended, namely, the maximum daily dose is 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. In severe liver disease (Child-Pugh score 10-15), the drug is contraindicated.

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 medicine should not be used in children and adolescents due to a lack of data on its efficacy and safety.

Method of application

Intramuscular administration. The contents of one ampoule (2 ml) should be slowly injected deep into the muscle.

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 administered intravenously slowly over 10–30 minutes.

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

Intravenous injection (bolus administration).

If necessary, the contents of one ampoule (2 ml of solution for injection) should be administered intravenously slowly 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.

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

Diluted infusion solutions should not be mixed with promethazine or pentazocine.

The medicine 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 solutions of the drug 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.

Dexpro is intended for single use, therefore any remaining solution should be discarded. Before administration, visually inspect the solution for clarity and colorlessness. Do not use a solution containing particulate matter.

Children

The medicine should not be used in children and adolescents due to a 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 following table lists the adverse reactions by organ system and frequency:

Gastrointestinal disorders were observed most frequently.

Ulcers, perforations or gastrointestinal bleeding, sometimes fatal, may occur, especially in the elderly. According to available data, nausea may occur during the use of the drug,