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

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

Composition

active ingredient: dexketoprofen trometamol;

1 ml of solution contains dexketoprofen trometamol equivalent to dexketoprofen 25 mg (1 ampoule of 2 ml contains dexketoprofen trometamol equivalent to dexketoprofen 50 mg);

Excipients: ethanol 96%, sodium chloride, sodium hydroxide and/or diluted hydrochloric acid, water for injections.

Dosage form

Solution for injection.

Main physicochemical properties: transparent colorless solution, free from insoluble solids and foreign particles.

Pharmacotherapeutic group

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

Pharmacological properties

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 into 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 in 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 Depiofen allows for a significant reduction in the dose of opiates when 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, 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 not appropriate, 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 in the medicinal product, Depiofen, solution for injection, 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 inhibition of platelet function and damage to the gastric and duodenal mucosa. If concomitant use is necessary, it should be carried out under close medical supervision with 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 the supervision of a physician and with careful monitoring of relevant laboratory parameters;

Corticosteroids: increased risk of developing ulcers in the digestive tract or gastrointestinal 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, 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 increased 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 (e.g., in cases of dehydration or in the elderly), the use of cyclooxygenase inhibitors with ACE inhibitors or angiotensin II receptor antagonists or antibacterial aminoglycosides may worsen renal function, which is usually reversible. When using dexketoprofen 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;

Sulfonylureas: NSAIDs can enhance the hypoglycemic effect of these agents by displacing sulfonylureas from their plasma protein binding.

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. Renal function should be monitored during combination therapy;

thrombolytic agents: increased risk of bleeding;

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding;

Probenecid: possible increase in dexketoprofen plasma concentration, which is probably 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 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: 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: 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 reduce the elimination of pemetrexed, therefore caution should be exercised when using high doses of NSAIDs. 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 Depiofen 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 sure that these diseases are in remission. Patients with existing symptoms of gastrointestinal pathology and a history of gastrointestinal diseases should be monitored for possible disorders during the use of the drug, especially gastrointestinal bleeding. NSAIDs should be prescribed with caution to patients with a history of gastrointestinal diseases (ulcerative colitis, Crohn's disease), since 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 agents, 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 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 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. 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

Patients with arterial hypertension and/or mild to moderate heart failure require monitoring and advice. Particular caution should be exercised when treating patients with a history of heart disease, in particular with previous episodes of heart failure (the risk of heart failure increases with the use of the drug), since fluid retention in the tissues and the formation of edema have been observed during treatment with NSAIDs. Clinical studies and epidemiological data suggest that the risk of arterial thrombosis (for example, myocardial infarction or stroke) may be slightly increased with the use of some NSAIDs (especially in high doses and for long periods). There is insufficient data to exclude such a risk with the use of dexketoprofen. Therefore, in case of uncontrolled arterial hypertension, congestive heart failure, ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease, dexketoprofen should be prescribed only after careful assessment of the patient's condition. Equally careful assessment should be performed before initiating long-term treatment in patients with risk factors for cardiovascular disease (such as hypertension, hyperlipidemia, diabetes mellitus, smoking).

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.

Very rare cases of serious skin reactions (some fatal) have been reported 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. Depiofen 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 Depiofen, 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 administration 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 the exacerbation of this infectious process. Therefore, Depiofen is not recommended for use in chickenpox.

Depiofen 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.

Each ampoule of Depiofen contains 12.35 vol.% ethanol, i.e. up to 200 mg per dose, which is equivalent to 5 ml of beer or 2.08 glasses 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 used by 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 free of free sodium.

Masking of symptoms of underlying infections: the drug may mask the symptoms of an infectious disease, which may delay the initiation of appropriate treatment and thereby complicate the course of the disease. This has been observed in bacterial community-acquired pneumonia and bacterial complications of varicella. When the drug is used for fever or to relieve pain in an infection, monitoring of the infectious disease is recommended. In the context of treatment outside a medical institution, the patient should consult a doctor if symptoms persist or worsen.

Use during pregnancy or breastfeeding

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

Pregnancy

From the 20th week of pregnancy onwards, the use of dexketoprofen may cause oligohydramnios due to fetal renal dysfunction. This may occur shortly after initiation of treatment and is usually reversible after discontinuation of treatment. During the first and second trimesters of pregnancy, dexketoprofen should not be administered unless clearly necessary. If dexketoprofen is used by women attempting to conceive or during the first and second trimesters of pregnancy, the dose should be kept as low and the duration of treatment as short as possible. Antenatal monitoring for oligohydramnios should be considered after exposure to dexketoprofen for several days from the 20th week of pregnancy onwards. Dexketoprofen should be discontinued if oligohydramnios is detected.

During the third trimester, all prostaglandin synthesis inhibitors pose risks to the fetus:

cardiopulmonary toxic syndrome (with obstruction of the ductus arteriosus and pulmonary hypertension);

renal dysfunction, which may progress to renal failure with the development of oligohydramnios (see above).

Risk to 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.

Therefore, dexketoprofen is contraindicated during the third trimester of pregnancy (see section "Contraindications").

Breast-feeding

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

The ability to influence the reaction speed when driving or working with other mechanisms

Dizziness, visual disturbances or drowsiness may occur while using Depiofen. 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 when 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 physiologically decreased renal function, a lower dose 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 drug should not be used in children and adolescents due to 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.

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 intravenously slowly over 10-30 minutes.

Depiofen, 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.

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.

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

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

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.

Depiofen 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.

The lowest effective dose should be used for the shortest time necessary to relieve symptoms (see section "Special instructions").

Children

The drug 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.

Side effects

The table below lists, by organ system and frequency, adverse reactions considered at least possibly related to dexketoprofen trometamol in clinical trials, as well as adverse reactions reported after the drug was marketed.

Gastrointestinal disorders were observed most frequently.

Ulcers, perforations, or gastrointestinal bleeding, sometimes fatal, may occur, especially in the elderly. According to available data, while taking the drug