Dexalgin® inject

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEXALGIN® INJECT (DEXALGIN® INJECT)

Composition:

Active substance: dexketoprofen trometamol;

1 ml of solution for injection/infusion contains 36.9 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: ethanol 96%, sodium chloride, sodium hydroxide, water for injections.

Pharmaceutical form. Solution for injection/infusion.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Propionic acid derivatives. Dexketoprofen. ATC code M01AE17.

Pharmacological Properties

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

Mechanism of Action

The mechanism of action of NSAIDs is based on reducing the synthesis of prostaglandins by inhibiting cyclooxygenase activity. Specifically, the conversion of arachidonic acid into cyclic endoperoxides PGG2 and PGH2 is inhibited, from which prostaglandins PGE1, PGE2, PGF2α, PGD2, as well as prostacyclin PGI2 and thromboxanes TxА2 and TxВ2 are formed. In addition, inhibition of prostaglandin synthesis may affect other mediators of inflammation such as kinins, which may also indirectly influence the primary drug effect.

Pharmacodynamics

Inhibitory effects of dexketoprofen trometamol on the activity of cyclooxygenase-1 and cyclooxygenase-2 have been demonstrated in laboratory animals and in humans.

Clinical Efficacy and Safety

Clinical studies in various types of pain have demonstrated that dexketoprofen trometamol exerts a pronounced analgesic effect. The analgesic effect of dexketoprofen trometamol after intramuscular and intravenous administration in patients with moderate to severe pain intensity has been studied in various surgical procedures (orthopedic and gynecological surgeries, abdominal operations), as well as in musculoskeletal pain (acute low back pain) and renal colic. In these studies, the analgesic effect of the drug began rapidly and reached its maximum within the first 45 minutes. The duration of analgesic action after administration of 50 mg of dexketoprofen trometamol is typically 8 hours. Clinical studies have shown that using Dexalgine® inject allows a significant reduction in opioid dosage when used concomitantly to manage postoperative pain. When patients receiving morphine via a patient-controlled analgesia device for postoperative pain relief were also administered dexketoprofen trometamol, they required significantly less morphine (by 30–45%) compared to patients receiving placebo.

Pharmacokinetics

Absorption

After intramuscular administration of dexketoprofen trometamol in humans, maximum concentration is reached approximately within 20 minutes (10–45 minutes). It has been demonstrated that after 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 plasma protein binding (99%), the volume of distribution of dexketoprofen averages 0.25 L/kg. The distribution half-life is approximately 0.35 hours, and the elimination half-life is 1–2.7 hours.

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

Biotransformation and Elimination

The metabolism of dexketoprofen occurs mainly via conjugation with glucuronic acid followed by renal excretion. After administration of dexketoprofen trometamol, only the S-(+) optical isomer is detected in urine, indicating the absence of transformation of the drug into the R-(-) optical isomer in humans.

Elderly Patients

After administration of single and multiple doses, the extent of drug exposure in elderly healthy volunteers (aged 65 years and older) participating in the study was significantly higher (up to 55%) compared to younger volunteers; however, no statistically significant differences in maximum concentration or time to reach it were observed. The mean elimination half-life was prolonged (by up to 48%), and the total systemic clearance was reduced.

Preclinical Safety Data

Standard preclinical studies—pharmacological safety, genotoxicity, and immunopharmacology—did not reveal any special hazard for humans. Chronic toxicity studies in animals identified the no-observed-adverse-effect level (NOAEL), which was 2 times higher than the recommended human dose. When higher doses were administered to monkeys, the main adverse reactions included fecal blood, reduced body weight gain, and at the highest dose, gastrointestinal lesions such as erosions. These reactions occurred at doses where drug exposure was 14–18 times higher than at the maximum recommended human dose. Carcinogenicity studies in animals have not been conducted.

Like all NSAIDs, dexketoprofen may lead to embryonic or fetal death in animals, either directly by affecting development or indirectly via maternal gastrointestinal tract injury.

Clinical characteristics.

Indications.

Symptomatic treatment of moderate to severe acute pain when oral administration of the drug is inappropriate, for example, in postoperative pain, renal colic, and low back pain.

Contraindications.

• Hypersensitivity to dexketoprofen, to any other nonsteroidal anti-inflammatory drug (NSAID), or to excipients of the drug;
• patients in whom administration of substances with similar action, such as acetylsalicylic acid or other NSAIDs, triggers attacks of bronchial asthma, bronchospasm, acute rhinitis, nasal polyps, urticaria, or angioedema;
• if photoallergic or phototoxic reactions occurred during treatment with ketoprofen or fibrates;
• gastrointestinal bleeding or perforation in medical history associated with NSAID therapy;
• active peptic ulcer/gastrointestinal bleeding, or history of gastrointestinal bleeding, ulcers, or perforations;
• chronic dyspepsia;
• active bleeding or increased bleeding tendency;
• Crohn’s disease or ulcerative colitis;
• severe heart failure;
• moderate to severe renal impairment (creatinine clearance ≤59 mL/min);
• severe hepatic impairment (10–15 points on the Child-Pugh scale);
• hemorrhagic diathesis and other coagulation disorders;
• in cases of severe dehydration (due to vomiting, diarrhea, or insufficient fluid intake);
• third trimester of pregnancy and breastfeeding period;

Due to the ethanol content in the medicinal product, Dexalgyn® inject is contraindicated for neuroaxial (intrathecal or epidural) administration.

Interaction with other medicinal products and other types of interactions.

Concomitant use of the following agents with NSAIDs is not recommended:

• other NSAIDs (including selective cyclooxygenase-2 inhibitors), including salicylates in high doses (≥ 3 g/day). Concurrent use of multiple NSAIDs increases the risk of gastrointestinal ulceration and gastrointestinal bleeding due to their mutually enhancing effects;
• anticoagulants: NSAIDs enhance the effect of anticoagulants, such as warfarin, due to high plasma protein binding of dexketoprofen, 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 performed under physician supervision 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 performed under physician supervision with careful monitoring of relevant laboratory parameters;
• corticosteroids: increased risk of gastrointestinal ulceration or gastrointestinal bleeding;
• lithium (reports exist for several NSAIDs): NSAIDs increase lithium blood levels, potentially leading to toxicity (reduced renal excretion of lithium). Therefore, lithium blood levels should be monitored at the start of dexketoprofen therapy, during dose adjustment, or upon discontinuation of the drug;
• high-dose methotrexate (≥ 15 mg per week): due to reduced renal clearance of methotrexate under NSAID therapy, its overall hematological toxicity is enhanced;
• hydantoin derivatives and sulfonamides: possible increase in toxicity of these substances.

Concomitant use of the following agents with NSAIDs requires caution:

• diuretics, angiotensin-converting enzyme (ACE) inhibitors, aminoglycoside antibiotics, and angiotensin II receptor antagonists. Dexketoprofen reduces the efficacy of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., due to dehydration or in elderly patients), concomitant use of agents that inhibit cyclooxygenase with ACE inhibitors, angiotensin II receptor antagonists, or aminoglycoside antibiotics may worsen renal function, which is usually reversible. When using dexketoprofen with any diuretic, ensure the patient is not dehydrated and monitor renal function at the beginning of treatment;
• low-dose methotrexate (< 15 mg per week): due to reduced renal clearance of methotrexate under NSAID therapy, its overall hematological toxicity is enhanced. During the first weeks of concomitant use, weekly blood tests are required. Even with mild renal impairment and in elderly patients, treatment should be closely supervised by a physician;
• pentoxifylline: risk of bleeding. Monitoring should be intensified, and bleeding time should be checked more frequently;
• zidovudine: risk of increased hematotoxicity on erythrocytes due to effects on reticulocytes, leading to severe anemia after one week of NSAID use. One to two weeks after starting NSAID therapy, a blood test and reticulocyte count should be performed;
• sulfonylurea drugs: NSAIDs may enhance the hypoglycemic effect of these agents by displacing sulfonylureas from plasma protein binding sites.

Potential interactions should be considered when using the following agents:

• beta-blockers: NSAIDs may reduce their antihypertensive effect by inhibiting prostaglandin synthesis;
• cyclosporine and tacrolimus: possible increase in nephrotoxicity due to NSAID effects 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, likely due to inhibition of renal tubular secretion and glucuronide conjugation of the drug, requiring dose adjustment of dexketoprofen;
• cardiac glycosides: NSAIDs may increase glycoside plasma concentrations;
• mifepristone: theoretically, there is a risk of altered mifepristone efficacy under the influence of prostaglandin synthetase inhibitors. Limited data suggest that concomitant administration of NSAIDs on the same day as prostaglandin does not adversely affect mifepristone or prostaglandin efficacy regarding cervical ripening or contractility, nor does it reduce the clinical efficacy of medical abortion agents;
• quinolone antibiotics: animal studies have shown that high-dose quinolone derivatives in combination with NSAIDs increase the risk of seizures;
• tenofovir: concomitant use with NSAIDs may increase plasma concentrations of blood urea nitrogen and creatinine; therefore, renal function should be monitored to assess potential effects of concomitant use;
• deferasirox: concomitant use with NSAIDs may increase the risk of gastrointestinal toxicity. Careful patient monitoring is required when using this medicinal product together with deferasirox;
• pemetrexed: concomitant use with NSAIDs may reduce pemetrexed elimination; therefore, particular caution is required when using NSAIDs at high doses. In patients with mild to moderate renal impairment (creatinine clearance 45–79 mL/min), NSAID use should be avoided for two days before and two days after pemetrexed administration.

Special precautions for use.

Use with caution in patients with a history of allergic conditions. Avoid using Dexalgin® inject in combination with other NSAIDs, including selective cyclooxygenase-2 inhibitors. Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to relieve symptoms.

Gastrointestinal safety

Gastrointestinal bleeding, ulceration, or perforation, sometimes fatal, have been reported with all NSAIDs at any time during therapy, regardless of the presence of prior gastrointestinal symptoms or a history of serious gastrointestinal disorders. If gastrointestinal bleeding or ulceration occurs, the drug should be discontinued. The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, in patients with a history of peptic ulcer, particularly if complicated by bleeding or perforation, and in elderly patients.

Elderly patients: Elderly patients have an increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, sometimes fatal. Treatment of these patients should be initiated with the lowest possible dose. As with all NSAIDs, patients with a history of esophagitis, gastritis, and/or peptic ulcer should be ensured to have these conditions in remission. Patients with existing gastrointestinal symptoms or a history of gastrointestinal disorders should be monitored during treatment for possible complications, particularly gastrointestinal bleeding. NSAIDs should be used with caution in patients with a history of gastrointestinal disorders (ulcerative colitis, Crohn’s disease), as there is a risk of exacerbation. For such patients and those taking low-dose acetylsalicylic acid or other agents increasing the risk of gastrointestinal adverse reactions, consider combination therapy with protective agents, such as misoprostol or proton pump inhibitors.

Patients, especially elderly ones, with a history of gastrointestinal adverse reactions, should inform their physician about any unusual gastrointestinal symptoms, including gastrointestinal bleeding, particularly during the initial stages of treatment.

Use with caution in patients concurrently 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 like acetylsalicylic acid.

Renal safety

The medicinal product should be administered with caution to patients with impaired renal function, as NSAIDs may worsen renal function, cause fluid retention, and edema. Due to the increased risk of nephrotoxicity, the drug should be used cautiously in patients receiving diuretics or those at risk of hypovolemia. During treatment, adequate fluid intake should be maintained to prevent dehydration, which may exacerbate renal toxicity. Like other NSAIDs, the drug may increase plasma urea nitrogen and creatinine levels. Similar to other prostaglandin synthesis inhibitors, its use may be associated with renal adverse reactions leading to glomerulonephritis, interstitial nephritis, papillary necrosis, nephrotic syndrome, and acute renal failure. Renal function disturbances occur most frequently in elderly patients.

Hepatic safety

The medicinal product should be administered with caution to patients with impaired liver function. Similar to other NSAIDs, the drug may cause transient and mild elevations in certain liver parameters, as well as marked increases in AST and ALT activity. If such elevations occur, therapy should be discontinued.

Hepatic function disturbances occur most frequently in elderly patients.

Cardiovascular and cerebrovascular safety

Patients with arterial hypertension and/or mild to moderate heart failure require monitoring and medical advice. Particular caution is required when treating patients with a history of heart disease, especially those with prior episodes of heart failure (the risk of heart failure development increases with drug use), as fluid retention and edema may occur during NSAID therapy. Clinical studies and epidemiological data suggest that the use of certain NSAIDs (especially at high doses and for prolonged periods) may slightly increase the risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Data to exclude such risks with dexketoprofen use are insufficient. Therefore, in cases of uncontrolled arterial hypertension, congestive heart failure, ischemic heart disease, peripheral artery disease, and/or cerebrovascular disease, dexketoprofen should be prescribed only after careful patient assessment. Similarly careful evaluation should be performed before initiating long-term treatment in patients with cardiovascular risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking).

Non-selective NSAIDs can reduce platelet aggregation and prolong bleeding time by inhibiting prostaglandin synthesis. The concomitant use of dexketoprofen trometamol and low-molecular-weight heparin at prophylactic doses in the postoperative period has been studied in clinical trials, with no effect on coagulation parameters observed. However, patients taking dexketoprofen trometamol concurrently with agents affecting hemostasis, such as warfarin, other coumarin derivatives, or heparins, should be closely monitored by a physician. Cardiovascular function disturbances occur most frequently in elderly patients.

Skin reactions

There have been reports of very rare cases of serious skin reactions (some fatal) associated with NSAID use, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The highest risk likely occurs early in treatment, with most cases appearing within the first month of therapy. If skin rashes, signs of mucosal involvement, or other hypersensitivity symptoms occur, Dexalgin® inject should be discontinued.

Masking symptoms of underlying infections

Dexalgin® inject may mask symptoms of infections, potentially interfering with diagnosis and timely treatment, thereby worsening infection outcomes. Such cases have been observed in bacterial pneumonia and bacterial complications of varicella. When Dexalgin® inject is administered to relieve pain associated with an infectious process, monitoring of the infection is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Other information

Particular caution should be exercised when prescribing the medicinal product to patients:

• with hereditary porphyrin metabolism disorders (e.g., acute intermittent porphyria);
• with dehydration;
• immediately after major surgical procedures.

If prolonged use of dexketoprofen is deemed necessary by the physician, liver and kidney function should be monitored regularly.

In very rare cases, severe acute hypersensitivity reactions (e.g., anaphylactic shock) have been observed. If early signs of severe hypersensitivity reactions occur after administration of Dexalgin® inject, treatment should be discontinued. Depending on symptoms, any necessary treatment should be administered under medical supervision.

Patients suffering from asthma in combination with chronic rhinitis, chronic sinusitis, and/or nasal polyps are at higher risk of allergy to acetylsalicylic acid and/or NSAIDs compared to other patients. Administration of this drug may trigger asthma attacks or bronchospasm, particularly in patients allergic to acetylsalicylic acid or NSAIDs.

Severe infectious complications involving skin and soft tissues may occur during varicella. Data to exclude a role of NSAIDs in exacerbating this infectious process are lacking. Therefore, Dexalgin® inject is not recommended during varicella.

Dexalgin® inject should be administered with caution to patients with coagulation disorders, systemic lupus erythematosus, and mixed connective tissue diseases.

Like other NSAIDs, dexketoprofen trometamol may mask symptoms of infectious diseases during its use. In some cases, activation of infections localized in soft tissues has been reported during NSAID use. Therefore, if symptoms of bacterial infection appear or worsen during treatment, patients are advised to seek immediate medical attention.

This medicinal product contains up to 200 mg of alcohol (ethanol) per 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.

The medicinal product contains less than 1 mmol of sodium (23 mg) per dose and is therefore practically sodium-free.

Use during pregnancy or breastfeeding.

The use of Dexalgin® inject is contraindicated in the third trimester of pregnancy and during breastfeeding.

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or fetal development. According to epidemiological studies, the use of drugs that inhibit prostaglandin synthesis during early pregnancy increases the risk of miscarriage, congenital heart defects, and gastroschisis. The absolute risk of cardiovascular malformations increases from <1% to approximately 1.5%. It is believed that the risk of such events increases with higher drug doses and longer duration of therapy. In animal studies, prostaglandin synthesis inhibitors have caused increased pre- and post-implantation losses and elevated embryofetal mortality. Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, increased incidence of fetal developmental abnormalities, including cardiovascular anomalies, has been observed. However, animal studies with dexketoprofen trometamol did not reveal reproductive toxicity. Use of dexketoprofen from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation of the drug. Additionally, cases of fetal ductus arteriosus constriction have been reported after maternal use of the drug in the second trimester, most of which resolved after discontinuation of treatment. Therefore, dexketoprofen trometamol may be prescribed during the first and second trimesters only if absolutely necessary. When prescribing dexketoprofen trometamol to women planning pregnancy or during the first and second trimesters of pregnancy, the lowest effective dose should be used for the shortest possible duration. Prenatal monitoring for oligohydramnios and fetal ductus arteriosus constriction should be considered if exposure to dexketoprofen occurs for several days starting from the 20th gestational week. Pregnant women should discontinue dexketoprofen if oligohydramnios or fetal ductus arteriosus constriction is detected.

During the third trimester, all prostaglandin synthesis inhibitors cause:

Risks to the fetus:

• cardiopulmonary toxic syndrome (constriction/occlusion of the ductus arteriosus and pulmonary hypertension);
• impaired renal function (see above);

Risks to the mother and newborn at the end of pregnancy:

• prolonged bleeding time (due to inhibition of platelet aggregation), which may occur even with low-dose use;
• delayed uterine contractions, leading to prolonged labor.

Breastfeeding

There are no data on the passage of dexketoprofen into breast milk. Dexalgin® inject is contraindicated during breastfeeding.

Fertility

Like all other NSAIDs, dexketoprofen trometamol may reduce female fertility and therefore is not recommended for women planning pregnancy. Women experiencing fertility problems or undergoing infertility investigations should consider discontinuing the drug.

Ability to affect reaction speed when driving or operating machinery.

Dizziness, visual disturbances, or somnolence may occur during treatment with Dexalgin® inject. In such cases, the ability to react quickly, orient in traffic situations, and drive or operate machinery may be impaired.

Method of Administration and Dosage

To minimize adverse reactions, the lowest effective dose for the shortest duration should be used (see section "Special Warnings and Precautions for Use").

Adults. The recommended dose is 50 mg every 8–12 hours. If necessary, the dose may be repeated after 6 hours. The maximum daily dose should not exceed 150 mg. Dexalgin® inject is intended for short-term use and should only be administered during episodes of acute pain (no longer than 2 days). Patients should be switched to oral analgesics as soon as possible, if feasible. For moderate to severe postoperative pain, the drug may be used as indicated at the same recommended doses in combination with opioid analgesics.

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

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

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

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

Method of Administration

Intramuscular injection. The contents of one ampoule (2 mL) should be administered slowly by deep intramuscular injection.

Intravenous infusion.

For intravenous infusion, the contents of one 2 mL ampoule should be diluted in 30–100 mL of 0.9% sodium chloride solution, glucose solution, or Ringer’s lactate solution. The infusion solution should be prepared under aseptic conditions, avoiding exposure to natural daylight. The prepared solution must be clear and transparent. The infusion should be administered intravenously over 10–30 minutes at a slow rate.

Dexalgin® inject diluted in 100 mL of 0.9% sodium chloride solution or glucose solution may be mixed with dopamine, heparin, hydroxyzine, lidocaine, morphine, pethidine, and theophylline.

Intravenous bolus injection.

If necessary, the contents of one ampoule (2 mL of injection solution) may be administered intravenously as a slow bolus over at least 15 seconds. The drug may be mixed in small volumes (e.g., in a syringe) with injection solutions of heparin, lidocaine, morphine, and theophylline.

Dexalgin® inject must not be mixed in small volumes (e.g., in a syringe) with dopamine, promethazine, pentazocine, pethidine, or hydroxyzine solutions, as precipitation may occur.

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

The drug should only be mixed with medicinal products listed above.

When administered intramuscularly or as an intravenous bolus, the drug should be administered immediately after being drawn from the ampoule.

No changes in active substance concentration due to adsorption have been observed during storage of diluted solutions in polyethylene bags or in administration devices made of ethylene-vinyl acetate, cellulose propionate, low-density polyethylene, or polyvinyl chloride.

Dexalgin® inject is intended for single use only; any unused portion of the prepared solution must be discarded. Prior to administration, the solution should be visually inspected to ensure it is clear and colorless. The solution must not be used if it contains particulate matter.

Children.

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

Overdose.

Symptoms of overdose are unknown. Similar medicinal products may cause gastrointestinal disturbances (vomiting, anorexia, abdominal pain) and nervous system effects (drowsiness, dizziness, disorientation, headache). In case of accidental overdose, symptomatic treatment appropriate to the patient's condition should be initiated immediately. Dexketoprofen trometamol is eliminated from the body by dialysis.

Adverse reactions.

The table below lists adverse reactions distributed by organ systems and frequency of occurrence, which are considered at least possible in relation to dexketoprofen trometamol based on clinical trial data, as well as adverse reactions reported after the drug Dexalgine® Inject was marketed.

Organs and organ systems	Common (≥1/100 – 1/10)		Occasional (≥ 1/1000 – <1/100)		Rare (≥ 1/10000 – < 1/1000)		Very rare (< 1/10000)
Blood and lymphatic system disorders	_		Anemia		_		Neutropenia, thrombocytopenia
Immune system disorders	_		_		Laryngeal edema		Anaphylactic reactions, including anaphylactic shock
Nutritional and metabolic disorders	_		_		Hypoglycemia, hyperglycemia, hypertriglyceridemia, anorexia, loss of appetite		_
Psychiatric disorders	_			Insomnia, restlessness	_		_
Nervous system disorders	_			Headache, dizziness, somnolence	Paraesthesia, loss of consciousness		_
Eye disorders	_			Blurred vision	_		_
Ear and labyrinth disorders	_			Vertigo	Tinnitus		_
Cardiac disorders	_	Palpitations			Extrasystoles, tachycardia		_
Vascular disorders	_	Arterial hypotension, flushing			Arterial hypertension, thrombophlebitis of superficial veins		_
Respiratory, thoracic and mediastinal disorders	_	_			Bradypnea		Bronchospasm, dyspnea
Gastrointestinal disorders	Nausea, vomiting	Abdominal pain, dyspepsia, diarrhea, constipation, vomiting with blood, dry mouth			Peptic ulcer, bleeding or perforation		Pancreatitis
Hepatobiliary disorders	_	_			Hepatocellular pathology		_
Skin and subcutaneous tissue disorders	_	Dermatitis, pruritus, rash, increased sweating			Urticaria, acne		Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), angioneurotic edema, facial swelling, photosensitization
Musculoskeletal and connective tissue disorders	_	_			Muscle rigidity, joint stiffness, muscle cramps, back pain		_
Renal and urinary disorders	_	_				Acute renal failure, polyuria, renal pain, ketonuria, proteinuria	Nephritis, nephrotic syndrome
Reproductive system disorders	_	_				Menstrual disorders, prostate gland dysfunction	_
General and administration site conditions	Pain at injection site, injection site reactions including inflammation, hematoma, bleeding	Chills, increased fatigue, pain, chills, asthenia, malaise				Tremor, peripheral edema	_
Investigations	_	_				Abnormal liver function tests	_

Gastrointestinal disorders were observed most frequently.

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

According to results of clinical studies and epidemiological data, the use of certain NSAIDs, particularly at high doses and over prolonged periods, may be associated with a small increased risk of arterial thrombotic events such as myocardial infarction and stroke.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product.

Healthcare professionals should report any suspected adverse reactions through the national reporting system.

Shelf life.

5 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

Store in a place protected from light, in the original packaging. After dilution, the solution should be stored for up to 24 hours at a temperature of 2 to 8°C. Keep out of the reach of children.

Incompatibility.

Dexalgin® Inject must not be mixed in small volumes (e.g., in a syringe) with solutions of dopamine, promethazine, pentazocine, meperidine, or hydroxyzine, as precipitation may occur.

Diluted infusion solutions prepared as described in the section "Dosage and administration" must not be mixed with promethazine or pentazocine.

Packaging.

2 ml amber glass ampoule; 1 ampoule in a blister pack, 1 blister pack in a cardboard box; or 5 ampoules in a blister pack, 1 blister pack in a cardboard box; or 5 ampoules in a blister pack, 2 blister packs in a cardboard box.

Prescription status. Prescription only.

Manufacturer: Alfasigma S.p.A.

Manufacturer's address.

Via Enrico Fermi, 1 - 65020 Alanno (PE), Italy.

Marketing Authorization Holder:

Menarini International Operations Luxembourg S.A.

Address of the Marketing Authorization Holder and/or its representative.

1, Avenue de la Gare, L-1611 Luxembourg.

INSTRUCTION

for medical use of the medicinal product

DEXALGIN® INJECT

(DEXALGIN® INJECT)

Composition:

Active ingredient: dexketoprofen trometamol;

1 ml of solution for injection/infusion contains 36.9 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: ethanol 96%, sodium chloride, sodium hydroxide, water for injections.

Pharmaceutical form. Solution for injection/infusion.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic drugs. Propionic acid derivatives. Dexketoprofen. ATC code M01A E17.

Pharmacological Properties

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

Mechanism of Action

The mechanism of action of NSAIDs is based on reducing the synthesis of prostaglandins by inhibiting cyclooxygenase activity. Specifically, the conversion of arachidonic acid into cyclic endoperoxides PGG2 and PGH2 is inhibited, from which prostaglandins PGE1, PGE2, PGF2α, PGD2, as well as prostacyclin PGI2 and thromboxanes TxА2 and TxВ2 are formed. In addition, inhibition of prostaglandin synthesis may affect other mediators of inflammation such as kinins, which may also indirectly influence the primary action of the drug.

Pharmacodynamics

Inhibitory effects of dexketoprofen trometamol on the activity of cyclooxygenase-1 and cyclooxygenase-2 have been demonstrated in laboratory animals and in humans.

Clinical Efficacy and Safety

Clinical studies in various types of pain have demonstrated that dexketoprofen trometamol exerts pronounced analgesic effects. The analgesic effect of dexketoprofen trometamol following intramuscular and intravenous administration in patients with moderate to severe pain has been studied in various pain conditions associated with surgical procedures (orthopedic and gynecological surgeries, abdominal surgeries), as well as musculoskeletal pain (acute low back pain) and renal colic. In these studies, the analgesic effect of the drug began rapidly and reached its maximum within the first 45 minutes. The duration of analgesic action after administration of 50 mg of dexketoprofen trometamol is typically 8 hours. Clinical studies have shown that using Dexalgine® inject allows a significant reduction in opioid dosage when used concomitantly to manage postoperative pain. When patients receiving morphine via a patient-controlled analgesia device for postoperative pain relief were also administered dexketoprofen trometamol, they required significantly less morphine (by 30–45%) compared to patients receiving placebo.

Pharmacokinetics

Absorption

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

Distribution

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

Pharmacokinetic studies with repeated administration of the drug demonstrated that Cmax and AUC after the last intramuscular or intravenous dose were not different from those after single administration, indicating the absence of drug accumulation.

Biotransformation and Elimination

Metabolism of dexketoprofen occurs mainly via conjugation with glucuronic acid followed by renal excretion. After administration of dexketoprofen trometamol, only the S-(+) optical isomer is detected in urine, indicating the absence of conversion of the drug into the R-(-) optical isomer in humans.

Elderly Patients

After administration of single and multiple doses, the extent of drug exposure in elderly healthy volunteers (aged 65 years and older) participating in the study was significantly higher (up to 55%) compared to younger volunteers; however, no statistically significant differences in maximum concentration or time to reach it were observed. The mean elimination half-life increased (by up to 48%), and the total clearance decreased.

Preclinical Safety Data

Standard preclinical studies—pharmacological safety, genotoxicity, and immunopharmacology—did not reveal any special hazard for humans. Chronic toxicity studies in animals identified the no-observed-adverse-effect level (NOAEL), which was 2 times higher than the dose recommended for humans. When higher doses were administered to monkeys, the main adverse reactions included fecal blood, reduced body weight gain, and, at the highest dose, gastrointestinal lesions such as erosions. These reactions occurred at doses where drug exposure was 14–18 times higher than at the maximum recommended human dose. Carcinogenicity studies in animals have not been conducted.

Like all NSAIDs, dexketoprofen may lead to embryonic or fetal death in animals, either directly by affecting development or indirectly via maternal gastrointestinal tract injury.

Clinical characteristics.

Indications.

Symptomatic treatment of moderate to severe acute pain when oral administration of the drug is inappropriate, for example, in postoperative pain, renal colic, and low back pain.

Contraindications.

• Hypersensitivity to dexketoprofen, to any other nonsteroidal anti-inflammatory drug (NSAID), or to excipients of the medicinal product;
• in patients in whom administration of substances with similar action, such as acetylsalicylic acid or other NSAIDs, triggers attacks of bronchial asthma, bronchospasm, acute rhinitis, nasal polyps, urticaria, or angioedema;
• if photoallergic or phototoxic reactions occurred during treatment with ketoprofen or fibrates;
• gastrointestinal bleeding or perforation in medical history associated with NSAID therapy;
• active peptic ulcer/gastrointestinal bleeding, or history of gastrointestinal bleeding, ulcers, or perforations;
• chronic dyspepsia;
• active bleeding or increased bleeding tendency;
• Crohn’s disease or ulcerative colitis;
• severe heart failure;
• moderate or severe renal impairment (creatinine clearance ≤59 mL/min);
• severe hepatic impairment (Child-Pugh score 10–15 points);
• hemorrhagic diathesis and other blood coagulation disorders;
• in cases of pronounced dehydration (due to vomiting, diarrhea, or insufficient fluid intake);
• third trimester of pregnancy and breastfeeding period;

Due to the ethanol content in the medicinal product, Dexalgyn® inject is contraindicated for neuroaxial (intrathecal or epidural) administration.

Interaction with other medicinal products and other types of interactions.

Concomitant use of the following agents with NSAIDs is not recommended:

• other NSAIDs (including selective cyclooxygenase-2 inhibitors), including salicylates in high doses (≥ 3 g/day). Concomitant use of multiple NSAIDs increases the risk of gastrointestinal ulceration and gastrointestinal bleeding due to their mutually enhancing effects;
• anticoagulants: NSAIDs enhance the effects of anticoagulants, such as warfarin, due to the high degree of plasma protein binding of dexketoprofen, 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 performed under physician supervision 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 performed under physician supervision with careful monitoring of relevant laboratory parameters;
• corticosteroids: increased risk of gastrointestinal ulceration or gastrointestinal bleeding;
• lithium (reports exist for several NSAIDs): NSAIDs increase blood lithium levels, potentially leading to toxicity (due to decreased renal excretion of lithium). Therefore, lithium blood levels should be monitored at the initiation of dexketoprofen therapy, during dose adjustments, or upon discontinuation;
• high-dose methotrexate (≥ 15 mg per week): due to reduced renal clearance of methotrexate in the context of NSAID use, its overall negative effect on the blood system is enhanced;
• hydantoin derivatives and sulfonamides: possible increase in toxicity of these substances.

Concomitant use of the following agents with NSAIDs requires caution:

• diuretics, angiotensin-converting enzyme (ACE) inhibitors, aminoglycoside antibiotics, and angiotensin II receptor antagonists. Dexketoprofen reduces the efficacy of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., due to dehydration or in elderly patients), concomitant use of agents that inhibit cyclooxygenase with ACE inhibitors, angiotensin II receptor antagonists, or aminoglycoside antibiotics may worsen renal function, which is usually reversible. When using dexketoprofen with any diuretic, ensure the patient is not dehydrated and monitor renal function at the start of treatment;
• low-dose methotrexate (< 15 mg per week): due to reduced renal clearance of methotrexate with NSAID use, its overall negative effect on the blood system is enhanced. During the first weeks of concomitant use, weekly blood tests are required. Even with mild renal impairment or in elderly patients, treatment should be closely supervised by a physician;
• pentoxifylline: risk of bleeding. Monitoring should be intensified, and bleeding time should be checked more frequently;
• zidovudine: risk of increased hematotoxicity on erythrocytes due to effects on reticulocytes, leading to severe anemia after one week of NSAID use. A blood test and reticulocyte count should be performed within 1–2 weeks after starting NSAID therapy;
• sulfonylurea agents: NSAIDs may enhance the hypoglycemic effect of these agents by displacing them from plasma protein binding sites.

Potential interactions should be considered when using the following agents:

• beta-blockers: NSAIDs may reduce their antihypertensive effect by inhibiting prostaglandin synthesis;
• cyclosporine and tacrolimus: possible increase in nephrotoxicity due to NSAID effects 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, likely due to inhibition of renal tubular secretion and glucuronide conjugation of the drug, requiring dose adjustment of dexketoprofen;
• cardiac glycosides: NSAIDs may increase glycoside plasma concentrations;
• mifepristone: theoretically, there is a risk of altered mifepristone efficacy due to prostaglandin synthetase inhibitors. Limited data suggest that concomitant administration of NSAIDs on the same day as prostaglandin does not adversely affect mifepristone or prostaglandin efficacy regarding cervical ripening or contractility, nor does it reduce the clinical efficacy of medical abortion agents;
• quinolone antibiotics: animal studies have shown that high-dose quinolone derivatives in combination with NSAIDs increase the risk of seizures;
• tenofovir: concomitant use with NSAIDs may increase plasma concentrations of blood urea nitrogen and creatinine; therefore, renal function should be monitored to assess potential effects of combined use;
• deferasirox: concomitant use with NSAIDs may increase the risk of gastrointestinal toxicity. Close monitoring is required when using this medicinal product with deferasirox;
• pemetrexed: concomitant use with NSAIDs may reduce pemetrexed elimination. Therefore, particular caution is required when using high-dose NSAIDs. In patients with mild to moderate renal impairment (creatinine clearance 45–79 mL/min), NSAID use should be avoided for two days before and two days after pemetrexed administration.

Special precautions for use

Use with caution in patients with a history of allergic conditions. Avoid using Dexalgin® inject in combination with other NSAIDs, including selective cyclooxygenase-2 inhibitors. Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to improve symptoms.

Gastrointestinal safety

Gastrointestinal bleeding, ulceration, or perforation, sometimes fatal, have been reported with all NSAIDs at various stages of treatment, regardless of the presence of warning symptoms or a history of serious gastrointestinal disorders. If gastrointestinal bleeding or ulceration occurs, treatment with the drug should be discontinued. The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, in patients with a history of peptic ulcer, especially complicated by bleeding or perforation, and in elderly patients.

Elderly patients: Elderly patients have an increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, sometimes fatal. Treatment of these patients should begin with the lowest possible dose. As with all NSAIDs, patients with a history of esophagitis, gastritis, and/or peptic ulcer should be ensured to have these conditions in remission. Patients with existing gastrointestinal symptoms or a history of gastrointestinal disorders should be monitored for possible gastrointestinal disturbances during treatment, particularly gastrointestinal bleeding. NSAIDs should be used cautiously in patients with a history of inflammatory bowel diseases (ulcerative colitis, Crohn’s disease) due to the risk of exacerbation. For such patients and those taking low-dose acetylsalicylic acid or other agents increasing the risk of gastrointestinal adverse reactions, combination therapy with protective agents (e.g., misoprostol or proton pump inhibitors) should be considered.

Patients, especially elderly ones, with a history of gastrointestinal adverse reactions should inform their physician about any unusual gastrointestinal symptoms, including gastrointestinal bleeding, particularly during the initial stages of treatment.

Use with caution in patients concurrently 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 like acetylsalicylic acid.

Renal safety

The medicinal product should be administered with caution in patients with impaired renal function, as NSAIDs may worsen kidney function, cause fluid retention, and edema. Due to the increased risk of nephrotoxicity, the drug should be used cautiously in patients receiving diuretics or those at risk of hypovolemia. During treatment, adequate fluid intake should be maintained to prevent dehydration, which may exacerbate renal toxicity. Like other NSAIDs, the drug may increase blood urea nitrogen and plasma creatinine concentrations. Similar to other prostaglandin synthesis inhibitors, its use may be associated with renal adverse reactions, including glomerulonephritis, interstitial nephritis, papillary necrosis, nephrotic syndrome, and acute renal failure. Renal function disturbances are most common in elderly patients.

Hepatic safety

The medicinal product should be administered with caution in patients with impaired liver function. As with other NSAIDs, the drug may cause transient and slight increases in certain liver parameters, as well as marked elevations in AST and ALT activity. If such increases occur, therapy should be discontinued.

Hepatic function disturbances are most common in elderly patients.

Cardiovascular and cerebrovascular safety

Patients with arterial hypertension and/or mild to moderate heart failure require monitoring and medical supervision. Particular caution is required in patients with a history of heart disease, especially previous episodes of heart failure (the risk of heart failure increases during treatment), as NSAIDs may cause fluid retention and edema. Clinical studies and epidemiological data suggest that some NSAIDs (especially at high doses and prolonged use) may slightly increase the risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Data excluding such risks with dexketoprofen use are insufficient. Therefore, dexketoprofen should be prescribed only after careful patient assessment in cases of uncontrolled arterial hypertension, congestive heart failure, ischemic heart disease, peripheral artery disease, and/or cerebrovascular disease. A similarly careful assessment should be performed before initiating long-term treatment in patients with cardiovascular risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes, smoking).

Non-selective NSAIDs can reduce platelet aggregation and prolong bleeding time by inhibiting prostaglandin synthesis. The concomitant use of dexketoprofen trometamol and low-molecular-weight heparin at prophylactic doses in the postoperative period has been studied in clinical trials, with no effect on coagulation parameters observed. However, patients receiving dexketoprofen trometamol concurrently with agents affecting hemostasis, such as warfarin, other coumarins, or heparins, require close medical supervision. Cardiovascular function disturbances are most common in elderly patients.

Skin reactions

There have been reports of very rare cases of severe skin reactions (some fatal) associated with NSAID use, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The highest risk likely occurs early in treatment, with most cases appearing within the first month of therapy. If skin rashes, signs of mucosal involvement, or other hypersensitivity symptoms occur, Dexalgin® inject should be discontinued.

Masking symptoms of underlying infections

Dexalgin® inject may mask symptoms of infections, potentially interfering with diagnosis and timely treatment, thereby worsening infection outcomes. Such cases have been observed in bacterial pneumonia and bacterial complications of varicella. When Dexalgin® inject is administered to relieve pain associated with an infectious process, monitoring of the infection is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Other information

Particular caution should be exercised when prescribing the medicinal product to patients:

• with hereditary disorders of porphyrin metabolism (e.g., acute intermittent porphyria);
• with dehydration;
• immediately after major surgical procedures.

If prolonged use of dexketoprofen is deemed necessary by the physician, liver and kidney function should be monitored regularly.

In very rare cases, severe acute hypersensitivity reactions (e.g., anaphylactic shock) have been observed. If early signs of severe hypersensitivity reactions occur after administration of Dexalgin® inject, treatment should be discontinued. Depending on symptoms, any necessary treatment should be administered under medical supervision.

Patients suffering from asthma combined with chronic rhinitis, chronic sinusitis, and/or nasal polyps are at higher risk of allergy to acetylsalicylic acid and/or NSAIDs than other patients. Administration of this drug may trigger asthma attacks or bronchospasm, especially in patients allergic to acetylsalicylic acid or NSAIDs.

Severe infectious complications of the skin and soft tissues may occur during varicella. Data excluding a role of NSAIDs in exacerbating this infection are lacking. Therefore, Dexalgin® inject is not recommended during varicella.

Dexalgin® inject should be administered with caution in patients with coagulation disorders, systemic lupus erythematosus, and mixed connective tissue diseases.

Like other NSAIDs, dexketoprofen trometamol may mask symptoms of infectious diseases during its use. In some cases, NSAID use has been associated with the activation of infections localized in soft tissues. Therefore, if symptoms of bacterial infection appear or worsen during treatment, patients are advised to seek immediate medical attention.

This medicinal product contains up to 200 mg of alcohol (ethanol) per 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 in this medicinal product will not have a noticeable effect.

The medicinal product contains less than 1 mmol of sodium (23 mg) per dose and is therefore practically sodium-free.

Use during pregnancy or breastfeeding

The use of Dexalgin® inject is contraindicated during the third trimester of pregnancy and during breastfeeding.

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or fetal development. According to epidemiological studies, the use of drugs that inhibit prostaglandin synthesis during early pregnancy increases the risk of miscarriage and congenital malformations, including cardiac defects and abdominal wall defects. The absolute risk of cardiovascular anomalies increases from <1% to approximately 1.5%. The risk is believed to increase with higher drug doses and longer treatment duration. In animal studies, prostaglandin synthesis inhibitors have caused increased pre- and post-implantation losses and higher embryofetal mortality. Additionally, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of fetal developmental abnormalities, including cardiovascular anomalies, has been observed. However, animal studies with dexketoprofen trometamol did not reveal reproductive toxicity. The use of dexketoprofen from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation of the drug. Additionally, cases of fetal arterial duct constriction have been reported after maternal use of the drug in the second trimester, most of which resolved after discontinuation of treatment. Therefore, dexketoprofen trometamol may be prescribed during the first and second trimesters only if absolutely necessary. When prescribing dexketoprofen trometamol to women planning pregnancy or during the first and second trimesters, the lowest effective dose for the shortest possible duration should be used. Prenatal monitoring for oligohydramnios and fetal arterial duct constriction should be considered if exposure to dexketoprofen occurs over several days starting from the 20th gestational week. Pregnant women should discontinue dexketoprofen if oligohydramnios or fetal arterial duct constriction is detected.

During the third trimester, all prostaglandin synthesis inhibitors cause:

Risks for the fetus:

• Cardio-pulmonary toxic syndrome (constriction/occlusion of the arterial duct and pulmonary hypertension);
• Impaired renal function (see above);

Risks for the mother and child at the end of pregnancy:

• Prolonged bleeding time (due to inhibition of platelet aggregation), which may occur even with low-dose use;
• Delayed uterine contractions, leading to delayed and prolonged labor.

Breastfeeding

There are no data on the passage of dexketoprofen into breast milk. Dexalgin® inject is contraindicated during breastfeeding.

Fertility

Like all other NSAIDs, dexketoprofen trometamol may reduce female fertility and should not be used in women attempting to conceive. Women experiencing fertility problems or undergoing infertility investigations should consider discontinuing the drug.

Ability to influence reaction speed when driving or operating machinery

Dizziness, visual disturbances, or drowsiness may occur during treatment with Dexalgin® inject. In such cases, the ability to react quickly, orient in traffic situations, and drive or operate machinery may be impaired.

Method of Administration and Dosage.

To minimize adverse reactions, the lowest effective dose should be used for the shortest duration possible (see section "Special Warnings and Precautions for Use").

Adults. The recommended dose is 50 mg every 8–12 hours. If necessary, the dose may be repeated after 6 hours. The maximum daily dose should not exceed 150 mg. Dexalgin® inject is intended for short-term use and should only be administered during episodes of acute pain (no longer than 2 days). Patients should be switched to oral analgesics as soon as possible, if feasible. For moderate to severe postoperative pain, the drug may be used as indicated at the same recommended doses in combination with opioid analgesics.

Elderly patients. Dose adjustment is generally not required. However, due to the physiological decline in renal function, a lower dose is recommended—specifically, the maximum daily dose should be limited to 50 mg in patients with mild renal impairment.

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

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

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

Method of Administration

Intramuscular injection. The contents of one ampoule (2 mL) should be administered slowly and deeply into the muscle.

Intravenous infusion.

For intravenous infusion, the contents of one 2 mL ampoule should be diluted in 30–100 mL of 0.9% sodium chloride solution, glucose solution, or Ringer’s lactate solution. The infusion solution should be prepared under aseptic conditions and protected from exposure to natural daylight. The prepared solution must be clear. The infusion should be administered intravenously over 10–30 minutes at a slow rate.

Dexalgin® inject, diluted in 100 mL of 0.9% sodium chloride solution or glucose solution, may be mixed with dopamine, heparin, hydroxyzine, lidocaine, morphine, pethidine, and theophylline.

Intravenous bolus injection.

If necessary, the contents of one ampoule (2 mL of injection solution) may be administered intravenously slowly over at least 15 seconds. The drug may be mixed in small volumes (e.g., in a syringe) with injection solutions of heparin, lidocaine, morphine, and theophylline.

Dexalgin® inject must not be mixed in small volumes (e.g., in a syringe) with dopamine, promethazine, pentazocine, pethidine, or hydroxyzine solutions, as precipitation may occur.

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

The drug may only be mixed with medicinal products specified above.

After drawing up the solution from the ampoule, the drug should be administered immediately when given by intramuscular or intravenous bolus injection.

No changes in active ingredient content due to adsorption have been observed during storage of diluted solutions in polyethylene bags or in administration devices made of ethyl vinyl acetate, cellulose propionate, low-density polyethylene, or polyvinyl chloride.

Dexalgin® inject is intended for single use only; any unused portion of the prepared solution should be discarded. Prior to administration, the solution should be visually inspected to ensure it is clear and colorless. Solutions containing particulate matter must not be used.

Children.

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

Overdose.

Symptoms of overdose are unknown. Similar medicinal products may cause gastrointestinal disturbances (vomiting, anorexia, abdominal pain) and nervous system effects (drowsiness, dizziness, disorientation, headache). In case of accidental overdose, symptomatic treatment appropriate to the patient’s condition should be initiated immediately. Dexketoprofen trometamol is eliminated from the body by dialysis.

Adverse reactions.

The table below lists adverse reactions by system organ class and frequency, which are considered at least possible in relation to dexketoprofen trometamol based on clinical trial data, as well as adverse reactions reported after the marketing of Dexalgin® Inject.

Organs and organ systems	Common (≥1/100 – 1/10)		Uncommon (≥ 1/1000 –<1/100)		Rare (≥ 1/10000 –< 1/1000)		Very rare (< 1/10000)
Blood and lymphatic system disorders	_		Anaemia		_		Neutropenia, thrombocytopenia
Immune system disorders	_		_		Laryngeal edema		Anaphylactic reactions, including anaphylactic shock
Metabolism and nutrition disorders	_		_		Hypoglycemia, hyperglycemia, hypertriglyceridemia, anorexia, loss of appetite		_
Psychiatric disorders	_			Insomnia, restlessness	_		_
Nervous system disorders	_			Headache, dizziness, somnolence	Paraesthesia, loss of consciousness		_
Eye disorders	_			Blurred vision	_		_
Ear and labyrinth disorders	_			Vertigo	Tinnitus		_
Cardiac disorders	_	Palpitations			Extrasystoles, tachycardia		_
Vascular disorders	_	Arterial hypotension, flushing			Arterial hypertension, superficial thrombophlebitis		_
Respiratory, thoracic and mediastinal disorders	_	_			Bradypnea		Bronchospasm, dyspnea
Gastrointestinal disorders	Nausea, vomiting	Abdominal pain, dyspepsia, diarrhea, constipation, vomiting with blood, dry mouth			Peptic ulcer, bleeding or perforation		Pancreatitis
Hepatobiliary disorders	_	_			Hepatocellular pathology		_
Skin and subcutaneous tissue disorders	_	Dermatitis, pruritus, rash, increased sweating			Urticaria, acne		Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), angioneurotic edema, facial edema, photosensitivity
Musculoskeletal and connective tissue disorders	_	_			Muscle rigidity, joint stiffness, muscle spasms, back pain		_
Renal and urinary disorders	_	_				Acute renal failure, polyuria, renal pain, ketonuria, proteinuria	Nephritis, nephrotic syndrome
Reproductive system disorders	_	_				Menstrual disorders, prostate gland dysfunction	_
General and administration site conditions	Pain at injection site, injection site reactions including inflammation, hematoma, bleeding	Malaise, fatigue, pain, chills, asthenia, discomfort				Tremor, peripheral edema	_
Investigations	_	_				Abnormal liver function tests	_

Gastrointestinal disorders were observed most frequently.

Peptic ulceration, perforation, or gastrointestinal bleeding, sometimes fatal, may occur, particularly in elderly patients. According to available data, nausea, vomiting, diarrhea, flatulence, constipation, dyspeptic symptoms, abdominal pain, melena, hematemesis, ulcerative stomatitis, exacerbation of colitis, and Crohn's disease may develop during treatment with the drug. Gastritis is observed less frequently. Edema, arterial hypertension, and heart failure, which may be associated with the use of NSAIDs, have also been reported. As with other NSAIDs, the following adverse reactions are possible: aseptic meningitis, which generally occurs in patients with systemic lupus erythematosus or mixed connective tissue disorders, and blood disorders (purpura, aplastic and hemolytic anemia; rarely agranulocytosis and bone marrow hypoplasia). Bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare), may also occur.

According to results of clinical studies and epidemiological data, the use of certain NSAIDs, especially at high doses and for prolonged periods, may be associated with a small increased risk of arterial thrombotic events, such as myocardial infarction and stroke.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product.

Healthcare professionals should report any suspected adverse reactions through the national reporting system.

Shelf life.

5 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

Store in a place protected from light, in the original packaging. After dilution, the solution can be stored for 24 hours at a temperature of 2 to 8°C. Keep out of reach of children.

Incompatibilities.

Dexalgin® inject must not be mixed in small volumes (e.g., in a syringe) with solutions of dopamine, promethazine, pentazocine, pethidine, or hydroxyzine, as precipitation may occur.

Diluted infusion solutions, prepared as described in the section "Dosage and administration", must not be mixed with promethazine or pentazocine.

Packaging.

2 ml amber glass ampoule; 1 ampoule in a blister pack, 1 blister pack in a cardboard box; or 5 ampoules in a blister pack, 1 blister pack in a cardboard box; or 5 ampoules in a blister pack, 2 blister packs in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

A. Menarini Manufacturing Logistics and Services S.r.l.

Manufacturer's location and address of place of business.

Via Sette Santi 3, 50131 Florence (FI), Italy.

Marketing Authorization Holder.

Menarini International Operations Luxembourg S.A.

Location of the Marketing Authorization Holder and/or its representative.

1, Avenue de la Gare, L-1611 Luxembourg.