Dexketoprofen

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEXKETOPROFEN (DEXKETOPROFEN)

Composition:

Active substance: dexketoprofen;

One film-coated tablet contains 36.9 mg of dexketoprofen trometamol, equivalent to 25 mg of dexketoprofen;

Excipients: microcrystalline cellulose, maize starch, sodium starch glycolate, glyceryl distearate;

Coating: hypromellose, titanium dioxide (E 171), polyethylene glycol 6000, propylene glycol.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, round, biconvex tablets with a score line on one side, film-coated.

Pharmacotherapeutic group.

Anti-inflammatory and antirheumatic agents. Propionic acid derivatives.

ATC code M01A E17.

Pharmacological properties.

Pharmacodynamics.

Dexketoprofen trometamol is a salt of propionic acid. It is an analgesic, anti-inflammatory, and antipyretic medicinal product belonging to the class of non-steroidal anti-inflammatory drugs (NSAIDs).

Mechanism of action.

The mechanism of action is based on the reduction of prostaglandin synthesis through inhibition of cyclooxygenase. 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, the inhibition of prostaglandin synthesis may affect other mediators of inflammation such as kinins, which may also indirectly influence the primary action of the drug.

Pharmacodynamic effect.

The inhibitory effect of dexketoprofen on the activity of cyclooxygenase-1 and cyclooxygenase-2 has been demonstrated in animals and humans.

Clinical efficacy and safety.

Clinical studies have shown that dexketoprofen exerts effective analgesic action, which develops within 30 minutes after administration of the drug and lasts for 4–6 hours.

Pharmacokinetics.

Absorption.

After oral administration of dexketoprofen trometamol, maximum plasma concentration (Cmax) is reached within 30 minutes (15–60 minutes).

When dexketoprofen trometamol is administered with food, the AUC values are not altered, however, Cmax is reduced and the absorption rate is decreased (tmax is prolonged).

Distribution.

The distribution time and elimination half-life of dexketoprofen trometamol are 0.35 and 1.65 hours, respectively. Due to the high degree of plasma protein binding (99%), the mean volume of distribution of dexketoprofen trometamol is less than 0.25 L/kg. Pharmacokinetic studies with multiple doses showed that after the last dose of dexketoprofen trometamol, the area under the curve (AUC) was not higher than after a single dose, indicating absence of drug accumulation.

Metabolism and elimination.

After administration of dexketoprofen trometamol, only the S-(+)-enantiomer is detected in urine, demonstrating the absence of its inversion into the R-(-)-enantiomer in the human body.

Elimination of dexketoprofen occurs primarily via glucuronidation followed by renal excretion.

Clinical characteristics.

Indications.

Symptomatic treatment of mild to moderate pain, for example, musculoskeletal pain, painful menstruation (dysmenorrhea), toothache.

Contraindications.

• Hypersensitivity to the active substance or to any other nonsteroidal anti-inflammatory drug (NSAID), or to any of the excipients.
• Use in patients in whom agents with a similar mechanism of action, for example acetylsalicylic acid and other NSAIDs, induce attacks of bronchial asthma, bronchospasm, acute rhinitis, or lead to the development of nasal polyps, urticaria, or angioedema.
• Known photoallergic or phototoxic reactions during treatment with ketoprofen or fibrates.
• Bleeding or perforation in the gastrointestinal tract in medical history associated with the use of NSAIDs.
• Active phase of peptic ulcer/gastrointestinal bleeding, recurrent course of peptic ulcer/gastrointestinal bleeding in medical history.
• Chronic dyspepsia.
• Bleeding in the active phase or increased bleeding tendency.
• Crohn's disease or non-specific ulcerative colitis.
• Severe heart failure.
• Moderate or severe renal impairment (creatinine clearance ≤ 59 ml/min).
• Severe hepatic impairment (10–15 points on the Child–Pugh scale).
• Hemorrhagic diathesis or other coagulation disorders.
• Severe dehydration (due to vomiting, diarrhea, or insufficient fluid intake).
• Third trimester of pregnancy and breastfeeding period (see "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

The drug interactions listed below generally apply to NSAID class drugs.

Unrecommended combinations

• Other NSAIDs (including selective cyclooxygenase-2 inhibitors and salicylates at high doses (≥ 3 g/day)): concomitant use of several NSAIDs may increase the risk of gastrointestinal ulcers and bleeding due to synergistic effects.
• Anticoagulants: NSAIDs enhance the effect of anticoagulants, for example 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 carried out under medical supervision and with careful monitoring of appropriate laboratory parameters.
• Heparin: increased risk of bleeding (due to inhibition of platelet function and damage to the gastric and duodenal mucosa). If concomitant use is necessary, it should be carried out under medical supervision and with careful monitoring of appropriate laboratory parameters.
• Corticosteroids: increased risk of peptic ulcers and gastrointestinal bleeding.
• Lithium preparations (reports have been reported for several NSAIDs): NSAIDs increase lithium blood levels up to toxic values due to reduced renal excretion. Therefore, lithium blood levels should be monitored at the beginning of dexketoprofen therapy, during dose adjustment, or upon discontinuation of the drug.
• Methotrexate when administered at high doses (from 15 mg/week): increased methotrexate blood levels due to reduced renal excretion, leading to toxic effects on the blood system.
• Hydantoin derivatives and sulfonamides: possible increase in toxicity of these substances.

Combinations requiring cautious use

• Diuretics, ACE inhibitors, aminoglycoside antibiotics, and angiotensin II receptor antagonists. Dexketoprofen reduces the effect of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., in dehydrated patients or elderly patients with renal impairment), their condition may worsen when used concomitantly with agents that inhibit cyclooxygenase activity, such as ACE inhibitors, angiotensin II receptor antagonists, and aminoglycoside antibiotics. This worsening is usually reversible. When using dexketoprofen concomitantly with any diuretic, it is necessary to ensure that the patient is adequately hydrated, and renal function should be monitored during treatment.
• Methotrexate when administered at low doses (less than 15 mg/week): possible increase in hematotoxic effects due to reduced renal excretion; if such a combination is necessary, weekly blood count monitoring is required, especially in the presence of even slight renal impairment, and in elderly patients.
• Pentoxifylline: increased risk of bleeding; therefore, patient monitoring and bleeding time control are necessary.
• Zidovudine: there is a risk of increased toxic effect of zidovudine on erythropoiesis (toxic effect on reticulocytes) up to the development of severe anemia one week after NSAID administration; therefore, blood analysis with reticulocyte count should be monitored during the first 1–2 weeks after initiation of NSAID therapy.
• Sulfonylurea derivatives: NSAIDs may enhance the hypoglycemic effect of sulfonylurea drugs due to their displacement from plasma protein binding sites.

Combinations to consider when using Dexketoprofen

• Beta-adrenoblockers: their antihypertensive effect may be reduced due to inhibition of prostaglandin synthesis.
• Cyclosporine and tacrolimus: enhanced nephrotoxic effects of these drugs due to the influence of NSAIDs on prostaglandin synthesis; regular monitoring of renal function is required when using such a combination.
• Thrombolytic agents: increased risk of bleeding.
• Platelet aggregation inhibitors and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding.
• Probenecid: increased plasma concentration of dexketoprofen due to reduced renal tubular secretion and glucuronidation; in such cases, dose adjustment of dexketoprofen is required.
• Cardiac glycosides: their plasma concentration may increase.
• Mifepristone: there is a theoretical risk that prostaglandin synthesis inhibitors may alter the effectiveness of mifepristone. Limited data suggest that concomitant use of NSAIDs and prostaglandins does not affect the action of mifepristone or prostaglandins, specifically cervical ripening or uterine contractility, and does not reduce the clinical efficacy of medical termination of pregnancy.
• Quinolone antibiotics: animal studies have shown that high-dose use of quinolone antibiotics in combination with NSAIDs increases the risk of seizures.
• Tenofovir: concomitant use with NSAIDs may increase blood urea nitrogen and creatinine levels; therefore, renal function should be monitored to control potential synergistic effects on kidney function.
• Deferasirox: concomitant use with NSAIDs may increase gastrointestinal toxicity and requires careful clinical monitoring.
• Pemetrexed: concomitant use with NSAIDs may reduce pemetrexed elimination from the body; therefore, caution should be exercised when administering higher NSAID doses. Patients with mild to moderate renal impairment (creatinine clearance from 45 to 79 ml/min) should avoid using NSAIDs for 2 days before and 2 days after pemetrexed administration.

Special precautions for use.

Dexketoprofen should be used with caution in patients with a history of allergic reactions.

Concomitant use of this drug with other NSAIDs, including selective COX-2 inhibitors, should be avoided. Adverse effects of the drug can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

Gastrointestinal safety

When using NSAIDs, peptic ulcers with or without perforation and gastrointestinal bleeding (even fatal) may occur in the gastrointestinal tract. These adverse events may occur at any time during treatment, with or without preceding symptoms, and are independent of a history of severe gastrointestinal disorders. If gastrointestinal bleeding or peptic ulcer develops during dexketoprofen therapy, treatment with the drug should be discontinued immediately.

The risk of these adverse events increases proportionally with higher NSAID doses and in patients with a history of gastric or duodenal ulcers and in elderly patients. During treatment, physicians should closely monitor patients for possible gastrointestinal bleeding. Prior to initiating treatment with dexketoprofen trometamol, and in patients with a history of esophagitis, gastritis, and/or peptic ulcer disease, it should be confirmed—as with other NSAIDs—that these conditions are in remission. Patients with existing gastrointestinal symptoms or a history of gastrointestinal disorders should be monitored for gastrointestinal complications, particularly gastrointestinal bleeding.

NSAIDs should be prescribed with caution in patients with a history of gastrointestinal disorders (ulcerative colitis, Crohn's disease), as there is a risk of exacerbation.

To reduce the risk of gastrointestinal adverse reactions, physicians may prescribe gastroprotective agents (misoprostol, proton pump inhibitors). This also applies to patients requiring concomitant low-dose acetylsalicylic acid or other agents that increase the risk of gastrointestinal complications.

Patients should be informed to report any abdominal discomfort (particularly gastrointestinal bleeding), especially at the beginning of treatment, to their physician.

Renal safety

The drug should be prescribed with caution in patients with impaired renal function, as NSAIDs may cause deterioration of renal function, 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, patients should receive adequate fluid intake to prevent dehydration, which may exacerbate renal toxicity.

Like all NSAIDs, the drug may increase plasma urea nitrogen and 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 occur most frequently in elderly patients.

Hepatic safety

The drug should be prescribed with caution in patients with impaired liver function. Like other NSAIDs, the drug may cause transient and mild elevation of 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, as the risk of developing heart failure increases during treatment: fluid retention and edema have been observed 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 this risk with dexketoprofen are insufficient. Therefore, dexketoprofen should be prescribed only after careful assessment of the patient's condition in cases of uncontrolled arterial hypertension, congestive heart failure, ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. Similarly careful evaluation is required before initiating long-term treatment in patients with cardiovascular risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking).

All non-selective NSAIDs can reduce platelet aggregation and prolong bleeding time by inhibiting prostaglandin synthesis. Therefore, dexketoprofen trometamol is not recommended for patients taking anticoagulants such as warfarin, other coumarins, or heparins. 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 is likely during the initial stages of treatment, with most cases occurring within the first month of therapy.

If early signs of skin rash, mucosal lesions, or other hypersensitivity symptoms appear, dexketoprofen should be discontinued.

Other information

Particular caution should be exercised when prescribing the drug 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 considered 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 taking dexketoprofen, treatment should be discontinued. Depending on symptoms, appropriate treatment should be administered under medical supervision.

Patients with asthma combined with chronic rhinitis, chronic sinusitis, and/or nasal polyps have a higher risk of developing 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.

In rare cases, severe infectious complications of the skin and soft tissues may occur during varicella. Currently, there are no data to fully exclude the role of NSAIDs in exacerbating this infectious process. Therefore, the use of dexketoprofen should be avoided during varicella.

Dexketoprofen should be used with caution in patients with coagulation disorders, systemic lupus erythematosus, and mixed connective tissue diseases.

Like other NSAIDs, dexketoprofen may mask symptoms of infectious diseases.

Masking symptoms of underlying infections

Dexketoprofen may mask symptoms of infectious diseases, potentially delaying appropriate treatment and thereby complicating the disease course. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. If dexketoprofen is used for fever or pain relief during infection, monitoring of the infectious disease is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Use during pregnancy or breastfeeding.

Dexketoprofen 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 fetal congenital heart defects and abdominal wall defects. The absolute risk of cardiovascular malformations increases from <1% to approximately 1.5%. The risk of such events is considered to increase with higher drug doses and longer duration of therapy. In animal studies, prostaglandin synthesis inhibitors caused increased pre- and post-implantation losses and increased embryofetal mortality. Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, the frequency of fetal developmental abnormalities, including cardiovascular malformations, increased. However, animal studies with dexketoprofen did not reveal toxic effects on reproductive organs. Starting from the 20th week of pregnancy, dexketoprofen use may cause oligohydramnios due to fetal renal dysfunction. This condition may occur soon after starting treatment and is usually reversible upon discontinuation of the drug. Dexketoprofen may be prescribed during the first and second trimesters of pregnancy only if absolutely necessary. When prescribing dexketoprofen 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 should be considered after several days of dexketoprofen use starting from the 20th week of pregnancy. Dexketoprofen should be discontinued if oligohydramnios is detected.

During the third trimester, all prostaglandin synthesis inhibitors cause:

Risks to the fetus:

• cardiovascular toxicity, e.g., premature closure of the ductus arteriosus and pulmonary hypertension;
• renal dysfunction, which may progress to renal failure and lead to oligohydramnios (see above).

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

• prolonged bleeding time due to inhibition of platelet aggregation, even with low-dose administration;
• inhibition of uterine contractility, leading to prolonged labor and delayed delivery.

Breastfeeding.

There are no data on the passage of dexketoprofen into breast milk. Dexketoprofen 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 evaluation should consider discontinuing the drug.

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

Ability to influence reaction rate when driving or operating machinery.

During treatment with dexketoprofen tablets, adverse effects such as dizziness, visual disturbances, or somnolence may occur, which may impair reaction speed, ability to drive vehicles, or operate machinery.

Method of administration and dosing.

Dosing.

Adults.

Depending on the type and intensity of pain, the recommended dose is 12.5 mg (½ film-coated tablet) every 4–6 hours or 25 mg (1 film-coated tablet) every 8 hours. The daily dose must not exceed 75 mg.

Adverse effects of the drug can be minimized by using the lowest effective dose for the shortest duration necessary to relieve symptoms (see section "Special precautions"). Dexketoprofen is not intended for long-term therapy; treatment continues only as long as symptoms are present.

Elderly patients. It is recommended to initiate treatment with low doses. The daily dose is 50 mg. If the drug is well tolerated, the dose may be increased to the usual level.

Hepatic impairment. In patients with mild to moderate hepatic dysfunction, treatment should be initiated at the lowest recommended dose and under strict medical supervision. The daily dose is 50 mg. Dexketoprofen tablets are contraindicated in patients with severe hepatic impairment.

Renal impairment. In patients with mild renal impairment (creatinine clearance 60–89 mL/min), the initial total daily dose should be reduced to 50 mg.

Dexketoprofen tablets are contraindicated in patients with moderate or severe renal impairment (creatinine clearance ≤ 59 mL/min).

Method of administration.

Tablets should be taken with sufficient fluid (e.g., a glass of water). Concomitant intake with food slows down drug absorption (see section "Pharmacokinetics"); therefore, in acute pain, the drug should be taken at least 30 minutes before meals.

Children.

The use of dexketoprofen in children has not been studied; therefore, safety and efficacy in children and adolescents have not been established, and the drug should not be administered to children and adolescents.

Overdose.

Symptoms of overdose are unknown. Similar medicinal products may cause gastrointestinal disturbances (vomiting, anorexia, abdominal pain) and nervous system effects (drowsiness, vertigo, disorientation, headache).

In case of accidental overdose, immediate symptomatic treatment according to the patient's clinical condition should be initiated. If an adult or child has ingested a dose exceeding 5 mg/kg body weight, activated charcoal should be administered within 1 hour. Hemodialysis may be used to eliminate dexketoprofen.

Adverse reactions.

The adverse reactions listed in the table below are considered to have, based on clinical data, at least a possible causal relationship with dexketoprofen trometamol, as well as adverse reactions reported during the post-marketing period.

Gastrointestinal side effects: gastrointestinal adverse reactions are most commonly observed. Peptic ulceration, gastrointestinal perforation or bleeding may occur, sometimes with fatal outcomes, particularly in elderly patients. According to available data, nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, vomiting with blood, ulcerative stomatitis, exacerbation of colitis, Crohn's disease may occur during treatment with the drug. Gastritis is observed less frequently. Also, edema, arterial hypertension, and heart failure may develop during treatment with NSAIDs.

As with other NSAIDs, aseptic meningitis may occur, primarily in patients with systemic lupus erythematosus or mixed connective tissue disease, as well as blood-related reactions (purpura, hypoplastic and hemolytic anemia, rarely agranulocytosis and bone marrow hypoplasia).

Bullous reactions may occur, including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare).

According to 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 (e.g., myocardial infarction or stroke).

Reporting of suspected adverse reactions.

Reporting of adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the drug. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of drug efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Do not use the drug after the expiry date stated on the packaging!

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 film-coated tablets in blisters.

10 film-coated tablets in a blister; 1, 3, 5 or 10 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

JSC "Lubnipharm".

Manufacturer's address and location of business activity.

16 Barvinkova St., Lubny, Poltava region, 37500, Ukraine.