Decenor

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT (Dekenor®)

Composition:

Active substance: dexketoprofen;

One tablet contains 25 mg of dexketoprofen (as dexketoprofen trometamol);

Excipients: microcrystalline cellulose, sodium croscarmellose, maize starch, colloidal anhydrous silicon dioxide, magnesium stearate;

Film coating: coating mixture: hypromellose, macrogol 6000, propylene glycol, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, round, biconvex, film-coated tablets with a breakline on one side. The tablet can be divided into two equal doses.

Pharmacotherapeutic group. Anti-inflammatory and antirheumatic agents. Propionic acid derivatives. ATC code: M01AE17.

Pharmacological properties.

Pharmacodynamics.

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

Mechanism of action

The mechanism of action of NSAIDs is related to the reduction of prostaglandin synthesis through inhibition of cyclooxygenase (COX).

Specifically, the conversion of arachidonic acid into cyclic endoperoxides PGG2 and PGH2 is inhibited, from which prostaglandins PGE1, PGE2, PGF2α, PGD2 are formed, as well as prostacyclin PGI2 and thromboxanes (TxА2 and TxВ2). 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.

Pharmacodynamic action

The inhibitory effect of dexketoprofen on COX-1 and COX-2 isoenzymes has been demonstrated in animals and humans.

Clinical efficacy and safety

Clinical studies in various types of pain have demonstrated effective analgesic action of dexketoprofen, which develops within 30 minutes after administration and lasts for 4–6 hours.

Pharmacokinetics.

Absorption

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

When dexketoprofen is administered with food, the area under the concentration-time curve (AUC) remains unchanged; however, Cmax is reduced and the absorption rate is decreased (tmax is prolonged).

Distribution

The distribution half-life and elimination half-life of dexketoprofen trometamol are 0.35 and 1.65 hours, respectively. Similar to other drugs highly bound to plasma proteins (99%), the volume of distribution of dexketoprofen is less than 0.25 L/kg. Multiple-dose pharmacokinetic studies have shown that after the last dose of dexketoprofen trometamol, AUC values do not differ from those after single administration, indicating absence of drug accumulation.

Biotransformation and elimination

After administration of dexketoprofen trometamol, only the S-(+) optical isomer is detected in urine, indicating absence of in vivo conversion of the drug into the R-(–) optical isomer. The main route of dexketoprofen elimination occurs primarily via glucuronic acid conjugation followed by renal excretion.

Clinical characteristics.

Indications.

For symptomatic treatment of mild to moderate pain, such as musculoskeletal pain, menstrual pain (dysmenorrhea), and dental pain.

Contraindications.

Dekonor® is contraindicated in the following cases:

• Hypersensitivity to dexketoprofen, to any other NSAID, or to excipients of the medicinal product;
• If substances of similar action, such as acetylsalicylic acid or other NSAIDs, provoke asthma attacks, bronchospasm, acute rhinitis, or cause nasal polyps, urticaria, or angioedema in the patient;
• If the patient has experienced photoallergic or phototoxic reactions during treatment with ketoprofen or fibrates;
• Gastrointestinal bleeding or perforation in medical history associated with previous NSAID therapy;
• Active phase of peptic ulcer/gastrointestinal bleeding or gastrointestinal bleeding, ulcerative disease, perforation in medical history;
• Chronic dyspepsia;
• Other bleeding in active phase or increased bleeding tendency;
• Crohn’s disease or ulcerative colitis;
• Severe heart failure;
• Moderate or severe renal function impairment (creatinine clearance ≤ 59 ml/min);
• Severe hepatic dysfunction (10–15 points on the Child–Pugh scale);
• Hemorrhagic diathesis and other coagulation disorders;
• Severe dehydration caused by vomiting, diarrhea, or insufficient fluid intake;
• Third trimester of pregnancy and breastfeeding period (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

The drug interactions listed below generally apply to NSAIDs.

Unrecommended combinations

• Other NSAIDs, including selective COX-2 inhibitors and salicylates at high doses (≥ 3 g per day): concomitant use of multiple NSAIDs increases the risk of gastrointestinal ulceration and gastrointestinal bleeding due to mutual enhancement of their effects.
• Anticoagulants: NSAIDs enhance the effect of anticoagulants, such as warfarin (see section "Special precautions for use"), due to the high degree of plasma protein binding of dexketoprofen, as well as inhibition of platelet function and damage to the gastric and duodenal mucosa. If concomitant use is necessary, it should be performed under close medical supervision with 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 performed under close medical supervision with monitoring of appropriate laboratory parameters.
• Corticosteroids: increased risk of gastrointestinal ulceration and gastrointestinal bleeding (see section "Special precautions for use").
• Lithium preparations (data 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 treatment, during dose adjustments, or upon discontinuation of the drug.
• Methotrexate when administered at high doses (≥ 15 mg per week): hematological toxicity of methotrexate is generally enhanced due to reduced renal clearance of methotrexate under NSAID therapy.
• Hydantoin derivatives and sulfonamides: possible increased toxicity of these substances.

Concomitant use requires caution

• Diuretics, angiotensin-converting enzyme (ACE) inhibitors, aminoglycoside antibiotics, and angiotensin II receptor antagonists (ARBs): 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), use of drugs that inhibit COX, concomitantly with ACE inhibitors, ARBs, 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 (see section "Special precautions for use").
• Methotrexate when administered at low doses (< 15 mg per week): hematological toxicity of methotrexate is generally enhanced due to reduced renal clearance under NSAID therapy. During the first weeks of concomitant use, a complete blood count should be performed weekly. Treatment should be closely monitored in patients with even mild renal impairment and in elderly patients.
• Pentoxifylline: risk of bleeding. Enhanced monitoring and more frequent assessment of bleeding time are required.
• Zidovudine: risk of increased toxic effect on erythrocytes due to effects on reticulocytes, which after 1 week of NSAID use may lead to severe anemia. Blood analysis and reticulocyte count should be performed within 1–2 weeks after starting NSAID therapy.
• Sulfonylurea preparations: NSAIDs may enhance the hypoglycemic effect of sulfonylureas by displacing them from plasma protein binding sites.

Potential interactions should be considered when using the following medicinal products

• Beta-blockers: NSAIDs may reduce their antihypertensive effect due to inhibition of prostaglandin synthesis.
• Cyclosporine and tacrolimus: possible increased nephrotoxicity due to the effect of NSAIDs on renal prostaglandins. Renal function should be monitored during combination therapy.
• Thrombolytic agents: increased risk of bleeding.
• Platelet aggregation inhibitors and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section "Special precautions for use").
• Probenecid: possible increase in plasma concentration of dexketoprofen, likely due to inhibition of tubular secretion and conjugation of the drug with glucuronic acid, requiring dose adjustment of dexketoprofen.
• Cardiac glycosides: NSAIDs may increase glycoside plasma concentrations.
• Mifepristone: there is a theoretical possibility of reduced efficacy of mifepristone under the influence of prostaglandin synthetase inhibitors. Individual data indicate that NSAID use on the day of prostaglandin administration does not negatively affect mifepristone or prostaglandin action on 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 quinolone derivatives in combination with NSAIDs increase the risk of seizures.
• Tenofovir: concomitant use with NSAIDs may increase blood urea nitrogen and creatinine concentrations. Renal function should be carefully monitored to control potential cumulative effects on kidney function.
• Deferasirox: concomitant use with NSAIDs increases the risk of gastrointestinal toxicity. Careful clinical monitoring is required when combining deferasirox with these agents.
• Pemetrexed: concomitant use with NSAIDs may reduce pemetrexed elimination; therefore, high-dose NSAIDs should be used cautiously. Patients with mild to moderate renal impairment (creatinine clearance 45–79 ml/min) should avoid concomitant use of pemetrexed with high-dose NSAIDs for 2 days before, on the day of, and for 2 days after pemetrexed administration.

Special precautions for use.

Use with caution in patients with a history of allergic conditions.

Avoid using the medicinal product Dekenor® in combination with other NSAIDs, including selective COX-2 inhibitors.

Adverse effects of the drug can be minimized by using the lowest effective dose for the shortest possible duration necessary to control symptoms.

Gastrointestinal safety

Gastrointestinal bleeding, ulcers, or perforation, in some cases fatal, have been observed during treatment with all NSAIDs at various stages, regardless of the presence of warning symptoms or a history of serious gastrointestinal disorders. If gastrointestinal bleeding or ulceration occurs during therapy, treatment with Dekenor® 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 if complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients.

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 (see section "Adverse reactions").

Prior to initiating treatment with dexketoprofen, as with all NSAIDs, patients with a history of esophagitis, gastritis, and/or peptic ulcer disease should be evaluated to ensure these conditions are 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.

Combination therapy with gastroprotective agents, such as misoprostol or proton pump inhibitors, may be appropriate for such patients and for those taking low-dose acetylsalicylic acid or other drugs that increase the risk of gastrointestinal adverse reactions (see section "Interaction with other medicinal products and other forms of interaction").

Patients, especially elderly ones, with a history of gastrointestinal adverse reactions should be advised to inform their physician about any unusual gastrointestinal symptoms, including gastrointestinal bleeding, particularly in the early stages of treatment.

The drug should be prescribed with caution in patients who are concurrently using medications that increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents such as acetylsalicylic acid (see section "Interaction with other medicinal products and other forms of interaction").

Elderly patients

In elderly patients, the frequency of NSAID-related adverse reactions, particularly gastrointestinal bleeding and perforation, sometimes fatal, is increased (see section "Dosage and administration"). Treatment in such patients should be initiated with the lowest possible dose.

Renal function impairment

The medicinal product should be prescribed with caution in patients with impaired renal function, as well as in those with hypertension and/or congestive heart failure, as NSAID use may lead to worsening renal function, fluid retention, and edema. Due to the increased risk of nephrotoxicity, the drug should be used cautiously in patients receiving diuretics or in those who may develop hypovolemia.

During therapy, adequate fluid intake should be ensured to prevent dehydration and the associated increase in renal toxicity.

Like all NSAIDs, the drug may increase blood urea nitrogen and creatinine levels in plasma. Similar to other prostaglandin synthesis inhibitors, it may cause renal adverse reactions, potentially leading to glomerulonephritis, interstitial nephritis, papillary necrosis, nephrotic syndrome, and acute renal failure.

Renal function impairment occurs more frequently in elderly patients (see section "Dosage and administration").

Hepatic function impairment

The medicinal product should be prescribed with caution in patients with impaired liver function. Like other NSAIDs, the drug may cause transient, slight increases in certain liver function tests, as well as significant elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Treatment should be discontinued if these parameters increase.

Hepatic function impairment most commonly occurs in elderly patients (see section "Dosage and administration").

Cardiovascular and cerebrovascular effects

Patients with mild to moderate hypertension and/or congestive heart failure should be under close medical supervision. Particular caution is required in treating patients with a history of heart disease, especially episodes of heart failure, as the risk of developing heart failure may increase due to possible fluid retention and edema during NSAID therapy.

According to available clinical and epidemiological data, the use of certain NSAIDs, particularly at high doses and for prolonged periods, slightly increases the risk of arterial thrombotic events such as myocardial infarction or stroke. Data are insufficient to exclude such risk with dexketoprofen use.

Therefore, dexketoprofen should be used only after careful patient assessment in cases of hypertension, congestive heart failure, confirmed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. The same applies to initiating long-term treatment in patients with cardiovascular risk factors such as hypertension, hyperlipidemia, diabetes mellitus, or smoking.

All non-selective NSAIDs can reduce platelet aggregation and prolong bleeding time by inhibiting prostaglandin synthesis. Therefore, careful monitoring is required in patients taking dexketoprofen concurrently with agents affecting hemostasis (e.g., warfarin, other coumarins, or heparins) (see section "Interaction with other medicinal products and other forms of interaction").

Cardiovascular adverse events occur most frequently in elderly patients (see section "Dosage and administration").

Cases of Kounis syndrome have been reported in patients receiving dexketoprofen. Kounis syndrome is characterized by cardiovascular symptoms due to coronary artery spasm resulting from an allergic or hypersensitivity reaction, potentially leading to myocardial infarction.

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 occurs early in treatment, with most cases appearing within the first month. If skin rashes, signs of mucosal involvement, or other hypersensitivity symptoms occur, Dekenor® should be discontinued.

Other information

Particular caution should be exercised when treating patients:

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

If long-term therapy with dexketoprofen is required, liver and kidney function should be monitored regularly, and blood tests should be performed.

Severe allergic reactions (e.g., anaphylactic shock) have been observed very rarely. If early signs of hypersensitivity reactions occur, treatment with Dekenor® should be discontinued. Depending on symptoms, appropriate medical treatment should be initiated by healthcare professionals.

Patients suffering from asthma attacks in combination with chronic rhinitis, chronic sinusitis, and/or nasal polyps are more prone to allergic reactions when using acetylsalicylic acid or other NSAIDs. The drug may provoke asthma attacks or bronchospasm, especially in patients with a history of allergic reactions to acetylsalicylic acid or other NSAIDs (see section "Contraindications").

In rare cases, chickenpox may lead to severe skin and soft tissue infections. The role of NSAIDs in worsening symptoms of such infections cannot currently be ruled out; therefore, it is advisable to avoid using the drug in cases of chickenpox.

Dekenor® should be used with caution in patients with coagulation disorders, systemic lupus erythematosus, or mixed connective tissue diseases.

Masking symptoms of underlying infections

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

The medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

The use of the medicinal product is contraindicated during the third trimester of pregnancy and during breastfeeding (see section "Contraindications").

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological studies indicate that using drugs that inhibit prostaglandin synthesis during early pregnancy increases the risk of miscarriage, congenital heart defects, and gastroschisis. The absolute risk of cardiovascular abnormalities increases from <1% to approximately 1.5%. The risk is believed to increase with higher drug doses and longer treatment duration. Animal studies have shown that prostaglandin synthesis inhibitors increase embryonic loss before and after implantation and embryonic/fetal mortality. Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of various malformations, including cardiovascular, has been observed. However, animal studies did not show reproductive toxicity of dexketoprofen. 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. Additionally, cases of fetal ductus arteriosus constriction have been reported after maternal use of the drug during the second trimester, most of which resolved after stopping treatment. Therefore, dexketoprofen should be prescribed during the first and second trimesters only if absolutely necessary. Women planning pregnancy or in the first or second trimester should use the lowest effective dose of dexketoprofen for the shortest possible duration.

Fetal monitoring for oligohydramnios and ductus arteriosus constriction should be considered if dexketoprofen is used for several days starting from the 20th gestational week. Pregnant women should discontinue dexketoprofen if oligohydramnios or ductus arteriosus constriction is detected.

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

• cardiovascular toxicity, e.g., premature constriction/closure of the ductus arteriosus and pulmonary hypertension;
• renal function impairment (see above).

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

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

Breastfeeding period

There are no data on the passage of dexketoprofen into breast milk. Dekenor® is contraindicated during breastfeeding (see section "Contraindications").

Fertility

Like other NSAIDs, Dekenor® may reduce female fertility and therefore is not recommended for women planning pregnancy. For women experiencing fertility problems or undergoing infertility evaluation, discontinuation of the drug should be considered.

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

Ability to affect reaction speed when driving or operating machinery.

During treatment with dexketoprofen film-coated tablets, adverse reactions such as dizziness, visual disturbances, or somnolence may occur, which can reduce reaction speed and impair the ability to drive or operate machinery.

Method of Administration and Dosage

Adults.

Depending on the type and intensity of pain, the recommended dose is 12.5 mg (1/2 film-coated tablet) every 4–6 hours or 25 mg (1 film-coated tablet) every 8 hours. The daily dose should not exceed 75 mg.

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

The medicinal product Dekenor® is not intended for long-term therapy; treatment should be limited to the period of symptom presence.

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 impairment, treatment should be initiated with the minimum recommended dose and under strict medical supervision. The daily dose is 50 mg. Dekenor® 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.

Dekenor® tablets are contraindicated in patients with moderate to 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 drug absorption (see section "Pharmacokinetics"); therefore, in acute pain, the drug is recommended to be taken at least 30 minutes before food.

Children.

The use of Dekenor® in children has not been studied; therefore, safety and efficacy in children and adolescents have not been established, and the medicinal product 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, dizziness, disorientation, headache).

In case of accidental overdose, symptomatic treatment appropriate to the patient's condition should be initiated immediately. If an adult or child has ingested a dose exceeding 5 mg/kg body weight, activated charcoal should be administered within 1 hour. Dexketoprofen is removed from the body by hemodialysis.

Adverse reactions.

The table below lists adverse reactions considered to be at least possibly related to dexketoprofen, tablets, based on data from clinical trials, as well as adverse reactions reported after the drug was marketed. Adverse reactions are categorized by system organ class and frequency of occurrence.

Gastrointestinal disorders were the most frequently observed. The development of peptic ulcer, gastrointestinal perforation or bleeding, sometimes fatal, especially in elderly patients, may occur (see section "Special precautions for use"). Available data indicate that nausea, vomiting, diarrhea, flatulence, constipation, dyspeptic symptoms, abdominal pain, melena, hematemesis, ulcerative stomatitis, exacerbation of colitis, and Crohn's disease may occur during treatment with the drug (see section "Special precautions for use"). Gastritis is observed less frequently.

Edema, arterial hypertension, and heart failure may also develop during treatment with NSAIDs.

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), are possible.

According to clinical trial results and epidemiological data, the use of certain NSAIDs, particularly at high doses and for prolonged periods, may slightly increase the risk of arterial thrombotic events such as myocardial infarction and stroke (see section "Special precautions for use").

Reporting of suspected adverse reactions.

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

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C. Keep out of reach of children.

Packaging.

10 tablets per blister; 1 or 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia / KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address and place of business.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.