Dexobel

INSTRUCTIONS for medical use of the medicinal product DEKSOBEL (DEKSOBEL)

Composition:

active substance: dexketoprofen;

1 film-coated tablet contains dexketoprofen trometamol equivalent to dexketoprofen 25 mg;

excipients: microcrystalline cellulose, maize starch, sodium starch glycolate (type A), glycerol dibehenate, Kollicoat IR White II coating*.

*Composition of Kollicoat IR White II coating: Kollicoat IR, Kollicoat VA64, titanium dioxide (E 171), kaolin, sodium lauryl sulfate.

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: round, biconvex film-coated tablets, white in color, with a break line on both sides.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic drugs. Propionic acid derivatives. ATC code M01AE17.

Pharmacological properties.

Pharmacodynamics.

Dexketoprofen trometamol is a propionic acid salt that exerts analgesic, anti-inflammatory, and antipyretic effects and belongs to the class of nonsteroidal anti-inflammatory drugs (NSAIDs). Its mechanism of action is based on reducing the synthesis of prostaglandins by inhibiting 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, inhibition of prostaglandin synthesis may affect other mediators of inflammation such as kinins, which may also indirectly influence the primary action of dexketoprofen. Inhibitory effects of dexketoprofen trometamol on COX-1 and COX-2 isoenzymes have been demonstrated in animals and humans. Clinical studies have shown that dexketoprofen trometamol provides effective analgesia, which develops within 30 minutes after administration and lasts for 4–6 hours.

Pharmacokinetics.

After oral administration of dexketoprofen trometamol, maximum plasma concentration (Cmax) is reached on average within 30 minutes (15–60 minutes). 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. Elimination of dexketoprofen trometamol occurs mainly via glucuronidation followed by renal excretion. After administration of dexketoprofen trometamol, only the S-(+)-enantiomer is detected in urine, confirming the absence of its inversion into the R-(+)-enantiomer in the human body. Pharmacokinetic studies with repeated dosing showed that after the last dose, the area under the concentration-time curve (AUC) was not higher than after single administration, indicating no drug accumulation. When dexketoprofen trometamol is administered with food, AUC values remain unchanged; however, Cmax is reduced and the rate of absorption decreases (tmax is prolonged).

Clinical characteristics.

Indications.

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

Contraindications.

• Hypersensitivity to the active substance or to any other non-steroidal anti-inflammatory drug (NSAID), or to any of the excipients.
• Administration to patients in whom substances with a similar mechanism of action, such as 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 perforations 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 ulcerative colitis.
• Severe heart failure.
• Moderate or severe renal function impairment (creatinine clearance < 59 mL/min).
• Severe hepatic function 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 following drug interactions generally characterize NSAID-class medicinal products.

Unrecommended combinations:

• Other NSAIDs, including selective cyclooxygenase-2 inhibitors and salicylates in high doses (≥ 3 g/day): concurrent use of multiple NSAIDs increases the risk of gastrointestinal ulcers and bleeding due to synergistic effects.
• Anticoagulants: NSAIDs enhance the effect 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 cannot be avoided, it should be carried out under medical supervision 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 cannot be avoided, it should be carried out under medical supervision with careful monitoring of appropriate laboratory parameters.
• Corticosteroids: increased risk of peptic ulcers and gastrointestinal bleeding.
• Lithium preparations (there have been reports with 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 treatment, during dose adjustment, or upon discontinuation of the medicinal product.
• Methotrexate when administered in 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 caution:

• Diuretics, angiotensin-converting enzyme (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 impaired renal function), further deterioration of renal function may occur when drugs that inhibit cyclooxygenase activity are used concomitantly with ACE inhibitors, angiotensin II receptor antagonists, and aminoglycoside antibiotics. This deterioration is usually reversible. When using dexketoprofen concomitantly with any diuretic, ensure the patient is adequately hydrated and monitor renal function during treatment.
• Methotrexate when administered in low doses (less than 15 mg/week): possible increase in toxic effects on the blood system 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 or in elderly patients.
• Pentoxifylline: increased risk of bleeding; therefore, patient observation and monitoring of bleeding time are necessary.
• Zidovudine: risk of increased toxic effect of zidovudine on erythropoiesis (toxic effect on reticulocytes), potentially leading to severe anemia one week after NSAID administration; therefore, blood analysis with reticulocyte count monitoring is required 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 the medicinal product Dexobel

• Beta-blockers: their antihypertensive effect may be reduced due to inhibition of prostaglandin synthesis.
• Cyclosporine and tacrolimus: enhanced nephrotoxic effects of these medicinal products due to the effect of NSAIDs on prostaglandin synthesis; regular monitoring of renal function is required when using such combinations.
• Thrombolytic medicinal products: 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; dose adjustment of dexketoprofen may be required.
• Cardiac glycosides: their plasma concentration may increase.
• Mifepristone: there is a theoretical risk that prostaglandin synthesis inhibitors may alter the efficacy of mifepristone. Limited data indicate that concomitant use of NSAIDs on the day of prostaglandin administration does not negatively 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 administration of quinolone antibiotics in high doses in combination with NSAIDs increases the risk of seizures.
• Tenofovir: concomitant use with NSAIDs may increase plasma levels of blood urea nitrogen and creatinine; therefore, monitoring of renal function is necessary 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 concomitant use with NSAIDs for 2 days before and 2 days after pemetrexed administration.

Special precautions for use.

Dexobel should be used with caution in patients with a history of allergic reactions. Concomitant use of the medicinal product with other NSAIDs, including selective cyclooxygenase-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 NSAID drugs, peptic ulcers with or without perforation and gastrointestinal bleeding (even fatal) may develop in the gastrointestinal tract. These adverse events may occur at any time during treatment, with or without preceding symptoms, and are independent of the presence of severe gastrointestinal disorders in the patient's history. If gastrointestinal bleeding or peptic ulcer develops during treatment with dexketoprofen, therapy should be discontinued immediately.

The risk of developing the above-mentioned adverse events increases proportionally with higher NSAID doses and in patients with a history of gastric or duodenal ulcers, as well as in elderly patients. During treatment, physicians should closely monitor patients due to the potential for gastrointestinal bleeding. Before initiating treatment with dexketoprofen trometamol, and in patients with a history of esophagitis, gastritis, and/or peptic ulcer disease, it should be ensured, as with other NSAIDs, that these conditions are in remission. Patients with existing gastrointestinal symptoms or gastrointestinal disorders in their history require monitoring for the development of gastrointestinal complications, particularly gastrointestinal bleeding.

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

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

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

Renal safety.

The medicinal product should be prescribed with caution in patients with impaired renal function, as NSAIDs may cause deterioration of kidney 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 nephrotoxic effects.

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 medicinal product should be prescribed with caution in patients with impaired liver function. Like other NSAIDs, the drug may cause temporary and slight increases in certain liver parameters, as well as marked elevations in AST and ALT activity. Therapy should be discontinued if such increases occur.

Hepatic function disturbances occur most frequently in elderly patients.

Cardiovascular and cerebral circulation 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 previous episodes of heart failure, as the risk of 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 over prolonged periods) may slightly increase the risk of arterial thrombosis (e.g., myocardial infarction or stroke). Data to exclude such risks with dexketoprofen use 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 should be performed before initiating long-term treatment in patients with risk factors for cardiovascular disease (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 drugs affecting hemostasis, such as warfarin, other coumarins, or heparins. Cardiovascular function disturbances occur most frequently in elderly patients.

Skin reactions.

Rare cases of serious skin reactions (some with fatal outcomes), including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported during NSAID use. The highest risk occurs at the beginning of treatment: most cases occurred within the first month of therapy.

Dexobel should be discontinued at the first signs of skin rash, mucosal lesions, or other symptoms of hypersensitivity.

Masking symptoms of underlying infections.

Dexketoprofen may mask symptoms of infectious diseases, potentially delaying appropriate treatment and thereby complicating the course of illness. Such symptom masking has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. If dexketoprofen is used to relieve pain associated with infection, monitoring of the infectious disease is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Elderly patients.

Elderly individuals have an increased risk of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and gastrointestinal tract perforations, which may be fatal. These patients should initiate treatment with the lowest effective dose (see section "Dosage and administration").

Elderly patients more frequently suffer from impaired renal, cardiovascular, or hepatic function (see section "Dosage and administration").

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);
• dehydration;
• immediately after major surgical procedures.

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

Rare cases of severe acute hypersensitivity reactions (e.g., anaphylactic shock) have been observed. Treatment should be discontinued at the first signs of severe hypersensitivity reactions after taking Dexobel. Depending on symptoms, appropriate treatment should be administered under medical supervision. Patients with bronchial asthma combined with chronic rhinitis, chronic sinusitis, and/or nasal polyps have a higher risk of allergy to acetylsalicylic acid and/or NSAIDs than other patients. Administration of this medicinal product may trigger asthma attacks or bronchospasm, particularly in patients allergic to acetylsalicylic acid or NSAIDs.

In exceptional cases, severe infectious complications of the skin and soft tissues may occur during varicella. Currently, there is insufficient information to completely exclude the role of NSAIDs in exacerbating this infectious process. Therefore, use of the medicinal product Dexobel should be avoided during varicella.

This medicinal product should be used with caution in patients with blood dyscrasias, systemic lupus erythematosus, and mixed connective tissue disorders.

This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

The medicinal product Dexobel is contraindicated in the third trimester of pregnancy and during lactation (see section "Contraindications").

Pregnancy.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or fetal development. According to epidemiological study results, the use of drugs that inhibit prostaglandin synthesis during early pregnancy increases the risk of miscarriage and congenital fetal heart defects and abdominal wall defects. Specifically, the absolute risk of cardiovascular abnormalities increases from < 1% to approximately 1.5%. It is believed that the risk of such events increases with higher drug doses and longer treatment duration. Administration of prostaglandin synthesis inhibitors in animals has 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 increased, including cardiovascular anomalies. However, animal studies with dexketoprofen did not reveal toxic effects on reproductive organs.

From the 20th week of pregnancy, dexketoprofen use may cause oligohydramnios due to fetal renal dysfunction. This disorder may occur soon after starting treatment and is usually reversible upon discontinuation. 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 treatment cessation. Therefore, dexketoprofen may be prescribed during the first and second trimesters only if absolutely necessary. If dexketoprofen is prescribed to women planning pregnancy or during the first and second trimesters, the lowest possible effective dose should be used for the shortest possible duration. Fetal monitoring for oligohydramnios and arterial duct constriction should be considered after exposure to dexketoprofen for several days starting from the 20th gestational week. 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:

• cardiovascular toxicity, e.g., premature constriction/closure of the arterial duct and pulmonary hypertension;
• renal dysfunction (see above).

Risks for the mother at the end of pregnancy and for 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.

Lactation period.

There are no data on the passage of dexketoprofen into breast milk. The medicinal product Dexobel is contraindicated during breastfeeding.

Fertility.

Like all other NSAIDs, dexketoprofen trometamol may reduce female fertility and therefore is not recommended for women planning pregnancy. For women experiencing infertility or undergoing fertility investigations, discontinuation of the drug should be considered.

If dexketoprofen is taken by a woman attempting to conceive or during the first and second trimesters 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 dexketoprofen use, adverse reactions such as dizziness, visual disturbances, or somnolence may occur, which can reduce reaction speed and the ability to drive vehicles or operate machinery.

Method of Administration and Dosage.

Dosage.

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 should not exceed 75 mg. The occurrence of adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to relieve symptoms (see section "Special Instructions"). Dexobel is not intended for long-term therapy; treatment continues only as long as symptoms persist.

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 minimum recommended dose and under strict medical supervision. The daily dose is 50 mg. The medicinal product Dexobel is 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. Dexobel is 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 the absorption of the drug (see section "Pharmacokinetics"); therefore, in acute pain, it is recommended to take the drug at least 30 minutes before a meal.

Children.

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

Overdose.

Symptoms.

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

Treatment.

In case of accidental overdose, immediate symptomatic therapy appropriate 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 table below lists adverse reactions for which a possible causal relationship with dexketoprofen trometamol has been recognized based on clinical data, as well as adverse reactions reported during the post-marketing period.

The most commonly observed adverse reactions are gastrointestinal in nature. Ulceration, perforation or gastrointestinal bleeding, sometimes fatal, particularly in elderly patients, may occur. According to available data, nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, exacerbation of colitis, and Crohn's disease may occur during treatment with the medicinal product. Gastritis is observed less frequently. Edema, arterial hypertension, and heart failure are also possible 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 skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare), are possible.

According to study results 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 suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 film-coated tablets per blister, 2 blisters per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

NOBEL ILAC SANAYI VE TICARET A.S.

Manufacturer's address and location of business activity.

Sankaklar Quarter, Eskisehir Yolu Akcakoca Highway No: 299, 81100 Duzce, Turkey.