Ketodexa

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

Composition:

Active substance: dexketoprofen;

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

Excipients: microcrystalline cellulose; corn starch; sodium starch glycolate; glyceryl distearate; coating: hypromellose, titanium dioxide (E 171), polyethylene glycol 6000.

Pharmaceutical form. Film-coated tablets.

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

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic agents. Propionic acid derivatives.

ATC code M01A E17.

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 through inhibition of cyclooxygenase. Specifically, it inhibits the conversion of arachidonic acid into cyclic endoperoxides PGG2 and PGH2, 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. The inhibitory effect of dexketoprofen trometamol on cyclooxygenase isoenzymes COX-1 and COX-2 has been demonstrated in animals and humans. Dexketoprofen trometamol produces analgesic action, 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 achieved 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 through 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. In studies of multiple-dose pharmacokinetics, the area under the concentration-time curve (AUC) after the last dose of dexketoprofen trometamol was not higher than after single administration, demonstrating lack of drug accumulation. When dexketoprofen trometamol is administered with food, AUC values remain unchanged, but Cmax is reduced and the rate of absorption is decreased (increased time to reach maximum concentration (tmax)).

Clinical characteristics.

Indications.

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

Contraindications.

• Hypersensitivity to dexketoprofen or to any other nonsteroidal anti-inflammatory drug (NSAID), or to any of the excipients of the medicinal product.
• Use in patients in whom agents with a similar mechanism of action, such as acetylsalicylic acid and other NSAIDs, induce asthma attacks, 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.
  • Active phase of peptic ulcer disease/gastrointestinal bleeding, recurrent peptic ulcer/gastrointestinal bleeding in history.
  • Chronic dyspepsia.
• Gastrointestinal bleeding or perforation in history associated with the use of NSAIDs.
• Gastrointestinal bleeding, other active bleeding, or increased bleeding tendency.
• Crohn’s disease or ulcerative colitis.
• History of bronchial asthma.
• 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.
• Chronic dyspepsia.
• Active bleeding or increased bleeding tendency.
• Moderate or severe renal impairment (creatinine clearance ≤ 59 mL/min).
• Severe dehydration (due to 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 NSAID class drugs.

Combinations not recommended for use with KETODEXA

• Other NSAIDs (including selective cyclooxygenase-2 inhibitors and salicylates at high doses (≥ 3 g/day)): concurrent use of multiple NSAIDs may increase 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 and due to inhibition of platelet function and damage to the gastric and duodenal mucosa. If concomitant use is necessary, it should be performed 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 is necessary, it should be performed under medical supervision with careful monitoring of appropriate laboratory parameters.
• Corticosteroids: increased risk of peptic ulcers and gastrointestinal bleeding.
• Lithium preparations (reports with several NSAIDs): NSAIDs increase lithium blood levels to toxic values by reducing its renal excretion. Therefore, lithium blood levels should be monitored at the start of dexketoprofen treatment, during dose adjustment, or upon discontinuation of the drug.
• Methotrexate when used at high doses (15 mg/week or more): increased methotrexate blood levels due to reduced renal excretion, leading to hematotoxic effects.
• Hydantoin derivatives and sulfonamides: possible increase in toxicity of these substances.

Combinations with KETODEXA requiring cautious use

• Diuretics, angiotensin-converting enzyme inhibitors ( ACE inhibitors), aminoglycoside antibiotics, and angiotensin II receptor antagonists. Dexketoprofen may reduce the efficacy of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydration or elderly patients), the condition may worsen when drugs that inhibit cyclooxygenase are used concomitantly with ACE inhibitors, angiotensin II receptor antagonists, and aminoglycoside antibiotics. This worsening is usually reversible. When using dexketoprofen concomitantly with any diuretic, ensure the patient is adequately hydrated and monitor renal function during treatment.

• Methotrexate when used at low doses (less than 15 mg/week): possible increased hematotoxic effects due to reduced renal excretion; weekly blood count monitoring is required if such combination is necessary, 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 required.

• Zidovudine: risk of increased toxic effect of zidovudine on erythropoiesis (toxic effect on reticulocytes), potentially leading to severe anemia within one week of NSAID use; therefore, blood analysis with reticulocyte count should be performed during the first 1–2 weeks after initiation of NSAID therapy.

• Sulfonylurea derivatives: NSAIDs may enhance the hypoglycemic effect of sulfonylurea drugs by displacing them from plasma protein binding sites.

Combinations with KETODEXA requiring caution during use

• β-adrenergic blockers: their antihypertensive effect may be reduced due to inhibition of prostaglandin synthesis.

• Cyclosporine and tacrolimus: enhanced nephrotoxic effects of these drugs due to NSAID effects on prostaglandin synthesis; regular monitoring of renal function is required when using such combinations.

• Thrombolytic agents: increased risk of bleeding.

• Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of peptic ulcers and gastrointestinal bleeding.

• Probenecid: increased plasma concentration of dexketoprofen due to reduced rate of its active 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 efficacy of mifepristone. Limited data suggest that concomitant use of NSAIDs and prostaglandins does not affect the action of mifepristone or prostaglandins (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 antibiotics in combination with NSAIDs increase 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, thus requiring 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 45–79 mL/min) should avoid NSAID use for 2 days before and 2 days after pemetrexed administration.

Special precautions for use.

The medicinal product KETODEXA should be used with caution in patients with a history of allergic reactions.

Concomitant use of the drug 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 disorders

Peptic ulcers, with or without perforation and gastrointestinal bleeding (including fatal outcomes), may occur during treatment with NSAIDs. These adverse events may occur at any time during therapy, with or without preceding symptoms, and are independent of a history of severe gastrointestinal disorders. If gastrointestinal bleeding or peptic ulcer develops during treatment with dexketoprofen, therapy 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 ulcer and in elderly patients. During treatment, physicians should closely monitor patients for possible gastrointestinal bleeding. Before initiating treatment with dexketoprofen trometamol, and in patients with a history of esophagitis, gastritis, and/or peptic ulcer, 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 should be monitored for the development of gastrointestinal complications, particularly gastrointestinal bleeding.

NSAIDs should be used cautiously 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 protective agents for the gastrointestinal mucosa (misoprostol, proton pump inhibitors). This also applies to patients requiring concomitant low-dose acetylsalicylic acid or other drugs 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 function disorders

The medicinal product should be used 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 also be used cautiously in patients receiving diuretics or those at risk of hypovolemia. During treatment, patients should receive adequate fluid intake to avoid dehydration, which may exacerbate renal toxicity.

Like all NSAIDs, KETODEXA may increase plasma urea nitrogen and creatinine levels. 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 disorders occur most frequently in elderly patients.

Hepatic function disorders

The medicinal product should be used 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 increases in AST and ALT activity. If significant elevations in these parameters occur, treatment should be discontinued.

Hepatic function disorders occur most frequently in elderly patients.

Cardiovascular and cerebral circulation safety

Patients with mild to moderate arterial hypertension and/or heart failure require monitoring and medical advice. Particular caution is required in patients with a history of heart disease, especially previous episodes of heart failure, as treatment with the drug may increase the risk of heart failure: fluid retention and edema have been reported during NSAID therapy. Clinical studies and epidemiological data suggest that the use of certain NSAIDs (particularly at high doses and for prolonged periods) may slightly increase the risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Data are insufficient to exclude such risk with dexketoprofen use. 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 (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 disorders occur most frequently in elderly patients.

Skin reactions

There have been reports of very rare cases of serious skin reactions (some with fatal outcomes) 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.

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

Masking symptoms of underlying infections

The medicinal product KETODEXA may mask symptoms of infectious diseases, potentially delaying appropriate treatment and thereby complicating the course of the illness. This has been observed in bacterial community-acquired pneumonia and bacterial complications of varicella. When this medicinal product is used to relieve pain associated with infection, monitoring for infectious disease 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);
• 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 taking KETODEXA, treatment should be discontinued. Depending on symptoms, appropriate treatment should be administered under medical supervision.

Patients suffering from 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. Use 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. Data are currently insufficient to completely exclude the role of NSAIDs in exacerbating this infectious process. Therefore, the use of the medicinal product KETODEXA should be avoided in varicella.

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

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 KETODEXA is contraindicated during the third trimester of pregnancy and during breastfeeding.

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or fetal development. Epidemiological studies indicate that the use of drugs inhibiting prostaglandin synthesis in early pregnancy increases the risk of miscarriage and congenital heart defects and gastroschisis in the fetus. The absolute risk of cardiovascular malformations increases from <1% to approximately 1.5%. The risk is considered to increase with higher drug doses and longer treatment duration. In animal studies, prostaglandin synthesis inhibitors increased pre- and post-implantation losses and embryofetal mortality. Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, the frequency of fetal developmental abnormalities, including cardiovascular anomalies, increased. Animal studies with dexketoprofen did not reveal toxic effects on reproductive organs.

Use of dexketoprofen from week 20 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 may be prescribed during the first and second trimesters only if absolutely necessary. When prescribing dexketoprofen 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 dexketoprofen is used for several days starting from week 20 of gestation. Pregnant women should discontinue dexketoprofen if oligohydramnios or fetal ductus arteriosus constriction is detected.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors cause:

• risks to the fetus:

• cardiovascular toxicity, e.g., premature constriction/closure of the ductus arteriosus and pulmonary hypertension;

• renal dysfunction (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 use;

• inhibition of uterine contractility, leading to prolonged labor and delayed delivery.

Breastfeeding period

There are no data on the passage of dexketoprofen into breast milk. The medicinal product 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 infertility or undergoing fertility evaluation should consider discontinuing the drug.

Women attempting to conceive or pregnant during the first and second trimesters should use the lowest effective dose of dexketoprofen for the shortest possible duration.

Ability to influence reaction speed when driving or operating machinery.

During treatment with KETODEXA tablets, adverse effects such as dizziness, visual disturbances, or somnolence may occur, which may reduce reaction speed and the ability to drive or operate machinery.

Method of Administration and Dosage

Adults

Use the lowest effective dose for the shortest duration necessary to relieve symptoms (see section "Special Precautions").

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 medicinal product KETODEXA is not intended for long-term therapy; treatment continues until symptoms resolve. Concomitant food intake reduces the absorption rate of the active substance; therefore, the drug should be taken at least 30 minutes before meals.

For elderly patients, treatment should be initiated 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

For patients with mild to moderate hepatic impairment, treatment should be initiated at the minimum recommended dose and under strict medical supervision. The daily dose is 50 mg. The drug (tablets) is contraindicated in patients with severe hepatic impairment.

Renal Impairment

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

For patients with moderate or severe renal impairment (creatinine clearance ≤ 59 mL/min), the medicinal product KETODEXA tablets are contraindicated.

Children

The use of the drug in children has not been studied; therefore, dexketoprofen should not be prescribed to this age group.

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).

Treatment. In case of accidental overdose, initiate immediate symptomatic therapy according to the patient's clinical condition. 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 below are categorized by frequency of occurrence: common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000).

Blood system disorders: very rare – neutropenia, thrombocytopenia.

Immune system disorders: rare – laryngeal edema; very rare – anaphylactic reactions, including anaphylactic shock.

Metabolism and nutrition disorders: rare – loss of appetite.

Psychiatric disorders: uncommon – insomnia, restlessness.

Nervous system disorders: uncommon – headache, dizziness, somnolence; rare – paresthesia, syncope.

Eye disorders: very rare – blurred vision.

Ear and labyrinth disorders: uncommon – vertigo; very rare – tinnitus.

Cardiac disorders: uncommon – palpitations, flushing; rare – arterial hypertension; very rare – tachycardia, arterial hypotension.

Respiratory system disorders: rare – bradypnea; very rare – bronchospasm, dyspnea.

Gastrointestinal disorders: common – nausea, vomiting, abdominal pain, diarrhea, dyspepsia; uncommon – gastritis, constipation, dry mouth, flatulence; rare – peptic ulcer, ulcer bleeding or perforation; very rare – pancreatitis.

Hepatobiliary disorders: rare – hepatitis, hepatocellular injury.

Skin and subcutaneous tissue disorders: uncommon – rash; rare – urticaria, acne, increased sweating; very rare – Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), pruritus, angioneurotic edema of the face, photosensitivity.

Musculoskeletal and connective tissue disorders: rare – back pain.

Renal and urinary disorders: rare – acute renal failure, polyuria; very rare – nephritis or nephrotic syndrome.

Reproductive system and breast disorders: rare – menstrual cycle disturbances, prostate gland function disorders.

General disorders and administration site conditions: uncommon – fatigue, pain, asthenia, muscle stiffness, malaise; rare – peripheral edema.

Investigations: rare – liver function test abnormalities.

Gastrointestinal disorders: Adverse reactions affecting the gastrointestinal tract are the most commonly observed. In particular, peptic ulcer disease, gastrointestinal perforation or bleeding may occur, sometimes with fatal outcomes, especially 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. Gastritis is observed less frequently. Edema, arterial hypertension, and heart failure may also occur during treatment with NSAIDs.

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

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

According to clinical trials and epidemiological data, the use of certain NSAIDs, particularly at high doses and for prolonged periods, is associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or 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.

Shelf life.

2 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister; 1 or 3 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

ASTRAFARM LLC, Ukraine.

Manufacturer's address.

6 Kyivska St., Vyshneve, Buchanskyi district, Kyiv region, 08132, Ukraine.

Marketing Authorization Holder. BAUM PHARM GmbH Representation Office LLC.

Address of the Marketing Authorization Holder.

66 Shyrokа St., Lviv, 79052, Ukraine.