Ketodexa

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

Composition:

Active substance: dexketoprofen trometamol;

1 sachet contains 36.90 mg of dexketoprofen trometamol, equivalent to 25 mg of dexketoprofen;

Excipients: compressed sugar, ammonium glycyrrhizinate, neohesperidin dihydrochalcone, lemon flavor, coloring agent "Quinoline yellow" (E 104).

Pharmaceutical form. Granules for oral solution.

Main physicochemical properties: yellow granules with a lemon odor.

Pharmacotherapeutic group. Non-steroidal 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. It is an analgesic, anti-inflammatory, and antipyretic medicinal product belonging to the group of nonsteroidal anti-inflammatory drugs (NSAIDs).

Mechanism of action

The action of nonsteroidal anti-inflammatory drugs is based on reducing the synthesis of prostaglandins by inhibiting cyclooxygenase activity. Specifically, NSAIDs inhibit the conversion of arachidonic acid into cyclic endoperoxides PGG2 and PGH2, which form prostaglandins PGE1, PGE2, PGF2α, PGD2, and PGI2 (prostacyclin), as well as thromboxanes TxA2 and TxB2. In addition, inhibition of prostaglandin synthesis may affect other mediators of inflammation, such as kinins, resulting in an indirect effect that complements the direct action.

Pharmacodynamic action

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

Clinical efficacy and safety

Clinical studies in various types of pain have shown that dexketoprofen has pronounced analgesic activity. According to some studies, analgesic effect begins within 30 minutes after administration. The duration of analgesic effect lasts 4–6 hours.

Pharmacokinetics

Absorption

Dexketoprofen trometamol is rapidly absorbed after oral administration. When administered in granule form, maximum plasma concentration is reached within 0.25–0.33 hours. Comparison of standard-release dexketoprofen tablets and granules at doses of 12.5 and 25 mg showed that the two formulations are biologically equivalent in terms of bioavailability (AUC). Peak concentrations (Cmax) after administration of granules were approximately 30% higher than after administration of tablets.

When administered with food, AUC is not altered, but Cmax of dexketoprofen trometamol is reduced and the rate of absorption decreases (tmax is prolonged).

Distribution

The distribution half-life and elimination half-life of dexketoprofen trometamol are 0.35 hours and 1.65 hours, respectively. Similar to other medicinal products with a high degree of plasma protein binding (99%), the volume of distribution of dexketoprofen averages less than 0.25 L/kg.

Metabolism and elimination

Dexketoprofen is eliminated primarily via conjugation with glucuronic acid, followed by renal excretion.

After administration of dexketoprofen trometamol, only the S-(+) optical isomer is found in urine, indicating the absence of in vivo conversion of the drug to the R-(-) optical isomer in humans.

Pharmacokinetic studies indicate that AUC values after repeated administration do not differ from those after single dosing, indicating no accumulation of the active substance.

Preclinical safety data

Standard preclinical studies—including pharmacological safety, genotoxicity, and immunopharmacology assessments—revealed no special hazard for humans. Chronic toxicity studies in mice and monkeys identified the no-observed-adverse-effect level (NOAEL), which was found to be 2 times higher than the maximum recommended human dose. At higher doses in monkeys, the main adverse reactions were fecal blood, reduced body weight gain, and at the highest dose, gastrointestinal lesions such as erosions. These effects occurred at exposure levels 14–18 times higher than those at the maximum recommended human dose. Carcinogenicity studies in animals have not been conducted.

Like all NSAIDs, dexketoprofen may cause embryonic or fetal death in animals due to a direct effect on development or indirectly via maternal gastrointestinal toxicity.

Clinical characteristics.

Indications.

Short-term symptomatic treatment of mild to moderate acute pain, such as musculoskeletal pain, dysmenorrhea, and dental pain.

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 substances with a similar mechanism of action, e.g. acetylsalicylic acid and other NSAIDs, induce asthma attacks, bronchospasm, acute rhinitis, or lead to nasal polyps, urticaria, or angioedema.

• Known photoallergic or phototoxic reactions during treatment with ketoprofen or fibrates.

• History of gastrointestinal bleeding or perforation associated with previous use of NSAIDs.

• Active phase of peptic ulcer disease/gastrointestinal bleeding, history of gastrointestinal bleeding, ulcer, or perforation.

• Chronic dyspepsia.

• Active bleeding or increased tendency to bleeding.

• Crohn’s disease or ulcerative colitis.

• Severe heart failure.

• Moderate or severe renal impairment (creatinine clearance ≤ 59 mL/min).

• Severe hepatic impairment (Child–Pugh score 10–15 points).

• Hemorrhagic diathesis or other coagulation disorders.

• 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 are generally characteristic of NSAID-class drugs.

Unrecommended combinations:

• Other NSAIDs (including selective cyclooxygenase-2 inhibitors and high-dose salicylates (≥ 3 g/day)): concomitant use of multiple NSAIDs may increase the risk of gastrointestinal ulcers and bleeding due to synergistic effects.

• Anticoagulants: NSAIDs enhance the effect of anticoagulants, e.g. warfarin, due to high plasma protein binding of dexketoprofen, as well as due to inhibition of platelet function and damage to the gastric and duodenal mucosa. If concomitant use is necessary, it should be performed under medical supervision with careful monitoring of relevant 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 relevant 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, monitoring of lithium levels is required at the beginning of treatment, during dose adjustment, and upon discontinuation of dexketoprofen.

• Methotrexate when administered at high doses (15 mg/week or more): increased blood levels of methotrex游戏副本

Special precautions for use.

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

Concomitant use of Ketedex with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see gastrointestinal and cardiovascular risks below).

Gastrointestinal safety.

Gastrointestinal bleeding, ulceration, or perforation have been reported with all NSAIDs at various stages of treatment, regardless of the presence of initial symptoms or a history of serious gastrointestinal pathology. If gastrointestinal bleeding or ulceration occurs during treatment with Ketedex, the drug should be discontinued.

The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, in patients with a history of peptic ulcer, particularly complicated by bleeding or perforation, and in elderly patients.

Elderly patients: Elderly patients have an increased frequency of adverse reactions to nonsteroidal anti-inflammatory drugs, especially gastrointestinal bleeding and perforation, which may be life-threatening. Treatment in these patients should begin with the lowest possible dose.

Before initiating treatment with dexketoprofen trometamol, patients with a history of esophagitis, gastritis, and/or peptic ulcer disease should have these conditions confirmed to be in complete remission, as with other NSAIDs. Patients with existing gastrointestinal symptoms or a history of gastrointestinal disorders should be monitored for possible complications during treatment, particularly gastrointestinal bleeding.

NSAIDs should be used with caution in patients with a history of gastrointestinal diseases (e.g., ulcerative colitis, Crohn’s disease), as there is a risk of exacerbation of these conditions.

For such patients and those taking low-dose acetylsalicylic acid or other agents that increase the risk of gastrointestinal adverse reactions, combination therapy with gastroprotective agents (e.g., misoprostol or proton pump inhibitors) should be considered.

Patients, especially elderly ones, with a history of gastrointestinal adverse reactions should report any unusual gastrointestinal symptoms (particularly gastrointestinal bleeding), especially during the initial stages of treatment.

The drug should be prescribed with caution to patients who are concurrently taking medications that may increase the risk of ulceration or bleeding: oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents such as acetylsalicylic acid.

Renal safety.

The drug should be used with caution in patients with impaired renal function, as NSAIDs may worsen renal function, cause fluid retention, and edema. Due to the increased risk of nephrotoxicity, the drug should be used cautiously in patients receiving diuretics or those at risk of hypovolemia.

During treatment, patients should maintain adequate fluid intake to prevent dehydration, which may exacerbate renal toxicity.

Like all NSAIDs, the drug may increase blood urea nitrogen and creatinine levels in plasma. Similar to other inhibitors of prostaglandin synthesis, 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 used with caution in patients with impaired liver function. Similar to other NSAIDs, the drug may cause transient and mild increases in certain liver parameters, as well as marked elevations in AST and ALT activity. If such increases occur, treatment should be discontinued.

Hepatic function disturbances occur most frequently in elderly patients.

Cardiovascular and cerebrovascular safety.

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

All nonselective NSAIDs can reduce platelet aggregation and prolong bleeding time by inhibiting prostaglandin synthesis. Therefore, dexketoprofen trometamol is not recommended for patients taking agents affecting hemostasis, 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) during NSAID use, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The risk is likely highest at the beginning of treatment, with most cases occurring within the first month.

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

Masking symptoms of underlying infections.

Ketedex may mask symptoms of infectious disease, potentially delaying appropriate treatment and worsening the disease course. This has been observed in bacterial community-acquired pneumonia and bacterial complications of varicella. When Ketedex is used to relieve pain associated with infection, monitoring for infection is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Other information.

Particular caution should be exercised when prescribing the drug to patients:

• with inherited 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, regular monitoring of liver and kidney function and blood counts should be performed.

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 Ketedex, treatment should be discontinued. Depending on symptoms, necessary 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 allergy to acetylsalicylic acid and/or NSAIDs than other patients. This drug may trigger asthma attacks or bronchospasm, especially in patients allergic to acetylsalicylic acid or NSAIDs.

In rare cases, severe skin and soft tissue infections may develop during varicella. Current data do not fully exclude a role of NSAIDs in exacerbating this infectious process. Therefore, Ketedex should be avoided during varicella.

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

This medicinal product contains sucrose. Patients with rare hereditary conditions such as fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this product. This should be considered in diabetic patients.

Children. Safety and efficacy in children and adolescents have not been established.

Use during pregnancy or breastfeeding.

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

Pregnancy.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic and fetal development. Epidemiological studies indicate that use of prostaglandin synthesis inhibitors during early pregnancy increases the risk of miscarriage and congenital heart defects and abdominal wall defects in the fetus.

For example, the absolute risk of cardiovascular malformations increases from less than 1% to approximately 1.5%. The risk is believed to increase with higher drug doses and longer treatment duration. Animal studies with prostaglandin synthesis inhibitors have shown increased pre- and post-implantation loss and elevated embryofetal mortality. In animals treated with prostaglandin synthesis inhibitors during organogenesis, a higher incidence of fetal malformations, including cardiovascular abnormalities, has been observed. However, animal studies with dexketoprofen did not reveal toxic effects on reproductive organs. 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 in 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. When prescribing dexketoprofen to women planning pregnancy or during the first and second trimesters, the lowest effective dose should be used 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 cause:

Risks to the fetus:

• cardiopulmonary toxicity, e.g., premature constriction/closure of the ductus arteriosus and pulmonary hypertension;
• renal dysfunction, which may progress to renal failure with development of oligohydramnios;

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

• prolonged bleeding time due to inhibition of platelet aggregation, even at low doses;
• inhibition of uterine contractility, leading to prolonged labor and delayed delivery.

Breastfeeding.

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

Fertility.

Like all other NSAIDs, Ketedex may reduce female fertility and is therefore not recommended for women attempting to conceive. Women experiencing infertility or undergoing fertility investigations should consider discontinuing dexketoprofen.

Effect on ability to drive vehicles or operate machinery.

During treatment with Ketedex granules, adverse effects such as dizziness, visual disturbances, or drowsiness may occur. In such cases, the ability to drive vehicles or operate machinery may be impaired.

Method of Administration and Dosage.

Dosing.

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

Adults.

Depending on the type and intensity of pain, the recommended dose is 25 mg every 8 hours. The daily dose must not exceed 75 mg.

Ketodex is intended only for short-term use necessary to relieve symptoms.

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. Due to the risk of adverse reactions of a certain profile, elderly patients should be under close medical supervision.

Hepatic impairment.

For patients with mild to moderate hepatic impairment, treatment should begin with the lowest recommended dose and under strict medical supervision. The daily dose is 50 mg. Ketodex is contraindicated in patients with severe hepatic dysfunction.

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. Ketodex is contraindicated in patients with moderate or severe renal impairment (creatinine clearance ≤ 59 mL/min).

Method of Administration.

Before use, dissolve the entire contents of one sachet in a glass of water and mix thoroughly for better dissolution. The resulting solution should be taken immediately after preparation.

Concomitant administration with food slows the absorption rate of the drug (see section "Pharmacokinetics"); therefore, in case of acute pain, it is recommended to take the drug at least 15 minutes before meals.

Children.

The use of Ketodex 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 of overdose are unknown. Similar medicinal products may cause gastrointestinal disorders (vomiting, anorexia, abdominal pain) and nervous system disorders (drowsiness, vertigo, disorientation, headache).

In case of accidental overdose or excessive use, symptomatic therapy should be initiated immediately according to the patient's clinical condition. If the ingested dose exceeds 5 mg/kg in an adult or child, activated charcoal should be administered within one hour. Dexketoprofen trometamol is eliminated from the body by dialysis.

Adverse reactions

The table below lists adverse reactions by system organ class and frequency of occurrence, which have been considered at least possibly related to the use of dexketoprofen (in tablet form) based on clinical trial data, as well as adverse reactions reported during the post-marketing period.

Since the Cmax plasma level for dexketoprofen in granule form is higher than that for tablets, an increased risk of adverse reactions (particularly gastrointestinal) cannot be excluded.

The most commonly observed adverse effects are those related to the gastrointestinal tract. Peptic ulcer, perforation, or gastrointestinal bleeding may occur, sometimes resulting in fatal outcomes, particularly in elderly patients. According to available data, nausea, vomiting, diarrhea, flatulence, constipation, dyspeptic symptoms, abdominal pain, melena, hematemesis, ulcerative stomatitis, and exacerbations of colitis and Crohn's disease may occur during treatment with the drug. Gastritis is reported less frequently. Edema, arterial hypertension, and heart failure have also been reported during treatment with NSAIDs.

According to results of clinical studies and epidemiological data, the use of certain NSAIDs, especially at high doses and over prolonged periods, may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

As with other NSAIDs, the following adverse reactions may occur: aseptic meningitis, primarily in patients with systemic lupus erythematosus or mixed connective tissue disorders, and blood-related reactions (purpura, aplastic and hemolytic anemia, rarely agranulocytosis and bone marrow hypoplasia).

Reporting of suspected adverse reactions

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

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

Sachets of 2.5 g; 10, 20, 30, or 40 sachets in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LLC "AstraPharm".

Manufacturer's location and address of business activity.

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

Marketing Authorization Holder. LLC "Representation BAUM PHARM GmbH".

Address of the Marketing Authorization Holder.

66, Shyrokа Street, Lviv, 79052, Ukraine.