Dexanta

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

Composition:

Active substance: dexketoprofen trometamol;

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

Excipients: aspartame (E 951), quinoline yellow (E 104), lemon flavor, sucrose, colloidal anhydrous silicon dioxide.

Pharmaceutical form. Granules for oral solution.

Main physicochemical properties: granules from light yellow to yellow in color with a lemon taste.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic drugs. Propionic acid derivatives. ATC code M01A E17.

Pharmacological Properties.

Pharmacodynamics.

Dexketoprofen trometamol is the trometamol 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 consists in reducing the synthesis of prostaglandins by inhibiting cyclooxygenase activity. In particular, NSAIDs inhibit the conversion of arachidonic acid into cyclic endoperoxides PGG2 and PGH2, which form prostaglandins PGE1, PGE2, PGF2α, PGD2, and PGI2 (prostacyclin) and thromboxanes TxA2 and TxB2. In addition, inhibition of prostaglandin synthesis may affect other mediators of inflammation, such as kinins, causing 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 trometamol has pronounced analgesic activity. According to some studies, analgesic effect begins within 30 minutes after administration. The duration of analgesic action is 4–6 hours.

Pharmacokinetics.

Absorption.

Dexketoprofen trometamol is rapidly absorbed after oral administration; after administration in granule form, maximum plasma concentration is achieved within 0.25–0.33 hours. A comparison of dexketoprofen tablets with standard release 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 unchanged, but Cmax of dexketoprofen trometamol is reduced and the rate of absorption decreases (tmax is prolonged).

Distribution.

The half-distribution and half-elimination times of dexketoprofen trometamol are 0.35 and 1.65 hours, respectively. Like 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.

Biotransformation and elimination.

Elimination of dexketoprofen occurs mainly via conjugation with glucuronic acid and subsequent renal excretion.

After administration of dexketoprofen trometamol, only the S-(+) optical isomer is detected in urine, indicating the absence of transformation of the drug into the R-(-) optical isomer in humans.

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

Preclinical safety data.

Standard preclinical studies—pharmacological safety, genotoxicity, and immunopharmacology studies—did not reveal any special hazard for humans. Chronic toxicity studies in mice and monkeys identified the no-observed-adverse-effect level (NOAEL), which was found to be twice the maximum recommended human dose. When higher doses were administered to monkeys, the main adverse reactions were fecal blood, reduced body weight gain, and, at the highest dose, gastrointestinal tract lesions such as erosions. These reactions occurred at doses where drug exposure was 14–18 times higher than at the maximum recommended human dose. Carcinogenicity studies in animals were not conducted.

Like all NSAIDs, dexketoprofen may cause embryonic or fetal death in animals, either directly by affecting development or indirectly via maternal gastrointestinal tract injury.

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 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.

Gastrointestinal bleeding or perforation in medical history associated with the use of NSAIDs.

Active phase of peptic ulcer/gastrointestinal bleeding, active bleeding, ulcer, or perforation in the gastrointestinal tract in medical history.

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 or 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.

Undesirable 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 effects of anticoagulants, e.g., warfarin, due to the high degree of plasma protein binding of dexketoprofen, as well as due to inhibition of platelet function and damage to the gastric and duodenal mucosa. If concomitant use is necessary, it should be 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 up to toxic values due to reduced renal excretion. Therefore, monitoring of lithium levels is required at the beginning of treatment, during dose adjustments, and upon discontinuation of dexketoprofen.

Methotrexate when administered in high doses (≥ 15 mg/week): increased methotrexate blood levels due to reduced renal excretion, leading to hematological toxicity.

Hydantoin derivatives and sulfonamides: possible increase in toxicity of these substances.

Combinations requiring caution

Diuretics, 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., dehydrated patients or elderly patients with renal impairment), 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 dexketoprofen is used concomitantly with any diuretic, ensure adequate fluid intake and monitor renal function at the beginning and periodically during treatment. Concomitant use of Dexanta and potassium-sparing diuretics may lead to hyperkalemia. Serum potassium levels should be monitored.

Methotrexate when administered in low doses (< 15 mg/week): possible increase in hematological toxicity due to reduced renal clearance during anti-inflammatory therapy; if necessary, weekly blood monitoring is required during the first weeks of such combination therapy, especially in patients with even mild renal impairment and in elderly patients.

Pentoxifylline: increased risk of bleeding; therefore, patient monitoring and bleeding time assessment are required.

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 should be monitored during the first 1–2 weeks after initiation of NSAID therapy.

Sulfonylurea derivatives: NSAIDs may enhance the hypoglycemic effect of sulfonylurea drugs due to their displacement from plasma protein binding sites.

Combinations to be considered

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

Cyclosporine and tacrolimus: enhanced nephrotoxicity of these drugs due to the effect of NSAIDs on prostaglandin synthesis; regular monitoring of renal function is required when using such combinations.

Thrombolytic agents: increased risk of bleeding.

Platelet aggregation inhibitors and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding.

Probenecid: increased plasma concentration of dexketoprofen due to reduced renal tubular secretion and glucuronidation; dose adjustment of dexketoprofen may be necessary.

Cardiac glycosides: their plasma concentration may increase.

Mifepristone: there is a theoretical risk that prostaglandin synthesis inhibitors may alter the effectiveness of mifepristone. Limited data suggest that concomitant use of NSAIDs and prostaglandins does not affect the action of mifepristone or prostaglandins, specifically cervical ripening or uterine contractility, and does not reduce the clinical efficacy of medical abortion.

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 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 45–79 mL/min) should avoid NSAID use for 2 days before and 2 days after pemetrexed administration.

Special precautions for use.

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

Concomitant use of Dexanta with other NSAIDs, including selective COX-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 preceding symptoms or a history of serious gastrointestinal disorders. If gastrointestinal bleeding or ulceration occurs during treatment with Dexanta, 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 of such 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 be confirmed to be in a state of complete remission, as with other NSAIDs. In patients with existing gastrointestinal symptoms or a history of gastrointestinal disorders, monitoring of the gastrointestinal tract for possible complications—particularly gastrointestinal bleeding—is necessary during treatment.

NSAIDs should be used cautiously in patients with a history of gastrointestinal disorders (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, consideration should be given to concomitant therapy with gastroprotective agents, such as misoprostol or proton pump inhibitors.

Patients, especially the elderly, 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 agents that may increase the risk of ulceration or bleeding: oral corticosteroids, anticoagulants (e.g., warfarin), SSRIs, 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 who may develop hypovolemia.

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

Like all NSAIDs, the drug may increase blood urea nitrogen and serum creatinine levels. Similar to other inhibitors of prostaglandin synthesis, its use may be associated with renal adverse reactions, potentially leading to 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. As with other NSAIDs, it may cause transient and mild increases in certain liver function 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 heart disease, especially those with prior episodes of heart failure, as treatment with the drug may increase the risk of heart failure due to fluid retention and edema. Clinical studies and epidemiological data suggest that some NSAIDs (particularly at high doses and over prolonged periods) may slightly increase the risk of arterial thrombotic events (e.g., myocardial infarction or stroke). 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 arterial disease, and/or cerebrovascular 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) associated with NSAIDs, including exfoliative dermatitis, Stevens–Johnson syndrome, and toxic epidermal necrolysis. The risk is likely highest during the initial stages of treatment, with most cases occurring within the first month.

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

Masking symptoms of underlying infections.

Dexanta may mask symptoms of infectious disease, potentially delaying appropriate treatment and worsening the course of illness. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. If Dexanta 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.

Special caution should be exercised when prescribing the medicinal product 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 deemed necessary by a physician, regular monitoring of liver and kidney function, as well as blood counts, is recommended.

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 Dexanta, treatment should be discontinued. Depending on symptoms, appropriate treatment should be administered under medical supervision.

Patients with asthma combined with chronic rhinitis, chronic sinusitis, and/or nasal polyps have a higher risk of developing allergy to acetylsalicylic acid and/or NSAIDs compared to other patients. Administration of this drug may trigger asthma attacks or bronchospasm, especially in patients allergic to acetylsalicylic acid or NSAIDs.

In rare cases, severe skin and soft tissue infections may occur during varicella. There is currently insufficient data to fully exclude a role of NSAIDs in exacerbating this infectious process. Therefore, use of Dexanta should be avoided in varicella.

The medicinal product Dexanta should be used with caution in patients with coagulation disorders, systemic lupus erythematosus, and 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 by patients with diabetes.

The product contains aspartame, a source of phenylalanine, which is dangerous for patients with phenylketonuria.

Children. Safety in children and adolescents has not been established.

Use during pregnancy or breastfeeding.

The medicinal product Dexanta 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 drugs inhibiting prostaglandin synthesis during early pregnancy increases the risk of miscarriage and fetal congenital heart defects and abdominal wall defects.

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 duration of therapy. In animal studies, prostaglandin synthesis inhibitors have caused increased pre- and post-implantation losses and higher embryofetal mortality. Additionally, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of fetal malformations, including cardiovascular anomalies, 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 during the second trimester, most of which resolved after stopping treatment. Therefore, dexketoprofen should only be prescribed during the first and second trimesters if absolutely necessary. When prescribing dexketoprofen to women planning pregnancy or during the first and second trimesters, the lowest effective dose for the shortest possible duration should be used. Fetal monitoring for oligohydramnios and ductus arteriosus constriction should be considered if exposure to dexketoprofen occurs over 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 may cause:

Risks to the fetus:

• cardiopulmonary 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 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. The medicinal product Dexanta is contraindicated during breastfeeding.

Fertility.

Like all other NSAIDs, Dexanta may reduce female fertility and therefore is not recommended for women planning pregnancy. Women experiencing infertility or undergoing fertility investigations should consider discontinuing dexketoprofen.

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

Dosage

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

Adults.

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

The medicinal product Dexanta is intended only for short-term use required 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 certain types of adverse reactions, elderly patients should be under close medical supervision.

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

Method of Administration

Before administration, 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 rate of drug absorption (see section "Pharmacokinetics"); therefore, for acute pain, it is recommended to take the drug at least 15 minutes before meals.

Children.

The use of Dexanta 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 disturbances (vomiting, anorexia, abdominal pain) and nervous system effects (drowsiness, vertigo, disorientation, headache).

In case of accidental overdose or excessive intake, symptomatic treatment should be initiated immediately according to the patient's clinical condition. Activated charcoal should be administered within one hour if more than 5 mg/kg has been ingested by an adult or child. Dexketoprofen trometamol is eliminated from the body by dialysis.

Adverse reactions

The table below lists adverse reactions distributed by organ systems and frequency of occurrence, which are considered at least possible in relation to the use of dexketoprofen (in tablet form) based on data from clinical studies, as well as adverse reactions reported during the post-marketing period.

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

The most commonly observed adverse reactions are gastrointestinal in nature. Peptic ulcer, gastrointestinal perforation or bleeding, sometimes fatal, especially in elderly patients, may occur. According to available data, 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. Gastritis is observed less frequently. Edema, arterial hypertension, and heart failure have also been reported during treatment with NSAIDs.

According to clinical studies and epidemiological data, the use of certain NSAIDs, particularly 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).

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 suspected adverse reactions.

Reporting of suspected adverse reactions after drug registration is of great importance.
This enables ongoing monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 2 years.

Do not use after the expiry date stated on the packaging.

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

Keep out of reach of children.

Packaging. 2.5 g per sachet. 10 or 30 sachets per cardboard box.

Prescription status. Prescription only.

Manufacturer.

JSC "CHEMICAL PHARMACEUTICAL PLANT "CHERVONA ZIRKA".

Manufacturer's address and location of business activity.

1, Gordienkivska Street, Kharkiv, Kharkiv Oblast, Ukraine, 61010