Dexa-health

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEXA-ZDOROVYE (DEXA-ZDOROVYE)

Composition:

Active substance: dexketoprofen;

1 sachet contains 25 mg of dexketoprofen;

Excipients: ammonium glycyrrhizinate; neohesperidin dihydrochalcone; sucrose; silicon dioxide; quinoline yellow (E 104); lemon flavor containing: flavoring extracts, maltodextrin, gum arabic (E 414), citric acid (E 330).

Pharmaceutical form. Granules for oral solution.

Main physico-chemical properties: contents of the sachet – a mixture of granules and powder of yellow color with lemon taste. A slight fruity odor is permissible.

Pharmacotherapeutic group. Nonsteroidal 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 non-steroidal anti-inflammatory drugs (NSAIDs).

Mechanism of action.

The action of non-steroidal 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), as well as 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 effect.

The inhibitory effect of dexketoprofen on the activity of cyclooxygenase-1 and cyclooxygenase-2 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 action is 4–6 hours.

Pharmacokinetics.

Absorption.

Dexketoprofen trometamol is rapidly absorbed after oral administration. Following administration in granule form, maximum plasma concentration is reached 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 tablet administration.

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 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 is on average less than 0.25 L/kg.

Biotransformation and elimination.

Elimination of dexketoprofen occurs mainly via conjugation with glucuronic acid followed by renal excretion.

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

Pharmacokinetic studies indicate that AUC values after repeated administration and after single dosing are not different, indicating no accumulation of the active substance.

Preclinical safety data.

Standard preclinical studies—pharmacological safety, genotoxicity, and immunopharmacology—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 lesions such as erosions. These effects occurred at doses where drug exposure was 14–18 times higher than at the maximum recommended human dose. Carcinogenicity studies in animals have not been conducted.

Like all NSAIDs, dexketoprofen may lead to embryo or fetal death in animals due to a direct effect on development or indirectly via maternal gastrointestinal tract injury.

Clinical characteristics.

Indications.

Short-term symptomatic treatment of mild to moderate acute pain, for example, 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 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.
• Bleeding or gastrointestinal tract perforation in medical history associated with the use of NSAIDs.
• Active phase of peptic ulcer/gastrointestinal bleeding, bleeding, ulcer, or perforation in the gastrointestinal tract in medical history.
• Chronic dyspepsia.
• Active bleeding or increased bleeding tendency.
• 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.

Unwanted 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, such as warfarin, due to the high degree of plasma protein binding of dexketoprofen, as well as due to platelet function inhibition and damage to the gastric and duodenal mucosa. If concomitant use is necessary, it should be carried out under medical supervision with careful monitoring of relevant laboratory parameters.
• Heparin: increased risk of bleeding (due to platelet function inhibition and damage to the gastric and duoden mucosa). If concomitant use is necessary, it should be carried out 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, this parameter requires monitoring at the start of treatment, during dose adjustments, and upon discontinuation of dexketoprofen.
• Methotrexate when administered 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 requiring caution

• Diuretics, ACE inhibitors, aminoglycoside antibiotics, and angiotensin II receptor antagonists. Dexketoprofen reduces the efficacy of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., due to dehydration or elderly patients with renal impairment), the condition may worsen when combining agents that inhibit cyclooxygenase 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 receives adequate fluid intake, and monitor renal function at the beginning and periodically after treatment initiation. Concomitant use of dexketoprofen and potassium-sparing diuretics may lead to hyperkalemia. Serum potassium concentration should be monitored.
• Methotrexate when administered at low doses (< 15 mg/week): possible increase in hematotoxic effects due to reduced renal clearance while taking anti-inflammatory agents; if necessary, weekly blood count monitoring is required during the first weeks of such combination therapy, especially in the presence of even slight 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) up to development of 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 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.
• 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; 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 indicate 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 dexketoprofen 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, sometimes fatal, have been reported with all NSAIDs at any time during therapy, regardless of the presence of prior symptoms or history of serious gastrointestinal disorders. If gastrointestinal bleeding or ulceration occurs during treatment with dexketoprofen, 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 if 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 these patients should be initiated with the lowest possible dose.

Before starting treatment with dexketoprofen trometamol, patients with a history of esophagitis, gastritis, and/or peptic ulcer disease, as with other NSAIDs, should be evaluated to ensure these conditions are in complete remission. In patients with existing gastrointestinal symptoms or gastrointestinal disorders in their history, monitoring of the gastrointestinal tract for possible complications should be performed during treatment, particularly for gastrointestinal bleeding.

NSAIDs should be used with caution in patients with a history of gastrointestinal disorders (e.g., ulcerative colitis, Crohn’s disease), due to the risk of exacerbation of these conditions.

For such patients and for 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 protective agents, such as misoprostol or proton pump inhibitors.

Patients, especially elderly patients, 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 used with caution in patients who are concurrently taking agents 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 administered with caution to 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 be used with caution in patients receiving diuretics and in 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 plasma urea and creatinine levels. Similar to other prostaglandin synthesis inhibitors, 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 administered with caution to patients with impaired liver function. As with other NSAIDs, the drug may cause transient and mild elevations in some liver function tests, as well as marked increases in AST and ALT activity. If such increases occur, therapy 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 when treating patients with a history of cardiac disorders, especially those with prior episodes of heart failure, as treatment with the drug may increase the risk of heart failure: fluid retention and edema have been observed 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 to exclude such risk with dexketoprofen are insufficient. Therefore, dexketoprofen should be prescribed only after careful assessment of the patient's condition in cases of uncontrolled 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 hypertension, hyperlipidemia, diabetes, smoking).

Cases of Kounis syndrome have been reported in patients receiving dexketoprofen. Kounis syndrome is defined as cardiovascular symptoms caused by an allergic or hypersensitivity reaction associated with coronary artery spasm, which may potentially lead to myocardial infarction.

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 agents affecting hemostasis, such as warfarin, other coumarins, or heparins.

Cardiovascular function disturbances occur most frequently in elderly patients.

Skin reactions.

Very rare cases of serious skin reactions (some fatal) have been reported during NSAID therapy, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The risk of such reactions is likely highest during the initial phase of treatment, with most cases occurring within the first month of therapy.

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

Masking symptoms of underlying infections.

Dexketoprofen may mask symptoms of infectious diseases, potentially delaying appropriate treatment and thereby complicating the course of the disease. This 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.

Other information.

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

• with inherited disorders of porphyrin metabolism (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 signs of severe hypersensitivity reactions occur after taking dexketoprofen, 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, particularly in patients allergic to acetylsalicylic acid or NSAIDs.

In rare cases, severe infectious complications of the skin and soft tissues may occur during varicella. Currently, there is insufficient information to completely rule out a role of NSAIDs in exacerbating this infectious process. Therefore, the use of dexketoprofen should be avoided in varicella.

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

This medicinal product contains sucrose. If the patient has been diagnosed with intolerance to certain sugars, consultation with a physician is recommended before taking this medicinal product. Also, due to the presence of sucrose, the product may be harmful to teeth.

Children.

Safety in children and adolescents has not been established.

Use during pregnancy or breastfeeding.

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

Pregnancy.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic or fetal development. According to epidemiological studies, the use of drugs that inhibit prostaglandin synthesis during early pregnancy increases the risk of miscarriage and congenital malformations, including cardiac defects and abdominal wall defects.

Specifically, 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 caused increased pre- and post-implantation loss and increased embryofetal mortality. Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of fetal developmental abnormalities, including cardiovascular malformations, was observed. However, animal studies with dexketoprofen did not reveal any toxic effects on reproductive organs.

Starting from the 20th week of pregnancy, the use of dexketoprofen may cause oligohydramnios due to fetal renal dysfunction. This may occur shortly after initiation of treatment and is usually reversible upon discontinuation of therapy. Additionally, there have been reports of arterial duct constriction following treatment in the second trimester, most of which resolved after stopping treatment. Therefore, the use of dexketoprofen during the first and second trimesters of pregnancy is possible only if absolutely necessary.

Fetal monitoring for oligohydramnios and arterial duct constriction should be considered after several days of dexketoprofen exposure, starting from the 20th gestational week. The drug should be discontinued if oligohydramnios or arterial duct constriction is detected.

When prescribing dexketoprofen to women planning pregnancy or during the first and second trimesters of pregnancy, the lowest effective dose for the shortest possible duration should be used.

During the third trimester, all prostaglandin synthesis inhibitors cause:

Risks for the fetus:

• cardiopulmonary toxicity, e.g., premature constriction/closure of the arterial duct and pulmonary hypertension;
• renal dysfunction, which may progress to renal failure with development of oligohydramnios (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 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. Dexketoprofen is contraindicated during breastfeeding.

Fertility.

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

Ability to affect reaction speed when driving or operating machinery.

During treatment with dexketoprofen granules, adverse effects such as dizziness, visual disturbances, or somnolence may occur. In such cases, the ability to react quickly when driving or operating 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 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.

Dexketoprofen is intended only for short-term use, required to relieve symptoms.

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. 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 be initiated at the lowest recommended dose and under strict medical supervision. The daily dose is 50 mg. Dexketoprofen 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. Dexketoprofen 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 a meal.

Children.

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

Overdose.

The 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 use, symptomatic treatment appropriate to the patient's clinical condition should be initiated immediately. If the ingested dose exceeds 5 mg/kg in an adult or child, activated charcoal should be administered within one hour. Dexketoprofen trometamol can be removed from the body by dialysis.

Adverse reactions.

The table below lists adverse reactions distributed by organs and systems and frequency of occurrence, which are 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 of dexketoprofen in granule form is higher than that of 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, sometimes with fatal outcomes, may occur, 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 appear during treatment with the drug. Gastritis is reported less frequently. Edema, arterial hypertension, and heart failure have also been reported during treatment with NSAIDs.

Based on clinical trial results and epidemiological data, the use of certain NSAIDs, especially at high doses and for prolonged periods, may be associated with a slight increase in the risk of thrombotic events (e.g., myocardial infarction or stroke).

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

Reporting of adverse reactions

Reporting suspected adverse reactions after the medicine has been authorized is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, as well as patients' legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: 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. 2.5 g of the drug in a sachet, pack of 10 (1×10), pack of 30 (1×30) in a carton.

Prescription status. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

Manufacturer's address and place of business.

22 Shevchenka Street, Kharkiv, Kharkiv Oblast, 61013, Ukraine.