Kever® sachet

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT KEIWER® SACHET (KEYWERSACHET)

Composition:

Active substance: dexketoprofen trometamol;

1 sachet contains 36.9 mg of dexketoprofen trometamol, equivalent to 25 mg of dexketoprofen;

Excipients: sucrose, ammonium glycyrrhizinate, neohesperidin dihydrochalcone, colloidal anhydrous silicon dioxide, lemon flavor.

Medicinal form. Granules for oral solution.

Main physicochemical properties: free-flowing granular powder of white or almost white color with a lemon odor.

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 agent belonging to the group of nonsteroidal anti-inflammatory drugs (NSAIDs).

Mechanism of action

The action of NSAIDs is due to reduced synthesis of prostaglandins by inhibition of cyclooxygenase activity. Specifically, NSAIDs inhibit the conversion of arachidonic acid into cyclic endoperoxides PGG2 and PGH2, which are precursors of prostaglandins PGE1, PGE2, PGF2α, PGD2, and PGI2 (prostacyclin), as well as thromboxanes TxA2 and TxB2. In addition, the 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 of the drug. 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 reached within 0.25–0.33 hours. Comparison of dexketoprofen tablets with standard release and granules at doses of 12.5 and 25 mg showed that the two formulations are bioequivalent in terms of bioavailability (AUC). Maximum concentration (Cmax) after administration of granules was 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 half-distribution and half-elimination periods of dexketoprofen trometamol are 0.35 and 1.65 hours, respectively. Similar to other drugs with a high degree of plasma protein binding (99%), the volume of distribution of dexketoprofen averages less than 0.25 L/kg.

Metabolism and excretion

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 found in urine, indicating absence of transformation of the drug into the R-(-) optical isomer in humans. Pharmacokinetic studies indicate that AUC values after repeated administration and single dosing are not different, indicating no accumulation of the active substance.

Preclinical safety data

Standard preclinical studies – including studies on pharmacological safety, genotoxicity, and immunopharmacology – revealed no special risk 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 pathologies 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 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 – due to maternal gastrointestinal tract damage.

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 of the medicinal product.
• Use in patients in whom substances with a similar mechanism of action, for example acetylsalicylic acid and other NSAIDs, induce attacks of bronchial asthma, bronchospasm, acute rhinitis, or lead to the development of nasal polyps, urticaria, or angioedema.
• Known photoallergic or phototoxic reactions during treatment with ketoprofen or fibrates.
• Bleeding or gastrointestinal 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 non-specific ulcerative colitis.
• Severe heart failure.
• Moderate or severe renal impairment (creatinine clearance ≤ 59 mL/min).
• Severe hepatic impairment (Child-Pugh score of 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 following interactions generally characterize 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 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 physician 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 physician 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 blood lithium levels up to toxic values due to reduced renal excretion. Therefore, monitoring of this parameter is required at the beginning of treatment, during dose adjustment, and upon discontinuation of dexketoprofen.
• Methotrexate when administered in high doses (15 mg/week or more): increased blood methotrexate 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 effect of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydration 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 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 of treatment and periodically thereafter. Concomitant use of Kever® Sache and potassium-sparing diuretics may lead to hyperkalemia. Blood potassium concentration should be monitored.
• Methotrexate when administered in low doses (<15 mg/week): possible increase in hematotoxic effects due to reduced renal clearance during anti-inflammatory treatment; if necessary, weekly blood count monitoring is required during the first weeks of using this combination, especially in the presence of even slight renal impairment and in elderly patients.
• Pentoxifylline: increased risk of bleeding; therefore, patient observation and monitoring of bleeding time 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.

Combinations to be considered:

• Beta-blockers: their antihypertensive effect may be reduced due to inhibition of prostaglandin synthesis.
• Cyclosporine and tacrolimus: increased nephrotoxic effects of these drugs due to the influence of NSAIDs on prostaglandin synthesis; regular monitoring of renal function is required when using such combination.
• 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 required in such cases.
• 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 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 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 using NSAIDs 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 Kever® Sache 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 Kever® Sache, 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, especially if complicated by bleeding or perforation, and in elderly patients.

Elderly patients: Elderly patients have an increased frequency of adverse reactions to NSAIDs, particularly 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 should be evaluated to ensure that these conditions are in complete remission, as with other NSAIDs. Patients with existing gastrointestinal symptoms or a history of gastrointestinal disorders should be monitored during treatment for possible complications, particularly gastrointestinal bleeding.

NSAIDs should be used with caution 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 for those taking low-dose acetylsalicylic acid or other medications that increase the risk of gastrointestinal adverse reactions, concomitant use of gastroprotective agents (e.g., misoprostol or proton pump inhibitors) should be considered.

Patients, especially elderly ones, with a history of gastrointestinal adverse reactions should promptly 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 ulcers or bleeding: oral corticosteroids, anticoagulants (e.g., warfarin), SSRIs, or antiplatelet agents such as acetylsalicylic acid.

Renal safety

Kever® Sache 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 diuretic therapy or those at risk of hypovolemia. During treatment, adequate fluid intake should be maintained to prevent dehydration, which may exacerbate renal toxicity.

As with all NSAIDs, Kever® Sache may increase plasma urea 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 disturbances occur most frequently in elderly patients.

Hepatic safety

Kever® Sache should be used with caution in 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, 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 advice. Particular caution is required when treating patients with a history of heart disease, especially those with previous episodes of heart failure, as treatment with this 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 some NSAIDs (especially 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 risks 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, or cerebrovascular disease. Similarly, careful evaluation is required before initiating long-term treatment in patients with risk factors for cardiovascular disease (e.g., hypertension, hyperlipidemia, diabetes, 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 medications affecting hemostasis, such as warfarin, other coumarin derivatives, or heparins. Cardiovascular adverse events occur most frequently in elderly patients.

Skin reactions

Rare cases of serious skin reactions (some fatal) have been reported with NSAIDs, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The risk appears to be 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, Kever® Sache should be discontinued.

Masking symptoms of underlying infections

Kever® Sache may mask symptoms of infectious diseases, potentially delaying appropriate treatment and worsening the course of illness. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When Kever® Sache 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 is required when prescribing the drug to patients:

• with hereditary disorders of porphyrin metabolism (e.g., acute intermittent porphyria);
• with dehydration;
• immediately after major surgical procedures.

If prolonged use of dexketoprofen is deemed necessary by the physician, regular monitoring of liver and kidney function and blood counts is recommended.

In very rare cases, severe acute hypersensitivity reactions (e.g., anaphylactic shock) have been observed. If signs of severe hypersensitivity reactions occur after taking Kever® Sache, treatment should be discontinued immediately. 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. Current data do not fully exclude a role of NSAIDs in exacerbating this infectious process. Therefore, the use of Kever® Sache should be avoided in varicella.

Kever® Sache should be used with caution in patients with blood coagulation disorders, systemic lupus erythematosus, and mixed connective tissue diseases.

This product contains sucrose. Patients with known sugar intolerance should consult their physician before taking this medication.

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

Use during pregnancy or breastfeeding.

Kever® Sache 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.

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 been associated with increased pre- and post-implantation loss and elevated embryofetal mortality. Furthermore, administration of prostaglandin synthesis inhibitors during organogenesis in animals has been linked to increased incidence of fetal malformations, including cardiovascular abnormalities. However, animal studies with dexketoprofen did not reveal any toxic effects on reproductive organs. From the 20th week of pregnancy, the use of Kever® Sache may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation. Dexketoprofen may be used during the first and second trimesters of pregnancy only if clearly 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 should be considered after several days of Kever® Sache exposure, starting from the 20th week of pregnancy. Treatment with Kever® Sache should be discontinued if oligohydramnios is detected.

During the third trimester, all prostaglandin synthesis inhibitors may cause:

Risks to the fetus:

• cardiopulmonary toxicity (e.g., premature closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure and lead to oligohydramnios.

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

Fertility

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

Breastfeeding period

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

Ability to affect reaction speed when driving or operating machinery.

During treatment with Kever® Sache, 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

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.

Side effects can be minimized by using the lowest effective dose for the shortest duration necessary to relieve symptoms.

Kever® Sache 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 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 minimum recommended dose and under strict medical supervision. The daily dose is 50 mg. Kever® Sache is contraindicated in patients with severe hepatic impairment.

Renal impairment. In patients with mild renal impairment (creatinine clearance 60–89 mL/min), the initial total daily dose should be reduced to 50 mg. Kever® Sache is contraindicated in patients with moderate to 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 intake with food slows down 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 dexketoprofen trometamol in granule form has not been studied in children. Therefore, safety and efficacy have not been established in children and adolescents. 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 disturbances (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, 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 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 effects are gastrointestinal (GI). Peptic ulcer, GI perforation or bleeding, sometimes fatal, may occur, particularly in elderly patients. 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 appear during treatment with the drug. Gastritis is observed less frequently. Edema, arterial hypertension, and heart failure have also been reported during NSAID therapy.

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

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 disorders (purpura, aplastic and hemolytic anemia, rarely agranulocytosis and bone marrow hypoplasia).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions.

Shelf life. 2 years.

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

Storage conditions. No special storage conditions required.

Keep out of reach of children.

Packaging.

2.5 g in sachets. 10, 20 or 30 sachets per pack.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.