Keiver granules for oral solution 25 mg sachet 2.5 g No. 30

Instructions for use: Keiver granules for oral solution 25 mg, sachet 2.5 g, No. 30

Composition

active ingredient: dexketoprofen trometamol;

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

excipients: sucrose, ammonium glycyrrhizate, neohesperidin dihydrochalcone, colloidal anhydrous silicon dioxide, lemon flavoring.

Dosage 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 drugs. Propionic acid derivatives. ATX code M01A E17.

Pharmacological properties

Pharmacodynamics.

Dexketoprofen trometamol is the tromethamine salt of (S)-(+)-2-(3-benzoylphenyl)propionic acid. It is an analgesic, anti-inflammatory, antipyretic drug belonging to the group of nonsteroidal anti-inflammatory drugs (NSAIDs).

Mechanism of action

The action of NSAIDs is to reduce prostaglandin synthesis by inhibiting cyclooxygenase activity. In particular, NSAIDs inhibit the conversion of arachidonic acid to the cyclic endoperoxides PGG2 and PGH2, which form the prostaglandins PGE1, PGE2, PGF2α, PGD2 and PGI2 (prostacyclin) and the thromboxanes TxA2 and TxB2. In addition, inhibition of prostaglandin synthesis may affect other inflammatory mediators, such as kinins, causing an indirect effect that would be additional to the direct effect.

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 a pronounced analgesic activity. According to some studies, the analgesic effect occurs 30 minutes after taking the drug. The duration of the analgesic effect is 4-6 hours.

Pharmacokinetics.

Absorption

Dexketoprofen trometamol is rapidly absorbed after oral administration, with peak plasma concentrations occurring 0.25-0.33 hours after administration of the granules. A comparison of dexketoprofen tablets with a standard release time and granules with a dosage of 12.5 and 25 mg showed that the two forms are bioequivalent in terms of bioavailability (AUC). The peak concentration (Cmax) after administration of the granules was approximately 30% higher than after administration of the tablets.

When administered with food, the AUC does not change, but the Cmax of dexketoprofen trometamol decreases and the rate of its absorption decreases (tmax increases).

Distribution

The half-life and elimination half-life of dexketoprofen trometamol are 0.35 and 1.65 hours, respectively. Similar to other drugs with a high degree of binding to plasma proteins (99%), the volume of distribution of dexketoprofen is on average less than 0.25 l/kg.

Biotransformation and excretion

Dexketoprofen is eliminated mainly by conjugation with glucuronic acid and subsequent renal excretion.

After administration of dexketoprofen trometamol, only the S-(+) optical isomer is detected in the urine, which indicates that the drug is not transformed into the R-(-) optical isomer in humans. Pharmacokinetic studies show that the AUC values after multiple administration of the drug and after a single dose do not differ, indicating that there is no cumulation of the drug substance.

Preclinical safety data

Standard preclinical studies – safety pharmacology, genotoxicity and immunopharmacology – revealed no special hazard for humans. Chronic toxicity studies in mice and monkeys revealed a maximum no-effect dose of the drug that was 2 times higher than the maximum recommended human dose. When higher doses of the drug were administered to monkeys, the main adverse reactions were blood in the stool, decreased body weight gain, and at the highest dose – gastrointestinal pathologies in the form of erosions. These reactions occurred at doses at which the 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 can cause embryo or fetal death in animals by directly affecting its development or indirectly by damaging the gastrointestinal tract of the mother.

Indication

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

Contraindication

Hypersensitivity to the active substance or to any other non-steroidal anti-inflammatory drug (NSAID) or to any of the excipients of the drug. Use in patients in whom substances with a similar mechanism of action, such as acetylsalicylic acid and other NSAIDs, cause 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. History of gastrointestinal bleeding or perforation associated with the use of NSAIDs. Active phase of peptic ulcer disease/gastrointestinal bleeding, history of bleeding, ulceration or perforation of the digestive tract. Chronic dyspepsia. Bleeding in the active phase or increased bleeding. Crohn's disease or nonspecific ulcerative colitis. Severe heart failure. Moderate or severe renal impairment (creatinine clearance ≤ 59 ml/min). Severe hepatic impairment (Child-Pugh score 10-15). Hemorrhagic diathesis or other blood clotting disorders. Severe dehydration (due to vomiting, diarrhea or insufficient fluid intake). Third trimester of pregnancy and lactation (see section "Use during pregnancy or lactation").

Interaction with other medicinal products and other types of interactions

The following drug interactions generally characterize the NSAID class of drugs.

Undesirable combinations:

Other NSAIDs (including selective cyclooxygenase-2 inhibitors and salicylates at high doses (≥3 g/day)): the use of several NSAIDs at the same time may increase the risk of gastrointestinal ulcers and bleeding due to a synergistic effect. Anticoagulants: NSAIDs enhance the effect of anticoagulants, such as warfarin, due to the high degree of binding of dexketoprofen to plasma proteins, 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 carried out under medical supervision and 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 carried out under medical supervision and with careful monitoring of relevant laboratory parameters. Corticosteroids: increased risk of peptic ulcers and bleeding in the digestive tract. Lithium preparations (reported for several NSAIDs): NSAIDs increase the level of lithium in the blood to toxic values by reducing its excretion by the kidneys. Therefore, this parameter requires monitoring at the beginning of treatment, during dose adjustment and when canceling dexketoprofen. Methotrexate when used in high doses (15 mg/week and more): the level of methotrexate in the blood increases by reducing its excretion by the kidneys, which leads to toxic effects on the blood system. Hydantoin derivatives and sulfonamides: possible increase in the toxicity of these substances.

Combinations requiring careful use:

Diuretics, ACE inhibitors, aminoglycoside antibiotics and angiotensin II receptor antagonists. Dexketoprofen weakens the effect of diuretics and other antihypertensive agents. In some patients with impaired renal function (for example, in case of dehydration or in elderly patients with impaired renal function), the condition may worsen when drugs that inhibit the action of cyclooxygenase are used simultaneously with ACE inhibitors, angiotensin II receptor antagonists and aminoglycoside antibiotics. This deterioration is usually reversible. When using dexketoprofen simultaneously with any diuretic, it is necessary to ensure that the patient receives enough fluid, and renal function should be monitored at the beginning of treatment and periodically thereafter. The simultaneous use of the drug Keiver® Sachet and potassium-sparing diuretics may lead to hyperkalemia. It is necessary to monitor the concentration of potassium in the blood. Methotrexate when used in low doses (less than 15 mg/week): possible increase in toxic effects on the blood system due to reduced renal clearance while taking anti-inflammatory drugs; if necessary, weekly blood count monitoring is necessary during the first weeks of using such a combination, especially in the presence of even a slight decrease in renal function, as well as in elderly people. Pentoxifylline: increased risk of bleeding, therefore it is necessary to monitor the patient and control bleeding time. Zidovudine: there is a risk of increased toxic effects of zidovudine on erythropoiesis (toxic effects on reticulocytes) up to the development of severe anemia a week after using NSAIDs, therefore in the first 1-2 weeks after starting NSAID therapy, it is necessary to monitor blood tests with a count of the number of reticulocytes. Sulfonylureas: NSAIDs may enhance the hypoglycemic effect of sulfonylureas by displacing them from blood protein binding.

Beta-blockers: their antihypertensive effect may be reduced due to inhibition of prostaglandin synthesis. Cyclosporine and tacrolimus: increased renal toxicity due to the effect of NSAIDs on prostaglandin synthesis; when using this combination, regular monitoring of renal function is necessary. Thrombolytic drugs: 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 a decrease in its renal tubular secretion and glucuronidation; in this case, a dose adjustment of dexketoprofen is required. Cardiac glycosides: their plasma concentration may increase. Mifepristone: there is a theoretical risk that prostaglandin synthesis inhibitors may change the efficacy of mifepristone. Limited data suggest that concomitant use of NSAIDs and prostaglandins does not affect the effects of mifepristone or prostaglandins, namely cervical ripening or uterine contractility, and does not reduce the clinical efficacy of medical abortion. Quinoline antibiotics: Animal studies have shown that high doses of quinoline antibiotics in combination with NSAIDs increase the risk of convulsions. Tenofovir: Concomitant use with NSAIDs may increase blood urea nitrogen and creatinine, therefore renal function should be monitored to monitor for potential synergistic effects on renal function. Deferasirox: Concomitant use with NSAIDs may increase gastrointestinal (GI) toxicity and requires close clinical monitoring. Pemetrexed: Concomitant use with NSAIDs may reduce the elimination of pemetrexed, therefore caution should be exercised when administering higher doses of NSAIDs. Patients with mild to moderate renal impairment (creatinine clearance 45 to 79 mL/min) should avoid NSAIDs for 2 days before and 2 days after pemetrexed administration.

Application features

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

The simultaneous use of Keiver® Sachet in combination 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 time necessary to relieve symptoms (see gastrointestinal and cardiovascular risks below).

Gastrointestinal safety

Gastrointestinal bleeding, ulceration or perforation, in some cases fatal, have been reported with all NSAIDs at various stages of treatment, regardless of the presence of warning symptoms or a history of serious gastrointestinal disease. If gastrointestinal bleeding or ulceration occurs during the use of Kevere® Sachet, the drug should be discontinued.

The risk of gastrointestinal bleeding, ulceration or perforation increases with increasing NSAID dose in patients with a history of ulcer, especially complicated by bleeding or perforation, and in elderly patients.

Elderly patients: Elderly patients are more likely to experience adverse reactions to NSAIDs, especially gastrointestinal bleeding and ulceration, which may be life-threatening. Treatment of these patients should be started at the lowest possible dose.

Before starting the use of dexketoprofen trometamol in patients with a history of esophagitis, gastritis and/or peptic ulcer disease, as in the case of the use of other NSAIDs, it should be ensured that these diseases are in complete remission. In patients with existing symptoms of gastrointestinal pathology and with a history of gastrointestinal diseases, the gastrointestinal tract should be monitored for possible disorders during the use of the drug, especially gastrointestinal bleeding.

NSAIDs should be prescribed with caution to patients with a history of gastrointestinal diseases (ulcerative colitis, Crohn's disease), as there is a risk of exacerbation of these diseases.

For such patients and patients taking low-dose acetylsalicylic acid or other drugs that increase the risk of gastrointestinal adverse reactions, combination therapy with protective drugs, such as misoprostol or proton pump inhibitors, should be considered.

Patients, especially the elderly, with a history of gastrointestinal adverse reactions should report, especially in the initial stages of treatment, any unusual symptoms related to the digestive system (in particular gastrointestinal bleeding).

Caution should be exercised when prescribing the drug to patients who are concomitantly taking medications that may increase the risk of ulceration or bleeding: oral corticosteroids, anticoagulants (e.g. warfarin), SSRIs or antiplatelet agents such as acetylsalicylic acid.

Patients with impaired renal function should be prescribed the drug with caution, since the use of NSAIDs may worsen renal function, fluid retention and edema. Given the increased risk of nephrotoxicity, the drug should be prescribed with caution in treatment with diuretics, as well as in patients who may develop hypovolemia. During treatment, the body should receive a sufficient amount of fluid to avoid dehydration, which can lead to increased toxic effects on the kidneys.

Like all NSAIDs, the drug is capable of increasing the level of urea nitrogen and creatinine in the blood plasma. Like other prostaglandin synthesis inhibitors, its use may be accompanied by adverse reactions from the kidneys, which can lead to glomerulonephritis, interstitial nephritis, papillary necrosis, nephrotic syndrome and acute renal failure. Most often, renal dysfunction occurs in elderly patients.

Liver safety

Patients with impaired liver function should be prescribed the drug with caution. As with other NSAIDs, the drug may cause a temporary and slight increase in some liver parameters, as well as a pronounced increase in the activity of AST and ALT. If these parameters increase, therapy should be discontinued.

Most liver dysfunction occurs in elderly patients.

Safety regarding the cardiovascular system and cerebral circulation

Patients with a history of hypertension and/or mild to moderate heart failure require monitoring and advice. Particular caution should be exercised when treating patients with a history of heart disease, in particular with previous episodes of heart failure, since the risk of developing heart failure is increased with the use of the drug; fluid retention in the tissues and the formation of edema have been observed with NSAIDs. Clinical studies and epidemiological data suggest that the risk of arterial thrombosis (for example, myocardial infarction or stroke) may be slightly increased with the use of some NSAIDs (especially in high doses and for long periods). There is insufficient data to exclude such a risk with the use of dexketoprofen. Therefore, in case of uncontrolled arterial hypertension, congestive heart failure, ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease, dexketoprofen should be prescribed only after careful assessment of the patient's condition. Equally careful consideration should be made before initiating long-term treatment in patients with risk factors for cardiovascular disease (arterial hypertension, hyperlipidemia, diabetes mellitus, smoking).

All non-selective NSAIDs can reduce platelet aggregation and increase bleeding time by inhibiting prostaglandin synthesis. Therefore, it is not recommended to prescribe dexketoprofen trometamol to patients taking drugs that affect hemostasis, such as warfarin, other coumarins or heparins. The greatest number of cardiovascular system disorders occurs in elderly patients.

Skin reactions

There have been very rare reports of serious skin reactions (some fatal) with NSAIDs, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis. The risk of these reactions is likely to be greatest at the start of treatment, with most patients experiencing them within the first month of treatment. At the first sign of skin rash, mucosal lesions or other signs of hypersensitivity, Kevere® Sachet should be discontinued.

Masking the symptoms of underlying infections

Keiver® Sachet may mask the symptoms of an infectious disease, which may delay the initiation of appropriate treatment and thereby complicate the course of the disease. This has been observed in bacterial community-acquired pneumonia and bacterial complications of varicella. When Keiver® Sachet is used to relieve pain in an infection, monitoring for the infectious disease is recommended. In the setting of treatment outside a medical facility, the patient should consult a doctor if symptoms persist or worsen.

Other information

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

with hereditary disorders of porphyrin metabolism (for example, in acute intermittent porphyria); with dehydration; immediately after major surgical interventions.

If the doctor considers that long-term use of dexketoprofen is necessary, liver and kidney function, as well as blood counts, should be regularly monitored.

Patients with asthma in combination with chronic rhinitis, chronic sinusitis and/or nasal polyps are at higher risk of developing allergy to acetylsalicylic acid and/or NSAIDs than other patients. The administration of this drug may cause asthma attacks or bronchospasm, especially in patients with allergy to acetylsalicylic acid or NSAIDs.

In special cases, severe infectious complications of the skin and soft tissues may develop in the setting of chickenpox. To date, there is no data that allows us to completely exclude the role of NSAIDs in the exacerbation of this infectious process. Therefore, the use of Keiver® Sachet should be avoided in chickenpox.

Keiver® Sachet should be used with caution in patients with hematopoietic disorders, systemic lupus erythematosus, and mixed connective tissue diseases.

This medicinal product contains sucrose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

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

Use during pregnancy or breastfeeding

Keiver® Sachet is contraindicated in the third trimester of pregnancy and during breastfeeding.

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryo-fetal development. Epidemiological studies have shown that the use of drugs that inhibit prostaglandin synthesis in early pregnancy increases the risk of miscarriage, fetal heart defects, and anterior abdominal wall nonunion.

Thus, the absolute risk of developing cardiovascular anomalies increased from less than 1% to approximately 1.5%. It is believed that the risk of such events increases with increasing dose and duration of therapy. The use of prostaglandin synthesis inhibitors in animals caused an increase in pre- and post-implantation losses and increased embryo-fetal mortality. In addition, in animals treated with prostaglandin synthesis inhibitors during the period of organogenesis, the incidence of fetal malformations, including cardiovascular anomalies, increased. However, studies of dexketoprofen in animals did not reveal toxic effects on the reproductive organs. Starting from the 20th week of pregnancy, the use of Keiver® Sachet may cause oligohydramnios due to fetal renal dysfunction. This can occur soon after the start of treatment and is usually reversible after discontinuation of treatment. The appointment of dexketoprofen in the I and II trimesters of pregnancy is possible only in case of extreme necessity. When prescribing dexketoprofen to women planning pregnancy or during the first and second trimesters of pregnancy, the lowest effective dose should be used for the shortest possible duration of treatment. Antenatal monitoring for oligohydramnios should be considered after exposure to Keiver® Sachet for several days, starting from the 20th week of pregnancy. Keiver® Sachet should be discontinued if oligohydramnios is detected.

During the third trimester, all prostaglandin synthesis inhibitors 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 with oligohydramnios

Risks for the woman at the end of pregnancy and for the newborn:

increased bleeding time due to inhibition of platelet aggregation, even when using the drug in low doses; inhibition of uterine contractile activity, which leads to prolongation and delay of labor.

Fertility

As with all NSAIDs, Kevere® Sachet may impair female fertility and is therefore not recommended in women attempting to conceive. Women who have difficulty conceiving or are undergoing investigation of infertility should consider discontinuing dexketoprofen.

Breastfeeding period

There is no data on the penetration of dexketoprofen into breast milk. Keiver® Sachet is contraindicated during breastfeeding.

Ability to influence reaction speed when driving vehicles or other mechanisms

When using the drug Keiver® Sachet, undesirable effects such as dizziness, visual disturbances or drowsiness may occur. In such cases, a decrease in the speed of reactions when driving vehicles or other mechanisms is possible.

Method of administration and doses

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 possible time necessary to relieve symptoms.

Keiver® Sachet is intended only for short-term use, as needed to relieve symptoms.

Elderly patients. It is recommended to start treatment with low doses. The daily dose is 50 mg. If the drug is well tolerated, the dose can be increased to the usual dose. Due to the risk of side effects of a certain profile, elderly patients should be under close medical supervision.

Patients with mild to moderate liver impairment should start treatment with the minimum recommended dose and under strict medical supervision. The daily dose is 50 mg. Keiver® Sachet is contraindicated in patients with severe liver impairment.

In 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. In patients with moderate or severe renal impairment (creatinine clearance ≤ 59 ml/min), Keiver® Sachet is contraindicated.

Method of application

Before use, dissolve the entire contents of 1 sachet in a glass of water and stir well for better dissolution. The resulting solution should be taken immediately after preparation.

Simultaneous use with food slows down the rate of absorption of the drug (see the "Pharmacokinetics" section), therefore, for acute pain, it is recommended to take the drug at least 15 minutes before a meal.

Children

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

Overdose

Symptoms of overdose are unknown. Similar drugs cause disorders of the gastrointestinal tract (vomiting, anorexia, abdominal pain) and the nervous system (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 more than 5 mg/kg is ingested by an adult or child, activated charcoal should be administered within one hour. Dexketoprofen trometamol is removed from the body by dialysis.

Side effects

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

Since the Cmax in plasma for dexkeprofen in the form of granules is higher than for tablets, an increased risk of adverse reactions (related to the gastrointestinal tract) cannot be excluded.

According to the results of clinical studies and epidemiological data, the use of some NSAIDs, especially in high doses and for a long time, may be accompanied by a slight increase in the risk of developing pathology caused by arterial thrombosis (for example, myocardial infarction or stroke).

As with other NSAIDs, the following adverse reactions are possible: aseptic meningitis, which mainly occurs in patients with systemic lupus erythematosus or mixed collagen diseases, and blood reactions (purpura, aplastic and hemolytic anemia, rarely - agranulocytosis and bone marrow hypoplasia).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicine has been authorised plays an important role. This allows for continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals should report any suspected adverse reactions.

Expiration date

2 years.

Do not use the drug after the expiration date indicated on the package.

Storage conditions

Does not require special storage conditions.

Keep out of reach of children.

Packaging

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

Vacation category

According to the recipe.

Producer

JSC "Farmak".

Address

Ukraine, 04080, Kyiv, Kyrylivska St., 74.