Kever

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KAYVER® (KEYWER)

Composition:

Active substance: dexketoprofen trometamol.

One tablet contains 36.9 mg of dexketoprofen trometamol calculated as 100% dry substance, equivalent to 25 mg of dexketoprofen.

Excipients: microcrystalline cellulose, pregelatinized starch, corn starch, sodium starch glycolate, glyceryl distearate.

Coating composition Aquarius Prime BAP218010 white: hypromellose, titanium dioxide (E 171), polyethylene glycol.

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: white or almost white, round, biconvex tablets with a score line on one side, film-coated.

Pharmacotherapeutic group.

Anti-inflammatory and antirheumatic agents. Propionic acid derivatives.

ATC code M01A E17.

Pharmacological Properties.

Pharmacodynamics.

Dexketoprofen trometamol is a salt of propionic acid. It is an analgesic, anti-inflammatory, and antipyretic medicinal product belonging to the class of nonsteroidal anti-inflammatory drugs (NSAIDs).

Mechanism of action.

Its mechanism of action is based on reducing the synthesis of prostaglandins by inhibiting cyclooxygenase. Specifically, the conversion of arachidonic acid into cyclic endoperoxides PGG2 and PGH2 is inhibited, from which prostaglandins PGE1, PGE2, PGF2α, PGD2, as well as prostacyclin PGI2 and thromboxanes TxА2 and TxВ2 are formed. In addition, inhibition of prostaglandin synthesis may affect other mediators of inflammation such as kinins, which may also indirectly influence the primary action of the drug.

Pharmacodynamic action.

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

Clinical efficacy and safety.

Clinical studies have shown that dexketoprofen provides effective analgesic action, which develops within 30 minutes after administration and lasts 4–6 hours.

Pharmacokinetics.

Absorption.

After oral administration of dexketoprofen trometamol, maximum plasma concentration (Cmax) is reached within 30 minutes (15–60 minutes).

When dexketoprofen trometamol is administered with food, the area under the curve (AUC) remains unchanged; however, Cmax is reduced and the absorption rate decreases (tmax is prolonged).

Distribution.

The distribution time and elimination half-life of dexketoprofen trometamol are 0.35 and 1.65 hours, respectively. Due to the high degree of plasma protein binding (99%), the mean volume of distribution of dexketoprofen trometamol is less than 0.25 L/kg. In studies of multiple-dose pharmacokinetics, the bioavailability AUC after the last dose was not higher than after a single dose, indicating no drug accumulation.

Metabolism and excretion.

After administration of dexketoprofen trometamol, only the S-(+)-enantiomer is detected in urine, confirming the absence of inversion into the R-(-)-enantiomer in the human body.

Excretion of dexketoprofen occurs mainly via glucuronidation followed by renal excretion.

Clinical characteristics.

Indications.

Symptomatic therapy for mild to moderate pain, e.g., musculoskeletal pain, painful menstruation (dysmenorrhea), 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, 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 perforation in history associated with the use of NSAIDs.

• Active phase of peptic ulcer/gastrointestinal bleeding, recurrent course of peptic ulcer/gastrointestinal bleeding in 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 and breastfeeding period (see "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

The interactions listed below are generally characteristic of NSAID class drugs.

Unwanted combinations:

• Other NSAIDs (including selective COX-2 inhibitors and salicylates in high doses (≥ 3 g/day)): simultaneous 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 inhibition of platelet function and damage to the gastric and duodenal mucosa. If concomitant use is necessary, it should be carried out under strict medical supervision and appropriate laboratory monitoring.
• 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 strict medical supervision and appropriate laboratory monitoring.
• Corticosteroids: increased risk of peptic ulcers and gastrointestinal bleeding.
• Lithium preparations (reports exist for several NSAIDs): NSAIDs increase lithium blood levels up to toxic values by reducing its renal excretion. Therefore, lithium blood levels should be monitored at the start of dexketoprofen therapy, during dose adjustments, or upon discontinuation of the drug.
• Methotrexate when administered in 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 cautious use:

• 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., in dehydrated patients or elderly patients with renal impairment), their condition may worsen when drugs that inhibit cyclooxygenase activity 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 is adequately hydrated, and monitor renal function during treatment.
• Methotrexate when administered in low doses (less than 15 mg/week): possible increase in hematotoxic effects due to reduced renal excretion; if such combination is necessary, weekly blood count monitoring is required, especially in patients with even slight renal impairment or elderly patients.
• Pentoxifylline: increased risk of bleeding; therefore, patient observation and bleeding time monitoring are necessary.
• Zidovudine: risk of increased zidovudine toxicity on erythropoiesis (toxic effect on reticulocytes), potentially leading to severe anemia within one week after NSAID administration; therefore, blood analysis with reticulocyte count should be monitored during the first 1–2 weeks after starting NSAID therapy.
• Sulfonylurea derivatives: NSAIDs may enhance the hypoglycemic effect of sulfonylurea drugs by displacing them from plasma protein binding sites.

Combinations to consider when using Keverâ:

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

• Cyclosporine and tacrolimus: increased 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 mifepristone efficacy. Limited data suggest that concomitant use of NSAIDs and prostaglandins does not affect mifepristone or prostaglandin action—namely, cervical ripening or uterine contractility—and does not reduce the clinical efficacy of medical abortion.

• Quinolone antibiotics: animal studies have shown that high-dose combination use with NSAIDs increases 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. Careful clinical monitoring is required when combining deferasirox with these agents.

• Pemetrexed: concomitant use with NSAIDs may reduce pemetrexed elimination from the body; therefore, caution is advised when administering higher NSAID doses. In patients with mild to moderate renal impairment (creatinine clearance 45–79 ml/min), NSAID use should be avoided 2 days before and 2 days after pemetrexed administration.

Special precautions for use.

Caver® should be used with caution in patients with a history of allergic reactions.

Concomitant use of the drug with other NSAIDs, including cyclooxygenase-2 inhibitors, should be avoided. Adverse effects of the drug can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

Gastrointestinal safety

When using NSAID-class drugs, peptic ulcers with or without perforation and gastrointestinal bleeding (even fatal) may develop in the gastrointestinal tract. These adverse events may occur at any time during treatment, with or without preceding symptoms, regardless of the presence of severe gastrointestinal disorders in the patient's history. If gastrointestinal bleeding or peptic ulcer develops during treatment with dexketoprofen, therapy should be discontinued immediately.

The risk of developing the aforementioned adverse events increases proportionally with higher NSAID doses, as well as in patients with a history of gastric or duodenal ulcers and in elderly patients. During treatment, physicians should carefully monitor patients for possible gastrointestinal bleeding. Before initiating treatment with dexketoprofen trometamol and in patients with a history of esophagitis, gastritis, and/or peptic ulcer disease, it is essential to ensure, as with other NSAIDs, that these conditions are in remission. Patients with existing gastrointestinal symptoms or a history of gastrointestinal disorders require monitoring for gastrointestinal complications, particularly gastrointestinal bleeding.

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

To reduce the risk of gastrointestinal adverse reactions, physicians may prescribe medications that protect the gastrointestinal mucosa (misoprostol, proton pump inhibitors). This also applies to patients requiring concomitant use of low-dose acetylsalicylic acid or other agents that increase the risk of gastrointestinal complications.

Patients should be informed that if they experience any discomfort in the abdominal area (particularly gastrointestinal bleeding), especially at the beginning of treatment, they should notify their physician.

Renal safety

The drug should be prescribed with caution to 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 undergoing diuretic therapy or in those at risk of developing hypovolemia. During treatment, patients should maintain adequate fluid intake to avoid dehydration, which may exacerbate renal toxicity.

Like all NSAIDs, the drug may increase plasma urea nitrogen and creatinine levels. Similar to other inhibitors of prostaglandin synthesis, its use may be associated with renal adverse effects, 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 prescribed with caution to patients with impaired liver function. Like other NSAIDs, the drug may cause temporary and slight increases in certain liver parameters, as well as marked elevations 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 arterial 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 NSAIDs may increase the risk of heart failure due to fluid retention and edema. Clinical studies and epidemiological data suggest that the use of certain NSAIDs (especially 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 risks with dexketoprofen use are insufficient. Therefore, in cases 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. Similarly, careful evaluation is required before initiating long-term treatment in patients with risk factors for cardiovascular disease (e.g., arterial hypertension, hyperlipidemia, diabetes, smoking).

All non-selective NSAIDs can reduce platelet aggregation and prolong bleeding time by inhibiting prostaglandin synthesis. Therefore, prescribing dexketoprofen trometamol is not recommended for patients taking medications 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 NSAID use, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The highest risk of such reactions likely occurs early in treatment, with most cases appearing within the first month of therapy.

If early signs of skin rash, mucosal lesions, or other hypersensitivity symptoms occur, Caver® should be discontinued.

Masking symptoms of underlying infections

Caver® may mask symptoms of infectious diseases, potentially delaying appropriate treatment and thereby complicating the disease course. This has been observed in bacterial community-acquired pneumonia and bacterial complications of varicella. When Caver® 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 should be exercised when prescribing the drug to patients with:

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

If prolonged use of dexketoprofen is considered necessary by the physician, liver and kidney function should be monitored regularly.

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

Patients suffering from asthma in combination with chronic rhinitis, chronic sinusitis, and/or nasal polyps are more prone to allergy to acetylsalicylic acid and/or NSAIDs than the general population. Administration of this drug may trigger asthma attacks or bronchospasm, particularly in patients allergic to acetylsalicylic acid or NSAIDs.

In rare cases, severe skin and soft tissue infections may develop during varicella. To date, data are insufficient to completely exclude the role of NSAIDs in exacerbating this infectious process. Therefore, the use of Caver® should be avoided in varicella.

Caver® should be used with caution in patients with blood dyscrasias, systemic lupus erythematosus, and mixed connective tissue diseases.

Use during pregnancy or breastfeeding.

Caver® is contraindicated during the third trimester of pregnancy and during breastfeeding.

Pregnancy.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or fetal development. According to epidemiological studies, the use of drugs that inhibit prostaglandin synthesis during early pregnancy increases the risk of miscarriage, congenital heart defects, and abdominal wall defects in the fetus. The absolute risk of cardiovascular abnormalities increases from less than 1% to approximately 1.5%. The risk of such events is considered to increase with higher drug doses and longer treatment duration. In animal studies, prostaglandin synthesis inhibitors caused increased pre- and post-implantation losses and higher embryofetal mortality. Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, the frequency of fetal malformations increased, including cardiovascular abnormalities. Nevertheless, animal studies with dexketoprofen did not reveal toxicity to reproductive organs. Starting from the 20th week of pregnancy, Caver® use may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation. Dexketoprofen may be prescribed during the first and second trimesters of pregnancy only 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 should be considered after several days of Caver® exposure starting from the 20th week of pregnancy. Caver® should be discontinued if oligohydramnios is detected.

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

Risks for the fetus:

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

In the mother at the end of pregnancy and in the newborn:

• prolonged bleeding time due to inhibition of platelet aggregation, even with low-dose administration;
• inhibition of uterine contractility, leading to delayed or prolonged labor.

Breastfeeding.

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

Fertility.

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

If dexketoprofen is used by a woman planning pregnancy or during the first or second trimester of pregnancy, the lowest effective dose for the shortest possible duration should be used.

Ability to affect reaction speed when driving or operating machinery.

During treatment with Caver®, adverse effects such as dizziness, visual disturbances, or drowsiness may occur. In such cases, reaction speed and the ability to actively participate in traffic and operate machinery may be reduced.

Method of Administration and Dosage.

Dosing.

Adults.

Depending on the type and intensity of pain, the recommended dose is 12.5 mg (1/2 film-coated tablet) every 4–6 hours or 25 mg (1 film-coated tablet) every 8 hours. The daily dose should not exceed 75 mg.

Adverse effects of the drug can be minimized by using the lowest effective dose for the shortest duration necessary to relieve symptoms. Keverâ is not intended for long-term therapy; treatment continues only as long as symptoms persist.

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.

Hepatic impairment. In patients with mild to moderate hepatic dysfunction, treatment should be initiated at the minimum recommended dose and under strict medical supervision. The daily dose is 50 mg. Keverâ 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.

Keverâ tablets are contraindicated in patients with moderate or severe renal impairment (creatinine clearance < 59 mL/min).

Method of Administration.

The tablets should be taken whole, with sufficient fluid (e.g., a glass of water). Concomitant intake with food slows down absorption of the drug (see section "Pharmacokinetics"); therefore, in case of acute pain, it is recommended to take the drug at least 30 minutes before a meal.

Children.

The use of Keverâ in children has not been studied; therefore, safety and efficacy in children and adolescents have not been established, and the medicinal product should not be used in 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, immediate symptomatic treatment appropriate to the patient's clinical condition should be initiated. If an adult or child has ingested a dose exceeding 5 mg/kg body weight, activated charcoal should be administered within 1 hour. Hemodialysis may be used to eliminate dexketoprofen.

Adverse reactions.

The adverse reactions listed in the table below are considered, based on clinical data, to have at least a minimal possible relationship with dexketoprofen trometamol, as well as adverse reactions reported during the post-marketing period.

The most common adverse reactions are gastrointestinal. Ulceration, perforation or gastrointestinal bleeding, sometimes fatal, especially in elderly patients, may occur. Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, vomiting with blood, ulcerative stomatitis, exacerbation of colitis, Crohn's disease may occur. Gastritis is observed less frequently. Edema, arterial hypertension, and heart failure may also occur during treatment with NSAIDs.

As with other NSAIDs, aseptic meningitis may develop, primarily in patients with systemic lupus erythematosus or mixed connective tissue disease, as well as blood disorders (purpura, hypoplastic and hemolytic anemia, rarely agranulocytosis and bone marrow hypoplasia).

Bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare) are possible.

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

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to 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.

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

Keep out of reach and sight of children.

Packaging. 10 tablets in a blister. 1, 3 or 5 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Address of the manufacturer and location of operation.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.