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.
Mechanism of action
The action of nonsteroidal anti-inflammatory drugs is to reduce the synthesis of prostaglandins by inhibiting the activity of cyclooxygenase. In particular, NSAIDs inhibit the conversion of arachidonic acid to cyclic endoperoxides PGG2 and PGH2, which form prostaglandins PGE1, PGE2, PGF2α, PGD2 and PGI2 (prostacyclin) and thromboxanes TxA2 and TxB2. In addition, inhibition of prostaglandin synthesis may affect other 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 pronounced analgesic activity. According to some studies, the analgesic effect occurs 30 minutes after administration. 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 in the form of 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). Peak concentrations (Cmax) after administration of granules were approximately 30% higher than after administration of 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 h, respectively. Similar to other drugs 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 excretion
Dexketoprofen is eliminated primarily 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 the absence of transformation of the drug into the R-(-) optical isomer in humans.
Pharmacokinetic studies show that AUC values after multiple administration of the drug and after a single dose do not differ, indicating the absence of cumulation of the drug substance.
Preclinical safety data
Standard preclinical studies - pharmacological safety studies, genotoxicity and immunopharmacology - did not reveal any particular hazard for humans. Chronic toxicity studies in mice and monkeys made it possible to identify the maximum dose of the drug that does not cause adverse reactions, which was 2 times higher than the maximum dose recommended for humans. When higher doses of the drug were administered to monkeys, the main adverse reaction was blood in the stool, decreased body weight gain, and at the highest dose - pathologies of the gastrointestinal tract in the form of erosions. These reactions occurred at doses at which the exposure to the drug was 14–18 times higher than at the maximum dose recommended for humans. Carcinogenicity studies in animals were not conducted.
Like all NSAIDs, dexketoprofen can cause embryo or foetal 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, e.g. 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 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 peptic ulcer disease/gastrointestinal bleeding, history of bleeding, ulceration or perforation of the digestive tract Chronic dyspepsia Active bleeding or increased bleeding Crohn's disease or ulcerative colitis Severe heart failure Moderate or severe renal impairment (creatinine clearance ≤ 59 ml/min) Severe hepatic impairment (Child-Pugh score 10–15) Bleeding diathesis or other coagulation disorders Severe dehydration (due to vomiting, diarrhea, or insufficient fluid intake)
· Third trimester of pregnancy and breastfeeding (see section "Use during pregnancy or breastfeeding")
Interaction with other medicinal products and other types of interactions
The following drug interactions generally characterize the NSAIDs 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 simultaneously may increase the risk of gastrointestinal ulcers and bleeding due to synergistic effects
Anticoagulants NSAIDs enhance the effect of anticoagulants, such as warfarin, due to the high degree of binding of dexketoprofen to blood 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 the supervision of a physician and with careful monitoring of relevant laboratory parameters. Heparin increases the 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 the supervision of a physician and with careful monitoring of relevant laboratory parameters.
Corticosteroids increase the risk of peptic ulcers and bleeding in the digestive tract
· Lithium preparations (reported for several NSAIDs) NSAIDs increase blood lithium levels to toxic levels by reducing its renal excretion. Therefore, this parameter requires monitoring at the beginning of treatment, during dose adjustment and when dexketoprofen is discontinued.
· Methotrexate when used in high doses (15 mg/week or more) increases the level of methotrexate in the blood due to a decrease in 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 caution
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 using agents that inhibit the action of cyclooxygenase with ACE inhibitors, angiotensin II receptor antagonists and aminoglycoside antibiotics. As a rule, this deterioration is reversible. When using dexketoprofen simultaneously with any diuretic, it is necessary to ensure that the patient receives enough fluid, and at the beginning and periodically after treatment, renal function should be monitored. Simultaneous use of Ketodex 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), may increase the toxic effect on the blood system due to a decrease in renal clearance against the background of taking anti-inflammatory drugs; if necessary, during the first weeks of using such a combination, weekly monitoring of the blood picture is necessary, especially in the presence of even a slight decrease in kidney function, as well as in elderly people
Pentoxifylline increases the risk of bleeding, so it is necessary to monitor the patient and control the bleeding time.
· Zidovudine: there is a risk of increasing the toxic effect of zidovudine on erythropoiesis (toxic effect on reticulocytes) up to the development of severe anemia a week after the use of NSAIDs, therefore, in the first 1–2 weeks after the start of NSAID therapy, blood tests with a reticulocyte count should be monitored.
Sulfonylurea derivatives NSAIDs may enhance the hypoglycemic effect of sulfonylurea drugs by displacing them from blood protein binding.
Beta-blockers may reduce their antihypertensive effect due to inhibition of prostaglandin synthesis Cyclosporine and tacrolimus increase the toxic effect of these drugs on the kidneys due to the effect of NSAIDs on prostaglandin synthesis; when using such a combination, regular monitoring of renal function is necessary Thrombolytic drugs increase the risk of bleeding Platelet aggregation inhibitors and selective serotonin reuptake inhibitors (SSRIs) increase the risk of gastrointestinal bleeding Probenecid increase the concentration of dexketoprofen in the blood plasma due to a decrease in its renal tubular secretion and glucuronidation; in this case, dose adjustment of dexketoprofen is required Cardiac glycosides may increase their plasma concentration Mifepristone There is a theoretical risk that prostaglandin synthesis inhibitors may alter 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 termination of pregnancy Quinoline antibiotics Animal studies have shown that the use of high doses of quinoline antibiotics in combination with NSAIDs increases the risk of convulsions
· Tenofovir co-administration with NSAIDs may increase blood urea nitrogen and creatinine levels in the blood plasma, therefore renal function should be monitored to monitor for potential synergistic effects on their function.
· Deferasirox co-administration with NSAIDs may increase gastrointestinal toxicity and requires careful 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.
Concomitant use of Ketodex 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 develops while taking Ketodex, 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 if complicated by bleeding or perforation, and in elderly patients.
Elderly patients Elderly patients have an increased frequency of adverse reactions to the use of nonsteroidal anti-inflammatory drugs, especially such as gastrointestinal bleeding and ulcer perforation, which can be life-threatening. Treatment of these patients should be started with 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 digestive tract pathology and with a history of digestive tract diseases, it is necessary to monitor the condition of the digestive tract 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 agents that increase the risk of gastrointestinal adverse reactions, combination therapy with protective agents, 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 taking concomitant medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g. warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents such as acetylsalicylic acid.
The drug should be prescribed with caution to patients with impaired renal function, since the use of NSAIDs may lead to deterioration of renal function, fluid retention in the body and edema. Given the increased risk of nephrotoxicity, the drug should be prescribed with caution when treated with diuretics, as well as to patients who may develop hypovolemia.
During treatment, the body must receive sufficient fluids 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 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 kidney dysfunction occurs in elderly patients.
Liver safety
The drug should be prescribed with caution to patients with impaired liver function. Similar to other NSAIDs, the drug may cause a temporary and slight increase in some liver parameters, as well as a pronounced increase in AST and ALT activity. 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 arterial hypertension and/or mild to moderate heart failure require monitoring and consultation. 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 the treatment of NSAIDs. Clinical studies and epidemiological data suggest that the risk of developing arterial thrombosis (for example, myocardial infarction or stroke) may be slightly increased with the use of some NSAIDs (especially in high doses and for a long time). 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 a careful assessment of the patient's condition. Equally careful A review of the condition should be performed before initiating long-term treatment in patients with risk factors for cardiovascular disease (such as hypertension, hyperlipidemia, diabetes mellitus, smoking)
All non-selective NSAIDs are able to 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 coumarin drugs or heparins. The greatest number of cardiovascular system dysfunctions occurs in elderly patients.
Skin reactions
There have been very rare reports of serious skin reactions (some fatal) with the use of 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 signs of skin rashes, mucosal lesions or other symptoms of hypersensitivity, Ketodex should be discontinued.
Masking the symptoms of underlying infections
Ketodex 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 Ketodex 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, with 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 suffering from 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, the development of severe infectious complications of the skin and soft tissues is possible against the background of chickenpox. To date, no data have been obtained that would allow us to completely exclude the role of NSAIDs in the exacerbation of this infectious process. Therefore, the use of Ketodex should be avoided in chickenpox.
Ketodex should be used with caution in patients with hematopoietic disorders, systemic lupus erythematosus, and mixed connective tissue diseases.
This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase deficiency should not take this medicinal product. This should be taken into consideration by patients with diabetes mellitus.
Children Safety of use in children and adolescents has not been established.
Use during pregnancy or breastfeeding
Ketodex 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. According to the results of epidemiological studies, the use of drugs that inhibit prostaglandin synthesis in early pregnancy increases the risk of miscarriage, fetal heart defects, and nonunion of the anterior abdominal wall.
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 of the drug 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. The use of dexketoprofen from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This can occur shortly after the start of treatment and is usually reversible after discontinuation of the drug. In addition, cases of narrowing of the ductus arteriosus in the fetus have been reported after taking the drug in pregnant women in the second trimester of pregnancy, most of which resolved after discontinuation of treatment. Therefore, the appointment dexketoprofen in the first and second trimesters of pregnancy is possible only in case of extreme necessity When prescribing dexketoprofen to women planning pregnancy or in the first and second trimesters of pregnancy, the lowest possible effective dose should be used for the shortest possible duration of treatment. Antenatal monitoring for oligohydramnios and narrowing of the ductus arteriosus in the fetus should be considered in case of exposure to dexketoprofen for several days, starting from the 20th week of gestation. Pregnant women should discontinue the use of dexketoprofen if oligohydramnios or narrowing of the ductus arteriosus in the fetus is detected.
During the third trimester, all prostaglandin synthesis inhibitors cause
risks to the fetus
Cardiopulmonary toxicity, such as premature narrowing/closure of the ductus arteriosus and pulmonary hypertension; renal dysfunction, which may progress to renal failure with the development of 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
Breastfeeding
There is no data on the penetration of dexketoprofen into breast milk. Ketodex is contraindicated during breastfeeding.
Fertility
Like all other NSAIDs, Ketodex may reduce female fertility and is therefore not recommended for use in women attempting to conceive. Women who have difficulty conceiving or are undergoing investigation of infertility should consider discontinuing dexketoprofen.
Ability to influence reaction speed when driving vehicles or other mechanisms
When using Ketodex granules, undesirable effects such as dizziness, visual disturbances or drowsiness may occur. In such cases, a decrease in the reaction rate when driving vehicles or other mechanisms is possible.
Method of administration and doses
Dosage
The lowest effective dose should be used for the shortest time necessary to control symptoms (see section "Special instructions 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.
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.
In case of liver dysfunction
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 of Ketodex, 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 moderate or severe renal impairment (creatinine clearance ≤ 59 ml/min), Ketodex is contraindicated
Method of administration and doses
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 Ketodex in children has not been studied, therefore safety and effectiveness in children and adolescents have not been established. The drug should not be prescribed to children and adolescents.
Overdose
Symptoms of overdose are unknown. Similar drugs cause disorders of the digestive 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 eliminated from the body by dialysis.
Adverse reactions
The table below lists, by system organ class and frequency, adverse reactions considered at least possibly related to the use of dexketoprofen (tablets) in clinical trials, as well as adverse reactions reported during the post-marketing period.
Since the plasma Cmax level for dexketoprofen in the form of granules is higher than for tablets, an increased risk of adverse reactions (related to the gastrointestinal tract) cannot be excluded.
Organ system
Often
(³1/100,
Sometimes
(³1/1000,
Rarely
(³1/10000,
Very rare/single messages
(
Blood and lymphatic system disorders
_
_
_
Neutropenia, thrombocytopenia
On the part of the immune system
_
_
Swelling of the larynx
Anaphylactic reactions, including anaphylactic shock
Nutritional and metabolic
_
_
Anorexia
_
From the psyche
_
Insomnia, anxiety
_
_
From the nervous system
_
Headaches, dizziness, drowsiness
Paresthesia, fainting
_
From the organs of vision
_
_
_
Blurred vision
From the side of the organs of hearing and labyrinth
The most common side effects are from the gastrointestinal tract. Yes, peptic ulcer, perforation or bleeding in the digestive tract may develop, sometimes with a fatal outcome, especially in elderly patients. According to available data, nausea, vomiting, diarrhea, flatulence, constipation, dyspeptic phenomena, abdominal pain, melena, bloody vomiting, ulcerative stomatitis, exacerbation of colitis and Crohn's disease may occur against the background of the drug. Gastritis is less common. Edema, arterial hypertension and heart failure have also been reported against the background of NSAID treatment.
According to clinical trial results and epidemiological data, the use of some NSAIDs, especially in high doses and for a long time, may be associated with a slight increased 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 adverse reactions after registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at https / aisf dec gov ua
Expiration date
2 years
Storage conditions
Store in original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
Sachets of 2.5 g; 10 or 30 sachets in a cardboard box
Vacation category
By prescription
Producer
AstraPharm LLC
Location of the manufacturer and address of its place of business
