Dexalgin sachet granules for oral solution 25 mg package No. 10

Instructions Dexalgin sachet granules for oral solution 25 mg package No. 10

Composition

active ingredient: dexketoprofen trometamol;

1 single-dose packet contains 36.90 mg of dexketoprofen trometamol, equivalent to 25 mg of dexketoprofen;

excipients: ammonium glycyrrhizate, neohesperidin dihydrochalcone, quinoline yellow (E 104), lemon flavoring, sucrose.

Dosage form

Granules for oral solution.

Main physicochemical properties: yellow granules with a lemon odor and taste.

Pharmacotherapeutic group

Nonsteroidal anti-inflammatory and antirheumatic drugs. Propionic acid derivatives. ATX code M01AE17.

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.

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 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 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 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). Peak concentrations (Cmax) after administration of the granules were 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 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 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 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 special hazard for humans. Chronic toxicity studies in mice and monkeys allowed us 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 administering higher doses of the drug 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 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.

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.

Photoallergic or phototoxic reactions are known during treatment with ketoprofen or fibrates.

Active peptic ulcer/gastrointestinal bleeding, history of bleeding, ulceration or perforation in 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 liver dysfunction (10–15 points on the Child-Pugh scale).

Hemorrhagic diathesis or other blood clotting 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 NSAID class of drugs.

Undesirable combinations:

Other NSAIDs (including selective cyclooxygenase-2 inhibitors and high-dose salicylates (≥ 3 g/day)): the simultaneous use of several NSAIDs 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 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 gastrointestinal bleeding.

Lithium (reported with several NSAIDs): NSAIDs increase blood lithium levels to toxic levels by reducing renal excretion. Therefore, this parameter requires monitoring at the start of treatment, during dose adjustment and when dexketoprofen is discontinued.

Methotrexate when used in high doses (15 mg/week or more): the level of methotrexate in the blood increases due to a decrease in its excretion by the kidneys, which leads to toxic effects on the blood system.

Hydantoin derivatives and sulfonamides: possible increased 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 cyclooxygenase inhibitors are used simultaneously 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 Dexalgin® sachets 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 against the background of taking anti-inflammatory drugs; if necessary, weekly monitoring of the blood picture is necessary during the first weeks of using such a combination, especially in the presence of even a slight decrease in kidney function, as well as in elderly people.

Pentoxifylline: the risk of bleeding increases, so it is necessary to monitor the patient and control the bleeding time.

Zidovudine: There is a risk of increased toxicity of zidovudine on erythropoiesis (toxicity of 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 reticulocyte counts should be monitored.

Sulfonylureas: NSAIDs may enhance the hypoglycemic effect of sulfonylureas by displacing them from blood protein binding.

Combinations to consider:

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; regular monitoring of renal function is necessary when using this combination.

Thrombolytic drugs: increased risk of bleeding.

Platelet aggregation inhibitors and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding.

Probenecid: increased plasma concentrations of dexketoprofen due to decreased renal tubular secretion and glucuronidation; in this case, dose adjustment of dexketoprofen is required.

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 abortion.

Quinoline antibiotics: Animal studies have shown that the use of high doses of quinoline antibiotics in combination 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 monitor for potential synergistic effects on renal function.

Deferasirox: Concomitant use 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.

The simultaneous use of Dexalgin® sachets 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 control 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 while taking Dexalgin® 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, particularly 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 with 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 condition of the gastrointestinal tract should be monitored for possible disorders, especially gastrointestinal bleeding, during the use of the drug.

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 who use acetylsalicylic acid in low doses or other agents that increase the risk of adverse reactions from the digestive tract, the possibility of 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 taking concomitant medications that may increase the risk of ulceration or bleeding: oral corticosteroids, anticoagulants (e.g. warfarin), selective serotonin reuptake inhibitors or antiplatelet agents such as acetylsalicylic acid.

Kidney safety.

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 in patients treated with diuretics, as well as in 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.

Most kidney 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 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 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 (such as 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.

Very 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 of these events 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, Dexalgin® sachets should be discontinued.

Masking the symptoms of underlying infections

Dexalgin® sachets 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 chickenpox. When Dexalgin® sachets are used to relieve pain in an infection, monitoring for the infectious disease is recommended. In outpatient settings, 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.

In very rare cases, severe acute hypersensitivity reactions (e.g. anaphylactic shock) have been observed. At the first signs of severe hypersensitivity reactions after taking Dexalgin® sachets, treatment should be discontinued. Depending on the symptoms, the treatment required in such cases should be carried out under the supervision of a physician.

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 Dexalgin® sachets should be avoided in chickenpox.

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

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

Use during pregnancy or breastfeeding

Dexalgin® sachets are 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. The use of dexketoprofen from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This may occur shortly after the start of treatment and is usually reversible after discontinuation of the drug. In addition, cases of fetal ductus arteriosus have been reported after administration of the drug to pregnant women in the second trimester, most of which resolved after discontinuation of treatment. Therefore, dexketoprofen should be prescribed in the first and second trimesters of pregnancy only if clearly needed. When dexketoprofen is prescribed to women planning a 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 and fetal ductus arteriosus should be considered in case of exposure to dexketoprofen for several days, starting from the 20th week of gestation. Pregnant women should discontinue dexketoprofen if oligohydramnios or fetal ductus arteriosus 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 hypertension in the pulmonary artery system;

kidney dysfunction (see above);

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;

suppression 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. Dexalgin® sachets are contraindicated during breastfeeding.

Fertility.

As with all NSAIDs, Dexalgin® 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.

Ability to influence reaction speed when driving vehicles or other mechanisms

When using Dexalgin® sachet granules, undesirable effects such as dizziness, visual disturbances or drowsiness may occur. In such cases, a decrease in the speed of reaction 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").

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.

Dexalgin Sachet is intended only for short-term use, necessary 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.

In case of liver dysfunction.

Patients with mild to moderate hepatic impairment should be started on the lowest recommended dose and under close medical supervision. The daily dose is 50 mg. Dexalgin Sachet is contraindicated in patients with severe hepatic 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), Dexalgin Sachet is contraindicated.

Method of application.

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 Dexalgin Sachet in children has not been studied, therefore safety and efficacy in children and adolescents have not been established. The medicine 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 removed from the body by dialysis.

Adverse reactions

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 level in blood plasma 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.

The most common side effects are from the gastrointestinal tract. Thus, 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 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 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

3 years.

Do not use the medicine after the expiry date stated on the packaging.

Storage conditions

No special storage conditions are required.

Packaging

10 or 30 single-dose sachets in a cardboard box.

Vacation category

According to the recipe.

Producer

Laboratorios Menarini S.A.

Location of the manufacturer and address of its place of business

Alfonso XII, 587, Badalona, Barcelona, 08918 Spain.

Applicant

Menarini International Operations Luxembourg S.A.

Applicant's location

1, Avenue de la Gare, L-1611, Luxembourg, Luxembourg.