NALBUFIN

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEXA-HEALTH (DEXA-ZDOROVYE)

Composition

active substance: dexketoprofen; 1 sachet contains 25 mg of dexketoprofen; excipients: ammonium glycyrrhizate; neohesperidin dihydrochalcone; sucrose; silicon dioxide; quinoline yellow (E 104); lemon flavor, which contains: aromatic extracts, maltodextrin, gum arabic (E 414), citric acid (E 330).

Pharmaceutical Form

Granules for oral solution.

Main Physico-Chemical Properties

The contents of the sachet are a mixture of yellow granules and powder with a lemon flavor. A slight fruity smell is allowed.

Pharmacotherapeutic Group

Nonsteroidal anti-inflammatory and antirheumatic products. Propionic acid derivatives. ATC code M01 AE17.

Pharmacological Properties

Pharmacodynamics

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

Mechanism of action.

The mechanism of action of nonsteroidal anti-inflammatory drugs involves reducing prostaglandin synthesis by inhibiting cyclooxygenase activity. 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. Additionally, the inhibition of prostaglandin synthesis may affect other mediators of inflammation, such as kinins, causing an indirect effect that is 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 within 30 minutes after administration. The duration of the analgesic effect is 4-6 hours.

Pharmacokinetics

Absorption

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

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

Distribution

The half-life and elimination half-life of dexketoprofen trometamol are 0.35 and 1.65 hours, respectively. Similarly to other medicinal products with a high degree of binding to plasma proteins (99%), the volume of distribution of dexketoprofen is approximately less than 0.25 L/kg.

Biransformation and Elimination

The elimination of dexketoprofen occurs mainly through conjugation with glucuronic acid and subsequent excretion by the kidneys.

After administration of dexketoprofen trometamol, only the optical isomer S-(+) is detected in the urine, which indicates the absence of transformation of the drug into the optical isomer R-(-) in humans.

Pharmacokinetic studies indicate that the AUC values after multiple administration of the drug and after single administration do not differ, which indicates the absence of accumulation of the medicinal substance.

Preclinical Safety Data

Standard preclinical studies - studies of pharmacological safety, genotoxicity, and immunopharmacology - did not reveal any special hazard to humans. Chronic toxicity studies in mice and monkeys made it possible to detect the maximum dose of the medicinal product that does not cause side effects, which was found to be twice as high as the maximum dose recommended for humans. When higher doses of the medicinal product were administered to monkeys, the main side effect was blood in the urine, decreased body weight gain, and at the highest dose - gastrointestinal tract pathology in the form of erosions. These reactions occurred at doses at which exposure to the medicinal product was 14-18 times higher than the maximum dose recommended for humans. No carcinogenicity studies were conducted in animals.

Like all NSAIDs, dexketoprofen can cause fetal death or damage due to its direct effect on development or indirectly - through damage to the mother's gastrointestinal tract.

Clinical Characteristics

Indications

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

Contraindications

• Increased sensitivity 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, 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.
• Bleeding or perforation in the digestive tract in the history, associated with the use of NSAIDs.
• Active phase of peptic ulcer/bleeding in the digestive tract, bleeding, ulcer, or perforation in the digestive tract in the history.
• Chronic dyspepsia.
• Bleeding in the active phase or increased bleeding tendency.
• Crohn's disease or nonspecific ulcerative colitis.
• Severe heart failure.
• Moderate or severe impairment of renal function (creatinine clearance ≤ 59 mL/min).
• Severe impairment of liver function (10-15 points on the Child-Pugh scale).
• Hemorrhagic diathesis or other coagulation disorders.
• Severe dehydration (due to vomiting, diarrhea, or insufficient fluid intake).
• Third trimester of pregnancy or breastfeeding period (see section "Use during pregnancy or breastfeeding").

Interaction with Other Medicinal Products and Other Types of Interactions

The following interactions of medicinal products are generally characteristic of NSAID preparations.

Undesirable combinations

• Other NSAIDs (including selective cyclooxygenase-2 inhibitors and salicylates in 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 synergistic action.
• Anticoagulants: NSAIDs enhance the action of anticoagulants, such as warfarin, due to the high degree of binding of dexketoprofen to plasma proteins, as well as due to the inhibition of platelet function and damage to the gastric mucosa and duodenum. If concurrent use is necessary, it should be carried out under medical supervision and with careful monitoring of relevant laboratory parameters.
• Heparin: the risk of bleeding increases (due to the inhibition of platelet function and damage to the gastric mucosa and duodenum). If concurrent use is necessary, it should be carried out under medical supervision and with careful monitoring of relevant laboratory parameters.
• Corticosteroids: the risk of peptic ulcers and bleeding in the digestive tract increases.
• Lithium preparations (there have been reports of several NSAIDs): NSAIDs increase the level of lithium in the blood up to toxic values due to reduced excretion by the kidneys. Therefore, this parameter requires monitoring at the beginning of treatment, when adjusting the dose, and when discontinuing dexketoprofen.
• Methotrexate at high doses (15 mg/week or more): the level of methotrexate in the blood increases due to reduced excretion by the kidneys, leading to toxic effects on the blood system.
• Sulfonylurea derivatives and sulfonamides: possible enhancement of the toxicity of these substances.

Combinations that require caution

• Diuretics, ACE inhibitors, aminoglycoside antibiotics, and angiotensin II receptor antagonists. Dexketoprofen reduces the effect of diuretic agents and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydration or elderly patients with impaired renal function), the condition may worsen when using cyclooxygenase inhibitors with ACE inhibitors, angiotensin II receptor antagonists, and aminoglycoside antibiotics. As a rule, this deterioration is reversible. When using dexketoprofen concurrently with any diuretic agent, it is necessary to ensure that the patient receives sufficient fluid and to monitor renal function at the beginning and periodically during treatment. Concurrent use of dexketoprofen and potassium-sparing diuretics may lead to hyperkalemia. It is necessary to monitor potassium levels in the blood.
• Methotrexate at low doses (less than 15 mg/week): possible increased toxic effect on the blood system due to reduced renal clearance during the use of anti-inflammatory agents; if necessary, weekly monitoring of the blood picture is necessary during the first weeks of using this combination, especially in the presence of even minor renal function impairment, as well as in elderly patients.
• Pentoxifylline: the risk of bleeding increases, so it is necessary to monitor the patient and control bleeding time.
• Zidovudine: there is a risk of increased toxic effect of zidovudine on erythropoiesis (toxic effect on reticulocytes) up to the development of severe anemia within a week after the use of NSAIDs, so during the first 1-2 weeks after the start of NSAID therapy, it is necessary to monitor the blood test with a reticulocyte count.
• Sulfonylurea derivatives: NSAIDs may enhance the hypoglycemic effect of sulfonylurea derivatives by displacing them from protein binding in the blood.

Combinations to be considered

• Beta-blockers: may decrease their antihypertensive effect due to the inhibition of prostaglandin synthesis.
• Cyclosporine and tacrolimus: increased toxic effect of these preparations on the kidneys due to the effect of NSAIDs on prostaglandin synthesis; when using this combination, regular monitoring of renal function is necessary.
• Thrombolytic agents: increased risk of bleeding.
• Platelet aggregation inhibitors and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding.
• Probenecid: increased concentration of dexketoprofen in plasma due to reduced renal tubular secretion and glucuronidation; in this case, dose adjustment of dexketoprofen is necessary.
• Cardiac glycosides: may increase their concentration in plasma.
• Mifepristone: there is a theoretical risk that prostaglandin synthesis inhibitors may alter the effectiveness of mifepristone. Limited data suggest that concurrent use of NSAIDs and prostaglandins does not affect the action of mifepristone or prostaglandins, namely the maturation of the cervix or the ability of the uterus to contract, and does not reduce the clinical effectiveness of medical abortion.
• Quinolone antibiotics: studies in animals have shown that the use of quinolone antibiotics in high doses in combination with NSAIDs increases the risk of seizures.
• Tenofovir: concurrent use with NSAIDs may increase the level of urea and creatinine in plasma, so it is necessary to monitor renal function to control the potential synergistic effect on their function.
• Deferasirox: concurrent use with NSAIDs may increase the toxic effect on the gastrointestinal tract and requires careful clinical monitoring.
• Pemetrexed: concurrent use with NSAIDs may reduce the excretion of pemetrexed from the body, so caution should be exercised when administering higher doses of NSAIDs. Patients with mild and moderate renal impairment (creatinine clearance from 45 to 79 mL/min) should avoid using NSAIDs for 2 days before and 2 days after taking pemetrexed.

Special Warnings and Precautions for Use

Caution should be exercised when administering to patients with a history of allergic reactions.

Concurrent use of dexketoprofen with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

Side effects can be minimized by using the lowest effective dose for the shortest time necessary to relieve symptoms (see risks related to the gastrointestinal tract and cardiovascular system below).

Safety Related to the Gastrointestinal Tract

Gastrointestinal bleeding, ulceration, or perforation, in some cases with a fatal outcome, have been reported for all NSAIDs at various stages of treatment, regardless of the presence of symptoms or a history of serious gastrointestinal pathology. If gastrointestinal bleeding or ulceration occurs during treatment with dexketoprofen, the drug should be discontinued.

The risk of gastrointestinal bleeding, ulceration, or perforation increases with the dose of NSAIDs in patients with a history of ulcers, especially if complicated by bleeding or perforation, as well as in elderly patients.

Elderly patients: in elderly patients, the frequency of side effects from the use of nonsteroidal anti-inflammatory drugs is increased, 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 treatment with dexketoprofen trometamol, patients who have a history of esophagitis, gastritis, and/or ulcer disease, as well as when using other NSAIDs, should be sure that these diseases are in a state of complete remission. In patients with existing symptoms of gastrointestinal pathology and with a history of gastrointestinal diseases, it is necessary to monitor the state of the gastrointestinal tract for possible disorders during treatment, 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 exacerbating these diseases.

For such patients and patients taking acetylsalicylic acid in low doses or other means that increase the risk of side effects from the gastrointestinal tract, it is necessary to consider the possibility of combined therapy with protective agents, such as misoprostol or proton pump inhibitors.

Patient monitoring, especially at the initial stages of treatment, is necessary to report 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 medications that may increase the risk of ulcers or bleeding: oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents, such as acetylsalicylic acid.

Safety Related to the Kidneys

Patients with impaired renal function should be prescribed the drug with caution, as NSAID use may worsen renal function, lead to fluid retention, and cause edema. Given the increased risk of nephrotoxicity, the drug should be prescribed with caution when treating with diuretics and in patients who may develop hypovolemia.

During treatment, the body should receive sufficient fluid to avoid dehydration, which can increase the toxic effect on the kidneys.

Like all NSAIDs, the drug can increase the level of urea and creatinine in plasma. Similarly to other prostaglandin synthesis inhibitors, its use may be accompanied by side effects from the kidneys, which can lead to glomerulonephritis, interstitial nephritis, papillary necrosis, nephrotic syndrome, and acute renal failure.

The most frequent renal function disorders occur in elderly patients.

Safety Related to the Liver

Patients with impaired liver function should be prescribed the drug with caution. Similarly to other NSAIDs, the drug may cause temporary and slight increases in some liver parameters, as well as significant increases in AST and ALT activity. If the specified parameters increase, therapy should be discontinued.

The most frequent liver function disorders occur in elderly patients.

Safety Related to the Cardiovascular System and Cerebral Circulation

Patients with arterial hypertension and/or heart failure of mild to moderate severity in their history require monitoring and consultation. Particular caution should be exercised when treating patients with a history of heart disease, especially with previous episodes of heart failure, as the risk of developing heart failure increases during treatment with the drug: edema and fluid retention in tissues have been observed during NSAID treatment. Clinical studies and epidemiological data suggest that the use of some NSAIDs (especially in high doses and for a long time) may slightly increase the risk of developing arterial thrombosis (e.g., myocardial infarction or stroke). There is insufficient data to exclude this risk when using dexketoprofen. Therefore, in cases of uncontrolled arterial hypertension, congestive heart failure, ischemic heart disease, peripheral artery disease, and/or cerebrovascular disease, dexketoprofen should be prescribed only after careful evaluation of the patient's condition. Similarly careful consideration should be given before starting long-term treatment in patients with risk factors for cardiovascular disease (such as arterial hypertension, hyperlipidemia, diabetes, smoking).

All non-selective NSAIDs can reduce platelet aggregation and increase bleeding time by inhibiting prostaglandin synthesis. Therefore, dexketoprofen trometamol is not recommended for patients taking medications that affect hemostasis, such as warfarin, other coumarin preparations, or heparin. The most frequent cardiovascular system disorders occur in elderly patients.

Skin Reactions

There have been reports of very rare cases of serious skin reactions (some with a fatal outcome) during the use of NSAIDs, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. It is likely that the greatest risk of their occurrence is at the beginning of treatment, and in most patients, they occurred within the first month of treatment.

Upon the appearance of the first signs of skin rash, mucous membrane lesions, or other symptoms of hypersensitivity, dexketoprofen should be discontinued.

Masking of Symptoms of Underlying Infections

Dexketoprofen may mask the symptoms of infectious diseases, which can lead to delayed 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. If dexketoprofen is needed to relieve pain during an infection, monitoring of the infectious disease is recommended. In the case of outpatient treatment, the patient should consult a doctor if symptoms persist or worsen.

Other Information

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

• with inherited porphyria metabolism disorders (e.g., acute intermittent porphyria);
• with dehydration;
• immediately after major surgical interventions.

If the doctor believes that long-term use of dexketoprofen is necessary, it is necessary to regularly monitor liver and kidney function, as well as the blood picture.

In very rare cases, severe acute hypersensitivity reactions (e.g., anaphylactic shock) have been observed. Upon the first signs of severe hypersensitivity reactions after taking dexketoprofen, treatment should be discontinued. Depending on the symptoms, treatment may be necessary under medical supervision.

Ability to Affect Reaction Speed When Driving or Operating Other Mechanisms

During the use of dexketoprofen granules, undesirable effects such as dizziness, visual disturbances, or drowsiness may occur. In such cases, the reaction speed when driving or operating other mechanisms may be reduced.

Method of Administration and Dosage

Dosage

The lowest effective dose should be used for the shortest time necessary to relieve symptoms (see section "Special Warnings and Precautions 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.

Dexketoprofen is intended only for short-term use, necessary to relieve symptoms.

Elderly Patients

Treatment should be started 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, elderly patients should be under close medical supervision.

In Case of Liver Function Impairment

Patient treatment should be started with the minimum recommended dose and under close medical supervision. The daily dose is 50 mg. Dexketoprofen is contraindicated in patients with severe liver function impairment.

In Case of Renal Function Impairment

Patients with mild renal impairment (creatinine clearance 60-89 mL/min) should have their initial total daily dose reduced to 50 mg. In case of moderate or severe renal impairment (creatinine clearance ≤ 59 mL/min), dexketoprofen is contraindicated.

Method of Administration

Before administration, the contents of 1 sachet should be dissolved in a glass of water and stirred well for better dissolution. The resulting solution should be taken immediately after preparation.

Concurrent use with food slows down the rate of absorption of the drug (see section "Pharmacokinetics"), so when treating acute pain, it is recommended to take the drug at least 15 minutes before meals.

Children

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

Overdose

The symptoms of overdose are unknown. Similar medicinal products cause gastrointestinal disorders (vomiting, anorexia, abdominal pain) and nervous system disorders (drowsiness, dizziness, disorientation, headache).

In case of accidental overdose or excessive use, symptomatic therapy should be started immediately, depending on the patient's clinical condition. If more than 5 mg/kg is taken by an adult or child, activated charcoal should be used within an hour. Dexketoprofen trometamol is excreted from the body by dialysis.

Side Effects

The following table lists the side effects distributed by organ and system and frequency of occurrence, the connection of which with the use of dexketoprofen (in the form of tablets) according to clinical studies is recognized as at least possible, as well as side effects reported in the post-marketing period.

The most common side effects are from the gastrointestinal tract. Thus, the development of peptic ulcers, perforation, or bleeding in the digestive tract is possible, sometimes with a fatal outcome, especially in elderly patients. According to available data, during treatment with the drug, nausea, vomiting, diarrhea, flatulence, constipation, dyspeptic symptoms, abdominal pain, melena, hematemesis, stomatitis, exacerbation of colitis, and Crohn's disease may occur. Less frequently, gastritis is observed. There have also been reports of edema, arterial hypertension, and heart failure during NSAID treatment.

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

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

Reporting of Side Effects

Reporting side effects after registration of the medicinal product is important. This allows monitoring the benefit/risk ratio of the use of this medicinal product. Medical and pharmaceutical workers, as well as patients or their legal representatives, should report all suspected side effects and lack of efficacy of the medicinal product through the automated information system for pharmacovigilance at: https://aisf.dec.gov.ua.

Shelf Life

2 years.

Storage Conditions

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

Store in a place inaccessible to children.

Packaging

2.5 g of the drug in a sachet, 10 (1x10) or 30 (1x30) sachets in a box.

Release Category

By prescription.

Manufacturer

Limited Liability Company "Pharmaceutical Company "Zdorov'ya"."

Location of the Manufacturer and Address of the Place of Business

Ukraine, 61013, Kharkiv region, Kharkiv, Shevchenko street, 22.