Dexalgine® sachet

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEXALGIN® SACHET

Composition:

Active substance: dexketoprofen trometamol;

One single-dose sachet contains 36.90 mg of dexketoprofen trometamol, equivalent to 25 mg of dexketoprofen;

Excipients: ammonium glycyrrhizinate, neohesperidin dihydrochalcone, quinoline yellow (E 104), lemon flavor, sucrose.

Pharmaceutical form. Granules for oral solution.

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

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Propionic acid derivatives. ATC code M01AE17.

Pharmacological Properties.

Pharmacodynamics.

Dexketoprofen trometamol is the tromethamine 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 (NSAIDs).

Mechanism of action.

The action of nonsteroidal anti-inflammatory drugs consists in reducing the synthesis of prostaglandins by inhibiting cyclooxygenase activity. In particular, NSAIDs inhibit the conversion of arachidonic acid into cyclic endoperoxides PGG2 and PGH2, which form prostaglandins PGE1, PGE2, PGF2α, PGD2, and PGI2 (prostacyclin) and thromboxanes TxA2 and TxB2. In addition, the inhibition of prostaglandin synthesis may affect other mediators of inflammation, such as kinins, causing an indirect effect that complements the direct action.

Pharmacodynamic action.

The inhibitory effect of dexketoprofen on the activity of cyclooxygenase-1 and cyclooxygenase-2 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, analgesic effect begins within 30 minutes after administration. The duration of analgesic action is 4–6 hours.

Pharmacokinetics.

Absorption.

Dexketoprofen trometamol is rapidly absorbed after oral administration. Following administration in granule form, maximum plasma concentration is reached within 0.25–0.33 hours. A comparison of dexketoprofen tablets with standard release and granules at doses of 12.5 and 25 mg showed that the two formulations are biologically equivalent 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, AUC is unchanged, but Cmax of dexketoprofen trometamol is reduced and the rate of absorption decreases (tmax is prolonged).

Distribution.

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

Biological transformation and elimination.

Elimination of dexketoprofen occurs mainly via conjugation with glucuronic acid and subsequent renal excretion.

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

Pharmacokinetic studies indicate that AUC values after repeated administration and after single dosing do not differ, indicating the absence of accumulation of the active substance.

Preclinical safety data.

Standard preclinical studies—pharmacological safety, genotoxicity, and immunopharmacology studies—did not reveal any special hazard for humans. Chronic toxicity studies in mice and monkeys identified the no-observed-adverse-effect level (NOAEL), which was found to be 2 times higher than the maximum recommended human dose. When higher doses were administered to monkeys, the main adverse reactions were fecal blood, reduced body weight gain, and, at the highest dose, gastrointestinal tract pathologies such as erosions. These reactions occurred at doses where drug exposure was 14–18 times higher than at the maximum recommended human dose. Carcinogenicity studies in animals have not been conducted.

Like all NSAIDs, dexketoprofen may lead to embryonic or fetal death in animals due to a direct effect on its development or indirectly—via maternal gastrointestinal tract damage.

Clinical characteristics.

Indications.

Short-term symptomatic treatment of mild to moderate acute pain, such as musculoskeletal pain, dysmenorrhea, and 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, e.g. acetylsalicylic acid and other NSAIDs, induce asthma attacks, bronchospasm, acute rhinitis, or lead to nasal polyps, urticaria, or angioedema.

• Known photoallergic or phototoxic reactions during treatment with ketoprofen or fibrates.

• History of gastrointestinal bleeding or perforation associated with previous use of NSAIDs.

• Active peptic ulcer/gastrointestinal bleeding, or history of gastrointestinal bleeding, ulcer, or perforation.

• 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 section "Use in pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

The drug interactions listed below generally apply to the class of NSAIDs.

Unrecommended combinations:

• Other NSAIDs (including selective cyclooxygenase-2 inhibitors and high-dose salicylates (≥ 3 g/day)): concomitant use of multiple NSAIDs may increase the risk of gastrointestinal ulcers and bleeding due to synergistic effects.

• Anticoagulants: NSAIDs enhance the effects of anticoagulants such as warfarin, due to the high degree of plasma protein binding of dexketoprofen and due to inhibition of platelet function and damage to the gastric and duodenal mucosa. If concomitant use is necessary, it should be performed under physician supervision 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 performed under physician supervision with careful monitoring of relevant laboratory parameters.

• Corticosteroids: increased risk of peptic ulcers and gastrointestinal bleeding.

• Lithium preparations (reports with several NSAIDs): NSAIDs increase serum lithium levels to toxic concentrations by reducing renal excretion. Therefore, monitoring of lithium levels is required at the start of treatment, during dose adjustments, and upon discontinuation of dexketoprofen.

• Methotrexate at high doses (15 mg/week or more): increased blood levels of methotrexate due to reduced renal excretion, leading to hematological toxicity.

• Hydantoin derivatives and sulfonamides: possible increase in toxicity of these agents.

Combinations requiring caution:

• Diuretics, ACE inhibitors, aminoglycoside antibiotics, and angiotensin II receptor antagonists. Dexketoprofen may reduce the effectiveness of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with renal impairment), concomitant use of drugs that inhibit cyclooxygenase with ACE inhibitors, angiotensin II receptor antagonists, and aminoglycoside antibiotics may worsen renal function. This deterioration is usually reversible. When dexketoprofen is used concomitantly with any diuretic, ensure adequate hydration and monitor renal function at the beginning and periodically during treatment. Concomitant use of Dexalgin® sachet and potassium-sparing diuretics may lead to hyperkalemia. Serum potassium levels should be monitored.
• Methotrexate at low doses (< 15 mg/week): possible increase in hematological toxicity due to reduced renal clearance during anti-inflammatory therapy; weekly blood monitoring is required during the first weeks of such combination therapy, especially in patients with even slight renal impairment or in elderly patients.
• Pentoxifylline: increased risk of bleeding; patient should be monitored and bleeding time controlled.
• Zidovudine: risk of increased toxic effect of zidovudine 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 initiation of NSAID therapy.
• Sulfonylurea derivatives: NSAIDs may enhance the hypoglycemic effect of sulfonylurea drugs by displacing them from plasma protein binding sites.

Combinations to be considered:

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

• Cyclosporine and tacrolimus: increased nephrotoxicity of these drugs due to NSAID effects on prostaglandin synthesis; regular monitoring of renal function is required when using this combination.

• Thrombolytic agents: increased risk of bleeding.

• Antiplatelet agents 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; dose adjustment of dexketoprofen may be necessary.

• Cardiac glycosides: their plasma concentration may increase.

• 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 action of mifepristone or prostaglandins—specifically cervical ripening or uterine contractility—and does not reduce the clinical efficacy of medical abortion.

• Quinolone antibiotics: animal studies have shown that high-dose quinolone antibiotics in combination with NSAIDs increase the risk of convulsions.

• Tenofovir: concomitant use with NSAIDs may increase plasma urea nitrogen and creatinine levels; therefore, renal function should be monitored to control for potential synergistic effects on kidney function.

• Deferasirox: concomitant use with NSAIDs may increase gastrointestinal toxicity and requires careful clinical monitoring.

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

Special precautions for use.

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

Concomitant use of Dexalgine® 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 duration necessary to control symptoms (see gastrointestinal and cardiovascular risks below).

Gastrointestinal safety.

Gastrointestinal bleeding, ulceration, or perforation have been reported with all NSAIDs at various stages of treatment, regardless of the presence of warning symptoms or a history of serious gastrointestinal pathology. If gastrointestinal bleeding or ulceration occurs during treatment with Dexalgine® sachets, the drug should be discontinued.

The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation, and in elderly patients.

Elderly patients: elderly patients have an increased frequency of adverse reactions to nonsteroidal anti-inflammatory drugs, particularly gastrointestinal bleeding and ulcer perforation, which may be life-threatening. Treatment in these patients should be initiated with the lowest possible dose.

Prior to initiating treatment with dexketoprofen trometamol, patients with a history of esophagitis, gastritis, and/or peptic ulcer disease, as with other NSAIDs, should be evaluated to ensure these conditions are in complete remission. Patients with existing gastrointestinal symptoms or a history of gastrointestinal disorders should be monitored during treatment for possible complications, particularly gastrointestinal bleeding.

NSAIDs should be used with caution in patients with a history of gastrointestinal disorders (ulcerative colitis, Crohn’s disease), as there is a risk of exacerbation of these conditions.

For such patients and for those taking low-dose acetylsalicylic acid or other agents that increase the risk of gastrointestinal adverse reactions, combination therapy with gastroprotective agents (e.g., misoprostol or proton pump inhibitors) should be considered.

Patients, especially elderly patients, with a history of gastrointestinal adverse reactions should report any unusual gastrointestinal symptoms (particularly gastrointestinal bleeding), especially during the initial stages of treatment.

The drug should be used with caution in patients concurrently taking agents 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.

Renal safety.

The drug should be used with caution in 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 receiving diuretics or those at risk of hypovolemia.

During treatment, adequate fluid intake should be maintained to prevent dehydration, which may exacerbate renal toxicity.

Like all NSAIDs, the drug may increase blood urea nitrogen and creatinine levels in plasma. Similar to other inhibitors of prostaglandin synthesis, its use may be associated with renal adverse reactions, including 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 used with caution in patients with impaired liver function. As with other NSAIDs, it may cause transient and mild elevations in certain liver function tests, as well as marked increases in AST and ALT activity. If such increases occur, treatment should be discontinued.

Hepatic function disturbances occur most frequently in elderly patients.

Cardiovascular and cerebrovascular safety.

Patients with a history of hypertension and/or mild to moderate heart failure require monitoring and medical supervision. Particular caution is required when treating patients with a history of cardiac disease, especially previous episodes of heart failure, as treatment with the drug may increase the risk of heart failure: fluid retention and edema have been observed during NSAID therapy. Clinical trials and epidemiological data suggest a slightly increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke) with some NSAIDs, particularly at high doses and with prolonged use. Data to exclude such risks with dexketoprofen are insufficient. Therefore, dexketoprofen should be prescribed only after careful assessment of the patient’s condition in cases of uncontrolled hypertension, congestive heart failure, ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. Similarly careful evaluation is required before initiating long-term treatment in patients with cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes, smoking).

All nonselective NSAIDs can reduce platelet aggregation and prolong bleeding time by inhibiting prostaglandin synthesis. Therefore, dexketoprofen trometamol is not recommended in patients taking agents affecting hemostasis, such as warfarin, other coumarins, or heparins. Cardiovascular adverse events occur most frequently in elderly patients.

Skin reactions.

There have been reports of very rare cases of serious skin reactions (some with fatal outcomes) during NSAID therapy, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The highest risk is likely during the initial phase of treatment, with most cases occurring within the first month.

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

Masking of symptoms of underlying infections.

Dexalgine® sachets may mask symptoms of infectious disease, potentially delaying appropriate treatment and thereby complicating the course of illness. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When Dexalgine® sachets are used to relieve pain associated with infection, monitoring for infection 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 inherited porphyrin metabolism disorders (e.g., acute intermittent porphyria);
• with dehydration;
• immediately after major surgical procedures.

If prolonged use of dexketoprofen is deemed necessary by the physician, regular monitoring of liver and kidney function and blood counts is recommended.

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 Dexalgine® sachets, 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 have a higher risk of developing allergy to acetylsalicylic acid and/or NSAIDs compared to other patients. Administration of this drug may trigger asthma attacks or bronchospasm, especially in patients allergic to acetylsalicylic acid or NSAIDs.

In rare cases, severe infectious complications of the skin and soft tissues may occur during varicella. Currently, there are insufficient data to fully exclude the role of NSAIDs in exacerbating this infectious process. Therefore, the use of Dexalgine® sachets should be avoided in varicella.

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

This medicinal product contains sucrose. Patients with rare hereditary conditions such as fructose intolerance, glucose-galactose malabsorption syndrome, or sucrase-isomaltase deficiency should not take this product. This should be considered in diabetic patients.

Children. Safety and efficacy in children and adolescents have not been established.

Use during pregnancy or breastfeeding.

Dexalgine® sachets are contraindicated during the third trimester of pregnancy and during breastfeeding.

Pregnancy.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic and fetal development. According to epidemiological studies, use of drugs that inhibit prostaglandin synthesis during early pregnancy increases the risk of miscarriage and congenital malformations, including cardiac defects and abdominal wall defects.

For example, the absolute risk of cardiovascular malformations increases from less than 1% to approximately 1.5%. The risk is believed to increase with higher drug doses and longer duration of therapy. In animal studies, prostaglandin synthesis inhibitors have caused increased pre- and post-implantation losses and increased embryofetal mortality. Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, the incidence of fetal developmental abnormalities, including cardiovascular malformations, was increased. However, animal studies with dexketoprofen did not reveal toxic effects on reproductive organs. Use of dexketoprofen from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation of the drug. Additionally, cases of fetal ductus arteriosus constriction have been reported after maternal use of the drug in the second trimester, most of which resolved after discontinuation of treatment. Therefore, dexketoprofen may be prescribed during the first and second trimesters 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. Prenatal monitoring for oligohydramnio and ductus arteriosus constriction should be considered if dexketoprofen is used for several days starting from the 20th gestational week. Pregnant women should discontinue dexketoprofen if oligohydramnios or ductus arteriosus constriction is detected.

During the third trimester, all prostaglandin synthesis inhibitors cause:

Risks to the fetus:

• cardiopulmonary toxicity, e.g., premature constriction/closure of the ductus arteriosus and pulmonary hypertension;
• renal dysfunction (see above);

Risks to the mother at the end of pregnancy and to the newborn:

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

Breastfeeding.

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

Fertility.

Like all other NSAIDs, Dexalgine® sachets may reduce female fertility and therefore are not recommended for women attempting to conceive. Women experiencing fertility problems or undergoing infertility evaluation should consider discontinuing dexketoprofen.

Ability to affect reaction speed when driving or operating machinery.

During use of Dexalgine® sachets granules, adverse effects such as dizziness, visual disturbances, or somnolence may occur. In such cases, reaction speed when driving or operating machinery may be reduced.

Method of Administration and Dosage.

Dosing.

The lowest effective dose should be used for the shortest duration 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.

Dexalgine\âsache is intended only for short-term use, sufficient to alleviate symptoms.

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. Due to the risk of adverse reactions of a certain profile, elderly patients should be under close medical supervision.

Hepatic impairment.

For patients with mild to moderate hepatic impairment, treatment should be initiated at the minimum recommended dose and under strict medical supervision. The daily dose is 50 mg. Dexalgine\âsache is contraindicated in patients with severe hepatic dysfunction.

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. Dexalgine\âsache is contraindicated in patients with moderate or severe renal impairment (creatinine clearance ≤ 59 mL/min).

Method of Administration.

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

Concomitant administration with food slows the rate of drug absorption (see section "Pharmacokinetics"); therefore, in acute pain, the drug should be taken at least 15 minutes before meals.

Children.

The use of Dexalgine\âsache in children has not been studied; therefore, safety and efficacy in children and adolescents have not been established. The medicinal product should not be administered to 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 or excessive intake, symptomatic treatment should be initiated immediately according to the patient's clinical condition. If the ingested dose exceeds 5 mg/kg in 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 adverse reactions by system organ class and frequency of occurrence, which have been considered at least possibly related to the use of dexketoprofen (in tablet form) based on clinical trial data, as well as adverse reactions reported during the post-marketing period.

Since the Cmax plasma level for dexketoprofen in granule form is higher than that for tablets, an increased risk of adverse reactions (particularly gastrointestinal) cannot be excluded.

The most common adverse effects are those affecting the gastrointestinal tract. Peptic ulcer, perforation or gastrointestinal bleeding, sometimes fatal, especially in elderly patients, may occur. According to available data, nausea, vomiting, diarrhea, flatulence, constipation, dyspeptic symptoms, abdominal pain, melena, hematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease may occur during treatment with the drug. Gastritis is observed less frequently. Edema, arterial hypertension, and heart failure have also been reported during NSAID therapy.

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

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

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals should report any suspected adverse reactions.

Shelf life. 3 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

No special storage conditions required.

Packaging.

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

Prescription status.

Prescription only.

Manufacturer.

Laboratorios Menarini S.A.

Manufacturer's address and location of operations.

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

Marketing Authorization Holder.

Menarini International Operations Luxembourg S.A.

Address of the Marketing Authorization Holder.

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