Dexalgin® oral solution

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEXALGINâ ORAL SOLUTION

Composition:

Active substance: dexketoprofen;

1 sachet (10 ml) contains dexketoprofen trometamol 36.90 mg, equivalent to dexketoprofen 25 mg;

Excipients: ammonium glycyrrhizinate; neohesperidin dihydrochalcone; methylparaben (E 218); sodium saccharin; sucrose; macrogol 400; lemon flavor; povidone-K90; anhydrous sodium hydrogen phosphate; sodium dihydrogen phosphate dihydrate; purified water.

Pharmaceutical form. Oral solution.

Main physicochemical properties: clear, slightly colored solution with a lemon odor and sweet lemon-citrus taste.

Pharmacotherapeutic group

Anti-inflammatory and antirheumatic agents. Propionic acid derivatives.

ATC code M01A E17.

Pharmacological Properties

Pharmacodynamics

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

Mechanism of action

The mechanism of action is based on the reduction of prostaglandin synthesis through inhibition of cyclooxygenase. Specifically, the conversion of arachidonic acid into cyclic endoperoxides PGG2 and PGH2 is inhibited, from which prostaglandins PGE1, PGE2, PGF2α, PGD2, as well as prostacyclin PGI2 and thromboxanes (TxA2 and TxB2) are formed. Additionally, inhibition of prostaglandin synthesis may affect other mediators of inflammation such as kinins, which may also indirectly influence the primary effect of the drug.

Pharmacodynamic effect

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 have shown that dexketoprofen exerts effective analgesic action, which develops within 30 minutes after administration of the drug and lasts for 4–6 hours.

Pharmacokinetics

Two studies were conducted in healthy volunteers to compare the bioequivalence of dexketoprofen 25 mg oral solution in sachets taken with or without water, and dexketoprofen in the form of film-coated tablets.

Comparison of dexketoprofen tablets and oral solution taken together with water showed that dexketoprofen in these pharmaceutical forms is bioequivalent with respect to total exposure (AUC). Peak concentrations (Cmax) were approximately 20% higher when administered as oral solution compared to tablets.

Comparison of dexketoprofen tablets and oral solution taken without water showed that dexketoprofen in these pharmaceutical forms is bioequivalent both with respect to AUC and Cmax.

Absorption

After oral administration, dexketoprofen trometamol is rapidly absorbed. Maximum plasma concentration (Cmax) is reached within 15–20 minutes (range 10–75 minutes) following administration of the oral solution.

When administered with food, AUC values remain unchanged; however, Cmax of dexketoprofen trometamol is reduced, and the rate of absorption is slowed (tmax is prolonged).

Distribution

The distribution phase and elimination half-life of dexketoprofen trometamol are 0.35 and 1.65 hours, respectively. Due to high plasma protein binding (99%), the mean volume of distribution of dexketoprofen trometamol is less than 0.25 L/kg. Multiple-dose pharmacokinetic studies have shown that after the last dose of dexketoprofen trometamol, AUC values were no higher than after single administration, indicating absence of drug accumulation (lack of cumulation).

Metabolism and elimination

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

Elimination of dexketoprofen occurs primarily via glucuronidation followed by renal excretion.

Clinical characteristics

Indications

Symptomatic treatment of mild to moderate pain, for example, musculoskeletal pain, painful menstruation (dysmenorrhea), toothache.

Contraindications

• Hypersensitivity to the active substance or to any other nonsteroidal anti-inflammatory drug (NSAID), or to any of the excipients.

• Asthma attacks, bronchospasm, acute rhinitis, or development of nasal polyps, occurrence of urticaria or angioedema in the patient due to administration of agents with a similar mechanism of action, such as acetylsalicylic acid and other NSAIDs.

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

• Bleeding or perforations in the gastrointestinal tract in medical history associated with the use of NSAIDs.

• Active phase of peptic ulcer/gastrointestinal bleeding, recurrent course of peptic ulcer/gastrointestinal bleeding in medical history.

• Chronic dyspepsia.

• Active bleeding or increased bleeding tendency.

• Crohn's disease or ulcerative colitis.

• Severe heart failure.

• Moderate or severe renal impairment (creatinine clearance ≤ 59 mL/min).

• Severe hepatic impairment (Child–Pugh score 10–15 points).

• Hemorrhagic diathesis or other coagulation disorders.

• Severe dehydration (due to vomiting, diarrhea, or insufficient fluid intake).

• Third trimester of pregnancy and breastfeeding period (see "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction

The interactions listed below generally describe NSAID class drugs.

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 effect of anticoagulants, such as warfarin, due to high 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 carried out under medical supervision with careful monitoring of appropriate 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 with careful monitoring of appropriate laboratory parameters.

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

• Lithium preparations (there have been reports with several NSAIDs): NSAIDs increase lithium blood levels up to toxic values due to reduced renal excretion. Therefore, lithium blood levels should be monitored at the start of dexketoprofen therapy, during dose adjustment, or upon discontinuation of the drug.

• Methotrexate when administered in high doses (15 mg/week or more): increased methotrexate blood levels due to reduced renal excretion, leading to hematotoxic effects.

• Hydantoin derivatives and sulfonamides: possible enhancement of toxicity of these substances.

Combinations requiring cautious use

• Diuretics, ACE inhibitors, aminoglycoside antibiotics, and angiotensin II receptor antagonists. Dexketoprofen reduces the efficacy of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydration or elderly patients with renal impairment), their condition may worsen when used concomitantly with agents that inhibit cyclooxygenase activity, such as ACE inhibitors, angiotensin II receptor antagonists, and aminoglycoside antibiotics. This worsening is usually reversible. When using dexketoprofen concomitantly with any diuretic, ensure the patient is adequately hydrated and monitor renal function during treatment.
• Methotrexate when administered in low doses (< 15 mg/week): possible increased hematotoxic effects due to reduced renal excretion; weekly monitoring of blood counts is required if such combination is necessary, especially in the presence of even slight renal impairment and in elderly patients.
• Pentoxifylline: increased risk of bleeding; therefore, patient status should be monitored and bleeding time controlled.
• Zidovudine: risk of increased toxic effect of zidovudine on erythropoiesis (toxic effect on reticulocytes) up to development of severe anemia one week after NSAID administration; therefore, blood parameters including 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.

Combinations to consider when using Dexalgyn® oral solution

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

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

• Thrombolytic agents: increased risk of bleeding.

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

• Probenecid: increased plasma concentration of dexketoprofen due to reduced renal tubular secretion and glucuronidation; dose adjustment of dexketoprofen may be required in such cases.

• Cardiac glycosides: their plasma concentration may increase.

• Mifepristone: there is a theoretical risk that prostaglandin synthesis inhibitors may alter mifepristone efficacy. Limited data suggest that concomitant use of NSAIDs and prostaglandins does not affect mifepristone or prostaglandin action—specifically cervical ripening or uterine contractility—and does not reduce the clinical efficacy of medical termination of pregnancy.

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

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

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

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

Special precautions for use

Dexalgine® oral solution should be used with caution in patients with a history of allergic reactions.

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

Gastrointestinal safety

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

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

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

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

Patients should be informed that they must report any abdominal discomfort (especially gastrointestinal bleeding), particularly at the beginning of treatment, to their physician.

Renal safety

The drug should be prescribed with caution in patients with impaired renal function, as NSAIDs may lead to worsening renal function, fluid retention, and edema. Due to the increased risk of nephrotoxicity, the drug should be used cautiously in patients undergoing diuretic therapy and in those who may develop hypovolemia. During treatment, patients should maintain adequate fluid intake to avoid dehydration, which may exacerbate renal toxicity.

Like all NSAIDs, the drug may increase plasma urea nitrogen and creatinine concentrations. Similar to other prostaglandin synthesis inhibitors, its use may be associated with renal adverse reactions leading to glomerulonephritis, interstitial nephritis, papillary necrosis, nephrotic syndrome, and acute renal failure. Renal function disturbances occur most frequently in elderly patients.

Hepatic safety

The drug should be prescribed with caution in patients with impaired liver function. Like other NSAIDs, the drug may cause transient and minor elevations in some liver parameters, 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 arterial hypertension and/or mild to moderate heart failure require monitoring and medical supervision. Particular caution is required in treating patients with a history of heart disease, especially those with prior episodes of heart failure, as the risk of developing heart failure increases during treatment: fluid retention and edema have been observed during NSAID therapy. Clinical studies and epidemiological data suggest that the use of certain NSAIDs (particularly at high doses and over prolonged periods) may slightly increase the risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Data to exclude such risks with dexketoprofen use are insufficient. Therefore, dexketoprofen should be prescribed only after careful assessment of the patient's condition in cases of uncontrolled arterial 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 (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking).

All non-selective NSAIDs can reduce platelet aggregation and prolong bleeding time by inhibiting prostaglandin synthesis. Therefore, dexketoprofen trometamol is not recommended in patients taking anticoagulants such as warfarin, other coumarins, or heparins. Cardiovascular complications occur most frequently in elderly patients.

Skin reactions

There have been reports of very rare cases of serious skin reactions (some fatal) during NSAID use, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The highest risk of such reactions likely occurs early in treatment, with most cases appearing within the first month of therapy.

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

Masking symptoms of underlying infections

Dexalgine® oral solution may mask symptoms of infectious diseases, potentially delaying appropriate treatment and thereby complicating the disease course. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When Dexalgine® oral solution is used to relieve pain associated with infection, monitoring for infectious disease is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Other information

Particular caution should be exercised when prescribing the drug to patients with:

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

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

In very rare cases, severe acute hypersensitivity reactions (e.g., anaphylactic shock) have been observed. If early signs of severe hypersensitivity reactions occur after taking Dexalgine® oral solution, treatment should be discontinued. Depending on symptoms, appropriate treatment should be administered under medical supervision.

Patients with asthma combined with chronic rhinitis, chronic sinusitis, and/or nasal polyps have a higher risk of developing allergy to acetylsalicylic acid and/or NSAIDs than other patients. Prescribing this drug may trigger asthma attacks or bronchospasm, particularly 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 no data to fully exclude the role of NSAIDs in exacerbating this infectious process. Therefore, the use of Dexalgine® oral solution should be avoided in varicella.

Dexalgine® oral solution should be used with caution in patients with coagulation disorders, systemic lupus erythematosus, and mixed connective tissue diseases.

This medicinal product contains methylparahydroxybenzoate (E 218) and may therefore cause allergic reactions (possibly delayed).

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

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding

Dexalgine® oral solution is contraindicated during the third trimester of pregnancy and during breastfeeding.

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or fetal development. According to epidemiological studies, the use of drugs that inhibit prostaglandin synthesis in early pregnancy increases the risk of miscarriage, congenital heart defects, and abdominal wall defects in the fetus. Specifically, the absolute risk of cardiovascular malformations increases from <1% to approximately 1.5%. The risk of such events is considered to increase with higher drug doses and longer treatment duration. Administration of prostaglandin synthesis inhibitors in animals has led to increased pre- and post-implantation losses and increased embryofetal mortality. Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, the frequency of fetal malformations, including cardiovascular anomalies, 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 arterial duct 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. Fetal monitoring for oligohydramnios and arterial duct 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 fetal arterial duct constriction is detected.

During the third trimester, all prostaglandin synthesis inhibitors cause:

Risks to the fetus:

• cardiovascular toxicity, e.g., premature constriction/closure of the arterial duct 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 use;
• 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® oral solution is contraindicated during breastfeeding.

Fertility

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

If dexketoprofen is used by a woman attempting to conceive or during the first and second trimesters of pregnancy, the lowest effective dose for the shortest possible duration should be applied.

Ability to influence reaction rate when driving or operating machinery

During treatment with Dexalgine® oral solution, adverse effects such as dizziness, visual disturbances, or drowsiness may occur, which may impair reaction speed, ability to drive vehicles, or operate machinery.

Method of Administration and Dosage

Dosing

Adults

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

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® oral solution is not intended for long-term therapy; treatment should continue only as long as symptoms persist.

Elderly Patients

Treatment should be initiated with low doses. The daily dose is 50 mg. If the drug is well tolerated, the dose may be increased to the usual level.

Hepatic Impairment

For patients with mild to moderate hepatic dysfunction, treatment should be initiated at the lowest recommended dose and under strict medical supervision. The daily dose is 50 mg. Dexalgin® oral solution is contraindicated in patients with severe hepatic impairment.

Renal Impairment

For patients with mild renal impairment (creatinine clearance 60–89 mL/min), the initial total daily dose should be reduced to 50 mg.

Dexalgin® oral solution is contraindicated in patients with moderate to severe renal impairment (creatinine clearance ≤ 59 mL/min).

Method of Administration

For oral use. The oral solution can be taken directly from the sachet or after dilution of the entire contents of the sachet in a glass of water. The contents of the sachet should be used immediately after opening.

Concomitant food intake slows the absorption rate of the drug (see section "Pharmacokinetics"); therefore, for acute pain, it is recommended to take the drug at least 15 minutes before a meal.

Children

The use of Dexalgin® oral solution in children has not been studied, and 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, symptomatic treatment appropriate to the patient's clinical condition should be initiated immediately. If an adult or child has ingested a dose exceeding 5 mg/kg body weight, activated charcoal should be administered within 1 hour. Hemodialysis may be used to eliminate dexketoprofen.

Adverse reactions

The table below lists adverse reactions whose association with dexketoprofen trometamol is considered at least possible based on clinical data, as well as adverse reactions reported during the post-marketing period.

Gastrointestinal system: Adverse reactions from the gastrointestinal tract are most commonly observed. Ulceration, perforation or gastrointestinal bleeding, sometimes fatal, may occur, particularly in elderly patients. According to available data, nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, vomiting with blood, ulcerative stomatitis, exacerbation of colitis, Crohn's disease may occur during treatment with the drug. Gastritis is observed less frequently. Edema, arterial hypertension, and heart failure may also develop during treatment with NSAIDs.

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

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

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life

3 years.

Storage conditions

No special storage conditions required. Keep out of reach of children.

Packaging

10 mL of oral solution in sachets; 10 sachets in a cardboard box.

Prescription status

Prescription only.

Manufacturer

Laboratorios Menarini S.A.

Manufacturer's address

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.