Dexalgin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEXALGINâ (DEXALGINâ)

Composition:

Active substance: dexketoprofen;

One film-coated tablet contains 36.9 mg of dexketoprofen trometamol, equivalent to 25 mg of dexketoprofen;

Excipients: microcrystalline cellulose, maize starch, sodium starch glycolate, glycerol distearate, hypromellose, titanium dioxide (E 171), polyethylene glycol 6000, propylene glycol.

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: white, biconvex film-coated tablets, with a break line on both sides.

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 nonsteroidal anti-inflammatory drugs (NSAIDs).

Mechanism of action.

The mechanism of action is based on the reduction of prostaglandin synthesis through inhibition of cyclooxygenase. In particular, 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 (TxА2 and TxВ2) are formed. In addition, inhibition of prostaglandin synthesis may affect other mediators of inflammation such as kinins, which may also indirectly influence the primary action of the drug.

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 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.

Absorption.

After oral administration of dexketoprofen trometamol, maximum plasma concentration (Cmax) is achieved within 30 minutes (15–60 minutes).

When dexketoprofen trometamol is administered with food, the AUC values are not altered, however, Cmax is reduced and the absorption rate is decreased (tmax is prolonged).

Distribution.

The distribution time and elimination half-life of dexketoprofen trometamol are 0.35 and 1.65 hours, respectively. Due to the high degree of binding to plasma proteins (99%), the mean volume of distribution of dexketoprofen trometamol is less than 0.25 L/kg. Pharmacokinetic studies with multiple doses have shown that after the last administration of dexketoprofen trometamol, the area under the curve (AUC) was no higher than after single administration, indicating absence of drug accumulation.

Biotransformation and elimination.

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

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

Clinical characteristics.

Indications.

Symptomatic treatment of mild to moderate pain, for example, musculoskeletal pain, painful menstruation (dysmenorrhea), 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 agents with a similar mechanism of action, such as acetylsalicylic acid and other NSAIDs, induce asthma attacks, 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 gastrointestinal perforation 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 nonspecific ulcerative colitis.

• Severe heart failure.

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

• Severe hepatic dysfunction (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 following drug interactions generally apply to NSAID class agents.

Unwanted 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, 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 physician 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 physician supervision with careful monitoring of appropriate laboratory parameters.

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

• Lithium preparations (reports with several NSAIDs): NSAIDs increase lithium blood levels up to toxic values due to reduced renal excretion. Therefore, monitoring of lithium blood levels is required at the beginning of dexketoprofen treatment, dose adjustment, or discontinuation of the drug.

• Methotrexate when administered at 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 increase in 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 cyclooxygenase-inhibiting agents are used concomitantly with ACE inhibitors, angiotensin II receptor antagonists, and aminoglycoside antibiotics. This deterioration 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 at low doses (< 15 mg/week): possible increase in hematotoxic effects due to reduced renal excretion; weekly blood count monitoring is required if such combination is necessary, especially in the presence of even slight renal impairment or in elderly patients.
• Pentoxifylline: increased risk of bleeding; therefore, patient observation and monitoring of bleeding time are required.
• 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 analysis with reticulocyte count monitoring is required during the first 1–2 weeks after initiation of NSAID therapy.
• Sulfonylurea derivatives: NSAIDs may enhance the hypoglycemic effect of sulfonylurea drugs due to displacement from plasma protein binding sites.

Combinations to be considered when using Dexalgineâ:

• Beta-adrenergic 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 combinations.

• 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.

• Cardiac glycosides: their plasma concentration may be increased.

• 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 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; therefore, 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.

Dexalgin® 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 with fatal outcomes) 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 severe gastrointestinal disorders in medical history. If gastrointestinal bleeding or a peptic ulcer develops during treatment with dexketoprofen, therapy with the drug should be discontinued immediately.

The risk of developing the aforementioned adverse events increases proportionally with higher NSAID doses, in patients with a history of gastric or duodenal ulcers, and in elderly patients. During treatment, physicians should carefully monitor patients for possible gastrointestinal bleeding. Before initiating treatment with dexketoprofen trometamol, and in patients with a history of esophagitis, gastritis, and/or peptic ulcer disease, it should be confirmed—as with other NSAIDs—that these conditions are in remission. In patients with existing gastrointestinal symptoms or gastrointestinal disorders in medical history, monitoring for gastrointestinal complications, particularly gastrointestinal bleeding, is required.

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 use of low-dose acetylsaline salicylic acid or other agents that increase the risk of gastrointestinal complications.

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

Renal safety

The drug should be prescribed with caution in patients with impaired renal function, as NSAID use 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 receiving diuretic therapy or those at risk of hypovolemia. During treatment, patients should receive adequate fluid intake to prevent dehydration, which may exacerbate renal toxicity.

Like all NSAIDs, the drug may increase plasma urea nitrogen and creatinine levels. 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 mild elevations in certain liver parameters, as well as marked increases in AST and ALT activity. If such elevations occur, therapy 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 when treating patients with a history of cardiac disease, especially those with prior episodes of heart failure, as the use of the drug increases the risk of heart failure: fluid retention and edema have been observed during NSAID therapy. Clinical studies and epidemiological data suggest that some NSAIDs (particularly at high doses and prolonged use) may slightly increase the risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Data to exclude such risk with dexketoprofen use are insufficient. Therefore, in cases of uncontrolled arterial hypertension, congestive heart failure, ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease, dexketoprofen should be prescribed only after careful patient assessment. Similarly, careful evaluation is required before initiating long-term treatment in patients with cardiovascular risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, or smoking).

All non-selective NSAIDs can reduce platelet aggregation and prolong bleeding time by inhibiting prostaglandin synthesis. Therefore, dexketoprofen trometamol is not recommended for patients taking agents affecting hemostasis, such as warfarin, other coumarin derivatives, or heparins. Cardiovascular function disturbances occur most frequently in elderly patients.

Skin reactions

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

If initial signs of skin rash, mucosal lesions, or other symptoms of hypersensitivity occur, Dexalgin® should be discontinued.

Masking symptoms of underlying infections

Dexalgin® may mask symptoms of infectious diseases, potentially delaying appropriate treatment and worsening disease progression. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When Dexalgin® 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 porphyrin metabolism disorders (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 Dexalgin®, 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 compared to other patients. Administration of this drug may trigger asthma attacks or bronchospasm, particularly in patients allergic to acetylsalicylic acid or NSAIDs.

In rare cases, severe skin and soft tissue infections may develop during varicella. Currently, there are insufficient data to fully exclude the role of NSAIDs in exacerbating this infectious process. Therefore, the use of Dexalgin® should be avoided in varicella.

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

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

Use during pregnancy or breastfeeding.

Dexalgin® is contraindicated during the third trimester of pregnancy and during breastfeeding.

Pregnancy.

Inhibition of prostaglandin synthesis may negatively 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 and congenital malformations such as cardiac defects and abdominal wall defects. The absolute risk of cardiovascular abnormalities increases from <1% to approximately 1.5%. The risk of such events is considered to increase with higher drug doses and longer treatment duration. In animal studies, prostaglandin synthesis inhibitors have caused increased pre- and post-implantation losses and elevated embryofetal mortality. Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, the incidence of fetal malformations, including cardiovascular abnormalities, increased. However, animal studies with dexketoprofen did not reveal toxic effects on reproductive organs. The 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 stopping treatment. Therefore, dexketoprofen may be prescribed during the first and second trimesters of pregnancy only if absolutely necessary. When prescribing dexketoprofen to women planning pregnancy or during the first and second trimesters, the lowest possible effective dose should be used for the shortest possible duration. 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. Dexalgin® is contraindicated during breastfeeding.

Fertility.

Like all other NSAIDs, dexketoprofen trometamol may reduce female fertility and is therefore not recommended for women planning pregnancy. Women experiencing infertility or undergoing fertility evaluation 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 should be used for the shortest possible duration.

Ability to affect reaction speed when driving or operating machinery.

During treatment with Dexalgin® tablets, adverse effects such as dizziness, visual disturbances, or drowsiness may occur, which can reduce reaction speed and the ability to drive 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 Precautions").

Depending on the type and intensity of pain, the recommended dose is 12.5 mg (1/2 film-coated tablet) every 4–6 hours or 25 mg (1 film-coated tablet) every 8 hours. The daily dose should not exceed 75 mg.

Dexalginâ is not intended for long-term therapy; treatment continues only as long as symptoms persist.

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.

Hepatic impairment. For patients with mild to moderate hepatic impairment, treatment should be initiated with the lowest recommended dose and under strict medical supervision. The daily dose is 50 mg. Dexalginâ tablets are 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.

Dexalginâ tablets are contraindicated in patients with moderate to severe renal impairment (creatinine clearance ≤ 59 mL/min).

Method of Administration.

Tablets should be taken with sufficient fluid (e.g., a glass of water). Concomitant intake with food slows down drug absorption (see section "Pharmacokinetics"); therefore, in acute pain, it is recommended to take the drug at least 30 minutes before meals.

Children.

The use of Dexalginâ 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, symptomatic treatment should be initiated immediately according to the patient's clinical condition. 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 adverse reactions listed in the table below are considered to have at least a possible causal relationship to dexketoprofen trometamol 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. Gastritis is less commonly observed. Also, edema, arterial hypertension, and heart failure may develop during treatment with NSAIDs.

As with other NSAIDs, aseptic meningitis may occur, primarily 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 are possible, including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare).

According to results of clinical trials 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).

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions.

Shelf life.

• For PVC/aluminum blister: 2 years;
• for aluminum/aluminum blister: 3 years.

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

Storage conditions.

• PVC/aluminum blister: Store at a temperature not exceeding 30 °C. Keep in the original packaging to protect from light and moisture.
• aluminum/aluminum blister: No special storage conditions required.

Keep out of reach and sight of children.

Packaging.

Blister pack containing 10 film-coated tablets; cardboard box containing 1, 3, or 5 blisters.

Prescription status.

Prescription only.

Manufacturer.

A. Menarini Manufacturing Logistics and Services S.r.l.

Manufacturer's location and address of operations.

Via Campo di Pile, 67100 L’Aquila (AQ), Italy.

Manufacturer.

Laboratorios Menarini S.A.

Manufacturer's location and address of operations.

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