Alfort dexta

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ALFORT DEXA (ALFORT DEXA)

Composition:

Active substance: dexketoprofen;

One film-coated tablet contains 25 mg of dexketoprofen in the form of dexketoprofen trometamol;

Excipients: microcrystalline cellulose (pH 101), maize starch, sodium starch glycolate (type A), glyceryl distearate;

Coating: Opadry II 85F18422 white (polyvinyl alcohol, titanium dioxide (E 171), polyethylene glycol, talc).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex tablets with a score line on both sides, coated with a film.

Pharmacotherapeutic group

Anti-inflammatory and antirheumatic agents. Propionic acid derivatives.

ATC code M01A E17.

Pharmacological Properties

Pharmacodynamics

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

Mechanism of action.

The mechanism of action is based on reducing the synthesis of prostaglandins by inhibiting 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 (TxА2 and TxВ2) are formed. In addition, inhibition of prostaglandin synthesis may affect other inflammatory mediators such as kinins, which may also indirectly influence the primary action 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 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 area under the bioavailability curve (AUC) remains unchanged; however, the Cmax value decreases and the absorption rate slows down (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 plasma protein binding (99%), the mean volume of distribution of dexketoprofen trometamol is less than 0.25 L/kg. Pharmacokinetic studies with repeated dosing showed that after the last dose of dexketoprofen trometamol, AUC values were no higher than after single administration, confirming the absence of drug accumulation.

Biological transformation and elimination. After administration of dexketoprofen trometamol, only the S-(+)-enantiomer is detected in urine, confirming the absence of its inversion into the R-(–)-enantiomer in the human body.

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

Clinical Characteristics

Indications

Symptomatic treatment of mild to moderate pain, for example musculoskeletal pain, menstrual pain (dysmenorrhea), dental pain.

Contraindications

• Hypersensitivity to the active substance or to any other non-steroidal anti-inflammatory drug (NSAID), or to any of the excipients.
• Contraindicated 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 perforation in the gastrointestinal tract in the medical history associated with the use of NSAIDs.
• Active phase of peptic ulcer disease / gastrointestinal bleeding, recurrent course of peptic ulcer disease / gastrointestinal bleeding in the 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 (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 and breastfeeding period (see "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction

The types of interactions listed below are typical for all NSAIDs.

Unrecommended combinations:

• Other NSAIDs, including selective cyclooxygenase-2 inhibitors and high-dose salicylates (≥ 3 g/day): concomitant use of multiple NSAIDs increases the risk of gastrointestinal ulcers and bleeding due to synergistic effects.
• Anticoagulants: NSAIDs enhance the effect of anticoagulants, such as warfarin, due to the high degree of binding of dexketoprofen to plasma proteins, as well as due to inhibition of platelet function and damage to the gastric and duodenal mucosa. If concomitant use is necessary, it should be carried out under medical supervision with careful monitoring of relevant laboratory parameters.
• Heparin: increased risk of bleeding (due to inhibition of platelet function and damage to the gastric and duodenal mucosa). If concomitant use is necessary, it should be carried out under medical supervision with careful monitoring of relevant 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, lithium blood levels should be monitored at the start of dexketoprofen treatment, 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 increase in toxicity of these substances.

Combinations requiring caution:

• Diuretics, angiotensin-converting enzyme (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., due to dehydration or elderly patients with renal impairment), the condition may worsen when NSAIDs are used concomitantly with ACE inhibitors, angiotensin II receptor antagonists, and aminoglycoside antibiotics. This worsening is usually reversible. When using dexketoprofen concomitantly with any diuretic, it is essential to ensure the patient is adequately hydrated and to monitor renal function during treatment.
• Methotrexate when administered in low doses (< 15 mg/week): possible increase in 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 or in elderly patients.
• Pentoxifylline: increased risk of bleeding; therefore, patient monitoring and bleeding time control are necessary.
• Zidovudine: risk of increased toxic effects of zidovudine on erythropoiesis (toxic effect on reticulocytes) up to severe anemia one week after NSAID administration; therefore, blood analysis with reticulocyte count should be performed during the first 1–2 weeks after initiation of NSAID therapy.
• Sulfonylurea derivatives: NSAIDs may enhance the hypoglycemic effect of sulfonylurea drugs due to their displacement from plasma protein binding sites.

Combinations with usage warnings:

• 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 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; in such cases, dose adjustment of dexketoprofen is required.
• 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 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; therefore, caution should be exercised when administering higher NSAID doses. Patients with mild to moderate renal impairment (creatinine clearance from 45 to 79 ml/min) should avoid using NSAIDs for 2 days before and 2 days after pemetrexed administration.

Special precautions for use

The medicinal product Alfolt Dexta 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 (including 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 the patient's history. If gastrointestinal bleeding or peptic ulceration occurs during treatment with dexketoprofen, therapy should be discontinued immediately.

The risk of these 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 closely 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 their history, monitoring for gastrointestinal complications, particularly gastrointestinal bleeding, is required.

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

To reduce the risk of gastrointestinal adverse effects, physicians may prescribe medications with protective effects on the gastrointestinal mucosa (e.g., 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 (particularly gastrointestinal bleeding), especially at the beginning of treatment, to their physician.

Renal safety

The medicinal product should be prescribed cautiously 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 with caution in patients undergoing 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 concentrations. Similar to other prostaglandin synthesis inhibitors, 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 medicinal product should be prescribed cautiously 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 aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity. If such increases 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 heart disease, especially those with previous episodes of heart failure, as the risk of heart failure increases during treatment due to fluid retention and edema formation. 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 are insufficient to exclude this risk with dexketoprofen. Therefore, dexketoprofen should be prescribed only after careful patient assessment in cases of uncontrolled arterial hypertension, congestive heart failure, ischemic heart disease, peripheral artery disease, and/or cerebrovascular disease. Similarly careful evaluation is required before initiating long-term treatment in patients with cardiovascular risk factors (e.g., 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 coumarin derivatives, or heparins. Cardiovascular function disturbances occur most frequently in elderly patients.

Cases of Kounis syndrome have been reported in patients receiving dexketoprofen. Kounis syndrome is defined as cardiovascular symptoms secondary to an allergic or hypersensitivity reaction associated with coronary artery spasm and potentially leading to myocardial infarction.

Skin reactions

Very rare cases of serious skin reactions (some with fatal outcomes) have been reported during NSAID use, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The risk is likely highest at the beginning of treatment, with most cases occurring within the first month.

If early signs of skin rash, mucosal lesions, or other hypersensitivity symptoms appear, the medicinal product Alfolt Dexta should be discontinued.

Masking symptoms of underlying infections

Alfolt Dexta may mask symptoms of infectious diseases, potentially delaying appropriate treatment and worsening disease progression. Such symptom masking has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When Alfolt Dexta 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 medicinal product to patients:

• with hereditary 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 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 Alfolt Dexta, 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 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 infectious complications involving the skin and soft tissues may occur during varicella. Currently, there are insufficient data to completely exclude the role of NSAIDs in exacerbating this infectious process. Therefore, use of the medicinal product Alfolt Dexta should be avoided during varicella.

Alfolt Dexta should be used with caution in patients with blood 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

The medicinal product Alfolt Dexta 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, use of drugs that inhibit prostaglandin synthesis during early pregnancy increases the risk of miscarriage and congenital heart defects and abdominal wall defects in the fetus. The absolute risk of cardiovascular abnormalities increases from <1% to approximately 1.5%. The risk is considered to increase with higher drug doses and longer treatment duration. In animal studies, prostaglandin synthesis inhibitors caused increased pre- and post-implantation losses and elevated embryofetal mortality. Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, the frequency of fetal malformations, including cardiovascular abnormalities, increased. However, animal studies with dexketoprofen did not reveal toxic effects on reproductive organs.

Starting from the 20th week of pregnancy, use of Alfolt Dexta may cause oligohydramnios due to fetal renal dysfunction. This condition may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, arterial duct constriction in the fetus has been reported after second-trimester use, which in most cases resolved after stopping treatment. Alfolt Dexta should not be prescribed during the first and second trimesters except in cases of extreme necessity. If Alfolt Dexta is used by women attempting to conceive or during the first and second trimesters of pregnancy, the dose should be as low as possible and treatment duration as short as possible. Fetal monitoring for oligohydramnios and arterial duct constriction may be advisable after several days of dexketoprofen exposure starting from the 20th week of pregnancy. Treatment with Alfolt Dexta should be discontinued if oligohydramnios or arterial duct constriction in the fetus is detected.

During the third trimester, all prostaglandin synthesis inhibitors may cause:

Risks to the fetus:

• cardiovascular toxicity, e.g., premature constriction/closure of the arterial duct and pulmonary hypertension;
• renal dysfunction, which may progress to renal failure with development of oligohydramnios.

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. Alfolt Dexta 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 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 should be used for the shortest possible duration.

Ability to influence reaction speed when driving or operating machinery

During use of Alfolt Dexta tablets, adverse effects such as dizziness, visual disturbances, or somnolence may occur, which may reduce reaction speed and impair the ability to drive or operate machinery.

Dosage and Administration

Dosage

Adults

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms (see section "Special precautions for use").

Depending on the type and intensity of pain, the recommended dose is 12.5 mg (½ 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.

Alfort Dexa 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. In patients with mild to moderate hepatic impairment, treatment should be initiated at the lowest recommended dose and under strict medical supervision. The daily dose is 50 mg. Alfort Dexa tablets are contraindicated in patients with severe hepatic impairment.

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.

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

Administration method.

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, the drug should be taken at least 30 minutes before meals.

Children

The use of Alfort Dexa in children has not been studied; therefore, safety and efficacy in children and adolescents have not been established—this 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 neurological disorders (drowsiness, dizziness, 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.

Side effects

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

The most commonly observed adverse reactions are gastrointestinal. For instance, peptic ulcer, gastrointestinal perforation or bleeding, sometimes fatal, especially in elderly patients, may occur. 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 appear during treatment. Gastritis is observed less frequently. Also, edema, arterial hypertension, and heart failure may occur during NSAID therapy.

As with other NSAIDs, aseptic meningitis may develop, 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 studies and epidemiological data, the use of certain NSAIDs, particularly at high doses and over prolonged periods, slightly increases the risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after authorization of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, are encouraged to report cases of suspected adverse reactions and lack of efficacy of the medicinal product to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua.

Shelf life

2 years.

Storage conditions

Store at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging

10 tablets per blister. 1, 2 or 3 blisters per cardboard box.

Prescription status

Prescription only.

Manufacturer

ABDI IBRAHIM Ilac Sanayi ve Ticaret A.S.

Manufacturer’s address and location of its business activity

Orhan Gazi Mahallesi, Tunc Caddesi No 3, Esenyurt, Istanbul, Turkey