Depiofen

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

Composition:

Active substance: dexketoprofen trometamol;

One tablet contains dexketoprofen trometamol equivalent to 25 mg of dexketoprofen;

Excipients: maize starch, microcrystalline cellulose, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate;

Tablet coating: titanium dioxide (E 171), hypromellose, polyethylene glycol 6000, talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, round, biconvex film-coated tablets with a break line on one side.

Pharmacotherapeutic group.

Anti-inflammatory and antirheumatic agents. Propionic acid derivatives.

ATC code M01A E17.

Pharmacological properties.

Pharmacodynamics.

Dexketoprofen trometamol is a propionic acid salt that exerts analgesic, anti-inflammatory, and antipyretic effects and belongs to the class of nonsteroidal anti-inflammatory drugs (NSAIDs).

Mechanism of action.

Its mechanism of action is based on reducing the synthesis of prostaglandins by inhibiting cyclooxygenase. Specifically, it inhibits the conversion of arachidonic acid into cyclic endoperoxides PGG2 and PGH2, 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 trometamol on the activity of cyclooxygenase-1 and cyclooxygenase-2 has been demonstrated in animals and humans. Dexketoprofen trometamol 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 reached within 30 minutes (15–60 minutes).

When dexketoprofen trometamol is administered with food, 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 its 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 multiple dosing showed that after the last dose of dexketoprofen trometamol, the area under the curve (AUC) was no higher than after a single dose, indicating absence of drug accumulation.

Biological transformation and elimination.

After administration of dexketoprofen trometamol, only the S-(+)-enantiomer is detected in urine, demonstrating absence of its inversion into the R-(-)-enantiomer in the human body. Elimination of dexketoprofen trometamol 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 substances with a similar mechanism of action, for example acetylsalicylic acid and other NSAIDs, cause 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 perforations in the gastrointestinal tract in the medical history associated with the use of NSAIDs.
• Active phase of peptic ulcer/gastrointestinal bleeding, recurrent course of peptic ulcer/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 (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 drug interactions listed below generally apply to NSAID class drugs.

Unrecommended combinations:

• Other NSAIDs (including selective cyclooxygenase-2 inhibitors and high-dose salicylates (> 3 g/day)): simultaneous use of multiple NSAIDs may increase the risk of gastrointestinal ulcers and bleeding due to synergistic effects.
• Anticoagulants: NSAIDs enhance the effects of anticoagulants, for example 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 have been reported for 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 therapy, during dose adjustment, or 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 toxic effects on the blood system.
• Hydantoin derivatives and sulfonamides: possible increase in toxicity of these substances.

Combinations requiring cautious use:

• Diuretics, angiotensin-converting enzyme inhibitors, aminoglycoside antibiotics, and angiotensin II receptor antagonists. Dexketoprofen reduces the effect of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., in dehydrated patients or elderly patients with renal impairment), their condition may worsen when used concomitantly with agents that inhibit cyclooxygenase activity, including 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 increase in hematotoxic effects due to reduced renal excretion; weekly monitoring of blood counts is required if such combination is necessary, especially in patients with even slight renal impairment or 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 their displacement from plasma protein binding sites.

Combinations to consider when using Depiofen:

• 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 the effect of NSAIDs 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.
• 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 seizures.
• Tenofovir: concomitant use with NSAIDs may increase blood urea nitrogen and creatinine levels; therefore, monitoring of renal function is required 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 45–79 mL/min) should avoid NSAID use for 2 days before and 2 days after pemetrexed administration.

Special precautions for use.

Use Difene with caution in patients with a history of allergic reactions. Concomitant use of this medication with other NSAIDs, including 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 medical history. 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. The risk is also elevated in patients with a history of gastric or duodenal ulcers and in elderly patients. During treatment, physicians should carefully monitor patients due to the potential for 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. Patients with existing gastrointestinal symptoms or a history of gastrointestinal disorders should be monitored for the development of gastrointestinal complications, particularly gastrointestinal bleeding.

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

To reduce the risk of gastrointestinal adverse reactions, physicians may prescribe medications that protect the gastrointestinal mucosa (e.g., misoprostol, proton pump inhibitors). This is also relevant for patients requiring concomitant low-dose acetylsalicylic acid or other agents that increase the risk of gastrointestinal complications. Patients should be informed that if they experience abdominal discomfort (particularly gastrointestinal bleeding), especially at the beginning of treatment, they should inform their physician.

Renal safety

The medication should be prescribed with caution in patients with impaired renal function, as NSAIDs may worsen kidney function, cause fluid retention, and edema. Due to the increased risk of nephrotoxicity, the drug should be used cautiously in patients undergoing diuretic therapy or in those who may develop hypovolemia. During treatment, patients should maintain 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 medication should be prescribed with caution in patients with impaired liver function. Like other NSAIDs, the drug may cause transient and mild increases in certain liver parameters, as well as marked elevations 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 when treating patients with a history of cardiac disease, especially those with prior episodes of heart failure, as treatment with this 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 risks with dexketoprofen use are insufficient. Therefore, dexketoprofen should be prescribed only after careful patient assessment 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 (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 system disturbances occur most frequently in elderly patients.

Skin reactions

There have been very rare reports of severe 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.

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

Other information

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

• inherited porphyrin metabolism disorders (e.g., acute intermittent porphyria);
• dehydration;
• immediately following 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 Difene, treatment should be discontinued. Depending on symptoms, appropriate treatment in such cases 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 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, Difene should be avoided during varicella.

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

Masking symptoms of underlying infections: the drug may mask symptoms of infectious disease, potentially delaying appropriate treatment and thereby complicating disease progression. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When the drug is used for fever or pain relief during infection, monitoring for infectious disease is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Use during pregnancy or breastfeeding.

Difene 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 fetal cardiac malformations 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 been associated with increased pre- and post-implantation losses and higher embryofetal mortality. Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, increased incidence of fetal developmental abnormalities, including cardiovascular anomalies, has been observed. However, animal studies with dexketoprofen did not reveal toxic effects on reproductive organs.

Starting from the 20th week of pregnancy, dexketoprofen use may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after treatment initiation and is usually reversible upon discontinuation. Dexketoprofen should not be prescribed during the first and second trimesters of pregnancy except in cases of extreme necessity. If dexketoprofen is used in 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 ultrasound monitoring for oligohydramnios should be considered after several days of dexketoprofen exposure starting from the 20th week of pregnancy. Dexketoprofen use should be discontinued if oligohydramnios is detected.

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

Risks to the fetus:

• cardiovascular toxicity, e.g., premature closure of the ductus arteriosus and pulmonary hypertension;
• renal dysfunction, which may progress to renal failure with oligohydramnios (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.

Therefore, dexketoprofen is contraindicated during the third trimester of pregnancy (see section "Contraindications").

Breastfeeding.

There are no data on the passage of dexketoprofen into breast milk. Difene 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 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 Difene tablets, adverse effects such as dizziness, visual disturbances, or drowsiness may occur, which can reduce reaction speed and impair the ability to drive or operate machinery.

Method of Administration and Dosage.

Dosing.

Adults. Depending on the type and intensity of pain, the recommended dose is 12.5 mg (1/2 tablet coated with a film coating) every 4–6 hours or 25 mg (1 tablet coated with a film coating) every 8 hours. The daily dose should not exceed 75 mg. Adverse effects of the drug can be minimized by using the lowest effective doses for the shortest duration necessary to control symptoms. Depiofen is not intended for long-term therapy; treatment continues only as long as symptoms are present.

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 at the minimum recommended dose and under strict medical supervision. The daily dose is 50 mg. Depiofen, film-coated tablets, is 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.

Depiofen, film-coated tablets, is contraindicated in patients with moderate or severe renal impairment (creatinine clearance ≤ 59 mL/min).

Method of Administration.

The 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 case of acute pain, the drug is recommended to be taken at least 30 minutes before a meal.

Children.

The use of Depiofen in children has not been studied; therefore, safety and efficacy in children and adolescents have not been established, and 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, immediate symptomatic treatment according to the patient's clinical condition should be initiated.

If an adult patient or a 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, based on clinical data, to have a minimal possible association with dexketoprofen trometamol, as well as adverse reactions reported during the post-marketing period.

The most commonly observed adverse reactions are gastrointestinal. For example, peptic ulcer, gastrointestinal perforation or hemorrhage, 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 occur during treatment with the drug. Gastritis is observed less frequently. Edema, arterial hypertension, and heart failure may also occur during treatment with NSAIDs. As with other NSAIDs, aseptic meningitis may occur, primarily in patients with systemic lupus erythematosus or mixed connective tissue disease, and blood-related reactions (purpura, hypoplastic and hemolytic anemia, rarely agranulocytosis and bone marrow hypoplasia) may also occur. Bullous reactions, including Stevens–Johnson syndrome and toxic epidermal necrolysis (very rare), are possible. According to results of 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 thrombotic events (e.g., myocardial infarction or stroke).

Reporting of suspected adverse reactions.

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

Shelf life. 2 years.

Storage conditions. Store at temperatures not exceeding 30 °C in the original packaging to protect from light. Keep out of reach and sight of children.

Packaging. 10 tablets in a blister, 1 blister per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Laboratorios Normon S.A.

Manufacturer's address and location of operations.

Ronda de Valdecarrizo, 6, Tres Cantos, 28760, Madrid, Spain.