Prodex

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

Composition:

Active substance: dexketoprofen;

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

Excipients: microcrystalline cellulose, corn starch, sodium starch glycolate, glycerol distearate;

Film coating: hypromellose, polyethylene glycol, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, film-coated tablets with a biconvex surface and a score 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. 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 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 (TxA2 and TxB2) 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 reached within 30 minutes (15–60 minutes).

When dexketoprofen trometamol is administered with food, the area under the plasma concentration-time curve (AUC) remains unchanged; however, Cmax is reduced and the absorption rate decreases (time to reach maximum concentration (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 of multiple doses have shown that after the last dose of dexketoprofen trometamol, AUC was not higher than after single administration, demonstrating the absence of drug accumulation (lack of cumulation).

Biotransformation 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 via glucuronidation and subsequent 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 NSAID, or to any of the excipients of the medicinal product.

• Use in patients in whom substances with a similar mechanism of action, for example acetylsalicylic acid and other NSAIDs, induce attacks of bronchial asthma, 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 medical history associated with the use of NSAIDs.

• Active peptic ulcer/gastrointestinal bleeding or any gastrointestinal bleeding, ulcer or perforation in medical history.

• Chronic dyspepsia.

• Bleeding in active phase or increased bleeding tendency.

• Crohn’s disease or non-specific ulcerative colitis.

• Severe heart failure.

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

• Severe hepatic function impairment (10–15 points on the Child–Pugh scale).

• Hemorrhagic diathesis or other disorders of blood coagulation.

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

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

Interaction with other medicinal products and other types of interactions.

The following drug interactions are generally characteristic of NSAID class drugs.

Unrecommended combinations:

• Other NSAIDs (including selective cyclooxygenase-2 inhibitors and high-dose salicylates (≥ 3 g/day)): simultaneous use of several NSAIDs may increase the risk of gastrointestinal ulcers and bleeding due to synergistic action.
• 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 cannot be avoided, it should be carried out under medical supervision and 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 cannot be avoided, it should be carried out under medical supervision and 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 beginning of dexketoprofen treatment, during dose adjustment, or upon discontinuation of the drug.
• Methotrexate when used 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 precautions:

• Diuretics, ACE 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), the condition may worsen with concomitant use of drugs that inhibit cyclooxygenase activity, ACE inhibitors, angiotensin II receptor antagonists, and aminoglycoside antibiotics. This worsening is usually reversible.

When combining dexketoprofen with diuretics, adequate hydration must be ensured, and renal function should be monitored during treatment.

• Methotrexate when used in low doses (less than 15 mg/week): possible increase in hematotoxic effects due to reduced renal excretion; if such combination is necessary, weekly blood count monitoring is required during the first weeks of treatment, especially in the presence of even slight renal function impairment, as well as in elderly patients.
• Pentoxifylline: increased risk of bleeding; therefore, patient observation and more frequent 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 starting NSAID treatment; therefore, blood analysis with reticulocyte count monitoring should be performed during the first 1–2 weeks after starting NSAID therapy.
• Sulfonylurea derivatives: NSAIDs may enhance the hypoglycemic effect of sulfonylurea drugs due to their displacement from plasma protein binding sites.

Combinations to be considered when using ProDex:

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

• Cyclosporine and tacrolimus: increased nephrotoxic effects of these drugs due to the influence of NSAIDs 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 effectiveness of mifepristone. Limited data suggest that concomitant use of NSAIDs on the day of prostaglandin administration does not negatively 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 45–79 mL/min) should avoid concomitant use with NSAIDs for 2 days before and 2 days after pemetrexed administration.

Special precautions for use.

The medicinal product Prodex should be used with caution in patients with a history of allergic reactions.

Concomitant use of the drug with other NSAIDs, including selective inhibitors of cyclooxygenase-2, 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 severe gastrointestinal disorders in the patient's history. If gastrointestinal bleeding or peptic ulcer develops during treatment with dexketoprofen, therapy should be discontinued immediately.

The risk of the above-mentioned adverse reactions increases proportionally with higher NSAID doses and in patients with a history of gastric or duodenal ulcer, as well as 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 is necessary—as with other NSAIDs—to ensure that these conditions are in remission. Patients with existing gastrointestinal symptoms or gastrointestinal disorders in their history should be monitored for the development of gastrointestinal complications, especially gastrointestinal bleeding.

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

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

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

Caution is advised in patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents such as acetylsalicylic acid (see section "Interaction with other medicinal products and other forms of interaction").

Renal safety

The drug should be prescribed with caution in patients with impaired renal function, as NSAID use may lead to renal dysfunction, fluid retention, and edema. Due to the increased risk of nephrotoxicity, the drug should be used cautiously in patients receiving diuretics or those at risk of hypovolemia. During treatment, patients should receive adequate fluid intake to prevent dehydration, which may exacerbate renal toxicity.

Like all NSAIDs, the medicinal product may increase plasma concentrations of blood urea nitrogen and creatinine. Similar to other inhibitors of prostaglandin synthesis, these changes may reflect adverse renal effects, potentially leading to glomerulonephritis, interstitial nephritis, papillary necrosis, nephrotic syndrome, and acute renal failure. Renal function impairment occurs more 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 aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity. Therapy should be discontinued if significant increases in these parameters occur.

Hepatic function disturbances occur more frequently in elderly patients.

Cardiovascular and cerebrovascular safety

Patients with arterial hypertension and/or mild to moderate heart failure require monitoring and medical advice. Particular caution is required when treating patients with a history of heart disease, especially those with previous 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 treatment. Clinical studies and epidemiological data suggest that the use of certain NSAIDs (especially at high doses and over prolonged periods) may slightly increase the risk of arterial thrombosis (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 artery disease, and/or cerebrovascular disease. Similarly careful evaluation should be performed 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 drugs affecting hemostasis, such as warfarin, other coumarins, or heparins. Cardiovascular function disturbances occur more frequently in elderly patients.

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

Skin reactions

Rare cases of serious skin reactions (some fatal) have been reported 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, Prodex should be discontinued.

Masking symptoms of underlying infections

Dexketoprofen may mask symptoms of infectious diseases, potentially delaying appropriate treatment and thereby complicating disease progression. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When dexketoprofen 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.

Elderly patients

Elderly individuals have an increased risk of adverse reactions to NSAIDs, including gastrointestinal bleeding and gastrointestinal tract perforation, which may be fatal. These patients should start treatment with the lowest effective dose (see section "Dosage and administration").

Elderly patients are more likely to have impaired renal, cardiovascular, or hepatic function (see section "Dosage and administration").

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, regular monitoring of liver and kidney function and blood parameters is recommended.

Rare cases of severe acute hypersensitivity reactions (e.g., anaphylactic shock) have been observed. If early signs of severe hypersensitivity reactions occur after taking Prodex, treatment should be discontinued. Depending on symptoms, appropriate treatment in such cases should be administered under medical supervision.

Patients suffering from bronchial 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 provoke attacks of bronchial asthma or bronchospasm, particularly in patients allergic to acetylsalicylic acid or NSAIDs.

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

This medicinal product 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.

The medicinal product Prodex 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 study results, the 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 less than 1% to approximately 1.5%. It is believed that the risk of such events increases 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 developmental abnormalities, including cardiovascular anomalies, increased. However, animal studies with dexketoprofen did not reveal toxic effects on reproductive organs.

Starting from the 20th week of pregnancy, the use of dexketoprofen may cause oligohydramnios due to fetal renal dysfunction. This may occur shortly after starting treatment and is usually reversible upon discontinuation. 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 of pregnancy, the lowest possible effective dose should be used for the shortest possible duration. Monitoring for oligohydramnios should begin after a few days of exposure to Prodex, starting from the 20th week of pregnancy. If oligohydramnios is detected, the drug should be discontinued.

During the third trimester, all prostaglandin synthesis inhibitors cause:

Risks to the fetus:

• cardiopulmonary toxicity, e.g., premature closure of the ductus arteriosus and pulmonary hypertension;
• renal dysfunction, which may progress to renal failure with the 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 drug use;
• inhibition of uterine contractility, leading to prolonged labor and delayed delivery.

Therefore, the medicinal product Prodex is contraindicated during the third trimester of pregnancy.

Breastfeeding period

There are no data on the passage of dexketoprofen into breast milk. The medicinal product Prodex is contraindicated during breastfeeding.

Fertility

Like all other NSAIDs, dexketoprofen trometamol may reduce female fertility; therefore, it is not recommended for use in women planning pregnancy. Women experiencing fertility problems or undergoing infertility evaluation should consider discontinuing the drug.

If dexketoprofen is used by a woman trying 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 Prodex, adverse reactions such as dizziness, visual disturbances, or drowsiness may occur, which may reduce reaction speed and 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 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.

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to relieve symptoms (see section "Special precautions"). The medicinal product Prodeks is not intended for long-term therapy; treatment should be limited to the period during which 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. The medicinal product Prodeks 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.

Prodeks is 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 drug absorption (see section "Pharmacokinetics"); therefore, in acute pain, the drug should be taken at least 30 minutes before a meal.

Children

The use of Prodeks 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 disorders (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 which, based on clinical data, are considered at least possibly related to dexketoprofen trometamol, as well as adverse reactions reported during the post-marketing period.

The most commonly observed adverse reactions are gastrointestinal in nature. Ulceration, perforation or gastrointestinal bleeding, sometimes with fatal outcome, particularly in elderly patients, may occur. According to available data, treatment with dexketoprofen may cause nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease. 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, primarily in patients with systemic lupus erythematosus or mixed connective tissue disease, as well as blood-related reactions (purpura, aplastic 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, especially at high doses and with prolonged treatment, may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after marketing authorization of a medicinal product is important. It allows continuous 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 via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store in original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 10 tablets per blister, 1 blister per carton.

Prescription status. Prescription only.

Manufacturer: Public Joint-Stock Company "Scientific and Production Center "Borshchahivskiy Chemical and Pharmaceutical Plant".

Manufacturer's address and location of business activity.

17 Miru Street, Kyiv, 03134, Ukraine