Prodex sachet

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PRODEX SACHET

Composition:

Active substance: dexketoprofen trometamol;

1 sachet contains 36.9 mg of dexketoprofen trometamol, equivalent to 25.0 mg of dexketoprofen;

Excipients: sucrose, orange flavor, sucralose.

Pharmaceutical form. Granules for oral solution.

Main physicochemical properties: granules or granular powder, white or almost white.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Propionic acid derivatives. ATC code M01A E17.

Pharmacological Properties

Pharmacodynamics

Dexketoprofen trometamol is the tromethamine salt of (S)-(+)-2-(3-benzoylphenyl) propionic acid. It is an analgesic, anti-inflammatory, and antipyretic medicinal product belonging to the group of nonsteroidal anti-inflammatory drugs (NSAIDs).

Mechanism of action

The action of nonsteroidal anti-inflammatory drugs consists in reducing the synthesis of prostaglandins by inhibiting cyclooxygenase activity. In particular, NSAIDs inhibit the conversion of arachidonic acid into the cyclic endoperoxides PGG2 and PGH2, which form prostaglandins PGE1, PGE2, PGF2α, PGD2, and PGI2 (prostacyclin) and thromboxanes TxA2 and TxB2. In addition, inhibition of prostaglandin synthesis may affect other mediators of inflammation, such as kinins, causing an indirect effect that complements the direct action.

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 in various types of pain have shown that dexketoprofen has pronounced analgesic activity. According to some studies, analgesic effect begins within 30 minutes after administration. The duration of analgesic effect is 4***–***6 hours.

Pharmacokinetics

Absorption

Dexketoprofen trometamol is rapidly absorbed after oral administration; following administration in granule form, maximum plasma concentration is reached within 0.25–0.33 hours. Comparison of dexketoprofen tablets with standard release and granules at doses of 12.5 and 25 mg showed that the two formulations are biologically equivalent in terms of bioavailability (AUC). Peak concentrations (Cmax) after administration of granules were approximately 30% higher than after administration of tablets.

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

Distribution

The distribution half-life and elimination half-life of dexketoprofen trometamol are 0.35 and 1.65 hours, respectively. As with other medicinal products highly bound to plasma proteins (99%), the volume of distribution of dexketoprofen averages less than 0.25 L/kg.

Metabolism and elimination

Elimination of dexketoprofen occurs mainly via conjugation with glucuronic acid and subsequent renal excretion.

After administration of dexketoprofen trometamol, only the S-(+) optical isomer is detected in urine, indicating the absence of conversion of the drug to the R-(-) optical isomer in humans.

Pharmacokinetic studies indicate that AUC values after multiple dosing and single administration do not differ, indicating no accumulation of the active substance.

Preclinical safety data

Standard preclinical studies—pharmacological safety, genotoxicity, and immunopharmacology studies—did not reveal any special hazard for humans. Chronic toxicity studies in mice and monkeys identified the no-observed-adverse-effect level (NOAEL), which was found to be twice the maximum recommended human dose. When higher doses were administered to monkeys, the main adverse reactions were fecal blood, reduced body weight gain, and, at the highest dose, gastrointestinal tract pathologies such as erosions. These reactions occurred at doses where drug exposure was 14–18 times higher than at the maximum recommended human dose. Carcinogenicity studies in animals have not been conducted.

Like all NSAIDs, dexketoprofen may lead to embryo or fetal death in animals due to a direct effect on development or indirectly due to maternal gastrointestinal tract injury.

Clinical characteristics.

Indications.

Short-term symptomatic treatment of mild to moderate acute pain, for example, musculoskeletal pain, dysmenorrhea, and 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, e.g., 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 perforation in the gastrointestinal tract in medical history associated with the use of NSAIDs.

• Active phase of peptic ulcer/gastrointestinal bleeding, history of gastrointestinal bleeding, ulcer, or perforation.

• 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 section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

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

Unwanted 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 effects.

• Anticoagulants: NSAIDs enhance the effects of anticoagulants, e.g., 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 medical supervision with careful monitoring of appropriate laboratory parameters.
• Heparin: increased risk of bleeding (due to inhibition of platelet function and damage to the gastric and duodenal mucosa). If concomitant use is necessary, it should be carried out under medical supervision with careful monitoring of appropriate laboratory parameters.
• Corticosteroids: increased risk of peptic ulcers and gastrointestinal bleeding.
• Lithium preparations (there have been reports with several NSAIDs): NSAIDs increase lithium blood levels up to toxic values due to reduced renal excretion. Therefore, this parameter requires monitoring at the beginning of treatment, during dose adjustment, and upon discontinuation of dexketoprofen.
• 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 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., in dehydrated patients or elderly patients with renal impairment), the condition may worsen when used concomitantly with agents that inhibit cyclooxygenase activity, such as ACE inhibitors, angiotensin II receptor antagonists, and aminoglycoside antibiotics. This worsening is usually reversible. When using dexketoprofen concomitantly with any diuretic, ensure the patient receives adequate fluid intake, and monitor renal function at the beginning and periodically after treatment initiation. Concomitant use of dexketoprofen and potassium-sparing diuretics may lead to hyperkalemia. Serum potassium concentration must be monitored.
• Methotrexate when administered in low doses (< 15 mg/week): possible increase in hematotoxic effects due to reduced renal clearance during anti-inflammatory therapy; if necessary, weekly blood count monitoring is required during the first weeks of such combination therapy, especially in patients with even slight renal impairment and in elderly individuals.
• Pentoxifylline: increased risk of bleeding; therefore, patient observation and monitoring of bleeding time are required.
• Zidovudine: risk of increased toxic effects 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 be considered

• 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 effectiveness 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 convulsions.

• 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 is required when administering higher NSAID doses. Patients with mild to moderate renal impairment (creatinine clearance 45–79 mL/min) should avoid using NSAIDs for 2 days before and 2 days after pemetrexed administration.

Special precautions.

Use with caution in patients with a history of allergic reactions.

Concomitant use of Prodex sachet with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see gastrointestinal and cardiovascular risks below).

Gastrointestinal safety.

Gastrointestinal bleeding, ulceration, or ulcer perforation, sometimes fatal, have been reported with all NSAIDs at any time during therapy, regardless of the presence of preceding symptoms or a history of serious gastrointestinal disorders. If gastrointestinal bleeding or ulceration occurs, the drug should be discontinued. The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation, and in elderly patients.

Elderly patients: Elderly patients have an increased frequency of adverse reactions to nonsteroidal anti-inflammatory drugs, particularly gastrointestinal bleeding and perforation, which may be life-threatening. Treatment of these patients should be initiated with the lowest possible dose.

Before starting treatment with dexketoprofen trometamol, patients with a history of esophagitis, gastritis, and/or peptic ulcer disease should be ensured to be in complete remission, as with other NSAIDs. Patients with gastrointestinal symptoms or a history of gastrointestinal disorders should be monitored for possible complications during treatment, particularly gastrointestinal bleeding.

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

For such patients and those taking low-dose acetylsalicylic acid or other agents increasing the risk of gastrointestinal adverse reactions, concomitant therapy with gastroprotective agents (e.g., misoprostol or proton pump inhibitors) should be considered.

Patients, especially elderly ones, with a history of gastrointestinal adverse reactions should promptly report any unusual gastrointestinal symptoms (particularly gastrointestinal bleeding), especially during the initial stages of treatment.

The drug should be prescribed with caution to patients concurrently taking agents that may increase the risk of ulceration or bleeding: oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents such as acetylsalicylic acid.

Kidney safety.

The drug should be administered with caution to patients with impaired renal function, as NSAIDs may worsen renal function, cause 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, adequate fluid intake should be maintained 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, including glomerulonephritis, interstitial nephritis, papillary necrosis, nephrotic syndrome, and acute renal failure.

Renal function disturbances occur most frequently in elderly patients.

Liver safety.

The drug should be administered with caution in patients with impaired liver function. Similar to other NSAIDs, the drug may cause transient and mild elevations in certain liver parameters, as well as marked increases in AST and ALT activity. Therapy should be discontinued if such increases occur.

Liver function disturbances occur most frequently in elderly patients.

Cardiovascular and cerebrovascular safety.

Patients with a history of hypertension and/or mild to moderate heart failure require monitoring and medical supervision. Particular caution is required in patients with a history of heart disease, especially previous episodes of heart failure, as treatment with NSAIDs increases the risk of heart failure due to fluid retention and edema. Clinical studies and epidemiological data suggest that some NSAIDs (especially 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 such risk with dexketoprofen. Therefore, dexketoprofen should be prescribed only after careful patient assessment in cases of uncontrolled 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., hypertension, hyperlipidemia, diabetes, 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 agents affecting hemostasis, such as warfarin, other coumarins, or heparins. Cardiovascular system disturbances occur most frequently in elderly patients.

Skin reactions.

There have been reports of very rare cases of serious skin reactions (some fatal) associated with NSAIDs, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The highest risk appears to occur early in treatment, with most cases developing within the first month.

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

Masking symptoms of underlying infections.

Dexketoprofen may mask symptoms of infectious diseases, potentially delaying appropriate treatment and worsening disease progression. This has been observed in bacterial community-acquired pneumonia and bacterial complications of varicella. When Prodex sachet is used to relieve pain associated with infection, monitoring for infection 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 considered necessary by the physician, regular monitoring of liver and kidney function and blood parameters should be performed.

In very rare cases, severe acute hypersensitivity reactions (e.g., anaphylactic shock) have been observed. If signs of severe hypersensitivity occur after taking the drug, treatment should be discontinued. Depending on symptoms, appropriate management should be performed under medical supervision.

Patients with asthma combined with chronic rhinitis, chronic sinusitis, and/or nasal polyps have a higher risk of allergy to acetylsalicylic acid and/or NSAIDs than 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. There is currently insufficient data to fully exclude the role of NSAIDs in exacerbating this infection. Therefore, the use of Prodex sachet should be avoided in varicella.

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

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

Children. Safety and efficacy in children and adolescents have not been established.

Use during pregnancy or breastfeeding.

Prodex sachet is contraindicated during the third trimester of pregnancy and during breastfeeding.

Pregnancy.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryofetal development. Epidemiological data indicate that use of prostaglandin synthesis inhibitors during early pregnancy increases the risk of miscarriage, congenital heart defects, and gastroschisis.

For example, the absolute risk of cardiovascular malformations increases from less than 1% to approximately 1.5%. The risk is considered to increase with higher drug doses and longer duration of therapy. Animal studies with prostaglandin synthesis inhibitors have shown increased pre- and post-implantation losses and higher embryofetal mortality. Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of fetal malformations, including cardiovascular anomalies, was observed. However, animal studies with dexketoprofen did not reveal toxic effects on reproductive organs. Use of dexketoprofen from week 20 of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation. 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 only if absolutely necessary. When prescribing dexketoprofen to women planning pregnancy or during the first and second trimesters, the lowest effective dose for the shortest possible duration should be used. Fetal monitoring for oligohydramnios and arterial duct constriction should be considered if exposure to dexketoprofen occurs for several days starting from week 20 of gestation. Women should discontinue dexketoprofen if oligohydramnios or arterial duct constriction is detected.

During the third trimester, all prostaglandin synthesis inhibitors cause:

Risks to the fetus:

• cardiopulmonary toxicity, e.g., premature constriction/closure of the ductus arteriosus 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 at low doses;
• inhibition of uterine contractility, leading to prolonged labor and delayed delivery.

Breastfeeding.

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

Fertility.

Like all other NSAIDs, Prodex sachet may reduce female fertility and is therefore not recommended for women attempting to conceive. Women experiencing infertility or undergoing fertility investigations should consider discontinuing dexketoprofen.

Ability to affect reaction speed when driving or operating machinery.

During treatment with Prodex sachet granules, undesirable effects such as dizziness, visual disturbances, or drowsiness may occur. In such cases, reaction speed when driving or operating machinery may be reduced.

Method of Administration and Dosage.

Dosing.

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

Adults.

Depending on the type and intensity of pain, the recommended dose is 25 mg every 8 hours. The daily dose should not exceed 75 mg.

Prodex sachet is intended only for short-term use necessary to relieve symptoms.

Elderly patients. Treatment should be initiated with low doses. The daily dose is 50 mg. If the patient tolerates the drug well, the dose may be increased to the usual level. Due to the risk of adverse reactions of a certain profile, elderly patients should be under close medical supervision.

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. Prodex sachet is contraindicated in patients with severe hepatic impairment.

Renal impairment. For patients with mild renal impairment (creatinine clearance 60–89 mL/min), the initial total daily dose should be reduced to 50 mg. Prodex sachet is contraindicated in patients with moderate or severe renal impairment (creatinine clearance ≤ 59 mL/min).

Method of Administration.

Before use, dissolve the entire contents of 1 sachet in a glass of water and mix thoroughly for better dissolution. The resulting solution should be taken immediately after preparation.

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

Children.

The use of Prodex sachet 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 or excessive use, symptomatic treatment should be initiated immediately according to the patient's clinical condition. If the dose exceeds 5 mg/kg in an adult or child, activated charcoal should be administered within one hour. Dexketoprofen trometamol is eliminated from the body by dialysis.

Adverse reactions.

The table below lists adverse reactions distributed by organs and systems and frequency of occurrence, whose association with the use of dexketoprofen (in tablet form) has been recognized in clinical trials as at least possible, as well as adverse reactions reported during the post-marketing period.

Since the Cmax level in blood plasma for dexketoprofen in granule form is higher than for tablets, an increased risk of adverse reactions (regarding the gastrointestinal tract) cannot be excluded.

The most commonly observed adverse effects are gastrointestinal in nature. Peptic ulcer, gastrointestinal perforation or hemorrhage, sometimes fatal, particularly in elderly patients, may occur. According to available data, nausea, vomiting, diarrhea, flatulence, constipation, dyspeptic symptoms, abdominal pain, melena, hematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease may occur during treatment with the drug. Gastritis is observed less frequently. Edema, arterial hypertension, and heart failure have also been reported during NSAID therapy.

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

As with other NSAIDs, the following adverse reactions may occur: aseptic meningitis, which occurs primarily in patients with systemic lupus erythematosus or mixed connective tissue disorders, and blood-related reactions (purpura, aplastic and hemolytic anemia; rarely agranulocytosis and bone marrow hypoplasia).

Reporting of adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of this medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

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

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 sachets with the instruction for medical use in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Public Joint-Stock Company "Scientific and Production Center "Borshchahivskyy Chemical and Pharmaceutical Plant".

Manufacturer's address and location of manufacturing activities.

17, Miru Street, Kyiv, 03134, Ukraine.