Duodiklaza

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

Composition:

1 modified-release capsule, hard, contains:

Active substances: sodium diclofenac – 75 mg, including sodium diclofenac in gastro-resistant pellets – 25 mg, sodium diclofenac in prolonged-release pellets – 50 mg; omeprazole – 20 mg;

Excipients:

Composition of gastro-resistant diclofenac pellets:

microcrystalline cellulose; povidone, K 25; colloidal anhydrous silicon dioxide; methacrylic acid copolymer (1:1) type A; sodium lauryl sulfate; polysorbate 80; propylene glycol; talc;

Composition of prolonged-release diclofenac pellets:

microcrystalline cellulose; povidone, K 25; colloidal anhydrous silicon dioxide; ammonium methacrylate copolymer (type B); ammonium methacrylate copolymer (type A); triethyl citrate; talc;

Composition of gastro-resistant omeprazole pellets:

methacrylic acid copolymer (1:1) dispersion 30% (dry substance); sodium lauryl sulfate; polysorbate 80; talc; mannitol (E 421); heavy magnesium carbonate; hydroxypropylcellulose (75–150 mPas/5% sol); hypromellose (6 mPas).

Capsule shell size 1:

pink to brown cap: titanium dioxide (E 171); iron oxide red (E 172); gelatin.

yellow body: titanium dioxide (E 171); iron oxide yellow (E 172); gelatin.

Pharmaceutical form. Hard modified-release capsules.

Main physicochemical properties: hard gelatin capsules, size 1, elongated, capsule cap opaque pink to brown, capsule body opaque yellow, capsule contents – pellets from white to slightly yellow.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Acetic acid derivatives and related substances. Diclofenac, combinations.

ATC code M01AB55.

Pharmacological properties.

Pharmacodynamics.

Diclofenac

Diclofenac is a non-steroidal medicinal product with pronounced analgesic and anti-inflammatory properties. It is an inhibitor of prostaglandin synthetase (cyclooxygenase).

Omeprazole

Mechanism of action

Omeprazole, a racemic mixture of two enantiomers, reduces gastric hydrochloric acid secretion through a targeted mechanism of action. Omeprazole is a specific inhibitor of the proton pump (PPI) in parietal cells. When administered once daily, omeprazole acts rapidly and provides control over hydrochloric acid secretion produced by gastric cells through reversible inhibition.

Omeprazole is a weak base that accumulates and is converted into its active form in the acidic environment of parietal cells, where it inhibits H+, K+-ATPase, thereby affecting the final stage of gastric acid secretion. This effect on the final step of gastric hydrochloric acid formation is dose-dependent and provides highly effective suppression of both basal and stimulated acid secretion, regardless of the type of stimulation.

Pharmacodynamic effects

All pharmacodynamic effects can be explained by the effect of omeprazole on hydrochloric acid secretion.

Oral administration of omeprazole once daily leads to rapid and effective inhibition of daytime and nighttime hydrochloric acid secretion by gastric parietal cells, with maximum effect achieved within 4 days of treatment. In patients with duodenal ulcer, mean reduction in gastric acidity (approximately 80%) occurs within 24 hours after administration of 20 mg omeprazole; mean reduction in peak acid output after pentagastrin stimulation is about 70% at 24 hours after omeprazole intake.

Oral administration of 20 mg omeprazole maintains intragastric pH ≥ 3 for an average of 17 hours out of a 24-hour period in patients with duodenal ulcer.

Due to reduced hydrochloric acid secretion and intragastric acidity, omeprazole reduces/normalizes the effect of hydrochloric acid on the esophagus in patients with gastroesophageal reflux disease, in a dose-dependent manner.

Inhibition of hydrochloric acid secretion correlates with the area under the plasma concentration–time curve (AUC) of omeprazole, rather than with the actual plasma concentration at that time.

No tachyphylaxis has been observed during omeprazole treatment.

Other effects related to inhibition of hydrochloric acid secretion

During long-term treatment, a slightly increased frequency of occurrence of glandular cysts in the stomach has been reported. These changes are a physiological consequence of acid secretion inhibition; the cysts are benign and reversible.

Reduced gastric acidity, regardless of the agent used, including PPIs, increases the number of bacteria normally present in the gastrointestinal tract. Treatment with acid-reducing agents slightly increases the risk of gastrointestinal infections, such as those caused by Salmonella and Campylobacter, and in hospitalized patients, possibly also those caused by Clostridium difficile.

During treatment with antisecretory medicinal products, plasma gastrin concentration increases as a result of reduced hydrochloric acid secretion. Due to reduced acid secretion, chromogranin A (CgA) levels increase. Elevated CgA concentration may affect diagnostic test results for neuroendocrine tumors.

Based on available published data, it is recommended that PPI intake be discontinued 5 to 14 days before planned measurements of CgA levels. This allows CgA levels, which may be falsely elevated during PPI use, to return to reference values.

During long-term omeprazole therapy, an increase in the number of enterochromaffin-like cells (ECL cells) has been observed in some patients (including both children and adults), possibly due to elevated serum gastrin levels. These findings are considered to have no clinical significance.

Pharmacokinetics.

Diclofenac

Sodium diclofenac is rapidly absorbed from the intestine and is characterized by pronounced first-pass metabolism. Maximum plasma concentration is reached within half an hour. Diclofenac binding to serum proteins is 99.7%, and the terminal elimination half-life averages 1–2 hours. Approximately 60% of the administered dose is excreted by the kidneys as metabolites and less than 1% unchanged. The remaining portion of the administered dose is excreted in metabolized form via bile.

After rapid passage through the stomach, the portion of diclofenac resistant to gastric juice is rapidly absorbed into the systemic circulation. The modified-release capsule formulation of diclofenac allows once-daily dosing of the medicinal product DUODICLAZA.

Special patient populations

Patients with renal impairment

It is known that diclofenac is primarily eliminated by the kidneys, and therefore the risk of developing toxic reactions with DUODICLAZA is higher in patients with renal impairment.

Omeprazole

Absorption

Omeprazole and omeprazole magnesium salt are acid-labile compounds and therefore are administered orally as enteric-coated granules in capsules or tablets. Omeprazole absorption is rapid, with peak plasma levels reached approximately 1–2 hours after a single dose. Absorption of omeprazole occurs in the small intestine and is usually complete within 3–6 hours. Concomitant food intake does not affect omeprazole bioavailability. Systemic availability (bioavailability) of a single dose of omeprazole is approximately 40%. After repeated once-daily dosing, bioavailability increases to about 60%.

Distribution

The apparent volume of distribution in healthy volunteers is approximately 0.3 L/kg body weight. Omeprazole is 97% bound to plasma proteins.

Biological transformation

Omeprazole is completely metabolized by the cytochrome P450 (CYP) system. The majority of its metabolism depends on the polymorphically expressed CYP2C19, responsible for the formation of hydroxyomeprazole, the main metabolite in plasma. Another portion depends on another specific isoform, CYP3A4, responsible for the formation of omeprazole sulfone. Due to omeprazole's high affinity for CYP2C19, competitive inhibition and metabolic interactions between medicinal products that are substrates for CYP2C19 are possible. However, due to low affinity for CYP3A4, omeprazole is not capable of inhibiting the metabolism of other CYP3A4 substrates. In addition, omeprazole does not exert inhibitory effects on major CYP enzymes.

Approximately 3% of individuals of Caucasian ethnicity and 15–20% of individuals of Asian ethnicity have deficiency of functional CYP2C19 enzyme and are therefore referred to as "poor metabolizers." In these individuals, omeprazole metabolism is likely primarily catalyzed by CYP3A4. After repeated administration of 20 mg omeprazole once daily, the AUC in "poor metabolizers" was 5–10 times higher than in subjects with functional CYP2C19 enzyme ("extensive metabolizers"). Mean peak plasma concentrations were also 3–5 times higher. These data do not affect omeprazole dosing.

Elimination

The elimination half-life of omeprazole from plasma is usually less than 1 hour, both after single and repeated once-daily administration. Omeprazole is completely eliminated from plasma between doses without tendency to accumulate when administered once daily. Nearly 80% of an oral dose of omeprazole is excreted in urine as metabolites, the remainder via bile in feces.

Omeprazole AUC increases with repeated administration. This increase is dose-dependent and results in non-linear AUC-dose relationship after repeated dosing. This time- and dose-dependent relationship is due to reduced first-pass metabolism and systemic clearance, likely caused by omeprazole and/or its metabolites (e.g., sulfone) inhibiting the CYP2C19 enzyme.

No effects of omeprazole metabolites on gastric hydrochloric acid secretion have been demonstrated.

Special patient populations

Hepatic impairment

Omeprazole metabolism is impaired in patients with hepatic dysfunction, leading to increased AUC. Omeprazole has not shown a tendency to accumulate when repeated doses are administered once daily.

Renal impairment

The pharmacokinetics of omeprazole, including systemic bioavailability and elimination rate, are not altered in patients with renal impairment.

Elderly patients

The rate of omeprazole metabolism is slightly reduced in elderly patients (75–79 years of age).

Clinical characteristics.

Indications.

DUODICLAZA is indicated for symptomatic treatment of rheumatoid arthritis and osteoarthritis adequately controlled with diclofenac and omeprazole in adult patients at risk of developing gastric and/or duodenal ulcers associated with nonsteroidal anti-inflammatory drug (NSAID) use.

Contraindications.

Hypersensitivity to the active substances, substituted benzimidazoles, or any excipient.

History of hypersensitivity reactions (such as asthma, urticaria, angioedema, or rhinitis) following administration of ibuprofen, aspirin, or other NSAIDs.

Severe hepatic, renal, or cardiac failure.

Inflammatory bowel diseases (Crohn’s disease or ulcerative colitis).

Third trimester of pregnancy and breastfeeding.

Active or recurrent peptic ulcer/bleeding in medical history (two or more documented episodes of ulcer or bleeding).

History of gastrointestinal bleeding or perforation associated with previous NSAID therapy.

Pediatric population (under 18 years of age).

DUODICLAZA, like other medicinal products containing proton pump inhibitors (PPIs), must not be used concomitantly with nelfinavir.

Established congestive heart failure (NYHA II–IV), ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease.

Treatment of perioperative pain following coronary artery bypass grafting (CABG) or use of cardiopulmonary bypass.

Uncontrolled arterial hypertension.

Conditions characterized by increased tendency to bleeding.

Interaction with other medicinal products and other forms of interaction.

Diclofenac

Other analgesics, NSAIDs, including selective cyclooxygenase-2 inhibitors

Concomitant use of two or more NSAIDs (including acetylsalicylic acid) should be avoided, as this increases the frequency of adverse effects (see section "Special warnings and precautions for use").

Diuretics, angiotensin-converting enzyme inhibitors (ACE inhibitors), and angiotensin II receptor antagonists

Possible reduction in diuretic and antihypertensive effects.

Combination therapy should be administered with caution and under blood pressure monitoring, especially in elderly patients. Adequate hydration should be ensured. Renal function should be monitored after initiation of combined therapy and periodically thereafter, particularly in patients receiving diuretics and ACE inhibitors due to increased risk of nephrotoxic effects.

Diuretics may increase the risk of NSAID nephrotoxicity. Concomitant use of potassium-sparing diuretics may lead to increased serum potassium levels; therefore, potassium levels should be monitored.

Cardiac glycosides

Concomitant use of cardiac glycosides and NSAIDs may promote worsening of heart failure, decreased glomerular filtration rate (GFR), and increased plasma concentration of glycosides.

Lithium

Cases of increased serum lithium concentrations have been reported; serum lithium levels should be closely monitored.

Cyclosporine

Possible increase in nephrotoxicity; therefore, diclofenac should be used at lower doses in patients receiving cyclosporine.

Probenecid

Medicinal products containing probenecid may delay the elimination of diclofenac.

Mifepristone

NSAIDs should not be used within 8–12 days after mifepristone administration, as NSAIDs may reduce its efficacy.

Corticosteroids

Increased risk of gastrointestinal bleeding or ulcers (see section "Special warnings and precautions for use").

Anticoagulant drugs and antiplatelet agents

Should be prescribed with caution, as concomitant use may increase the risk of bleeding (see section "Special warnings and precautions for use"). Although clinical studies do not indicate an effect of diclofenac on anticoagulant activity, isolated data suggest an increased risk of hemorrhage in patients receiving diclofenac and anticoagulants simultaneously. Therefore, careful monitoring of such patients is recommended.

Quinolone antibiotics

Isolated reports of convulsions (animal studies) possibly related to concomitant use of quinolone derivatives and NSAIDs. Convulsions may occur in patients receiving quinolone derivatives and NSAIDs concomitantly.

Selective serotonin reuptake inhibitors (SSRIs)

Increased risk of gastrointestinal bleeding (see section "Special warnings and precautions for use").

Zidovudine

Increased risk of hematological toxicity when zidovudine is used concomitantly with NSAIDs. Data indicate an increased risk of hemarthrosis and hematomas in HIV-infected individuals with hemophilia receiving zidovudine and ibuprofen concomitantly.

Cholestyramine and colestipol

These agents may cause delayed or reduced absorption of diclofenac. Therefore, diclofenac should be administered at least 1 hour before or 4–6 hours after cholestyramine/colestipol.

Potent CYP2C9 inhibitors

Caution should be exercised when using diclofenac concomitantly with potent CYP2C9 inhibitors (e.g., sulfaphenazole and voriconazole), as this may lead to a significant increase in Cmax and exposure of diclofenac due to inhibition of its metabolism.

Inducers of CYP2C9. Caution is required when diclofenac is co-administered with CYP2C9 inducers (e.g., rifampicin), as this may lead to a significant decrease in plasma concentration and exposure of diclofenac.

Antidiabetic medicinal products

Clinical studies have shown that diclofenac can be used with oral antidiabetic agents without affecting their therapeutic effect. However, there are some reports of isolated cases of both hypoglycemia and hyperglycemia, necessitating adjustment of antidiabetic agent dosage during diclofenac treatment. Therefore, as a precautionary measure, blood glucose levels should be monitored during combination therapy.

Digoxin

Increased digoxin blood concentration has been observed; therefore, monitoring of serum digoxin levels is recommended.

Methotrexate

NSAIDs should be used with caution less than 24 hours before methotrexate treatment. Diclofenac may inhibit renal tubular clearance of methotrexate, thereby increasing its levels.

Tacrolimus

Increased risk of nephrotoxicity may occur when NSAIDs are administered concomitantly with tacrolimus.

Phenytoin

When phenytoin and diclofenac are used concomitantly, plasma phenytoin concentration should be monitored due to expected increased exposure.

Omeprazole

Effect of omeprazole on the pharmacokinetics of other active substances

Active substances with pH-dependent absorption

Reduced gastric acidity during omeprazole treatment may affect the absorption of certain drugs whose absorption depends on gastric pH.

Nelfinavir, atazanavir

Concomitant use of omeprazole reduces plasma levels of nelfinavir and atazanavir.

Concomitant use of omeprazole and nelfinavir is contraindicated (see section "Contraindications"). Concomitant use of omeprazole (40 mg once daily) reduces mean nelfinavir exposure by approximately 40%; mean exposure of the pharmacologically active metabolite M8 is reduced by approximately 75–90%. This interaction may also affect CYP2C19 inhibition.

Concomitant use of omeprazole and atazanavir is not recommended (see section "Special warnings and precautions for use"). Concomitant use of omeprazole (40 mg once daily) with atazanavir 300 mg and ritonavir 100 mg in healthy volunteers resulted in a 75% reduction in atazanavir exposure. Increasing the atazanavir dose to 400 mg did not compensate for the effect of omeprazole on atazanavir exposure. Concomitant use of omeprazole (20 mg once daily) with atazanavir 400 mg and ritonavir 100 mg in healthy volunteers resulted in approximately a 30% reduction in atazanavir exposure compared to atazanavir 300 mg and ritonavir 100 mg combination.

Digoxin

Concomitant use of omeprazole (20 mg once daily) and digoxin in healthy volunteers increased digoxin bioavailability by 10%. Cases of digoxin-induced toxicity have been rarely reported. However, caution should be exercised when prescribing high doses of omeprazole to elderly patients. Therapeutic drug monitoring of digoxin should be intensified.

Clopidogrel

A pharmacokinetic (PK)/pharmacodynamic (PD) interaction between clopidogrel (loading dose 300 mg / maintenance dose 75 mg daily) and omeprazole (80 mg daily orally) was observed in healthy volunteers, resulting in a mean reduction of 46% in AUC of clopidogrel's active metabolite and a mean reduction of 16% in maximum inhibitory effect (ADP-induced) of platelet aggregation.

Conflicting data on clinical implications of this PK/PD interaction regarding major cardiovascular events have been reported in observational and clinical studies. As a precautionary measure, concomitant use of omeprazole and clopidogrel should be avoided (see section "Special warnings and precautions for use").

Other medicinal products

Absorption of posaconazole, erlotinib, ketoconazole, and itraconazole is significantly reduced, and thus clinical efficacy may be diminished. Concomitant use with posaconazole and erlotinib should be avoided.

Medicinal products metabolized by CYP2C19

Omeprazole exerts moderate inhibitory effect on CYP2C19—the main enzyme responsible for omeprazole metabolism. Thus, metabolism of concomitantly administered medicinal products metabolized by CYP2C19 may be reduced, and systemic exposure to these agents may be increased. Examples include R-warfarin and other vitamin K antagonists, cilostazol, diazepam, and phenytoin.

Cilostazol

In healthy volunteers, administration of omeprazole 40 mg increased the maximum plasma concentration (Cmax) and AUC of cilostazol by 18% and 26%, respectively, and one of its active metabolites by 29% and 69%, respectively.

Phenytoin

Plasma phenytoin concentration monitoring is recommended during the first two weeks after starting omeprazole treatment. If phenytoin dose adjustment is required, monitoring and further dose adjustments should continue after discontinuation of omeprazole.

Unknown mechanism

Saquinavir

Concomitant use of omeprazole with saquinavir/ritonavir increased plasma levels of saquinavir by approximately 70%, which was associated with acceptable tolerability in HIV-infected patients.

Methotrexate

Increased methotrexate levels have been reported in some patients receiving concomitant PPIs. In case of necessity to use high-dose methotrexate, temporary discontinuation of omeprazole should be considered.

Tacrolimus

Increased serum levels of tacrolimus have been reported with concomitant use of omeprazole. Intensified monitoring of tacrolimus concentration and renal function (creatinine clearance) is required, and dose adjustment of tacrolimus may be necessary.

Effect of other medicinal products on omeprazole pharmacokinetics

Inhibitors of CYP2C19 and/or CYP3A4

Since omeprazole is metabolized by CYP2C19 and CYP3A4 enzymes, medicinal products that inhibit CYP2C19 or CYP3A4 activity (e.g., clarithromycin and voriconazole) may increase omeprazole serum levels due to slowed metabolism. Concomitant use of voriconazole resulted in more than a twofold increase in omeprazole AUC. As high omeprazole doses are generally well tolerated, dose adjustment is usually not required. However, dose adjustment should be considered in patients with severe hepatic impairment and during long-term treatment.

Inducers of CYP2C19 and/or CYP3A4

Medicinal products that induce CYP2C19 or CYP3A4 activity or both (e.g., rifampicin and St. John’s wort) may reduce omeprazole serum levels due to accelerated metabolism.

Special precautions for use.

Diclofenac

All patient groups.

In rare cases, as with other NSAIDs, allergic reactions including anaphylactic/anaphylactoid reactions may occur, even without prior exposure to the drug. Hypersensitivity reactions may also progress to Kounis syndrome, a serious allergic reaction that may cause myocardial infarction. Symptoms of such reactions may include chest pain occurring in combination with an allergic reaction to diclofenac. Due to its pharmacodynamic properties, the medicinal product DUODIKLAZA may mask signs and symptoms of infection.

Concomitant use of DUODIKLAZA with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided due to lack of evidence for synergistic effect and potential adverse effects (see section "Interaction with other medicinal products and other forms of interaction").

Elderly patients

Caution should be exercised when prescribing DUODIKLAZA to elderly patients. Elderly patients have an increased risk of experiencing adverse reactions to NSAIDs, particularly gastrointestinal bleeding, ulceration, or perforation, which may be fatal (see section "Method of administration and dosage"). Patients with low body weight should be prescribed the lowest effective dose.

Respiratory disorders

Patients with bronchial asthma, seasonal allergic rhinitis, nasal mucosal swelling (nasal polyps), chronic obstructive lung diseases, or chronic respiratory tract infections (especially those associated with allergic, rhinitis-like symptoms) are more prone than others to develop NSAID-related reactions resembling asthma exacerbations (so-called analgesic intolerance/analgesic-induced asthma), angioedema (Quincke's edema), or urticaria. Therefore, special precautions (readiness for emergency treatment) are recommended for such patients. This also applies to patients with allergies to other substances manifesting as skin reactions, pruritus, or urticaria (see section "Contraindications").

Cardiovascular, renal, and hepatic insufficiency

Diclofenac should be prescribed to patients with risk factors for cardiovascular diseases (such as arterial hypertension, hyperlipidemia, diabetes mellitus, or smoking) only after careful assessment of their condition.

Since cardiovascular risks associated with diclofenac use may increase with higher doses and longer duration of treatment, the drug should be used for the shortest possible duration and at the lowest effective dose. The patient's need for symptomatic relief and response to therapy should be periodically reviewed.

Close medical monitoring is required when diclofenac is prescribed to patients with impaired liver function, as their condition may worsen.

As with other NSAIDs, during diclofenac use, the level of one or more liver enzymes may increase. In addition to elevated liver enzyme levels, rare serious hepatic reactions have been reported, including jaundice, fulminant hepatitis, hepatic necrosis, and liver failure, some of which have been fatal. As a precautionary measure during long-term diclofenac therapy, regular monitoring of liver function is recommended. If liver function abnormalities persist or worsen, or if clinical signs or symptoms suggestive of progressive liver disease occur, or if other manifestations appear (e.g., eosinophilia, rash), the drug should be discontinued. Hepatitis may occur without prodromal symptoms. Caution is advised when using diclofenac in patients with hepatic porphyria due to the potential risk of provoking an attack.

Since fluid retention and edema have been reported during treatment with NSAIDs, including diclofenac, particular attention should be paid to patients with impaired cardiac or renal function; history of arterial hypertension; elderly patients; patients receiving concomitant diuretic therapy or drugs significantly affecting renal function; and patients with significant reduction in extracellular fluid volume for any reason, e.g., before or after major surgery (see section "Contraindications"). As a precautionary measure, monitoring of renal function is recommended in such cases. Discontinuation of therapy usually leads to return to the pre-treatment state.

NSAID use may cause dose-dependent reduction in prostaglandin formation and may exacerbate renal impairment. The highest risk of this reaction occurs in patients with impaired renal function, heart failure, hepatic dysfunction, patients taking diuretics, and elderly patients. Renal function should be monitored regularly in these patients (see section "Contraindications").

Effects on cardiovascular system and cerebral circulation

Appropriate monitoring and recommendations are required for patients with a history of arterial hypertension and/or mild to moderate congestive heart failure, as fluid retention and edema have been reported with NSAID use.

Clinical trial data and epidemiological evidence suggest that diclofenac use, particularly at high doses (150 mg daily) and during prolonged treatment, may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Patients should be vigilant for serious signs and symptoms of atherothrombosis (such as chest pain, dyspnea, weakness, speech disturbances), which may occur at any time. Patients should be advised to seek immediate medical attention if such symptoms occur.

Diclofenac is contraindicated in patients with uncontrolled arterial hypertension, congestive heart failure (NYHA II–IV), stable ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease (see section "Contraindications"). A careful assessment should be performed before initiating long-term treatment in patients with risk factors for cardiovascular events (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, or smoking).

Gastrointestinal bleeding, ulceration, and perforation

As with other NSAIDs, potentially fatal gastrointestinal bleeding, ulceration, or perforation may occur at any time during treatment, with or without prior symptoms or serious gastrointestinal disorders in medical history.

The risk of gastrointestinal bleeding, ulceration, or perforation is higher with increased NSAID dosage, in patients with a history of peptic ulcer (especially complicated by bleeding or perforation) (see section "Contraindications"), and in elderly patients. To reduce the risk of toxicity, such patients should start treatment with the lowest effective dose.

Patients with a history of gastrointestinal toxicity, particularly elderly patients, should report any unusual abdominal symptoms (especially gastrointestinal bleeding), especially in the early stages of treatment.

Patients receiving concomitant medications that increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants (e.g., warfarin), antiplatelet agents (e.g., acetylsalicylic acid), or selective serotonin reuptake inhibitors, should also be warned (see section "Interaction with other medicinal products and other forms of interaction").

If gastrointestinal bleeding or ulceration develops in patients receiving DUODIKLAZA, treatment should be discontinued.

The medicinal product is contraindicated in patients with ulcerative colitis or Crohn's disease (see section "Contraindications").

Use of all NSAIDs, including diclofenac, may be associated with a risk of anastomotic dehiscence and leakage. Close medical monitoring and caution are recommended when using diclofenac in patients after gastrointestinal surgery. As with all NSAIDs, including diclofenac, careful medical monitoring and special caution are required when prescribing diclofenac to patients with symptoms suggesting gastrointestinal disorders or with suspected ulcer, bleeding, or perforation of the stomach or intestine in medical history (see section "Adverse reactions").

Systemic lupus erythematosus and Sharp syndrome

Patients with systemic lupus erythematosus and Sharp syndrome may have an increased risk of aseptic meningitis (see section "Adverse reactions").

Skin reactions

In very rare cases, serious skin reactions, some of which have been fatal, have been reported after NSAID use, including exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and generalized fixed bullous drug eruption associated with diclofenac use (see section "Adverse reactions"). During initial therapy, patients appear to be at highest risk of these reactions, which in most cases occur within the first month of treatment. DUODIKLAZA should be discontinued at the first signs of skin rash, mucosal lesions, or any other signs of hypersensitivity.

Effects on hematological parameters

Like other NSAIDs, diclofenac may temporarily inhibit platelet aggregation. Careful monitoring is required in patients with coagulation disorders.

Use of DUODIKLAZA at a dose of 75 mg/20 mg is recommended only for short-term treatment. With long-term use of diclofenac, as with other NSAIDs, monitoring of blood parameters is recommended.

Omeprazole

In the presence of any adverse symptom (e.g., significant unintentional weight loss, frequent vomiting, dysphagia, hematemesis, or melena) and in diagnosed or suspected gastric ulcer, malignancy should be excluded, as drug intake may mask its symptoms and delay correct diagnosis.

Concomitant use of atazanavir with a proton pump inhibitor is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). If a combination of atazanavir with PPIs cannot be avoided, careful clinical monitoring (e.g., viral load) combined with increasing the atazanavir dose to 400 mg with 100 mg ritonavir is recommended; the omeprazole dose should not exceed 20 mg.

Omeprazole, like all drugs that inhibit gastric acid secretion, may reduce absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with low body weight or risk factors for reduced vitamin B12 absorption during long-term therapy.

Omeprazole is a CYP2C19 inhibitor. Potential interactions with drugs metabolized by CYP2C19 should be considered at the beginning or end of omeprazole treatment. An interaction between clopidogrel and omeprazole has been observed (see section "Interaction with other medicinal products and other forms of interaction"). The clinical significance of this interaction remains unclear. As a precaution, concomitant use of omeprazole and clopidogrel should be avoided.

Severe hypomagnesemia has been reported in patients taking PPIs, including omeprazole, for at least 3 months, with most cases occurring after approximately one year of treatment. Hypomagnesemia may present with serious symptoms such as fatigue, tetany, delirium, seizures, dizziness, ventricular arrhythmias, but may also be asymptomatic and remain undiagnosed. In most patients, symptoms resolve and magnesium levels normalize after magnesium supplementation and PPI discontinuation. In patients planned for long-term PPI use or concomitant use with digoxin or other drugs that may reduce magnesium levels (e.g., diuretics), serum magnesium concentration should be measured before starting PPI therapy and periodically during treatment.

PPIs, especially when used at high doses and for prolonged periods (>1 year), slightly increase the risk of fractures of the spine, wrist, and femur, particularly in elderly individuals and those with predisposing factors. Observational studies indicate that PPIs increase the overall fracture risk by 10–40%. Part of the increased risk may be attributable to other factors. Patients at risk of osteoporosis should receive appropriate support according to current clinical guidelines and adequate intake of vitamin D and calcium.

PPI treatment slightly increases the risk of gastrointestinal infections, e.g., caused by Salmonella and Campylobacter, and in hospitalized patients possibly also by Clostridium difficile (see section "Pharmacodynamics").

Patients taking DUODIKLAZA for a prolonged period, especially if treatment lasts more than 1 year, require regular medical monitoring.

Subacute cutaneous lupus erythematosus (SCLE)

PPI use may occasionally cause SCLE. If skin manifestations appear, particularly in sun-exposed areas, and are accompanied by arthralgia, immediate medical attention should be sought and discontinuation of omeprazole considered. A history of SCLE following PPI use increases the risk of SCLE with other PPIs.

Renal function disorders

Acute tubulointerstitial nephritis (ATIN) has been observed in patients taking omeprazole and may occur at any time during omeprazole therapy (see section "Adverse reactions"). Acute tubulointerstitial nephritis may progress to renal failure.

If ATIN is suspected, omeprazole should be discontinued and appropriate treatment initiated immediately.

Effects on laboratory test results

Elevated chromogranin A (CgA) levels may affect diagnostic tests for neuroendocrine tumors. To obtain accurate results, omeprazole should be temporarily discontinued 5 days before CgA testing (see section "Pharmacodynamics"). If CgA and gastrin levels do not return to reference ranges after initial measurements, these parameters should be rechecked 14 days after discontinuation of PPI therapy.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

Diclofenac

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data suggest an increased risk of miscarriage and risk of cardiac defects and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increased from less than 1% to approximately 1.5%. The risk may increase with higher doses and longer duration of treatment. Animal studies have shown that prostaglandin synthesis inhibitors lead to increased pre- and post-implantation loss and embryonic/fetal mortality.

Furthermore, in animals receiving prostaglandin synthesis inhibitors during organogenesis, an increased frequency of various developmental abnormalities, including cardiovascular defects, was observed. Diclofenac should not be prescribed during the first and second trimesters of pregnancy unless absolutely necessary. If sodium diclofenac is used by a woman trying to conceive or in the first trimester of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible.

During the first trimester of pregnancy, all prostaglandin synthesis inhibitors may affect the fetus as follows:

• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• impaired renal function, which may progress to renal failure with oligohydramnios;

on the mother towards the end of pregnancy and on the newborn:

• prolonged bleeding time, anti-aggregatory effect, which may occur even at very low doses;
• inhibition of uterine contractions, leading to delayed or prolonged labor.

The medicinal product DUODIKLAZA is contraindicated during the third trimester of pregnancy.

Omeprazole

Results from three prospective epidemiological studies indicate no adverse effects of omeprazole on pregnancy or fetal/neonatal health. Omeprazole may be used during pregnancy.

Breastfeeding

Diclofenac

According to limited available study data, NSAIDs pass into breast milk in small amounts. NSAIDs should not be used in women during breastfeeding to avoid potential adverse effects on the infant.

Omeprazole

Omeprazole passes into breast milk, but the likelihood of effects on the infant is low when used at therapeutic doses.

Fertility

Diclofenac

Diclofenac may negatively affect female fertility and is therefore not recommended for women planning pregnancy. For women experiencing fertility problems or undergoing infertility investigations, discontinuation of DUODIKLAZA should be considered.

Omeprazole

Oral administration of racemic omeprazole in animal studies did not affect reproductive function.

Ability to affect reaction speed when driving or operating machinery.

Adverse effects such as visual disturbances, dizziness, vertigo, somnolence, central nervous system disorders, lethargy, or fatigue may occur after NSAID use. Adverse reactions such as dizziness and visual disturbances may also occur after omeprazole use (see section "Adverse reactions"). If such disorders occur, patients should not drive or operate machinery.

Method of Administration and Dosage

Dosage

Adults

The recommended dose of the medicinal product DUODICLAZA is one capsule per day (diclofenac 75 mg / omeprazole 20 mg).

In patients switching to treatment with DUODICLAZA, adequate control should first be achieved using single-component agents at the same doses as the recommended combination. If symptom control is not achieved with once-daily dosing, the treatment regimen should be changed by switching to alternative medications. Administration of more than one dose of DUODICLAZA 75 mg/20 mg per day may result in excessive exposure to omeprazole.

Treatment should continue until the therapeutic goal is achieved for the individual patient, with regular review and discontinuation if no benefits are observed.

Special Patient Groups

Patients with Renal Impairment

Data indicate that DUODICLAZA should be used with caution in patients with mild to moderate renal impairment, and renal function should be carefully monitored (see section "Pharmacokinetics").

DUODICLAZA is contraindicated in patients with severe renal impairment (see sections "Contraindications" and "Special Warnings and Precautions for Use").

Patients with Hepatic Impairment

Data indicate that DUODICLAZA should be used with caution in patients with mild to moderate hepatic impairment, and liver function should be carefully monitored.

DUODICLAZA is contraindicated in patients with severe hepatic impairment (see sections "Contraindications" and "Special Warnings and Precautions for Use").

Elderly Patients (>65 years)

Elderly patients are at increased risk of serious adverse reactions. If NSAID therapy is considered necessary, it should be administered for the shortest possible duration and at the lowest effective dose. During NSAID treatment, patients should be monitored for the development of gastrointestinal bleeding (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics").

Children (≤18 years)

DUODICLAZA is not recommended for use in children due to lack of information on safety and efficacy in this patient population.

Route of Administration

DUODICLAZA capsules should be swallowed whole with a large amount of water.

DUODICLAZA is preferably taken with food.

Monitoring of Treatment

During long-term treatment with DUODICLAZA, regular laboratory blood tests should be performed, and liver and kidney function should be monitored.

Children

DUODICLAZA should not be used in children due to lack of information on safety and efficacy in this patient population (see section "Contraindications").

Overdose

Diclofenac

Symptoms

Symptoms include headache, nausea, vomiting, abdominal pain, gastrointestinal bleeding, rarely diarrhea, confusion, excitement, coma, drowsiness, dizziness, tinnitus, fainting, and occasionally seizures. In severe poisoning, acute renal failure and liver damage may occur.

Treatment

Management of acute NSAID poisoning primarily involves supportive measures and symptomatic treatment. Within 1 hour after ingestion of a potentially toxic dose, administration of activated charcoal orally should be considered. In addition, in adults, gastric lavage should be considered within 1 hour after ingestion of a potentially toxic dose.

Forced diuresis should be implemented.

Careful monitoring of renal and hepatic function is recommended.

Patients should be under medical observation for at least 4 hours after ingestion of potentially toxic amounts of the drug.

Frequent or prolonged seizures should be treated by intravenous administration of diazepam.

Other interventions may be instituted depending on the patient's clinical condition. Special treatment methods such as forced diuresis, dialysis, or hemoperfusion are unlikely to be effective in removing NSAIDs due to their high protein binding and rapid metabolism.

Supportive measures and symptomatic treatment should be provided for complications such as arterial hypotension, renal failure, seizures, gastrointestinal disturbances, and respiratory distress.

Omeprazole

Information on the consequences of omeprazole overdose in humans is limited. Cases of doses up to 560 mg have been reported. Isolated reports describe single oral doses of omeprazole reaching 2400 mg (120 times higher than the usual recommended clinical dose). Symptoms reported include nausea, vomiting, dizziness, abdominal pain, diarrhea, and headache. In isolated cases, lethargy, depression, and confusion have also been reported. The elimination rate of the drug was not altered (first-order kinetics) with increasing dose. Treatment for overdose is symptomatic.

Adverse reactions.

If serious adverse reactions occur, use of the medicinal product DUODIKLAZA should be discontinued.

Adverse reactions observed during clinical, epidemiological, and post-marketing studies with diclofenac and omeprazole are listed in the table below.

When using diclofenac, gastrointestinal disorders are the most commonly observed.

When using omeprazole, the development of adverse reactions is likely unrelated to dosage. The most frequently reported reactions (occurring in 1% to 10% of patients) are headache, abdominal pain, constipation, diarrhea, bloating, and nausea/vomiting.

The following categories are used to define the frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and frequency not known.

Frequency	Diclofenac	Omeprazole
From the blood and lymphatic system
Rare		Leukopenia, thrombocytopenia.
Very rare	Leukopenia, neutropenia, thrombocytopenia, hemolytic anemia, aplastic anemia, agranulocytosis.	Agranulocytosis, pancytopenia.
From the immune system
Rare	Non-specific allergic reactions, anaphylactoid reactions (including arterial hypotension and anaphylactic shock), and anaphylaxis. Respiratory tract reactivity, including asthma, worsening of asthma, bronchospasm, or dyspnea.	Hypersensitivity reactions, e.g.: fever, angioneurotic edema, and anaphylactic reaction/shock.
Very rare	Angioedema, angioneurotic edema (especially facial swelling).
From the metabolism and nutrition system
Rare		Hypnatremia.
Frequency unknown		Hypomagnesemia, severe form of hypomagnesemia which may lead to the development of hypocalcemia. Hypomagnesemia may also result from the development of hypokalemia.
Psychiatric disorders
Uncommon		Insomnia.
Rare		Anxiety, confusion, depression.
Very rare	Depression, disorientation, insomnia, irritability, psychotic reactions, nightmares.	Aggressiveness, hallucinations.
Nervous system disorders
Common	Headache, dizziness.	Headache.
Uncommon		Dizziness, paresthesia, somnolence.
Rare	Somnolence.	Taste disturbance.
Very rare	Memory impairment, paresthesias, aseptic meningitis (especially in patients with autoimmune disorders such as lupus, Sharp syndrome), with symptoms such as nuchal rigidity, headache, nausea, vomiting, fever, or disorientation. Confusion, hallucinations, weakness, fatigue, dizziness, taste changes, chills, seizures, restlessness, stroke.
Eye disorders
Rare		Diplopia.
Very rare	Blurred vision (visual disturbances), clouding of vision, diplopia, optic neuritis.
Ear and labyrinth disorders
Common	Vertigo.
Uncommon		Vertigo.
Very rare	Hearing disorders, tinnitus (ringing in the ears).
Cardiovascular system disorders
Rare	Edema.
Very rare	Arterial hypertension, arterial hypotension, vasculitis, tachycardia, chest pain, heart failure, slight increase in risk of vascular thrombotic events (e.g., myocardial infarction or stroke).
Frequency unknown	Kounis syndrome.
Respiratory, thoracic and mediastinal disorders
Rare	Asthma (especially dyspnea).			Bronchospasm.
Very rare	Pneumonia, pneumonitis.
Gastrointestinal disorders
Common	Nausea, vomiting, diarrhea, dyspepsia, abdominal pain, flatulence, anorexia.			Abdominal pain, constipation, diarrhea, flatulence, nausea/vomiting, fundic gland polyps (benign).
Rare	Gastritis, hematemesis, hemorrhagic diarrhea, melena, peptic ulcer of the stomach and duodenum (with or without bleeding or perforation), gastric ulcer, perforation or gastrointestinal hemorrhage, sometimes fatal, especially in elderly patients, loss of appetite.			Dry mouth, stomatitis, candidiasis of the gastrointestinal tract.
Very rare	Exacerbation of colitis and Crohn's disease, constipation, ulcerative stomatitis, glossitis, esophageal disorders, gastroenterological disorders, pancreatitis.
Frequency unknown				Microscopic colitis.
Hepatobiliary disorders
Common	Elevated transaminase levels.
Uncommon				Elevated liver enzymes.
Rare	Jaundice, liver function disorders, hepatitis (fulminant in isolated cases).			Hepatitis with or without jaundice.
Very rare	Liver necrosis, liver failure.			Liver failure, encephalopathy in patients with liver disease.
Skin and subcutaneous tissue disorders
Common	Skin rash.
Uncommon			Dermatitis, pruritus, rash, urticaria.
Rare	Urticaria.		Alopecia, photosensitivity.
Very rare	Photosensitivity, rash, bullous rash, eczema, erythema, multiform erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), hair loss, exfoliative dermatitis, purpura, including allergic, pruritus.		Multiform erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Frequency unknown	Fixed drug eruption, generalized bullous fixed drug eruption.		Subacute cutaneous lupus erythematosus.
Renal and urinary system disorders
Rare			Interstitial nephritis.
Very rare	Nephrotoxicity in various forms, including interstitial nephritis, proteinuria, papillary necrosis, nephrotic syndrome, acute renal failure, micturition disorders (e.g., hematuria).
Unknown			Tubulointerstitial nephritis (with possible progression to renal failure)
Musculoskeletal and connective tissue disorders
Uncommon			Femur, wrist, or spine fracture.
Rare			Arthralgia, myalgia.
Very rare			Muscle weakness.
Reproductive system and breast disorders
Very rare	Impotence.		Gynecomastia.
General disorders
Uncommon			Malaise, peripheral edema.
Rare			Increased sweating, elevated body temperature.

Clinical trial data and epidemiological evidence indicate that the use of diclofenac, particularly at high doses (150 mg/day) and over prolonged periods, may be associated with a small increase in the risk of arterial thrombotic events (e.g. myocardial infarction or stroke) (see sections "Contraindications" and "Special precautions for use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is of important significance. 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, should report all suspected adverse reactions and lack of efficacy of the medicinal product to the State Expert Centre of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua/.

Shelf life.

4 years.

Storage conditions.

Store at temperatures not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

10 capsules in a blister, 2 blisters per carton.

Prescription status.

Prescription only.

Manufacturer.

Swiss Caps GmbH.

Manufacturer's address and place of business.

Grassingerstrasse 9, Bad Aibling, Bavaria, 83043, Germany.

Marketing Authorization Holder.

UAB "Farmlyga".

Address of the Marketing Authorization Holder.

Antakalnio g. 48A-304, Vilnius, Republic of Lithuania.