INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NAKLOFEN DUO (NAKLOFEN® DUO)

Composition:

Active substance: diclofenac;

1 capsule contains 75 mg of sodium diclofenac (25 mg in the form of enteric-coated granules and 50 mg in the form of prolonged-release granules);

Excipients: spherical sugar, hydroxypropylcellulose, hypromellose, heavy magnesium carbonate, methacrylic acid copolymer dispersion, triethyl citrate, talc, titanium dioxide (E 171), sodium carboxymethylcellulose, macrogol 6000, sodium hydroxide, ammonio-methacrylate copolymer (type A), ammonio-methacrylate copolymer (type B), indigocarmine (E 132), gelatin.

Pharmaceutical form. Capsules.

Main physicochemical properties: capsules with a white body and a blue cap, filled with white or cream-colored granules.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Diclofenac. ATC code M01AB05.

Pharmacological properties.

Pharmacodynamics.

Diclofenac, the active substance of Naclofen Duo, is a non-steroidal compound with pronounced anti-rheumatic, antipyretic, analgesic, and anti-inflammatory properties. The primary mechanism of action of diclofenac, established under experimental conditions, is considered to be the inhibition of prostaglandin synthesis. Prostaglandins play an important role in the pathogenesis of inflammation, pain, and fever.

In vitro, sodium diclofenac at concentrations equivalent to those achieved during treatment of patients does not inhibit proteoglycan biosynthesis in cartilage tissue.

In rheumatic diseases, the anti-inflammatory and analgesic effects of Naclofen Duo lead to a significant reduction in pain intensity (both at rest and during movement), morning stiffness, joint swelling, and thus improve the patient's functional status.

In cases of inflammation caused by trauma or surgical intervention, Naclofen Duo rapidly relieves both spontaneous pain and pain during movement, as well as reduces inflammatory tissue edema and swelling at the surgical wound site. When used concomitantly with opioids for postoperative pain relief, Naclofen Duo significantly reduces the need for opioids.

Clinical studies have demonstrated that diclofenac also exerts a strong analgesic effect in moderate to severe non-rheumatic pain. Clinical trials have shown that diclofenac is capable of relieving pain and reducing the severity of bleeding in primary dysmenorrhea.

Pharmacokinetics.

Absorption

After oral administration, diclofenac is rapidly absorbed. Absorption exceeds 90%, but due to first-pass metabolism in the liver, bioavailability is approximately 60%. In oral formulations, maximum plasma concentration is reached within 1–4 hours, depending on the type of preparation.

Since diclofenac is absorbed in the duodenum and small intestine, food slows the rate of absorption, resulting in delayed and reduced peak concentrations of the active substance in plasma. Although food intake reduces the rate of absorption, it does not reduce the overall extent of absorption. After repeated dosing, food has no effect on plasma levels of diclofenac.

Distribution

Approximately 99% of diclofenac is bound to plasma proteins, primarily to albumins.

Diclofenac readily penetrates into synovial fluid, where its concentration reaches 60–70% of the plasma level. After 3–6 hours, the concentration of the drug and its metabolites in synovial fluid becomes higher than in plasma. Diclofenac is eliminated from synovial fluid significantly more slowly than from plasma.

Metabolism and elimination

The elimination half-life of diclofenac is 1–2 hours. It remains unchanged in cases of mild renal or hepatic impairment.

Diclofenac is almost entirely metabolized in the liver, primarily through hydroxylation and methoxylation. Approximately 70% of diclofenac is excreted in urine as pharmacologically inactive metabolites. Only 1% of the drug is excreted in unchanged form. The remainder of metabolites is excreted via bile and feces.

In elderly individuals, there are no significant changes in the absorption, distribution, metabolism, or elimination of diclofenac.

Clinical characteristics.

Indications.

Inflammatory rheumatic diseases: rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, spondyloarthritis, pain syndrome of various localizations, periarticular rheumatism;
Post-traumatic and postoperative pain, inflammatory processes and edema;
Painful and/or inflammatory conditions in gynecology (e.g. primary dysmenorrhea, adnexitis).

Naklofen Duo is also effective in migraine attacks.

Contraindications.

Hypersensitivity to diclofenac or to any other component of the drug.
Active gastric and/or duodenal ulcer or recurrent peptic ulcer disease/bleeding in history (two or more separate episodes of confirmed ulcer or bleeding); gastrointestinal bleeding or perforation in history associated with previous treatment with nonsteroidal anti-inflammatory drugs (NSAIDs).
Severe renal (creatinine clearance <30 mL/min) or hepatic insufficiency (Child-Pugh class C, cirrhosis or ascites).
Inflammatory bowel diseases (Crohn’s disease or ulcerative colitis).
Third trimester of pregnancy and breastfeeding.
In children under 18 years of age.
Congestive heart failure (NYHA II–IV).
Ischemic heart disease in patients with angina pectoris or history of myocardial infarction.
Cerebrovascular diseases in patients with history of stroke or transient ischemic attacks.
Peripheral arterial disease.
Uncontrolled arterial hypertension.
Treatment of perioperative pain following coronary artery bypass grafting or use of cardiopulmonary bypass apparatus.
Naklofen Duo, like other NSAIDs, is contraindicated in patients in whom administration of ibuprofen, acetylsalicylic acid, or other drugs capable of inhibiting prostaglandin synthetase triggers attacks of bronchial asthma, angioedema, urticaria, acute rhinitis, nasal polyps, or other allergic symptoms.

Interaction with other medicinal products and other forms of interaction.

The interactions listed below have been observed with the use of Naklofen Duo and/or other formulations of diclofenac.

Litium. When used concomitantly, diclofenac may increase plasma lithium concentrations. Monitoring of serum lithium levels is recommended.

Digoxin. When used concomitantly, diclofenac may increase plasma digoxin concentrations. Monitoring of serum digoxin levels is recommended.

Diuretics and antihypertensive agents. As with other NSAIDs, concomitant use of diclofenac may attenuate the antihypertensive effect of diuretics or antihypertensive drugs (e.g. beta-blockers, angiotensin-converting enzyme (ACE) inhibitors) by inhibiting the synthesis of vasodilatory prostaglandins. Therefore, such combinations should be used with caution, and patients, especially elderly ones, should be closely monitored for blood pressure. Adequate hydration is recommended, and monitoring of renal function should be performed after initiation of concomitant therapy and regularly thereafter, particularly with diuretics and ACE inhibitors, due to increased risk of nephrotoxicity.

Medicinal products known to cause hyperkalemia. Concomitant use of potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may lead to increased serum potassium levels; therefore, more frequent monitoring of patients is recommended.

Other NSAIDs, including selective cyclooxygenase-2 inhibitors, and corticosteroids. Concomitant use of diclofenac with other systemic NSAIDs or corticosteroids may increase the risk of gastrointestinal bleeding or ulceration. Therefore, concomitant use of two or more NSAIDs should be avoided (see section "Special precautions for use").

Like other NSAIDs, diclofenac at high doses may temporarily inhibit platelet aggregation.

Anticoagulants and antithrombotic agents. Should be prescribed with caution, as concomitant use may increase the risk of bleeding; therefore, precautionary measures are recommended (see section "Special precautions for use").

Although clinical studies have not demonstrated that diclofenac affects the efficacy of anticoagulants, data exist on an increased risk of bleeding in patients receiving diclofenac and anticoagulants concomitantly. Therefore, careful monitoring of patients receiving diclofenac and anticoagulants simultaneously is recommended, and dose adjustment of anticoagulants may be necessary.

Potent CYP2C9 inhibitors. Diclofenac should be used with caution when administered concomitantly with potent CYP2C9 inhibitors (e.g. voriconazole), as this may lead to a significant increase in diclofenac plasma maximum concentration and exposure due to inhibition of diclofenac metabolism.

Antidiabetic agents. Clinical studies have shown that diclofenac can be administered together with oral antidiabetic agents without affecting their clinical efficacy. However, isolated reports of both hypoglycemic and hyperglycemic reactions following diclofenac administration have been reported, requiring adjustment of antidiabetic agent dosage. For this reason, blood glucose levels should be monitored as a precaution during combination therapy.

Phenytoin. When phenytoin is used concomitantly with diclofenac, monitoring of plasma phenytoin concentrations is recommended due to expected increased phenytoin exposure.

Cholestyramine and colestipol. Concomitant use of cholestyramine with diclofenac may significantly reduce diclofenac bioavailability (diclofenac absorption is reduced by approximately 30–60%). Colestipol causes a similar, though less pronounced, effect. Therefore, diclofenac should be administered at least 1 hour before or 4–6 hours after cholestyramine/colestipol.

Methotrexate. Diclofenac may inhibit tubular renal clearance of methotrexate, thereby increasing methotrexate levels. NSAIDs, including diclofenac, should be used with caution when administered less than 24 hours before or after methotrexate treatment, as methotrexate blood levels may rise and its toxicity may be enhanced. Cases of severe toxicity have been observed when methotrexate and NSAIDs, including diclofenac, were administered within 24 hours of each other. This interaction is mediated by methotrexate accumulation due to impaired renal excretion in the presence of NSAIDs.

Probenecid. Medicinal products containing probenecid may delay diclofenac elimination.

Cyclosporine. Diclofenac, like other NSAIDs, may enhance the nephrotoxicity of cyclosporine by affecting renal prostaglandins. Therefore, the drug should be administered at lower doses than in patients not receiving cyclosporine.

Tacrolimus. The risk of nephrotoxicity may increase when NSAIDs are administered concomitantly with tacrolimus. This may be mediated through inhibition of renal prostaglandins by both NSAIDs and calcineurin inhibitors.

Quinolone antibiotics. Due to interaction between quinolone antibiotics and NSAIDs, seizures may occur. This may be observed both in patients with epilepsy or history of seizures and in those without such history. Therefore, caution should be exercised when considering the use of quinolones in patients already receiving NSAIDs.

Cardiac glycosides. Concomitant use of cardiac glycosides and NSAIDs may exacerbate heart failure, reduce glomerular filtration rate, and increase plasma levels of glycosides.

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

Selective serotonin reuptake inhibitors (SSRIs).

Concomitant use of NSAIDs, including diclofenac, and SSRIs may increase the risk of gastrointestinal bleeding.

Special precautions for use.

General

The undesirable effects can be minimized by using Naclofen Duo at the lowest effective dose for the shortest possible duration necessary to control (alleviate) symptoms (see gastrointestinal and cardiovascular risks below).

Concomitant use of Naclofen Duo with systemic NSAIDs, such as selective cyclooxygenase-2 inhibitors, should be avoided due to lack of evidence for synergistic effect and potential additive adverse effects. Caution is required in elderly patients. Use with caution in patients aged 65 years and older. In particular, the lowest effective dose is recommended for frail elderly patients or those with low body weight.

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, may occur even without prior exposure to diclofenac. Hypersensitivity reactions may also progress to Kounis syndrome, a serious allergic reaction that may lead to myocardial infarction. Symptoms of such reactions may include chest pain associated with an allergic reaction to diclofenac.

Due to its pharmacodynamic properties, Naclofen Duo, like other NSAIDs, may mask signs and symptoms of infection.

As with all analgesics, prolonged use of the drug for headache treatment may lead to improvement or worsening of the condition (medication-overuse headache). If headache develops due to excessive use of analgesics, the dose of analgesics should not be increased; in such cases, treatment should be discontinued. Medication-overuse headache should be suspected in patients with frequent or daily headache attacks occurring despite (or because of) regular use of analgesics.

Gastrointestinal effects

When using all NSAIDs, including diclofenac, cases of gastrointestinal bleeding, ulceration, or perforation, which may be fatal, have been reported. These events may occur at any time during treatment, with or without warning symptoms or prior history of serious gastrointestinal events. These events are generally more serious in elderly patients. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the drug should be discontinued.

As with other NSAIDs, including diclofenac, medical monitoring and special caution are required in patients with symptoms indicating gastrointestinal (GI) disorders, with a history of gastrointestinal ulcers, ulcerative colitis, or Crohn’s disease, as the patient's condition may worsen (see section "Adverse reactions").

The risk of GI bleeding, ulceration, or perforation increases with higher NSAID doses, including diclofenac. Elderly patients have an increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal. To reduce the risk of such GI toxicity, treatment should be initiated and maintained at the lowest effective doses. For such patients, as well as those requiring concomitant use of low-dose acetylsalicylic acid (ASA)/aspirin or other drugs likely to increase the risk of GI adverse effects, consideration should be given to using combination therapy with protective agents (e.g., proton pump inhibitors or misoprostol).

Patients with a history of gastrointestinal toxicity, especially the elderly, should report any unusual abdominal symptoms (particularly GI bleeding). Caution is also required in patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants (e.g., warfarin), antiplatelet agents (e.g., ASA), or selective serotonin reuptake inhibitors (see section "Interaction with other medicinal products and other forms of interaction").

NSAIDs, including diclofenac, may be associated with an increased risk of gastrointestinal anastomotic leakage. Careful medical monitoring and caution are recommended when using diclofenac after gastrointestinal surgery.

Hepatic effects

Careful medical monitoring is required when prescribing Naclofen Duo to patients with impaired liver function, as their condition may worsen (see section "Adverse reactions").

As with other NSAIDs, including diclofenac, levels of one or more liver enzymes may increase.

In addition to elevated liver enzyme levels, serious hepatic reactions have been rarely reported, including jaundice, fulminant hepatitis, liver necrosis, and hepatic failure, some of which have been fatal.

During long-term treatment with Naclofen Duo, regular monitoring of liver function and liver enzyme levels is recommended as a precaution. If liver function impairment persists or worsens, if clinical signs or symptoms suggest progressive liver disease, or if other manifestations occur (e.g., eosinophilia, rash), Naclofen Duo should be discontinued. Diseases such as hepatitis may progress without prodromal symptoms. Caution is required when prescribing Naclofen Duo to patients with hepatic porphyria due to the potential to provoke an attack.

Renal effects

Since fluid retention and edema have been reported during treatment with NSAIDs, including diclofenac, special attention should be given to patients with impaired cardiac or renal function, a history of arterial hypertension, elderly patients, patients receiving concomitant diuretic therapy or drugs significantly affecting renal function, and patients with significant extracellular fluid volume depletion due to any cause, such as before or after major surgery (see section "Contraindications"). In such cases, monitoring of renal function is recommended as a precaution. Discontinuation of therapy usually leads to return to the pre-treatment state.

Skin and subcutaneous tissue disorders

Serious skin reactions (some of which have been fatal), including exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and generalized bullous fixed drug eruption, have been very rarely reported with diclofenac use (see section "Adverse reactions"). The highest risk of these reactions occurs at the beginning of therapy, with most cases appearing within the first month of treatment. Naclofen Duo should be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity.

SLE and mixed connective tissue disorders

Patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders may have an increased risk of aseptic meningitis.

Cardiovascular and cerebrovascular effects

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, including diclofenac.

A slight increase in the risk of arterial thrombotic events (e.g., myocardial infarction or stroke) may be associated with diclofenac use, particularly at high doses (150 mg/day) and with prolonged treatment.

Diclofenac therapy is generally not recommended for patients with established cardiovascular disease (patients with heart failure, stable ischemic heart disease).

Diclofenac may be prescribed to patients with significant cardiovascular risk factors (such as arterial hypertension, hyperlipidemia, diabetes, smoking) only after careful clinical evaluation and only at a dose ≤100 mg daily, if treatment does not exceed four weeks.

Since cardiovascular risks of diclofenac may increase with dose and duration of treatment, it should be used for the shortest possible duration and at the lowest effective dose. The patient's need for diclofenac and response to therapy should be periodically reviewed. Patients should be vigilant for signs and symptoms of serious atherothrombotic events (e.g., 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.

Hematological effects

With long-term use of this drug, as with other NSAIDs, monitoring of complete blood count is recommended.

Diclofenac may temporarily inhibit platelet aggregation. Careful monitoring is required in patients with hemostatic disorders, hemorrhagic diathesis, or hematological disorders.

History of asthma

Patients with asthma, seasonal allergic rhinitis, nasal mucosal swelling (i.e., nasal polyps), chronic obstructive lung diseases, or chronic respiratory tract infections (especially those associated with allergic, rhinitis-like symptoms) are more likely to experience NSAID-related reactions such as asthma exacerbation (so-called analgesic intolerance/analgesic-induced asthma), Quincke's edema, or urticaria. Therefore, special precautionary measures (readiness for emergency care) are recommended for such patients. This also applies to patients with allergic reactions to other substances, such as rash, pruritus, or urticaria.

Like other drugs that inhibit prostaglandin synthetase activity, sodium diclofenac and other NSAIDs may provoke bronchospasm when administered to patients with bronchial asthma or a history of bronchial asthma.

Special warnings regarding excipients

Since Naclofen Duo contains spherical sugar, it is not recommended for patients with diabetes mellitus and patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

Use during pregnancy or breastfeeding.

Pregnancy

Like other NSAIDs, diclofenac is contraindicated in the third trimester of pregnancy (possible inhibition of uterine contractions and premature closure of the ductus arteriosus). From the 20th week of pregnancy, diclofenac use may cause oligohydramnios due to fetal renal dysfunction. This disorder may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, cases of ductus arteriosus constriction have been reported after treatment in the second trimester, which resolved in most cases after stopping treatment. Therefore, diclofenac should not be prescribed during the first and second trimesters of pregnancy unless absolutely necessary. If diclofenac is used during the first or second trimester, the dose should be as low as possible and the duration of treatment as short as possible. Prenatal monitoring for oligohydramnios and ductus arteriosus constriction may be advisable if diclofenac exposure occurred for several days starting from the 20th week of pregnancy. If oligohydramnios or ductus arteriosus constriction is detected, diclofenac use should be discontinued.

Inhibition of prostaglandin synthesis may adversely affect the course of pregnancy and/or embryonic/fetal development. Epidemiological data suggest an increased risk of miscarriage and/or risk of cardiac defects and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular defects increased from less than 1% to approximately 1.5%.

The risk may increase with dose and duration of treatment. In animal studies, administration of a prostaglandin synthesis inhibitor has been shown to increase pre- and post-implantation loss and embryonic/fetal mortality.

Furthermore, in animals receiving a prostaglandin synthesis inhibitor during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular defects, has been observed. If Naclofen Duo is used by a woman trying to conceive or during the first and second trimesters of pregnancy, the drug dose should be as low as possible and the treatment duration as short as possible.

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

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

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.

Breastfeeding

Like other NSAIDs, diclofenac passes into breast milk in small amounts. Therefore, to avoid adverse effects on the infant, diclofenac should not be used during breastfeeding. If diclofenac use is absolutely necessary, the infant should be switched to artificial feeding.

Female fertility

Like other NSAIDs, diclofenac may negatively affect female fertility; therefore, it is not recommended for women planning pregnancy. For women with conception difficulties or undergoing infertility investigations, discontinuation of the drug should be considered.

Ability to affect reaction speed when driving or operating machinery.

Patients who experience visual disturbances, dizziness, vertigo, somnolence, central nervous system disorders, lethargy, or fatigue during Naclofen Duo therapy should not drive or operate complex machinery.

Dosage and Administration

The recommended initial dose of the drug for adults is 75–150 mg daily (1–2 capsules), depending on the severity of disease symptoms.

During long-term therapy, administration of 1 capsule of Naclofen Duo daily is generally sufficient. If disease symptoms are most pronounced during the night or in the morning, Naclofen Duo should be administered in the evening.

Capsules should be swallowed whole with a small amount of liquid, taken during or immediately after a meal.

The drug should be used at the lowest effective dose for the shortest possible duration, taking into account the individual treatment regimen for each patient (see section "Special Instructions").

Children.

Naclofen Duo capsules should not be used in children due to the high content of active substance per capsule.

Overdose.

Symptoms. There is no typical clinical picture of diclofenac overdose. Symptoms of diclofenac overdose may include headache, nausea, epigastric pain, vomiting, gastrointestinal bleeding, diarrhea, dizziness, disorientation, coma, drowsiness, excitement, tinnitus, and seizures. In cases of significant poisoning, acute renal failure and liver damage are possible.

Treatment. Treatment of acute poisoning with NSAIDs consists of supportive and symptomatic therapy. Supportive and symptomatic treatment is indicated for complications such as arterial hypotension, renal failure, seizures, gastrointestinal disturbances, and respiratory depression. Forced diuresis, hemodialysis, or hemoperfusion are unlikely to be beneficial for elimination of NSAIDs, as the active substances of these drugs are highly bound to plasma proteins and undergo extensive metabolism.

Within 1 hour after ingestion of a potentially toxic dose, administration of activated charcoal should be considered. Additionally, in adults, gastric lavage should be considered within 1 hour after ingestion of a potentially toxic amount. In cases of frequent or prolonged seizures, intravenous diazepam should be administered. Other measures may be indicated depending on the patient's clinical condition. Treatment is symptomatic.

Adverse Reactions

Adverse effects that may occur during the use of diclofenac are classified into the following groups according to their frequency:

very common ≥ 1/10;
common ≥ 1/100, < 1/10;
uncommon ≥ 1/1000, < 1/100;
rare ≥ 1/10000, < 1/1000;
very rare < 1/10000, including isolated cases;
frequency not known (cannot be estimated from available data).

The undesirable effects listed below include events reported during short-term or long-term use of the drug.

Blood and lymphatic system disorders: very rare – thrombocytopenia, leukopenia, anemia (including hemolytic anemia and aplastic anemia), agranulocytosis.

Immune system disorders: rare – hypersensitivity, anaphylactic and anaphylactoid reactions (including arterial hypotension and shock); very rare – angioedema (including facial swelling).

Psychiatric disorders: very rare – disorientation, depression, insomnia, irritability, nightmares, psychotic disorders.

Nervous system disorders: common – headache, dizziness; rare – somnolence; very rare – paresthesia, memory impairment, convulsions, restlessness, tremor, aseptic meningitis, taste disturbances, stroke; frequency not known – confusion, hallucinations, sensory disturbances, malaise.

Eye disorders: very rare – visual disturbances, blurred vision, diplopia; frequency not known – optic neuritis.

Ear and labyrinth disorders: common – vertigo; very rare – tinnitus, hearing disturbances.

Cardiovascular system disorders: very rare – palpitations, chest pain, heart failure, myocardial infarction, arterial hypertension, arterial hypotension, vasculitis; frequency not known – Kounis syndrome.

Respiratory, thoracic and mediastinal disorders: rare – asthma (including dyspnea); very rare – pneumonitis.

Gastrointestinal disorders: common – nausea, vomiting, diarrhea, dyspepsia, abdominal pain, flatulence, anorexia; rare – gastritis, gastrointestinal hemorrhage (hematemesis, melena, bloody diarrhea), gastric and intestinal ulcers with or without bleeding or perforation (sometimes fatal, especially in elderly patients), loss of appetite; very rare – colitis (including hemorrhagic colitis and exacerbation of ulcerative colitis or Crohn’s disease), constipation, stomatitis (including ulcerative stomatitis), glossitis, esophageal dysfunction, membrane strictures, pancreatitis.

Hepatobiliary disorders: common – increased transaminase levels; rare – hepatitis, jaundice, liver disorders; very rare – fulminant hepatitis, liver necrosis, liver failure.

Skin and subcutaneous tissue disorders: common – rash; rare – urticaria; very rare – blistering rash, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, Lyell’s syndrome (toxic epidermal necrolysis), exfoliative dermatitis, alopecia, photosensitivity reactions, purpura (including allergic purpura), pruritus; frequency not known – fixed drug eruption, generalized bullous fixed drug eruption.

Renal and urinary disorders: very rare – acute renal failure, hematuria, proteinuria, interstitial nephritis, nephrotic syndrome, renal papillary necrosis.

General disorders: rare – edema, fatigue.

Reproductive system and breast disorders: very rare – impotence.

Clinical studies and epidemiological data indicate an increased risk of thrombotic complications (e.g., myocardial infarction or stroke) associated with the use of diclofenac, particularly at high therapeutic doses (150 mg daily) and during prolonged treatment.

If serious adverse reactions occur, treatment should be discontinued.

Reporting of suspected adverse reactions.

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

Shelf life. 3 years.

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

Packaging. 10 capsules in a blister; 2 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. KRKA, d.d., Novo mesto / KRKA, d.d., Novo mesto.

Manufacturer's address and location of business activity.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.

Naklofen duo