ARGETTE DUO

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ARGETT DUO (ARGETTDUO)

Composition:

Active substance: diclofenac;

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

Excipients: talc, microcrystalline cellulose, povidone K 25, colloidal anhydrous silicon dioxide, propylene glycol, ammonio-methacrylate copolymer (type A), ammonio-methacrylate copolymer (type B), methacrylate copolymer (type A), triethyl citrate, gelatin, indigocarmine (E 132), titanium dioxide (E 171), sodium lauryl sulfate, printing ink (shellac, propylene glycol, titanium dioxide (E 171)).

Pharmaceutical form. Modified-release hard capsules.

Main physicochemical properties: hard gelatin capsules of size 2, with white imprint "D75M" on both cap and body; capsule cap: light blue opaque; capsule body: colorless transparent; capsule content: granules from white to creamy color.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents; acetic acid derivatives and related substances. ATC code M01A B05.

Pharmacological properties.

Pharmacodynamics.

Argetto Duo contains sodium diclofenac, a non-steroidal compound exerting pronounced anti-inflammatory, analgesic and antipyretic effects. The main mechanism of action of diclofenac is considered to be inhibition of prostaglandin biosynthesis. 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.

Pharmacokinetics.

After oral administration of the modified-release capsule, maximum plasma concentration is reached depending on gastric emptying time, on average within 2–3 hours.

Protein binding in plasma is 99.7%, primarily with albumin (99.4%). The apparent volume of distribution is 0.12–0.17 L/kg.

Diclofenac penetrates into synovial fluid, where its maximum concentration is achieved 2–4 hours later than in plasma. The apparent elimination half-life from synovial fluid is 3–6 hours. Two hours after peak plasma concentration, diclofenac concentration in synovial fluid exceeds that in plasma, and remains higher for up to 12 hours.

Metabolism of diclofenac occurs partially via glucuronidation of the unchanged molecule, but primarily through mono- and poly-methoxylation, leading to the formation of several phenolic metabolites (3’-hydroxy-, 4’-hydroxy-, 5’-hydroxy-, 4’,5-dihydroxy-, and 3’-hydroxy-4’-methoxy-diclofenac), most of which are converted into glucuronide conjugates. Two of these phenolic metabolites are biologically active, but to a much lesser extent than diclofenac.

Total systemic plasma clearance of diclofenac is 263 ± 56 mL/min. The terminal elimination half-life is 1–2 hours. The elimination half-life of four metabolites, including two pharmacologically active ones, is also short—1–3 hours. One of the metabolites, 3’-hydroxy-4’-methoxy-diclofenac, has a longer half-life, but this metabolite is completely inactive.

Approximately 60% of the administered dose is excreted in urine as glucuronide conjugates of the unchanged active substance, as well as in the form of metabolites, most of which are glucuronide conjugates. Less than 1% of diclofenac is excreted unchanged. The remainder of the administered dose is excreted via bile and feces as metabolites.

Pharmacokinetics in specific patient groups

In patients with impaired renal function, administration of Argetto Duo at usual single doses does not result in accumulation of diclofenac. However, when creatinine clearance is less than 10 mL/min, calculated steady-state concentrations of hydroxymetabolites of diclofenac are approximately four times higher than in healthy volunteers. Nevertheless, ultimately these metabolites are eliminated via bile.

In patients with chronic hepatitis or compensated liver cirrhosis, pharmacokinetic parameters of diclofenac are similar to those in patients without liver disease.

Clinical characteristics.

Indications.

Symptomatic treatment of pain and inflammation in:

• Rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, spondyloarthritis, pain syndrome of various localizations, periarticular rheumatism;
• Swelling with pain syndrome or post-traumatic inflammation.

Contraindications.

• Hypersensitivity to diclofenac, soy, peanuts, or other components of the drug;
• Gastric or intestinal ulcer, gastrointestinal bleeding or perforation;
• Patients in whom administration of acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs) triggers attacks of bronchial asthma, urticaria, or acute rhinitis;
• Third trimester of pregnancy;
• Proctitis, hemorrhoidal symptoms, rectal bleeding, or other active bleeding;
• Severe impairment of liver or kidney function;
• Severe impairment of heart function;
• Unexplained disorders of hematopoiesis;
• 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;
• Treatment of perioperative pain associated with coronary artery bypass grafting (or use of cardiopulmonary bypass apparatus).

Interaction with other medicinal products and other forms of interaction.

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

Lithium. Diclofenac may increase plasma lithium concentrations when used concomitantly. Monitoring of serum lithium levels is recommended.

Digoxin. Diclofenac may increase plasma digoxin concentrations when used concomitantly. 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 is advised after initiation and on a regular basis during concomitant therapy, 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 transiently inhibit platelet aggregation.

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

Although clinical studies have not demonstrated that diclofenac affects the efficacy of anticoagulants, data indicate an increased risk of bleeding in patients receiving diclofenac and anticoagulants simultaneously. Therefore, careful monitoring of patients receiving both diclofenac and anticoagulants 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 maximum plasma concentration and exposure of diclofenac due to inhibition of diclofenac metabolism.

Antidiabetic agents. Clinical studies have shown that diclofenac can be co-administered with oral antidiabetic agents without affecting their clinical efficacy. However, isolated reports of both hypoglycemic and hyperglycemic reactions following diclofenac use have been received, requiring dose adjustment of antidiabetic agents. For this reason, blood glucose levels should be monitored as a precautionary measure 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 therapy, as methotrexate blood levels may rise and its toxicity may increase. Cases of severe toxicity have been reported 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.

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

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

Quinolone antibiotics. Seizures may occur due to interaction between quinolone antibiotics and NSAIDs. This may occur 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 glycoside levels.

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.

Probenecid and sulfinpyrazone. Medicinal products containing probenecid or sulfinpyrazone may delay elimination of diclofenac.

Special precautions for use.

General

Undesirable effects may be minimized by using the lowest effective dose of Argét Duo for the shortest possible duration necessary to control (alleviate) symptoms (see gastrointestinal and cardiovascular risks below).

Concomitant use of Argét Duo with systemic NSAIDs, such as selective cyclooxygenase-2 inhibitors, should be avoided due to lack of evidence of synergistic effect and potential for 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, in isolated cases, administration of diclofenac may cause allergic reactions, including anaphylactic/anaphylactoid reactions, even in individuals who have not previously taken the drug. Hypersensitivity reactions may progress to Kounis syndrome (acute allergic coronary syndrome), which may lead to myocardial infarction. Symptoms of such allergic reactions to diclofenac include chest pain.

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

Gastrointestinal effects

When using all NSAIDs, including diclofenac, cases of gastrointestinal bleeding, ulceration, or perforation, which may be fatal, have been reported. These may occur at any time during treatment, with or without warning symptoms or prior history of serious gastrointestinal events. These events generally have more serious consequences 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 mandatory in patients with symptoms indicating gastrointestinal (GI) disorders (e.g., history of peptic 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 doses of NSAIDs, 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 dose. For such patients, as well as those requiring concomitant use of low-dose acetylsalicylic acid (ASA)/aspirin or other drugs likely to increase GI adverse effects, consideration should be given to combination therapy with protective agents (e.g., proton pump inhibitors or misoprostol).

Patients with a history of gastrointestinal toxicity, especially elderly patients, should report any unusual abdominal symptoms (particularly gastrointestinal 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").

Use of all NSAIDs, including diclofenac, may be associated with a risk of impaired anastomotic healing and leakage. Careful medical monitoring and caution are recommended when using diclofenac in patients after gastrointestinal surgery.

Hepatic effects

Careful medical monitoring is required when prescribing Argét 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, hepatic necrosis, and liver failure, some of which have been fatal.

During long-term treatment with Argét Duo, regular monitoring of liver function and liver enzyme levels is recommended as a precautionary measure. If liver function abnormalities persist or worsen, or if clinical signs or symptoms suggest progressive liver disease, or if other manifestations occur (e.g., eosinophilia, rash), Argét Duo should be discontinued. Diseases such as hepatitis may progress without prodromal symptoms. Caution is required when prescribing Argét 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, 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 that significantly affect renal function, and patients with substantial reduction in extracellular fluid volume for any reason, e.g., before or after major surgery (see section "Contraindications"). In such cases, monitoring of renal function is recommended as a precautionary measure. Discontinuation of therapy usually leads to reversal of the condition.

Skin effects

Serious skin reactions (some of which have been fatal), including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been very rarely reported in association with NSAIDs, including Argét Duo. The highest risk of these reactions occurs early in the course of treatment: most cases appear within the first month of therapy. Argét 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

An increased risk of aseptic meningitis may occur in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders.

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 NSAIDs, including diclofenac.

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

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

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

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

During 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 coagulation disorders, hemorrhagic diathesis, or hematological disorders.

History of asthma

Patients with asthma, seasonal allergic rhinitis, nasal mucosal swelling (e.g., nasal polyps), chronic obstructive pulmonary diseases, or chronic respiratory 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 intervention) 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.

Use during pregnancy or breastfeeding.

Pregnancy.

Use of the drug from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation of the drug. During the first and second trimesters of pregnancy, the drug may be prescribed only when the expected benefit to the mother outweighs the potential risk to the fetus, and only at the lowest effective dose, with treatment duration kept as short as possible. Prenatal monitoring for oligohydramnios should be considered if exposure occurs over several days starting from the 20th week of pregnancy. The drug should be discontinued if oligohydramnios is detected. As with other NSAIDs, the drug is contraindicated in the third trimester of pregnancy (due to possible inhibition of uterine contractility and premature closure of the ductus arteriosus in the fetus).

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data suggest an increased risk of miscarriage and/or congenital heart 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 dose and duration of treatment. Animal studies have shown that administration of prostaglandin synthesis inhibitors leads to increased pre- and post-implantation loss and embryonic/fetal mortality.

Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular malformations, has been observed. If Argét Duo is used by a woman planning pregnancy, the dose should be as low as possible and treatment duration as short as possible.

During the third 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;

and may affect the mother and newborn, especially near term:

• possible prolonged bleeding time, antiplatelet 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 undesirable 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 and therefore is not recommended for women planning pregnancy. For women experiencing infertility or undergoing fertility investigations, discontinuation of the drug should be considered.

Ability to influence reaction speed when driving or operating machinery.

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

Dosage and Administration

The drug should be used for the treatment of adult patients, starting with a daily dose of 75–150 mg depending on the severity of symptoms. In cases of mild symptoms, as well as for long-term therapy, a dose of 75 mg/day is sufficient. If disease symptoms are most pronounced during the night or in the morning, the drug Argette Duo should be administered in the evening. The daily dose must not exceed 150 mg.

The drug should be used at the lowest effective dose for the shortest duration necessary, taking into account the individual treatment goals for each patient.

Argette Duo tablets should be taken whole, without chewing, and swallowed with sufficient fluid during or immediately after meals.

Elderly patients

No specific dose adjustment is required; however, the drug should be used with caution.

Renal impairment

Dose reduction is not required in patients with mild to moderate renal impairment.

Hepatic impairment

Dose reduction is not required in patients with mild to moderate hepatic impairment.

Children Not to be used.

Overdose

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

Treatment Management of acute NSAID poisoning 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 in removing NSAIDs due to their high plasma protein binding and 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. For 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, leucopenia, anaemia (including haemolytic anaemia and aplastic anaemia), 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 – paraesthesia, 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.

Cardiac 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 dyspnoea); very rare – pneumonitis.

Gastrointestinal disorders: common – nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, anorexia; rare – gastritis, gastrointestinal haemorrhage (haematemesis, melena, bloody diarrhoea), gastric and intestinal ulcers with or without bleeding or perforation (sometimes fatal, especially in elderly patients), loss of appetite; very rare – colitis (including haemorrhagic colitis and exacerbation of ulcerative colitis or Crohn's disease), constipation, stomatitis (including ulcerative stomatitis), glossitis, oesophageal disorders, 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 – bullous rash, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, Lyell's syndrome (toxic epidermal necrolysis), exfoliative dermatitis, alopecia, photosensitivity reactions, purpura (including allergic purpura), pruritus.

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

General disorders: rare – oedema, 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 per day) and during prolonged treatment.

If serious adverse effects occur, treatment should be discontinued.

Shelf life. 4 years.

Storage conditions.

Store out of reach and sight of children at a temperature not exceeding 25 °C.

Store in the original packaging to protect from moisture.

Packaging.

10 capsules in a blister; 1, 2, or 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Swiss Caps GmbH.

Manufacturer's address.

Grassingerstrasse 9, 83043 Bad Aibling, Germany.

Marketing Authorisation Holder.

Delta Medical Promotions AG.

Address of the Marketing Authorisation Holder.

26 Oetenbachgasse, Zurich CH-8001, Switzerland.