Instructions for Argette Duo hard capsules with modified release 75 mg blister No. 20
Composition
active ingredient: diclofenac;
1 capsule contains 75 mg of diclofenac sodium (25 mg of diclofenac sodium in enteric-coated form, 50 mg of diclofenac sodium in prolonged-release form);
excipients: talc, microcrystalline cellulose, povidone K 25, colloidal anhydrous silica, propylene glycol, ammonium methacrylate copolymer (type A), ammonium methacrylate copolymer (type B), methacrylate copolymer (type A), triethyl citrate, gelatin, indigo carmine (E 132), titanium dioxide (E 171), sodium lauryl sulfate, printing ink (shellac, propylene glycol, titanium dioxide (E 171)).
Dosage form
Modified-release capsules are hard.
Main physicochemical properties: hard gelatin capsules, size 2, with white imprint "D75M" on the cap and body; capsule cap: light blue opaque; capsule body: colorless transparent; capsule contents: white to cream-colored granules.
Pharmacotherapeutic group
Nonsteroidal anti-inflammatory and antirheumatic drugs; acetic acid derivatives and related substances. ATX code M01A B05.
Pharmacological properties
Pharmacodynamics.
Argett Duo contains diclofenac sodium, a nonsteroidal compound that has a pronounced anti-inflammatory, analgesic and antipyretic effect. The main mechanism of action of diclofenac is considered to be inhibition of prostaglandin biosynthesis. Prostaglandins play an important role in the genesis of inflammation, pain and fever.
In vitro, diclofenac sodium at concentrations equivalent to those achieved in the treatment of patients does not inhibit the biosynthesis of cartilage proteoglycans.
Pharmacokinetics.
After oral administration of the modified-release capsule, peak plasma levels are achieved depending on the duration of gastric transit, on average after 2-3 hours.
Serum protein binding is 99.7%, mainly to albumin (99.4%). The apparent volume of distribution is 0.12-0.17 l/kg.
Diclofenac penetrates into the synovial fluid, where its maximum concentration is reached 2-4 hours later than in blood plasma. The apparent half-life from the synovial fluid is 3-6 hours. 2 hours after reaching the maximum plasma concentration, the concentration of diclofenac in the synovial fluid is higher than in plasma, and its values remain higher for 12 hours.
The metabolism of diclofenac is carried out partly by glucuronidation of the unchanged molecule, but mainly by single and multiple methoxylation, leading to the formation of several phenolic metabolites (3'-hydroxy-, 4'-hydroxy-, 5'-hydroxy-, 4',5-dihydroxy- and 3'-hydroxy-4'-methoxydiclofenac), most of which are converted to glucuronide conjugates. Two of these phenolic metabolites are biologically active, but to a much lesser extent than diclofenac.
The total systemic plasma clearance of diclofenac is 263±56 ml/min. The terminal half-life is 1-2 hours. The half-life of 4 metabolites, including two pharmacologically active ones, is also short - 1-3 hours. One of the metabolites, 3'-hydroxy-4'-methoxydiclofenac, has a longer half-life, but this metabolite is completely inactive.
About 60% of the administered dose is excreted in the 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 rest of the administered dose is excreted in the form of metabolites with bile and feces.
Pharmacokinetics in certain patient groups
In patients with impaired renal function, when using the drug Argette Duo in usual single doses, no accumulation of diclofenac was observed. In the case when creatinine clearance is less than 10 ml/min, the estimated equilibrium concentrations of diclofenac hydroxymetabolites are approximately 4 times higher than in healthy volunteers. However, the metabolites are ultimately excreted in the bile.
In patients with chronic hepatitis or compensated cirrhosis, the pharmacokinetics of diclofenac are similar to those in patients without liver disease.
Indication
Symptomatic treatment of pain and inflammation in:
rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, spondyloarthritis, pain syndrome of various localization, extra-articular rheumatism;
edema with pain syndrome or post-traumatic inflammation.
Contraindication
Hypersensitivity to diclofenac, soy, peanuts or other ingredients of the drug;
stomach or intestinal ulcer, gastrointestinal bleeding or perforation;
patients who experience attacks of bronchial asthma, urticaria or acute rhinitis in response to taking acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (NSAIDs);
III trimester of pregnancy;
proctitis, hemorrhoidal symptoms, rectal bleeding, or other active bleeding;
severe liver or kidney dysfunction;
severe heart failure;
unexplained disorders of hematopoiesis;
congestive heart failure (NYHAII-IV);
cerebrovascular disease in patients who have had a stroke or have episodes of transient ischemic attacks;
peripheral artery disease;
treatment of perioperative pain during coronary artery bypass grafting (or the use of a cardiopulmonary bypass machine).
Interaction with other medicinal products and other types of interactions
The following are interactions observed with the use of Argett Duo and/or other pharmaceutical forms of diclofenac.
Lithium: Diclofenac may increase plasma lithium concentrations when used concomitantly. Monitoring of serum lithium levels is recommended.
Digoxin: Diclofenac may increase plasma concentrations of digoxin when used concomitantly. Monitoring of serum digoxin levels is recommended.
Diuretics and antihypertensives. As with other NSAIDs, concomitant use of diclofenac may reduce 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 a combination should be used with caution and patients, especially the elderly, should be closely monitored for blood pressure. Patients should be adequately hydrated and monitoring of renal function is recommended after initiation of concomitant therapy and regularly thereafter, especially with diuretics and ACE inhibitors, due to the increased risk of nephrotoxicity.
Drugs known to cause hyperkalemia: Concomitant treatment with potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may be associated with increases in serum potassium levels, and patients should be monitored more frequently.
Other NSAIDs, including selective cyclooxygenase-2 inhibitors, and corticosteroids. The concomitant use of diclofenac and other systemic NSAIDs or corticosteroids may increase the risk of gastrointestinal bleeding or ulceration. Therefore, the concomitant use of two or more NSAIDs should be avoided (see section 4.4).
Like other NSAIDs, diclofenac in high doses may temporarily inhibit platelet aggregation.
Anticoagulants and antithrombotic agents: Caution is recommended as concomitant use may increase the risk of bleeding, therefore precautions should be taken (see section "Special warnings and precautions for use").
Although clinical studies have not shown that diclofenac affects the effectiveness of anticoagulants, there is evidence of an increased risk of bleeding in patients receiving diclofenac and anticoagulants concomitantly. Therefore, careful monitoring of patients receiving diclofenac and anticoagulants is recommended and, if necessary, adjustment of the anticoagulant dosage.
Potent CYP2C9 inhibitors: Caution is recommended when administering diclofenac concomitantly with potent CYP2C9 inhibitors (e.g. voriconazole), which may lead to a significant increase in maximum plasma concentrations and exposure to diclofenac due to inhibition of diclofenac metabolism.
Antidiabetic agents. Clinical studies have shown that diclofenac can be administered concomitantly with oral antidiabetic agents without affecting the clinical effect of the latter. However, there have been isolated reports of both hypoglycaemic and hyperglycaemic reactions following the use of diclofenac, necessitating dose adjustment of the antidiabetic agent. For this reason, it is recommended to monitor blood glucose levels as a precautionary measure during combination therapy.
Phenytoin: When phenytoin is used concomitantly with diclofenac, monitoring of phenytoin plasma concentrations is recommended due to the expected increase in phenytoin exposure.
Colestipol and cholestyramine. When cholestyramine is used concomitantly with diclofenac, the bioavailability of diclofenac may be significantly reduced (absorption of diclofenac is reduced by approximately 30-60%), colestipol has a similar but smaller effect. Therefore, it is recommended to take diclofenac at least 1 hour before or 4-6 hours after taking colestipol/cholestyramine.
Methotrexate. Diclofenac may inhibit the renal tubular clearance of methotrexate, leading to increased methotrexate levels. NSAIDs, including diclofenac, should be used with caution when administered less than 24 hours before or after treatment with methotrexate, as methotrexate blood levels may increase and methotrexate toxicity may be enhanced. Cases of serious toxicity have been observed when methotrexate and NSAIDs, including diclofenac, were administered within 24 hours of each other. This interaction is mediated by accumulation of methotrexate as a result of impaired renal excretion in the presence of NSAIDs.
Tacrolimus: There is a possible increased risk of nephrotoxicity when NSAIDs are administered concomitantly with tacrolimus. This may be mediated through the mechanism of inhibition of renal prostaglandins by both the NSAID and the calcineurin inhibitor.
Quinolone antibiotics. Interactions between quinolone antibiotics and NSAIDs may lead to seizures. This may occur in patients with or without a history of epilepsy or seizures. 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 for 8-12 days after taking mifepristone, 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 the elimination of diclofenac.
Application features
General
Undesirable effects can be minimized by using Arget Duo at the lowest effective dose for the shortest possible period and as needed to control (relieve) symptoms (see gastrointestinal and cardiovascular risks below).
Concomitant use of Arget Duo with systemic NSAIDs such as cyclooxygenase-2 selective inhibitors should be avoided due to the lack of any evidence of a synergistic effect and due to potential additive side effects. Caution is required in elderly patients. Use with caution in patients over 65 years of age. In particular, it is recommended to use the lowest effective dose in frail elderly patients or those with low body weight.
As with other NSAIDs, in rare cases, diclofenac may cause allergic reactions, including anaphylactic/anaphylactoid reactions, in individuals who have not previously taken it. Hypersensitivity reactions may progress to the development of Kounis syndrome (acute allergic coronary syndrome), which can lead to myocardial infarction. Symptoms of this type of allergic reaction to diclofenac include chest pain.
Due to its pharmacodynamic properties, Arget Duo, like other NSAIDs, may mask the signs and symptoms of infection.
Effects on the digestive tract
Gastrointestinal bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs, including diclofenac, and can occur at any time during treatment with or without warning symptoms or a previous history of serious gastrointestinal events. These events are usually more severe in the elderly. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the drug should be discontinued.
As with other NSAIDs, including diclofenac, in patients with symptoms suggestive of gastrointestinal (GI) disorders and a history of gastrointestinal ulcers, ulcerative colitis or Crohn's disease, medical supervision and special caution are mandatory, as the patient's condition may deteriorate (see section "Adverse reactions").
The risk of gastrointestinal bleeding, ulceration or perforation increases with increasing dose of NSAIDs, including diclofenac. Elderly patients have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which can be fatal. To reduce the risk of such gastrointestinal toxicity, treatment should be initiated and maintained at the lowest effective dose. For such patients, as well as those requiring concomitant use of medicinal products containing low doses of acetylsalicylic acid (ASA)/aspirin or other medicinal products that are likely to increase the risk of gastrointestinal adverse reactions, combination therapy with protective agents (e.g. proton pump inhibitors or misoprostol) should be considered.
Patients with a history of gastrointestinal toxicity, especially the elderly, should report any unusual abdominal symptoms (especially 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), antithrombotic agents (e.g. ASA) or selective serotonin reuptake inhibitors (see section 4.5).
All NSAIDs, including diclofenac, may be associated with the risk of anastomotic failure and leakage. Close medical supervision and caution are recommended when using diclofenac in patients undergoing gastrointestinal surgery.
Effect on the liver
As with other NSAIDs, including diclofenac, the level of one or more liver enzymes may increase.
In addition to elevated liver enzymes, severe hepatic reactions, including jaundice and fulminant hepatitis, hepatic necrosis and hepatic failure, some of which were fatal, have been reported rarely.
During long-term treatment with Arget Duo, regular monitoring of liver function and liver enzyme levels should be performed as a precautionary measure. If liver function abnormalities persist or worsen, and if clinical signs or symptoms suggestive of progressive liver disease or if other manifestations (e.g. eosinophilia, rash) occur, Arget Duo should be discontinued. Diseases such as hepatitis may occur without prodromal symptoms. Caution is advised when Arget Duo is used in patients with hepatic porphyria, as it may precipitate an attack.
Effects on the kidneys
Since cases of fluid retention and edema have been reported with NSAIDs, including diclofenac, special attention should be paid to patients with impaired cardiac or renal function, a history of hypertension, elderly patients, patients receiving concomitant therapy with diuretics or drugs that significantly affect renal function, as well as patients with a significant decrease in extracellular fluid volume for any reason, for example 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 a return to the state that existed before treatment.
Effects on the skin
Serious skin reactions (some of which were fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported very rarely in association with the use of NSAIDs, including Arget Duo. Patients are at highest risk of developing these reactions at the beginning of therapy: the onset of the reaction is noted in most cases within the first month of treatment. Arget Duo should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.
SLE and mixed connective tissue diseases
Patients with systemic lupus erythematosus (SLE) and mixed connective tissue diseases may be at increased risk of developing aseptic meningitis.
Cardiovascular and cerebrovascular effects
Appropriate monitoring and advice is required for patients with a history of hypertension and/or mild to moderate congestive heart failure, as fluid retention and oedema have been reported in association with the use of NSAIDs, including diclofenac.
A small increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke) may be associated with the use of diclofenac, especially at high doses (150 mg/day) and with long-term treatment.
Treatment with diclofenac is generally not recommended for patients with established cardiovascular disease (patients with heart failure, stable ischemic heart disease).
Diclofenac should be prescribed to patients with significant risk factors for cardiovascular events (such as hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful clinical evaluation and only at a dose of ≤100 mg daily, if treatment lasts no more than four weeks.
Since the cardiovascular risks of diclofenac may increase with increasing dose and duration of treatment, it should be used for the shortest possible period and at the lowest effective dose. The patient's need for diclofenac to relieve symptoms and the response to therapy should be reviewed periodically. Patients should be alert for the appearance of serious signs and symptoms of atherothrombosis (e.g. chest pain, shortness of breath, weakness, speech disorders), which may occur at any time. Patients should be warned that in such cases they should immediately consult a doctor.
Effect on hematological parameters
With prolonged use of this drug, as with other NSAIDs, monitoring of complete blood counts is recommended.
Diclofenac may temporarily inhibit platelet aggregation. Patients with impaired hemostasis, hemorrhagic diathesis or hematological disorders should be carefully monitored.
History of asthma
Like other drugs that inhibit prostaglandin synthetase activity, diclofenac sodium and other NSAIDs can provoke the development of bronchospasm when used in patients suffering from bronchial asthma or in patients with 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 shortly after the start of treatment and is usually reversible after discontinuation of the drug. In the first and second trimesters of pregnancy, the drug should be prescribed only if the expected benefit to the mother outweighs the potential risk to the fetus and only in the minimum effective dose, and the duration of treatment should be as short as possible. Antenatal monitoring for oligohydramnios should be considered in case of exposure to the drug for 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 last trimester of pregnancy (possible suppression of uterine contractility and premature closure of the ductus arteriosus in the fetus).
Inhibition of prostaglandin synthesis may adversely affect the course of pregnancy and/or embryo/foetal development. Epidemiological data suggest an increased risk of miscarriage and/or cardiac malformations and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk of cardiovascular malformations was increased from less than 1% to approximately 1.5%.
It is possible that the risk increases with dose and duration of treatment. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo/fetal lethality.
In addition, an increased incidence of various malformations, including cardiovascular, has been reported in animals treated with a prostaglandin synthesis inhibitor during organogenesis. If Argette Duo is used by a woman attempting to conceive, the dose should be as low as possible and the duration of treatment as short as possible.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may affect the fetus in the following ways:
cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
renal dysfunction, which may progress to renal failure with oligohydramnios;
on the mother and newborn, as well as at the end of pregnancy:
possible prolongation of bleeding time, antiplatelet effect, which can be observed even at very low doses;
inhibition of uterine contractions, leading to delayed or prolonged labor.
Breast-feeding.
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 the use of diclofenac is absolutely necessary, the child should be transferred to artificial feeding.
Fertility in women.
As with other NSAIDs, diclofenac may impair female fertility and is therefore not recommended for use in women attempting to conceive. In women who have difficulty conceiving or are undergoing investigation of infertility, discontinuation of the drug should be considered.
Ability to influence reaction speed when driving vehicles or other mechanisms
Patients who experience visual disturbances, dizziness, vertigo, drowsiness, central nervous system disorders, lethargy or fatigue during therapy with ArgettDuo should not drive or operate complex machinery.
Method of administration and doses
The drug is used to treat adult patients, starting with a daily dose of 75-150 mg depending on the severity of symptoms. For mild symptoms, as well as for long-term therapy, a dose of 75 mg/day is sufficient. If the symptoms of the disease are most pronounced during the night or in the morning, the drug Argette Duo should be used in the evening. The daily dose of the drug should not exceed 150 mg.
The drug should be used in the lowest effective doses for the shortest period of time, taking into account the treatment objectives of each individual patient.
Argette Duo should be taken without chewing and with sufficient liquid during or immediately after meals.
Elderly patients.
No special dose adjustment is required, but the drug should be used with caution.
Kidney dysfunction.
No dose reduction is required for patients with mild to moderate renal impairment.
Liver dysfunction.
No dose reduction is required in patients with mild to moderate hepatic impairment.
Children: Do not use.
Overdose
Treatment. Treatment of acute NSAID poisoning consists of supportive and symptomatic therapy. Supportive and symptomatic treatment is indicated for complications such as hypotension, renal failure, convulsions, gastrointestinal disturbances, and respiratory depression. Forced diuresis, hemodialysis, or hemoperfusion are unlikely to be useful in removing NSAIDs because the active substances of these drugs are highly bound to plasma proteins and are extensively metabolized.
Activated charcoal should be considered within 1 hour of ingestion of a potentially toxic amount of the drug. In addition, gastric lavage should be considered in adults within 1 hour of ingestion of a potentially toxic amount of the drug. Diazepam should be administered intravenously if seizures are frequent or prolonged. Other measures may be indicated depending on the clinical condition of the patient. Treatment is symptomatic.
Side effects
Side effects that may occur when taking diclofenac are classified into the following groups according to their frequency:
very often ≥ 1/10;
common ≥ 1/100, < 1/10;
uncommon ≥ 1/1000, <1/100;
rare ≥ 1/10,000, < 1/1,000;
very rarely < 1/10,000, including isolated cases;
frequency unknown (cannot be estimated from available data).
The following undesirable effects include those reported with short-term or long-term use of the drug.
Blood and lymphatic system disorders: very rarely - thrombocytopenia, leukopenia, anemia (including hemolytic anemia and aplastic anemia), agranulocytosis.
Immune system disorders: Rare: hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock); very rare: angioedema (including facial edema).
Mental disorders: very rarely - disorientation, depression, insomnia, irritability, nightmares, psychotic disorders.
From the nervous system: often - headache, dizziness; rarely - drowsiness; very rarely - paresthesia, memory impairment, convulsions, anxiety, tremor, aseptic meningitis, taste disorders, stroke; frequency unknown - confusion, hallucinations, sensory disturbances, general malaise.
On the part of the organs of vision: very rarely - visual disturbances, blurred vision, diplopia; frequency unknown - optic neuritis.
From the side of the organs of hearing and labyrinth: often - vertigo; very rarely - tinnitus, hearing disorders.
Cardiovascular system: very rarely - palpitations, chest pain, heart failure, myocardial infarction, hypertension, hypotension, vasculitis; frequency unknown - Kounis syndrome.
Respiratory, thoracic and mediastinal disorders: rarely - asthma (including dyspnea); very rarely - pneumonitis.
Gastrointestinal: often - nausea, vomiting, diarrhea, dyspepsia, abdominal pain, flatulence, anorexia; rarely - gastritis, gastrointestinal bleeding (hemorrhage, melena, diarrhea with blood), gastric and intestinal ulcers, accompanied or not accompanied by bleeding or perforation (sometimes fatal, especially in elderly patients), loss of appetite; very rarely - colitis (including hemorrhagic colitis and exacerbation of ulcerative colitis or Crohn's disease), constipation, stomatitis (including ulcerative stomatitis), glossitis, esophageal dysfunction, membrane strictures, pancreatitis.
From the hepatobiliary system: often - increased transaminase levels; rarely - hepatitis, jaundice, liver disorders; very rarely - 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, hair loss, photosensitivity reactions, purpura, including allergic, itching.
From the kidneys and urinary system: very rarely - acute renal failure, hematuria, proteinuria, interstitial nephritis, nephrotic syndrome, papillary necrosis of the kidney.
General disorders: rarely - edema, fatigue.
From the reproductive system and mammary glands: very rarely - impotence.
Clinical trial data and epidemiological data suggest 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 with long-term use.
If severe side effects occur, treatment should be discontinued.
Expiration date
4 years.
Storage conditions
Store out of the reach of children at a temperature not exceeding 25 °C.
Store in original packaging to protect from moisture.
Packaging
10 capsules in a blister; 1 or 2 or 3 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
Swiss Caps GmbH / Swiss Caps GmbH.
Location of the manufacturer and address of its place of business.
Grassingerstrasse 9, 83043 Bad Aibling, Germany/Grassingerstrasse 9, 83043 Bad Aibling, Germany.
Applicant
Delta Medical Promotions AG.
Oetenbachgasse 26, Zurich CH-8001, Switzerland/26 Oetenbachgasse, Zurich CH-8001, Switzerland.
