Instructions for use Ortofen-Zdorovya forte enteric-coated tablets 50 mg blister No. 30
Composition
active ingredient: 1 tablet contains diclofenac sodium 50 mg;
Excipients: lactose monohydrate; crospovidone; microcrystalline cellulose; croscarmellose sodium; magnesium stearate; colloidal anhydrous silicon dioxide; dry mixture "Acryl-eze white", containing talc, titanium dioxide (E 171), methacrylate copolymer (type C), sodium lauryl sulfate, sodium bicarbonate, silicon dioxide; macrogol 6000; ponceau 4 R (E 124); azorubine (E 122).
Dosage form
The film-coated tablets are enteric-coated.
Main physicochemical properties: film-coated tablets, pink to pink with a red tint. Two layers are visible on cross-section.
Pharmacotherapeutic group
Nonsteroidal anti-inflammatory and antirheumatic drugs.
ATX code M01A B05.
Pharmacological properties
Pharmacodynamics
The drug contains diclofenac sodium, a substance with a non-steroidal structure that has a pronounced analgesic and anti-inflammatory effect.
It is an inhibitor of prostaglandin synthetase (cyclooxygenase).
In vitro, diclofenac sodium at concentrations equivalent to those achieved in the treatment of patients does not inhibit the biosynthesis of cartilage proteoglycans.
Pharmacokinetics
Although absorption is complete, the onset of action may be delayed as a result of gastric transit, which may be affected by food, which delays gastric emptying. Mean peak plasma concentrations of 1.48 ± 0.65 μg/ml (1.5 μg/ml = 5 μmol/l) are reached on average 2 hours after administration of a 50 mg tablet.
About half of the administered diclofenac is metabolized during the first pass through the liver (first-pass effect); the area under the concentration curve (AUC) after oral administration is approximately half of that obtained with an equivalent parenteral dose.
The pharmacokinetic characteristics of the drug do not change with repeated administration. Accumulation does not occur if the recommended dosage is observed.
The binding of diclofenac to serum proteins is 99.7%, and to albumin – 99.4%.
Diclofenac penetrates into the synovial fluid, where its Cmax is reached 2-4 hours later than in blood plasma. T½ from the synovial fluid is 3-6 hours. 2 hours after reaching Cmax in plasma, the concentration of diclofenac in the synovial fluid remains higher; this phenomenon is observed for 12 hours.
Diclofenac was detected in low concentrations (100 ng/ml) in breast milk from one woman. The estimated amount of drug reaching the infant via breast milk is equivalent to a dose of 0.03 mg/kg/day.
Diclofenac is metabolized partly by glucuronidation of the unchanged molecule, but mainly by single and multiple hydroxylation and methoxylation, leading to the formation of several phenolic metabolites, most of which form conjugates with glucuronic acid. Two of these phenolic metabolites are biologically active, but much less so than diclofenac.
The total systemic clearance of diclofenac from plasma is 263 ± 56 ml/min (mean ± SD). The terminal T½ from plasma is 1-2 hours. The T½ from plasma of four metabolites, including two pharmacologically active ones, is also short and is 1-3 hours. About 60% of the administered dose of the drug is excreted in the urine as a glucuronide conjugate of the intact molecule and as metabolites, most of which are also converted to glucuronide conjugates. Less than 1% of diclofenac is excreted unchanged. The remainder of the administered dose of the drug is excreted as metabolites with feces.
No effect of patient age on absorption, metabolism, or elimination was observed, except that in five elderly patients, a 15-minute intravenous infusion resulted in plasma concentrations that were 50% higher than expected in young healthy subjects.
In patients with renal impairment receiving therapeutic doses, no accumulation of unchanged active substance is expected based on the kinetics of the drug after a single dose. In patients with creatinine clearance less than 10 ml/min, the estimated steady-state plasma concentrations of hydroxylated metabolites were approximately 4-fold higher than in healthy subjects. However, all metabolites were ultimately excreted in the bile.
In patients with chronic hepatitis or compensated cirrhosis, the pharmacokinetics and metabolism of diclofenac are similar to those in patients without liver disease.
Indication
l Inflammatory and degenerative forms of rheumatic diseases (rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, spondyloarthritis);
l pain syndromes in the spine;
l rheumatic diseases of extra-articular soft tissues;
l acute attacks of gout;
l post-traumatic and postoperative pain syndromes accompanied by inflammation and edema, for example after dental and orthopedic interventions;
l as an adjuvant for severe inflammatory diseases of the ENT organs, accompanied by severe pain syndrome, for example, with pharyngotonsillitis, otitis.
l According to general therapeutic principles, the underlying disease should be treated with basic therapy. Fever alone is not an indication for the use of the drug.
Contraindication
l Hypersensitivity to the components of the drug.
l Acute stomach or intestinal ulcer; gastrointestinal bleeding or perforation.
l History of gastrointestinal bleeding or perforation related to previous treatment with nonsteroidal anti-inflammatory drugs (NSAIDs).
l Active ulcer/bleeding or history of recurrent ulcer/bleeding (two or more separate episodes of diagnosed ulcer or bleeding).
l Inflammatory bowel diseases (such as Crohn's disease or ulcerative colitis).
Liver failure.
Kidney failure.
l Congestive heart failure (NYHA II-IV).
l Ischemic heart disease in patients with angina pectoris or previous myocardial infarction.
l Cerebrovascular disease in patients who have had a stroke or have episodes of transient ischemic attacks.
l Peripheral artery disease.
l Treatment of perioperative pain in coronary artery bypass grafting (or use of a cardiopulmonary bypass machine).
l The drug, like other NSAIDs, is contraindicated in patients who experience attacks of bronchial asthma, angioedema, urticaria or acute rhinitis, nasal polyps and other allergic symptoms in response to the use of ibuprofen, acetylsalicylic acid or other NSAIDs.
Interaction with other medicinal products and other types of interactions
The interactions observed with the use of diclofenac in tablet form and/or other dosage forms are listed below.
Lithium: Diclofenac may increase plasma lithium concentrations when used concomitantly. Monitoring of serum lithium levels is recommended.
Digoxin: Diclofenac may increase the plasma concentration of digoxin when used concomitantly. Monitoring of serum digoxin levels is recommended.
Diuretics and antihypertensives. As with other NSAIDs, concomitant use of diclofenac with diuretics and antihypertensives (e.g. β-blockers, angiotensin-converting enzyme (ACE) inhibitors) may lead to a reduction in their antihypertensive effect by inhibiting the synthesis of vasodilator 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, and patients should be monitored more frequently.
Anticoagulants and antithrombotic agents. Concomitant use may increase the risk of bleeding, therefore, precautions are recommended. Although available clinical trial data do not indicate an effect of diclofenac on the activity of anticoagulants, there is some evidence of an increased risk of bleeding in patients receiving diclofenac and anticoagulants concomitantly. Therefore, close monitoring of such patients is recommended to ensure that no changes in the dosage of anticoagulants are required. As with other NSAIDs, diclofenac in high doses may transiently inhibit platelet aggregation.
Other NSAIDs, including selective cyclooxygenase-2 inhibitors, and corticosteroids. Concomitant use of diclofenac and other NSAIDs or corticosteroids may increase the risk of gastrointestinal bleeding or ulceration. The concomitant use of two or more NSAIDs should be avoided.
Selective serotonin reuptake inhibitors: Concomitant use of NSAIDs and SSRIs may increase the risk of gastrointestinal bleeding.
Methotrexate. Diclofenac may inhibit the renal tubular clearance of methotrexate, leading to increased methotrexate levels. Caution should be exercised when NSAIDs, including diclofenac, are administered less than 24 hours before methotrexate, as this may increase the blood concentration of methotrexate and increase its toxicity. Serious toxicity has been reported when the interval between administration of methotrexate and NSAIDs, including diclofenac, was within 24 hours. This interaction is mediated by accumulation of methotrexate as a result of impaired renal excretion in the presence of NSAIDs.
Cyclosporine. The effect of diclofenac, like other NSAIDs, on prostaglandin synthesis in the kidneys may enhance the nephrotoxicity of cyclosporine; therefore, diclofenac should be used in lower doses than for patients not taking cyclosporine.
Tacrolimus: There is a possible increased risk of nephrotoxicity when NSAIDs are used with tacrolimus, which may be mediated through the renal antiprostaglandin effects of the NSAID and the calcineurin inhibitor.
Quinolone antibacterials. Convulsions may occur in patients receiving concomitant quinolones and NSAIDs. This may occur in patients with or without a history of epilepsy and seizures. Therefore, caution should be exercised when considering the use of a quinolone in patients already receiving NSAIDs.
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. These drugs may delay or reduce the absorption of diclofenac. Therefore, it is recommended to administer diclofenac at least 1 hour before or 4-6 hours after colestipol/cholestyramine.
Cardiac glycosides. Concomitant use of cardiac glycosides and NSAIDs may exacerbate heart failure, reduce GFR, and increase plasma glycoside levels.
Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration, as NSAIDs may reduce the effect of mifepristone.
Potent CYP2C9 inhibitors: Caution is advised when co-administering diclofenac with potent CYP2C9 inhibitors (e.g. voriconazole), which may lead to a significant increase in plasma Cmax and diclofenac exposure due to inhibition of diclofenac metabolism.
Application features
To minimize undesirable effects, treatment should be initiated at the lowest effective dose for the shortest duration necessary to control symptoms. The patient's need for diclofenac should be reassessed periodically to improve symptoms and increase response to therapy.
Concomitant use of the drug with systemic NSAIDs, such as selective cyclooxygenase-2 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. In particular, it is recommended to use the lowest effective dose in frail elderly patients or those with low body weight. The drug should be used with caution in patients over 65 years of age.
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 cause myocardial infarction. Symptoms of such reactions may include chest pain associated with an allergic reaction to diclofenac.
Due to its pharmacodynamic properties, the drug, like other NSAIDs, may mask the signs and symptoms of infection.
The drug contains lactose, therefore, if the patient has been diagnosed with intolerance to some sugars, you should consult a doctor before taking this drug.
Ponceau 4 R (E 124) and azorubine (E 122) may cause allergic reactions.
Gastrointestinal (GI) effects: Gastrointestinal bleeding (hemorrhage, melena), ulceration or perforation, which can be fatal and can occur at any time during treatment with or without warning symptoms or a previous history of serious GI events, have been reported with all NSAIDs, including diclofenac. These events are usually more severe in the elderly. If GI bleeding or ulceration occurs in patients receiving diclofenac, the drug should be discontinued.
The use of NSAIDs, including diclofenac, may be associated with an increased risk of "anastomotic leak". As with other NSAIDs, including diclofenac, medical supervision is mandatory for patients with symptoms suggestive of gastrointestinal disorders and special caution is advised when using it after surgery on the gastrointestinal tract. The risk of gastrointestinal bleeding, ulceration or perforation increases with increasing dose of NSAIDs, including diclofenac.
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) or other medicinal products likely to increase the risk of gastrointestinal adverse effects, combination therapy with protective agents (e.g. proton pump inhibitors or misoprostol) should be considered. Patients with a history of gastrointestinal toxicity, particularly the elderly, should report any unusual abdominal symptoms (especially gastrointestinal bleeding). Caution is also required in patients receiving concomitant medicinal products 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 (SSRIs).
Hepatic effects: Close medical supervision is required if the drug is prescribed to patients with impaired liver function, as their condition may worsen.
As with other NSAIDs, including diclofenac, the level of one or more liver enzymes may increase.
During long-term treatment with the drug, regular monitoring of liver function and liver enzyme levels is prescribed as a precautionary measure. If liver function abnormalities persist or worsen and if clinical signs or symptoms that may be associated with progressive liver disease or if other manifestations are observed (e.g. eosinophilia, rash), the drug should be discontinued. The course of diseases such as hepatitis may occur without prodromal symptoms. Caution is necessary if the drug is used in patients with hepatic porphyria, due to the possibility of provoking an attack.
Renal effects: Since cases of fluid retention and oedema have been reported with NSAIDs, including diclofenac, special attention should be paid to patients with impaired cardiac or renal function, a history of hypertension, the elderly, patients receiving concomitant therapy with diuretics or drugs that significantly affect renal function, and patients with a significant decrease in extracellular fluid volume for any reason, such as before or after major surgery. In such cases, monitoring of renal function is recommended as a precautionary measure. Discontinuation of therapy usually leads to a return to the pre-treatment state.
Skin effects. Serious skin reactions (some fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and Lyell's syndrome) have been reported very rarely in association with the use of NSAIDs, including the drug. Patients are at greatest 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. The drug 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: For patients with a history of hypertension and/or mild to moderate congestive heart failure, appropriate monitoring and advice is necessary, as fluid retention and oedema have been reported in association with the use of NSAIDs, including diclofenac.
Existing evidence suggests that diclofenac, especially at high doses (150 mg/day) and with long-term use, may slightly increase the risk of arterial thrombotic events (e.g. myocardial infarction or stroke).
Diclofenac is not recommended for use in patients with uncontrolled hypertension, congestive heart failure, stable ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease; if necessary, use is possible only after a careful risk/benefit assessment only at a dosage not exceeding 100 mg per day, 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). A similar assessment should be carried out before starting long-term treatment in patients with significant risk factors for cardiovascular events (e.g. with arterial hypertension, hyperlipidemia, diabetes mellitus, and patients who smoke) - the appointment of diclofenac is possible only after a careful clinical assessment.
Patients should be informed about the possibility of serious antithrombotic events (chest pain, shortness of breath, weakness, speech disorders) that may occur at any time. In this case, a doctor should be consulted immediately.
The drug may temporarily inhibit platelet aggregation. Patients with impaired hemostasis, hemorrhagic diathesis, or hematological disorders should be carefully monitored.
History of asthma. Patients with asthma, seasonal allergic rhinitis, nasal mucosal edema (i.e. nasal polyps), chronic obstructive pulmonary disease or chronic respiratory tract infections (especially those associated with allergic rhinitis-like symptoms) are more likely to experience reactions to NSAIDs such as exacerbation of asthma (so-called analgesic intolerance/analgesic asthma), angioedema or urticaria. Therefore, special precautions (emergency medical attention) are recommended for such patients. This also applies to patients with allergic reactions to other substances such as rash, itching or urticaria.
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. From the 20th week of pregnancy, the use of diclofenac may cause oligohydramnios due to fetal renal dysfunction. This may occur shortly after the start of treatment and is usually reversible after discontinuation of treatment. 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 after exposure to diclofenac for several days, starting from the 20th week of pregnancy. Diclofenac should be discontinued if oligohydramnios is detected.
Inhibition of prostaglandin synthesis may adversely affect the course of pregnancy and/or the development of the embryo/foetus. There is evidence from epidemiological studies that suggest an increased risk of miscarriage and/or the risk of 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, in animals treated with a prostaglandin synthesis inhibitor during organogenesis, an increased incidence of various malformations, including those of the cardiovascular system, was recorded. If the drug is used by a woman attempting to conceive, or in the first trimester of pregnancy, the dose of the drug 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);
- impaired renal function, which may progress to renal failure with oligohydramnios (see above).
For 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;
- suppression of uterine contractions, leading to delayed or prolonged labor.
Therefore, the drug is contraindicated during the third trimester of pregnancy.
Breastfeeding. Like other NSAIDs, diclofenac is excreted in small amounts in breast milk. In this regard, the drug should not be used by women during breastfeeding to avoid undesirable effects on the infant.
Female fertility: As with other NSAIDs, the drug 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 drug therapy should not drive or operate complex machinery.
Method of administration and doses
In order to minimize undesirable effects, the drug should be used in the lowest effective dose for the shortest period of time necessary to control symptoms, taking into account the treatment goals of each individual patient. The tablets should preferably be taken before meals, with liquid, and should not be divided or chewed.
In primary dysmenorrhea, the daily dose is selected individually, usually it is 50-150 mg. The initial dose can be 50-100 mg per day, but if necessary, it can be increased over several menstrual cycles to a maximum of 200 mg per day. The drug should be started after the first painful symptoms appear and continued for several days, depending on the dynamics of symptom regression.
Children aged 14 to 18 years should take the drug at a dose of 75 to 150 mg per day in 2 or 3 doses.
The daily dose of the drug should not exceed 150 mg.
If it is necessary to prescribe diclofenac sodium at a dose of 75 mg, use the drug in the appropriate dosage or dosage form.
Elderly: Although the pharmacokinetics of the drug are not impaired to any clinically significant extent in elderly patients, NSAIDs should be used with caution in elderly patients, who are generally more susceptible to adverse reactions. In particular, the lowest effective dose is recommended for frail elderly patients or patients with low body mass; patients should also be monitored for gastrointestinal bleeding during treatment with NSAIDs.
Children
The drug should not be used in children under 14 years of age due to the high content of the active substance.
Overdose
There is no typical clinical picture of diclofenac overdose. Overdose may cause symptoms such as headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, diarrhea, dizziness, disorientation, agitation, coma, drowsiness, tinnitus, or convulsions. Acute renal failure and liver damage are possible in severe intoxication.
Treatment. Treatment of acute poisoning with NSAIDs, including diclofenac, consists of supportive and symptomatic therapy. This includes the treatment of manifestations such as arterial hypotension, renal failure, convulsions, gastrointestinal disorders, respiratory depression. It is unlikely that such specific therapeutic measures as forced diuresis, dialysis or hemoperfusion will be effective in removing NSAIDs, including diclofenac, since the active substances of these drugs are largely bound to blood proteins and undergo intensive metabolism. Activated charcoal may be used after ingestion of potentially toxic doses, and gastric decontamination (e.g., induction of vomiting, gastric lavage) after ingestion of potentially life-threatening doses.
Adverse reactions
The following undesirable effects include those reported with short-term or long-term use of diclofenac.
Blood and lymphatic system disorders: thrombocytopenia, leukopenia, anemia (including hemolytic anemia and aplastic anemia), agranulocytosis.
Immune system disorders: hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock), angioedema (including facial edema).
Mental disorders: disorientation, depression, insomnia, irritability, nightmares, psychotic disorders.
From the nervous system: headache, dizziness, drowsiness, fatigue, paresthesia, memory impairment, convulsions, anxiety, tremor, aseptic meningitis, taste disorders, stroke, confusion, hallucinations, sensory disturbances, general malaise.
From the organs of vision: visual disturbances, blurred vision, diplopia, optic neuritis.
From the side of the organs of hearing and labyrinth: vertigo, tinnitus, hearing disorders.
Cardiovascular system: palpitations, chest pain, heart failure, myocardial infarction, hypertension, hypotension, vasculitis, Kounis syndrome.
Respiratory, thoracic and mediastinal disorders: asthma (including dyspnea), pneumonitis.
Gastrointestinal: nausea, vomiting, diarrhea, dyspepsia, abdominal pain, flatulence, anorexia, 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), colitis (including hemorrhagic colitis and exacerbation of ulcerative colitis or Crohn's disease), constipation, stomatitis (including ulcerative stomatitis), glossitis, esophageal dysfunction, diaphragmatic stenosis of the intestine, pancreatitis.
From the hepatobiliary system: increased transaminase levels, hepatitis, jaundice, liver disorders, fulminant hepatitis, liver necrosis, liver failure.
Skin and subcutaneous tissue disorders: rash, urticaria, blistering rash, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, Lyell's syndrome, exfoliative dermatitis, hair loss, photosensitivity reactions, purpura, including allergic, itching.
Renal and urinary disorders: edema, acute renal failure, hematuria, proteinuria, interstitial nephritis, nephrotic syndrome, renal papillary necrosis.
From the reproductive system and mammary glands: impotence.
Existing 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.
Expiration date
3 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25°C.
Keep out of reach of children.
Packaging
Tablets No. 10 (10×1), No. 30 (10×3) in blisters in a box.
Vacation category
According to the recipe.
Producer
Limited Liability Company "Pharmaceutical Company "Zdorovya".
Limited Liability Company "PHARMEX GROUP".
Location of the manufacturer and address of its place of business
Ukraine, 61013, Kharkiv region, Kharkiv city, Shevchenko street, building 22.
(Limited Liability Company "Pharmaceutical Company "Zdorovya")
Ukraine, 08301, Kyiv region, Boryspil city, Shevchenko street, building 100.
(Limited Liability Company "PHARMEX GROUP")
