Pharmacological properties
Pharmacodynamics. Rapten retard is an NSAID with antirheumatic, anti-inflammatory, analgesic and antipyretic effects. The main mechanism of action of diclofenac is to slow down the biosynthesis of prostaglandins by inhibiting the COX isoenzymes - COX-1 and COX-2. Prostaglandins play an important role in the occurrence of inflammation, pain and fever. Diclofenac sodium in vitro does not inhibit the biosynthesis of proteoglycan in cartilage tissue at concentrations equivalent to those achieved in humans.
The anti-inflammatory and analgesic effect of diclofenac in rheumatic diseases is manifested by a decrease in the intensity of pain at rest and during movement, morning stiffness, a decrease in edema and an increase in the functional activity of the patient. Diclofenac quickly reduces the severity of spontaneous pain and pain during movement, reduces inflammatory edema and wound edema in post-traumatic and postoperative inflammation. Diclofenac has an analgesic effect in moderate and severe pain of non-rheumatic origin, reduces pain during the first painful menstruation and shortens the duration of bleeding.
Rapten retard is specially designed for patients with a clinical picture in which an adequate dose of diclofenac is 100 mg/day. The daily dose, taken once, is adequate for long-term treatment, as it increases patient compliance and reduces the possibility of errors in dose titration.
Pharmacokinetics. When taking diclofenac in the form of prolonged-release tablets, the same amount of active substance is released and absorbed as when using diclofenac in the form of film-coated tablets. C max in blood plasma is reached after approximately 4 hours and is 0.508 ± 0.185 μg/ml. Due to the slow release of the substance, its plasma concentration reaches 13 ng/ml 24 hours after taking the drug. Food does not affect the absorption of the drug.
The systemic bioavailability of diclofenac in the form of retard tablets with a slow release of the active substance is ≈82% of the bioavailability of diclofenac in film-coated tablets. Due to the slow release of the active substance, C max in the blood plasma is lower than after taking an equivalent dose in film-coated tablets. Pharmacokinetic parameters do not change with repeated administration. Accumulation of the drug does not occur if diclofenac is used in doses that correspond to the recommended intervals between doses. The average plasma concentration of the retard form of diclofenac is ≈22 ng / ml.
Diclofenac is highly bound to plasma proteins (99.7%), mainly to albumin (99.4%). Penetrates into synovial fluid, reaching C max 2-4 hours after its C max in plasma has been reached. T ½ from synovial fluid is 3-6 hours. 2 hours after C max in plasma has been reached, the concentration of the active substance in synovial fluid becomes higher than in plasma, and they remain higher for 12 hours.
Biotransformation of the drug occurs partly by glucuronidation of the parent molecule and mainly by hydroxylation and methoxylation, followed by the formation of phenolic metabolites, most of which are converted to glucuronic acid conjugates. The two phenolic metabolites are active, although to a much lesser extent than diclofenac.
The total systemic clearance of diclofenac in blood plasma is 263 ± 56 ml/min. The final elimination T ½ is 1-2 h. Four metabolic products, including active ones, are also characterized by a short final elimination T ½ from blood plasma, which is 1-3 h. Approximately 60% of the dose taken is excreted in the urine in the form of glucuronide conjugates of the initial molecule and products of its metabolism, which are also largely converted into glucuronide conjugates. Less than 1% is excreted unchanged. The remainder of the dose taken is excreted in the form of metabolic products by the liver, with bile and feces.
Elderly people
No significant differences in absorption, metabolism, or excretion were observed in the elderly.
Patients with renal impairment
Accumulation of unchanged active substance - given the kinetic parameters after a single dose - does not occur in patients with impaired renal function, if the drug was taken according to the recommended dosage regimen. At a creatinine clearance of 10 ml/min, the balance of hydroxymetabolites in the blood plasma was approximately 4 times higher than in healthy individuals, and they are excreted mainly with bile.
Patients with hepatic impairment
In patients with chronic hepatitis or cirrhosis in the compensated stage, the kinetics and metabolism of diclofenac are similar to those in patients without liver function disorders.
Indication
Inflammatory and degenerative forms of rheumatic diseases (rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, spondyloarthritis), pain syndrome localized in the spine, non-articular rheumatism; post-traumatic and postoperative pain syndrome accompanied by inflammation and edema; gynecological diseases accompanied by pain syndrome and inflammation (algomenorrhea, adnexitis); acute attacks of gout.
Application
Adults are prescribed 1 tablet (100 mg) once a day. The tablets should be taken before meals, without chewing, with water. If the symptoms become more intense at night or in the morning, then taking 100 mg of Rapti retard tablets is recommended in the evening.
In general, it is recommended to select the dose individually, and also to take the lowest effective dose for the shortest possible time.
The maximum daily dose is 200 mg.
Contraindication
Hypersensitivity to the drug and its components; gastric and duodenal ulcers; history of gastrointestinal bleeding caused by the use of NSAIDs; urticaria or acute rhinitis caused by acetylsalicylic acid, ibuprofen and other NSAIDs; rare hereditary diseases such as fructose intolerance, glucose and galactose malabsorption or sucrose-isomaltase deficiency; severe heart, liver or kidney failure; pregnancy; age up to 18 years.
Side effects
Disorders of the hematopoietic and lymphatic systems: very rarely - thrombocytopenia, leukopenia, anemia (including hemolytic and aplastic anemia) and agranulocytosis.
Immune system disorders: rarely - hypersensitivity reactions such as asthma, anaphylactic and anaphylactoid reactions (including hypotension); very rarely - angioedema.
Mental disorders: very rarely - disorientation, depression, insomnia, nightmares, irritability, psychotic disorders.
Central nervous system disorders: often - headache, dizziness; rarely - drowsiness; very rarely - paresthesia, memory impairment, convulsions, anxiety, fear and anxiety, tremor, aseptic meningitis, tactile disorders, taste disorders, cerebral circulation disorders.
Visual disturbances: very rarely - diplopia, blurred vision.
Hearing disorders: often - dizziness; very rarely - tinnitus, hearing impairment.
Cardiovascular system disorders: very rarely - tachycardia, chest pain, hypertension, vasculitis, heart failure, myocardial infarction.
Respiratory system disorders: rarely - asthma (including dyspnea); very rarely - pneumonitis.
Gastrointestinal disorders: often - nausea, vomiting, diarrhea, dyspepsia, lower abdominal pain, flatulence and anorexia; rarely - gastritis, gastrointestinal bleeding, hematemesis, melena, gastric or intestinal ulcer (with or without bleeding or perforation); very rarely - colitis (including hemorrhagic colitis and exacerbation of ulcerative colitis or Crohn's disease), constipation, stomatitis, glossitis, esophageal disorders, diaphragmatic strictures of the intestine, pancreatitis.
Liver and biliary tract disorders: often - increased transaminase levels; rarely - hepatitis, jaundice, liver function disorders; very rarely - fulminant (lightning) hepatitis.
Skin and Appendages Disorders: Common: rash; Rare: urticaria; Very rare: bullous rash, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), exfoliative dermatitis, alopecia, photosensitivity, purpura, pruritus.
Urinary system disorders: very rarely - acute renal failure, hematuria, proteinuria, nephrotic syndrome, interstitial nephritis, medullary renal necrosis.
General disorders: rarely - edema.
Special instructions
Caution is advised and regular monitoring is recommended in patients with symptoms of gastrointestinal disorders, as well as in patients with a history of gastrointestinal ulcers or inflammatory bowel disease (Crohn's disease). Gastrointestinal bleeding, ulcers, perforation, haematemesis and melena are serious adverse reactions to NSAIDs, which occur more often in elderly patients. Bleeding or ulceration rarely occurs after taking diclofenac. If such adverse reactions occur, further use of the drug should be discontinued. The risk of gastrointestinal bleeding increases with increasing NSAID doses in patients with a history of gastrointestinal ulcers (particularly those complicated by bleeding or perforation) and in elderly patients. Treatment is initiated and continued with the lowest effective maintenance dose of diclofenac to reduce the risk. Similarly, it is necessary to simultaneously prescribe medications (for example, proton pump inhibitors or misoprostol) for this group of patients and for patients who are simultaneously taking acetylsalicylic acid in small doses or other drugs that increase the risk of gastrointestinal complications.
Regular monitoring of patients with severe hepatic impairment is recommended, as exacerbation or worsening of hepatic impairment is possible. Elevations of one or more liver enzymes may occur, as with other NSAIDs. Regular monitoring of liver function is recommended during long-term treatment with diclofenac. If elevated liver enzyme levels persist or increase, and clinical signs and symptoms of hepatic impairment or other reactions (eosinophilia, rash, etc.) occur, diclofenac should be discontinued. Caution should be exercised in patients with hepatic porphyria, as diclofenac is a possible trigger for exacerbation of the disease.
As with other non-steroidal anti-inflammatory drugs, severe skin reactions such as exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported very rarely during treatment with diclofenac. The risk is highest at the beginning of therapy (the peak incidence is recorded during the first month of treatment with the drug). If a rash, mucosal lesions or other signs of hypersensitivity occur, diclofenac therapy should be discontinued.
As with other non-steroidal anti-inflammatory drugs, in rare cases, after the use of diclofenac without prior sensitivity testing, allergic reactions, including anaphylactic and anaphylactoid reactions, bronchospasm, apnea, may occur. As with other non-steroidal anti-inflammatory drugs, diclofenac may mask the signs and symptoms of infection.
The simultaneous use of diclofenac and systemic NSAIDs, including selective COX-2 inhibitors, is not recommended. The drug should be prescribed with particular caution to elderly patients and people with insufficient body weight; for them it is recommended to use the minimum effective dose of diclofenac.
Diclofenac should be used with caution in patients with bronchial asthma, seasonal allergic rhinitis, nasal polyposis, COPD or chronic respiratory tract infections (particularly if associated with allergic rhinitis) due to the possibility of adverse reactions to NSAIDs such as exacerbation of asthma, angioedema and urticaria. Caution should be exercised in treating patients with allergies to other drugs (manifested as pruritus or urticaria).
The use of nonsteroidal anti-inflammatory drugs may have a negative effect on female fertility, so drugs in this group are not recommended for women planning pregnancy or patients with infertility.
Oedema may occur after taking non-steroidal anti-inflammatory drugs. Therefore, caution should be exercised and regular monitoring of renal function should be carried out when prescribing diclofenac to patients with impaired cardiac or renal function, high blood pressure, elderly patients and those taking diuretics or drugs that affect renal function (e.g. aminoglycosides), as well as patients with severe dehydration - regardless of the cause (e.g. before or after major surgery). Impaired renal function is reversible after discontinuation of diclofenac.
Regular monitoring of blood parameters is recommended during long-term use of diclofenac. Diclofenac may temporarily inhibit platelet aggregation. Caution and regular monitoring are recommended in patients with impaired hemostasis.
Rapten retard tablets contain sucrose as an excipient. The drug is not recommended for patients with hereditary fructose intolerance, glucose-galactose malabsorption syndrome or sucrase-isomaltase deficiency.
Use during pregnancy and breastfeeding. Due to the lack of data on the use of diclofenac during pregnancy, its use is not recommended in the I-II trimester of pregnancy, unless the expected benefit to the mother outweighs the potential risk to the fetus. The use of diclofenac is contraindicated during the III trimester of pregnancy, since a decrease in uterine contractions and / or premature closure of the ductus arteriosus is possible.
Animal studies have not revealed any direct or indirect negative effects on pregnancy, embryonal and fetal development, the postpartum period, or neonatal development.
Diclofenac passes into breast milk in small amounts. Diclofenac is not recommended for use during the entire period of breastfeeding in order to avoid undesirable side effects in the newborn. Like other non-steroidal anti-inflammatory drugs, diclofenac may impair fertility and is therefore not recommended for use in women planning to become pregnant. Women who have difficulty conceiving should stop taking diclofenac.
Ability to influence the reaction rate when driving vehicles or working with other mechanisms. If dizziness, drowsiness or other CNS disorders, including visual disturbances, occur during treatment with Rapten retard, then in this case it is not recommended to drive vehicles or work with other mechanisms.
Interactions
Lithium and digoxin. Diclofenac may cause an increase in the concentration of lithium and digoxin with simultaneous use, therefore it is recommended to regularly monitor their concentrations in the blood plasma. The combined use of diclofenac and digitalis glycoside may cause exacerbation of cardiovascular diseases, a decrease in glomerular blood flow and an increase in the concentration of glycosides in the blood plasma.
Diuretics and antihypertensives. Diclofenac may reduce the antihypertensive effect of diuretics and antihypertensives (e.g. β-blockers, ACE inhibitors) when used concomitantly, as it slows down prostaglandin synthesis. Caution should be exercised when using these drugs together and blood pressure should be monitored periodically, especially in the elderly. Patients should be adequately hydrated. It is recommended to monitor renal function at the beginning of treatment and periodically after its completion, especially when using diuretics and ACE inhibitors simultaneously, as the risk of nephrotoxic effects increases. Concomitant use with potassium-sparing drugs may increase the concentration of potassium in the blood plasma, therefore regular monitoring of potassium concentration is recommended.
Other NSAIDs and corticosteroids: Concomitant use of diclofenac and other non-steroidal anti-inflammatory drugs or corticosteroids may increase the incidence of gastrointestinal adverse reactions.
Anticoagulants. It is recommended to exercise special caution and regularly monitor patients when diclofenac is used concomitantly with anticoagulants, as the risk of bleeding is increased. Like other non-steroidal anti-inflammatory drugs, diclofenac in high doses can reversibly slow platelet aggregation. Although clinical studies have not shown an effect of diclofenac on the activity of anticoagulants, in isolated cases an increased risk of bleeding has been reported with concomitant administration.
Selective serotonin reuptake inhibitors: Concomitant use of NSAIDs and selective serotonin reuptake inhibitors may increase the risk of gastrointestinal bleeding.
Oral antidiabetic agents. Clinical studies have shown that diclofenac can be used concomitantly with antidiabetic agents without affecting the clinical effect of the latter. However, isolated cases of hyper- or hypoglycemia have been reported with concomitant administration of oral antidiabetic agents and diclofenac. Monitoring of glycemia is recommended when these drugs are administered concomitantly.
Methotrexate: Caution should be exercised when NSAIDs are taken within 24 hours of the next dose of methotrexate, as this may increase the plasma concentration of methotrexate and its toxic effects.
Colestipol and cholestyramine. Concomitant use of diclofenac with colestipol or cholestyramine reduces the absorption of diclofenac by approximately 30 and 60%, respectively. The drugs should be taken several hours apart.
Drugs that induce drug-metabolizing enzymes. Drugs that induce enzymes, such as rifampicin, carbamazepine, phenytoin, St. John's wort (Hypericum perforatum), and others, are theoretically capable of reducing the concentration of diclofenac in the blood plasma.
Cyclosporine: Like other NSAIDs, diclofenac may increase the nephrotoxicity of cyclosporine due to its effect on prostaglandin synthesis in the kidneys. It is recommended to use diclofenac in low doses when co-administered with cyclosporine.
Quinolone antibacterial drugs. In isolated cases, seizures have been reported, which were probably a consequence of the interaction between NSAIDs and quinolone antibiotics. Convulsions occur in patients with a history of epilepsy or seizures and convulsions, and in patients without them. Caution is recommended when taking quinolone antibiotics in patients undergoing therapeutic treatment with NSAIDs.
Mifepristone. NSAIDs are not recommended for 8-12 days after taking mifepristone, as NSAIDs may weaken its effect.
Overdose
Therapeutic measures include supportive care and symptomatic treatment and are used in cases of complications such as hypotension, renal failure, convulsions, gastrointestinal dysfunction and respiratory depression. Special measures such as forced diuresis, dialysis or blood transfusion do not accelerate the elimination of NSAIDs, since NSAIDs have a high percentage of binding to plasma albumin and extensive metabolism.
Activated charcoal is recommended for potentially toxic doses, while induced emesis and gastric lavage are recommended for potentially fatal doses.
Storage conditions
At a temperature not exceeding 30 °C.
