Pharmacological properties
Pharmacodynamics. Rapten 75 contains diclofenac sodium, Rapten rapid - diclofenac potassium, non-steroidal compounds with pronounced antirheumatic, anti-inflammatory, analgesic and antipyretic properties. Suppression of prostaglandin biosynthesis, which has been demonstrated in experiments, is considered the main mechanism of its action. Prostaglandins play an important role in the occurrence of inflammation, pain and fever.
In rheumatic diseases, the anti-inflammatory and analgesic properties of the drug cause a clinical response, which is characterized by a pronounced disappearance of signs and symptoms: pain at rest and with movement, morning stiffness and swelling of the joints, as well as a noticeable improvement in function.
The drug is able to enhance the pronounced analgesic effect on moderate and severe pain of non-rheumatic origin within 15-30 minutes.
The drug also demonstrated a significant effect on migraine attacks.
In post-traumatic and postoperative conditions with inflammation, the drug quickly relieves spontaneous pain and pain during movement and reduces swelling caused by inflammation and wounds.
If the drug is used simultaneously with opioid analgesics to relieve postoperative pain, the drug significantly reduces their need.
The drug is especially necessary for the initiation of treatment of inflammatory and degenerative rheumatic diseases and pain due to inflammation of non-rheumatic origin.
Pharmacokinetics. Absorption. After administration of 75 mg of diclofenac by intramuscular injection, absorption begins immediately, and the average C max in blood plasma is approximately 2.5 μg/ml (8 μmol/l), which is achieved after approximately 20 minutes. The extent of absorption may be linearly dependent on the dose.
When 75 mg diclofenac is administered by intravenous infusion over 2 hours, the mean Cmax in plasma is about 1.9 μg/ml (5.9 μmol/l). Shorter infusion times lead to higher Cmax in plasma, while longer infusions lead to concentrations proportional to the infusion rate after 3-4 hours. After intramuscular injection or administration of acid-resistant tablets or suppositories, plasma concentrations decrease rapidly after reaching peak levels.
The area under the concentration curve (AUC) after i / m or i / v administration is approximately twice as large as after oral or rectal administration, since approximately half of the active substance is metabolized during the first pass through the liver (first-pass effect) when the drug is administered orally or rectally.
Pharmacokinetic properties do not change after repeated administration. When the recommended dosing intervals are observed, drug accumulation does not occur.
Distribution: 99.7% of diclofenac is bound to plasma proteins, mainly albumin (99.4%). The volume of distribution is 0.12-0.17 l/kg.
Diclofenac enters the synovial fluid, where Cmax is achieved 2-4 hours after peak plasma levels. The apparent T½ from synovial fluid was 3-6 hours. 2 hours after peak plasma levels, diclofenac concentrations in synovial fluid exceed those in plasma and remain high for 12 hours.
Biotransformation. The metabolism of diclofenac occurs partly by glucuronidation of the intact molecule, but mainly by single and multiple hydroxylation and methoxylation, which leads 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 to glucuronide conjugates. Two of these phenolic metabolites are biologically active, but their effect is much less pronounced than that of diclofenac.
Elimination. The total systemic clearance of diclofenac in plasma is 263 ± 56 ml/min (mean ± SD). The terminal T½ from plasma is 1-2 h. Four of the metabolites, including the two active ones, also have short T½s of 1-3 h. One metabolite, 3'-hydroxy-4'-methoxy-diclofenac, has a much longer T½ from blood. However, this metabolite is virtually inactive.
Approximately 60% of the administered dose is excreted in the urine as the glucuronide conjugate of the intact molecule and as metabolites, most of which are also converted to glucuronide conjugates. Less than 1% is excreted as unchanged substance. The remainder of the dose is eliminated as metabolites via the bile and feces.
Special patient groups. No age-related differences in absorption, metabolism, or excretion of the drug were observed. However, in some elderly patients, a 15-minute IV infusion resulted in plasma concentrations that were 50% higher than those observed in young healthy subjects.
In patients with impaired renal function, when the usual dosage regimen is followed, accumulation of the active substance is not expected. In conditions of creatinine clearance less than 10 ml/min, the levels of hydroxymetabolites in the blood plasma at steady state are approximately 4 times higher than in normal individuals.
Thus, metabolites are ultimately excreted through the bile.
In patients with chronic hepatitis or non-decompensated cirrhosis, the kinetics and metabolism of diclofenac are the same as in patients without liver disease.
Indication
For short-term treatment (maximum 2 weeks) of the following acute diseases:
post-traumatic pain, inflammation and swelling, for example, due to sprains; postoperative pain, inflammation and swelling, for example, after dental or orthopedic operations; pain and / or inflammation accompanying inflammatory gynecological diseases, for example, primary dysmenorrhea or adnexitis; pain syndromes from the spine; rheumatic diseases of soft tissues; as an adjuvant in infections of the ENT organs, for example, in pharyngotonsillitis, otitis, accompanied by severe pain and inflammation.
Adult patients only:
migraine attacks with or without precursors.
In accordance with generally accepted approaches to the treatment of infectious and inflammatory diseases, it is also necessary to use etiotropic agents. An isolated increase in body temperature is not an indication for the use of the drug Rapten Rapid.
R-r
The drug for intramuscular administration is intended for the treatment of:
inflammatory and degenerative forms of rheumatism, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, spondyloarthritis, vertebral pain syndrome, non-articular rheumatism; acute attacks of gout; renal and biliary colic; pain and swelling after injuries and operations; severe migraine attacks.
The drug, when administered as an intravenous infusion, is intended for the treatment or prevention of postoperative pain.
Application
pills
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.
The film-coated tablets should be swallowed whole, without chewing, with water, preferably before meals.
For children over 14 years of age, the daily dose is 50-100 mg, which should be divided into 2-3 doses. The maximum daily dose of 150 mg should not be exceeded. There is currently no data on the use of Rapten Rapid for the treatment of migraine attacks in children.
For adults, the recommended dose is 100-150 mg/day. In case of moderate symptoms, a dose of 75-100 mg/day is usually sufficient. The daily dose should be divided into 2-3 doses.
In primary dysmenorrhea, the daily dose of Rapten Rapid should be selected individually. The daily dose is usually 50-100 mg. If necessary, during the next few menstrual cycles, the dose is increased to a maximum of 200 mg/day (4 film-coated tablets).
The use of the drug Rapten Rapid should be started when the first symptoms appear and continued for several days depending on the patient's response to therapy and symptoms.
Migraine. The drug should be used at the first signs of an attack. The recommended single dose is 50 mg. The next 50 mg can be used 2 hours after the first dose. If necessary, the drug can be continued after 4-6 hours, but it should be remembered that the maximum dose is 200 mg/day.
R-r
General recommendation - the dose should be selected individually, starting with the minimum effective dose. The drug should be used in the lowest effective dose for the shortest period of time, taking into account the treatment objectives of each individual patient.
Rapten 75, solution for injection should not be used for more than 2 days; if necessary, treatment can be continued with the use of other dosage forms (tablets or suppositories).
Intramuscular injection. To prevent damage to nerves or other tissues at the site of intramuscular injection, the following rules should be followed.
The dose is usually one ampoule of 75 mg/day by deep intramuscular injection into the upper outer sector of the gluteus maximus muscle. In severe cases (e.g. colic), the daily dose may be increased to two injections of 75 mg, several hours apart (one injection in each buttock). Alternatively, one ampoule of 75 mg may be combined with other dosage forms with a total maximum daily dose of 150 mg.
In the setting of a migraine attack, clinical experience is limited to cases with the initial use of one 75 mg ampoule, the dose should be administered if possible immediately after the use of 100 mg suppositories on the same day (if necessary). The total daily dose should not exceed 175 mg on the first day.
Intravenous infusion. Rapten 75, solution for injection, should not be administered as a bolus intravenous injection.
Immediately before the start of the IV infusion of Rapten 75, depending on its required duration, it should be diluted in 100-500 ml of 0.9% sodium chloride solution or 5% glucose solution, buffered with sodium bicarbonate solution for injection (0.5 ml of 8.4% solution or 1 ml of 4.2% or the corresponding volume of another concentration), which was taken from a freshly opened container; add to this solution the contents of one ampoule of the drug Rapten 75. Only clear solutions can be used. If there are crystals or sediment in the solution, it cannot be used for infusion.
Two alternative dosing regimens for Rapten 75, solution for injection are recommended. For the treatment of moderate to severe postoperative pain, 75 mg should be administered continuously over 30 minutes to 2 hours. If necessary, treatment may be repeated after a few hours, but the dose should not exceed 150 mg in any 24-hour period.
For the prevention of postoperative pain, a loading dose of 25-50 mg should be administered 15 min-1 h after surgery, followed by a continuous infusion of approximately 5 mg/h up to a maximum daily dose of 150 mg.
Hypersensitivity to the active substance, metabisulfite or to any of the other ingredients of the drug. Allergic reaction to other non-steroidal anti-inflammatory drugs, such as acetylsalicylic acid, which may manifest as bronchospasm, urticaria, acute rhinitis, nasal polyps or other allergic symptoms. Active gastric or intestinal ulcer, bleeding or perforation. Inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis). Severe liver failure (Child-Pugh class C, cirrhosis and ascites). Moderate and severe renal failure (creatinine clearance 30 ml/min). Congestive heart failure (NYHA II-IV). Coronary artery disease in patients with angina pectoris, previous myocardial infarction. Cerebrovascular disease in patients with stroke or transient ischemic attacks. Peripheral artery disease. treatment of perioperative pain in coronary artery bypass grafting (or the use of a cardiopulmonary bypass machine). patients with a high risk of developing postoperative bleeding, blood clotting disorders, hemostasis disorders, hematopoietic disorders or cerebrovascular bleeding.
Side effects
The following undesirable effects include phenomena associated with the administration of Rapten 75 solution for injection and/or other dosage forms of diclofenac in conditions of short-term and long-term use.
Infections and infestations: abscess at the injection site.
From the hematopoietic system: thrombocytopenia, leukopenia, anemia (including hemolytic and aplastic anemia), agranulocytosis.
Immune system disorders: hypersensitivity, anaphylactic and pseudoanaphylactic reactions (including hypotension and shock); angioedema (including facial swelling).
Mental disorders: disorientation, depression, insomnia, nightmares, irritability, mental disorders.
From the nervous system: headache, dizziness, drowsiness, paresthesia, memory impairment, convulsions, anxiety, tremor, aseptic meningitis, taste disturbance, stroke, touch disturbance.
On the part of the organ of vision: visual impairment, blurred vision, diplopia.
From the side of the organs of hearing and labyrinth: vertigo; tinnitus, hearing impairment.
Cardiac: palpitations, chest pain, myocardial infarction.
From the vascular system: arterial hypertension, vasculitis.
Respiratory, thoracic and mediastinal disorders: asthma (including dyspnea), bronchospasm, pneumonitis.
On the part of the digestive system: nausea, vomiting, diarrhea, dyspepsia, abdominal pain, flatulence; gastritis, intestinal bleeding, vomiting with blood, hemorrhagic diarrhea, melena, gastric or intestinal ulcer (with or without bleeding, perforation); colitis (including hemorrhagic colitis and exacerbation of ulcerative colitis, Crohn's disease), constipation, stomatitis, glossitis, pharyngeal disorders such as diaphragmatic intestinal strictures, pancreatitis.
Hepatobiliary disorders: increased transaminase levels; hepatitis, jaundice, liver function abnormalities; transient hepatitis, hepatonecrosis, liver failure.
Skin and subcutaneous tissue disorders: rash, urticaria, bullous rash, eczema, erythema, erythema multiforme, various types of erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), exfoliative dermatitis, hair loss, photosensitivity reaction, purpura, allergic purpura, itching.
Renal and urinary disorders: acute renal failure, hematuria, proteinuria, nephrotic syndrome, interstitial nephritis, renal papillary necrosis.
General disorders and administration site conditions: injection site reaction, pain, induration; injection site swelling, necrosis, abscess.
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/day) and with long-term use.
Special instructions
With all NSAIDs, gastrointestinal bleeding, ulceration or perforation can be fatal and may occur at any time during treatment, with or without warning symptoms or a history of serious gastrointestinal events. In elderly patients, these events are usually more severe. If gastrointestinal bleeding occurs in patients receiving Rapti 75 / Rapten Rapid, this drug should be discontinued.
Renal effects of NSAIDs include fluid retention with edema and/or hypertension. Therefore, diclofenac should be used with caution in patients with cardiac dysfunction and other conditions that lead to fluid retention. Caution is also indicated in patients receiving diuretics or concomitant ACE inhibitors, or who are at increased risk of hypovolemia.
Serious skin reactions, some fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with the use of NSAIDs, including diclofenac. Patients are at greatest risk of these reactions at the beginning of treatment, with the majority of these reactions occurring within the first month of treatment. Diclofenac should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.
As with other non-steroidal anti-inflammatory drugs, allergic reactions, including anaphylactic/anaphylactoid reactions, may also occur rarely without prior exposure to diclofenac. Metabisulfite in the solution for injection may lead to isolated severe hypersensitivity reactions and bronchospasm.
NSAIDs may increase the risk of serious cardiovascular thrombotic events, myocardial infarction and stroke, which can be fatal, and therefore the drug is not recommended for the treatment of postoperative pain during coronary artery bypass graft surgery.
Like other nonsteroidal anti-inflammatory drugs, the drug, due to its pharmacodynamic properties, may mask the signs and symptoms of infection.
Diclofenac should only be prescribed to patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidemia, diabetes mellitus, smoking) after careful clinical evaluation. 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 should be periodically reviewed to assess the relief of symptoms and the response to therapy. Use with caution in patients over 65 years of age.
Precautions: General: The use of the drug with systemic NSAIDs, including selective COX-2 inhibitors, should be avoided due to the lack of any synergistic benefit and the possibility of additional side effects.
Caution should be exercised when prescribing the drug to the elderly. In particular, the lowest effective dose is recommended for elderly people with frail health and for patients with low body mass.
History of asthma. Patients with bronchial 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 than others to experience reactions to NSAIDs that resemble asthma exacerbations (which are also associated with analgesic/analgesic asthma), angioedema, and urticaria. Therefore, special precautions (emergency preparedness) are recommended for such patients. This also applies to patients allergic to other substances, e.g. with skin reactions, itching, or urticaria.
Special precautions are recommended when the drug is administered parenterally to patients with asthma, as symptoms may be exacerbated.
Effects on the digestive tract. As with other nonsteroidal anti-inflammatory drugs, medical supervision and special caution are required when prescribing the drug to patients with symptoms suggestive of digestive tract disorders or with a history suggesting the presence of gastric or intestinal ulcers, bleeding and perforation. The risk of gastrointestinal bleeding increases with increasing dose and in patients with a history of ulcers, especially with complications in the form of bleeding or perforation, and in the elderly.
To reduce the risk of gastrointestinal toxicity in patients with a history of ulcer, especially those complicated by bleeding or perforation, and in the elderly, treatment should be initiated and maintained at low effective doses.
For such patients, as well as patients who require concomitant use of medicinal products containing low doses of acetylsalicylic acid or other medicinal products likely to increase the risk of undesirable effects on the digestive tract, the use of 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, antithrombotic agents, or selective serotonin reuptake inhibitors.
Effects on the liver: Careful medical supervision is necessary when the drug is prescribed to patients with impaired liver function, as their condition may worsen.
As with other NSAIDs, elevations of one or more liver enzymes may occur. During prolonged treatment with the drug, regular monitoring of liver function is indicated as a precautionary measure. If liver function abnormalities persist or worsen, if clinical signs or symptoms suggestive of progressive liver disease occur, or if other manifestations occur (e.g., eosinophilia, rash), the drug should be discontinued. Diseases such as hepatitis may occur without prodromal symptoms.
Caution is necessary when the drug is used in patients with hepatic porphyria due to the possibility of provoking an attack.
Renal effects: Since fluid retention and edema have been reported with NSAIDs, special care should be taken in patients with impaired cardiac or renal function (including functional renal failure due to hypovolemia, nephrotic syndrome, lupus nephropathy, and decompensated cirrhosis), a history of hypertension, the elderly, patients receiving diuretic therapy or drugs that significantly affect renal function, and in 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 results in a return to pre-treatment status.
Effect on hematological parameters. With prolonged use of the drug, as with other NSAIDs, monitoring of blood tests is recommended.
Like other nonsteroidal anti-inflammatory drugs, the drug may temporarily inhibit platelet aggregation. Patients with impaired hemostasis should be carefully monitored.
Use during pregnancy and breastfeeding. Pregnancy. Rapten 75 / Rapten Rapid should not be used during the first two trimesters of pregnancy, except in cases where the potential benefit to the mother outweighs the risk to the fetus. As with other NSAIDs, use in the third trimester of pregnancy is contraindicated due to the possible development of absence of uterine contractions and / or premature closure of the ductus arteriosus.
Breastfeeding. Like other non-steroidal anti-inflammatory drugs, diclofenac passes into breast milk in small amounts. Therefore, to avoid undesirable effects on the infant, Rapten 75 / Rapten Rapid should not be used during breastfeeding.
Fertility. Like other nonsteroidal anti-inflammatory drugs, Rapten 75 / Rapten Rapid may affect female fertility. The drug is not recommended for women planning to become pregnant. Women who have difficulty conceiving or who have undergone investigation for infertility should discontinue use of the drug.
Children. Due to the significant effect of the drug Rapten 75 in this dosage form, the solution for injection should not be used in children. Rapten Rapid, film-coated tablets, are not recommended for use in children under 14 years of age due to the high content of the active substance.
Ability to influence the reaction rate when driving vehicles or operating other mechanisms. Patients who experience visual disturbances, dizziness, drowsiness or other central nervous system disorders during treatment with the drug should refrain from driving vehicles and operating mechanisms.
Interactions
Below are the interactions that have been observed with the use of Rapten 75, solution for injection and/or other dosage forms of diclofenac.
Lithium: Diclofenac may increase plasma lithium concentrations when used concomitantly. Monitoring of plasma lithium levels is recommended.
Digoxin: Diclofenac may increase plasma concentrations of digoxin when used concomitantly. Monitoring of digoxin plasma levels is recommended.
Diuretics and antihypertensives. As with other NSAIDs, concomitant use of diclofenac with diuretics or antihypertensives (e.g. β-blockers, ACE inhibitors) may lead to a reduction in their antihypertensive effect. 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. Concomitant treatment with potassium supplements may be associated with an increase in plasma potassium levels, which requires close monitoring.
Anticoagulants and antithrombotic agents. Caution is advised as concomitant administration may increase the risk of bleeding. Although clinical studies have not shown an effect of diclofenac on the activity of anticoagulants, there is some evidence of an increased risk of bleeding in patients receiving diclofenac and these drugs concomitantly. Therefore, close monitoring of such patients is recommended.
Selective serotonin reuptake inhibitors (SSRIs): Concomitant use of systemic NSAIDs and SSRIs may increase the risk of gastrointestinal bleeding.
Antidiabetic drugs. Clinical studies have shown that diclofenac can be used together with oral hypoglycemic agents without affecting their clinical effect. However, isolated cases of both hypoglycemic and hyperglycemic effects have been reported, requiring a change in the dosage of antidiabetic drugs during treatment with diclofenac. Such conditions require monitoring of blood glucose levels, which is a precautionary measure during concomitant therapy.
Colestipol and cholestyramine. The simultaneous use of diclofenac and colestipol or cholestyramine reduces the absorption of diclofenac by approximately 30 and 60%, respectively. The drugs should be taken with an interval of several hours.
Drugs that induce drug-metabolizing enzymes. Drugs that induce enzymes, such as rifampicin, carbamazepine, phenytoin, St. John's wort (Hypericum perforatum), etc., are theoretically capable of reducing diclofenac plasma concentrations.
Methotrexate: Caution is advised when NSAIDs are administered less than 24 hours before or after methotrexate treatment, as blood concentrations of methotrexate may increase and toxicity of this substance may increase.
Cyclosporine and tacrolimus. Diclofenac, like other NSAIDs, may increase the nephrotoxicity of cyclosporine through its effects on renal prostaglandins. This risk is increased in patients treated with tacrolimus. Therefore, it should be used in lower doses than in patients not receiving cyclosporine.
Quinolone antibacterials: There are isolated reports of seizures that may result from the concomitant use of quinolones and NSAIDs.
Incompatibility. As a rule, Rapten 75, solution for injection cannot be mixed with other solutions for injection.
Infusion solutions of sodium chloride 0.9% or glucose 5% without sodium bicarbonate as an additive pose a risk of supersaturation, which may lead to the formation of crystals or precipitate. Other infusion solutions should not be used.
Overdose
Symptoms. There is no typical clinical picture of the consequences of diclofenac overdose. Overdose may cause symptoms such as vomiting, gastrointestinal bleeding, diarrhea, dizziness, tinnitus or convulsions. In case of severe poisoning, acute respiratory distress syndrome and liver damage are possible.
Treatment. Treatment of acute NSAID poisoning consists primarily of supportive measures and symptomatic treatment. Supportive measures and symptomatic treatment are necessary to eliminate complications such as hypotension, renal failure, seizures, gastrointestinal disorders and respiratory depression.
Special measures such as forced diuresis, dialysis or hemoperfusion cannot guarantee the elimination of NSAIDs due to their high binding to plasma proteins and intensive metabolism.
Storage conditions
Tablets: at a temperature not exceeding 25 °C in the original packaging (to protect from light and moisture).
Solution: at a temperature not exceeding 25 °C.
