Pharmacological properties
Pharmacodynamics: In 15 clinical trials in which diclofenac was administered rectally for the treatment of postoperative pain in children aged ≈8 years, the use of rescue medications (especially opiates) was reduced (only for the 25 mg suppositories).
Voltaren contains diclofenac sodium, a nonsteroidal substance with a pronounced analgesic and anti-inflammatory effect. It is an inhibitor of prostaglandin synthetase (COX).
Only for 25 mg suppositories. Experience with diclofenac in clinical trials in pediatric patients with juvenile rheumatoid arthritis (JRA)/juvenile idiopathic arthritis (JIA) is limited. In a randomized, double-blind, 2-week, parallel-group study in children aged 3-15 years with JRA/JIA, the efficacy and safety of diclofenac at a dose of 2-3 mg/kg body weight per day were compared with those of acetylsalicylic acid (ASA 50-100 mg/kg/day) and placebo (15 patients in each group). Overall, an improvement in the patients' condition was observed (11 out of 15 patients in the diclofenac group, 6 out of 12 patients in the ASA group and 4 out of 15 patients in the placebo group) with a statistically significant difference (p<0.05). The number of tender joints decreased with diclofenac and ASA, but increased with placebo. In another randomized, double-blind, parallel-group, 6-week study in children aged 4-15 years with JRA/JIA, the efficacy of diclofenac (daily dose 2-3 mg/kg body weight, n = 22) was comparable to that of indomethacin (daily dose 2-3 mg/kg body weight, n = 23).
Pharmacokinetics: Limited kinetic data are available in 6 children aged 6-16 years with juvenile chronic arthritis who received diclofenac once daily for 2 weeks. After correction for a body weight of 75 kg, the kinetic parameters were similar to those in adults (only for the 25 mg suppositories).
Absorption is rapid, but slower than with enteric-coated tablets. After administration of Voltaren suppositories at a dose of 50 mg, Cmax plasma concentration is reached after 1 hour, but Cmax per dose unit is about ⅔ of the blood concentration after administration of enteric-coated tablets (1.95 ± 0.8 μg/ml (1.9 μg/ml = 5.9 μmol/l)).
Bioavailability. As with oral dosage forms, AUC is approximately half that obtained with parenteral dosing. Pharmacokinetics do not change after multiple doses. No accumulation of the drug is observed at recommended dosing intervals. Plasma concentrations in children given equivalent doses (mg/kg body weight) are similar to those observed in adults (25 mg suppositories only).
Distribution. The binding of diclofenac to plasma proteins is 99.7%, mainly to albumin - 99.4%.
Diclofenac penetrates into the synovial fluid, where its C max is reached 2-4 hours later than in blood plasma. The apparent T ½ from the synovial fluid is 3-6 hours. 2 hours after reaching C max in blood plasma, the concentration of diclofenac in the synovial fluid remains higher than in blood plasma; this phenomenon is observed for 12 hours.
Diclofenac was detected in low concentrations (100 ng/ml) in the breast milk of one lactating woman. The estimated amount of drug that reaches the infant in breast milk is equivalent to a dose of 0.03 mg/kg/day.
Metabolism: 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.
Elimination. The total systemic clearance of diclofenac from plasma is 263 ± 56 ml/min (mean ± standard deviation). The terminal T½ from plasma is 1-2 h. The T½ from plasma of four metabolites, including two pharmacologically active ones, is also short and is 1-3 h. About 60% of the dose 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. 1% of diclofenac is excreted unchanged. The remainder of the administered dose is excreted as metabolites in the feces.
Pharmacokinetics in individual patient groups. The effect of the patient's age on the absorption, metabolism and excretion of the drug was not observed, except for the fact that in 5 elderly patients a 15-minute intravenous infusion led to a 50% increase in the concentration of the drug in the blood plasma than expected in healthy young volunteers.
Patients with impaired liver function. In patients with chronic hepatitis or compensated cirrhosis, the pharmacokinetics and metabolism of diclofenac are similar to those in patients without liver disease.
Indication
Inflammatory and degenerative forms of rheumatism: rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, including spondyloarthritis; pain syndrome from the spine; rheumatic diseases of extra-articular soft tissues; post-traumatic and postoperative pain syndrome, accompanied by inflammation and edema, especially after dental and orthopedic operations; gynecological diseases, accompanied by pain syndrome and inflammation, such as primary dysmenorrhea and adnexitis; migraine attacks; acute gout attack; as an adjuvant in severe inflammatory diseases of the ENT organs, accompanied by pain, such as pharyngotonsillitis, otitis.
According to general therapeutic principles, the underlying disease should be treated with basic therapy. Fever in itself is not an indication for the use of the drug.
Application
To minimize side effects, the minimum effective dose should be used for the shortest period of time.
Do not take orally, for rectal administration only.
Suppositories should be inserted into the rectum as deeply as possible, preferably after bowel cleansing.
The initial dose is usually 100-150 mg/day. For mild symptoms and long-term therapy, a dose of 75-100 mg/day is sufficient.
The daily dose is divided into 2-3 doses. To avoid night pain or morning stiffness, Voltaren is prescribed in the form of rectal suppositories before bedtime (the daily dose of the drug should not exceed 150 mg).
In primary dysmenorrhea, the daily dose is selected individually, usually it is 50-150 mg/day. The initial dose may be 50-100 mg/day, but if necessary it can be increased over several menstrual cycles to the maximum, which is 200 mg/day. The drug should be started after the first pain symptoms appear and continued for several days, depending on the dynamics of symptom regression.
For the treatment of migraine attacks, the course is started at a dose of 100 mg at the first signs of the onset of the attack. If necessary, a second suppository (100 mg of diclofenac) can be used on the same day. If necessary, the treatment can be continued in the following days (the daily dose of the drug should not exceed 150 mg, the dose is divided into 2-3 doses).
Children (aged 1 year - 14 years) with juvenile chronic arthritis: 1-3 mg/kg/day in several doses (only for 25 mg suppositories).
Children (ages 6-14) with acute postoperative pain: 1-2 mg/kg/day in divided doses. Duration of use for acute postoperative pain should be limited to 4 days (25 mg suppositories only).
For example, for a child weighing 30 kg, the daily dose may be from 30 to 60 mg. Based on this range, the child may be prescribed 1 suppository of 25 mg 2 times a day.
Children aged 14 and over can be prescribed 50 mg suppositories.
Elderly patients: Although the pharmacokinetics of Voltaren are not altered to any clinically significant extent in the elderly, NSAIDs should be used with caution in such patients, as they are generally more susceptible to adverse effects. In particular, it is recommended that the drug be used in low effective doses in debilitated elderly patients or in those with insufficient body weight; patients should also be monitored for gastrointestinal bleeding when treated with NSAIDs.
Contraindication
Hypersensitivity to the active substance or to any of the excipients; history of gastrointestinal bleeding or perforation related to previous NSAID use; active peptic ulcer/bleeding or history of recurrent peptic ulcer/bleeding (≥2 separate episodes of established ulceration or bleeding); third trimester of pregnancy; inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis); hepatic insufficiency; renal insufficiency; severe heart failure (stages III-IV); treatment of postoperative pain after coronary artery bypass grafting (or use of a cardiopulmonary bypass machine).
Voltaren, like other nonsteroidal anti-inflammatory drugs, is contraindicated in patients who develop attacks of bronchial asthma, urticaria, angioedema or acute rhinitis in response to taking ASA or other nonsteroidal anti-inflammatory drugs; proctitis.
Side effects
The frequency category of adverse reactions, starting with the most frequent, is defined as follows: very common (≥1/10); common (≥1/100, 1/10); uncommon (≥1/1000, 1/100); rare (≥1/10,000, 1/1000); very rare (1/10,000); frequency unknown (cannot be estimated from the available data).
From the blood and lymphatic system: very rarely - thrombocytopenia, leukopenia, anemia (hemolytic anemia, aplastic anemia), agranulocytosis.
Immune system disorders: Rare: hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock); very rare: angioedema (including facial swelling).
From the nervous system: often - headache, dizziness; rarely - drowsiness, fatigue; 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 organ 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 impairment.
From the cardiovascular system: very rarely - palpitations, chest pain, heart failure, myocardial infarction, hypertension, arterial hypotension, vasculitis.
Respiratory, thoracic and mediastinal disorders: rarely - asthma (including dyspnea); very rarely - pneumonitis.
From the digestive system: often - nausea, vomiting, diarrhea, dyspepsia, abdominal pain, flatulence, anorexia; rarely - gastritis, gastrointestinal bleeding, hematemesis, melena, hemorrhagic diarrhea, gastric and intestinal ulcers, with or without bleeding or perforation (sometimes fatal, especially in the elderly); very rarely - colitis (including hemorrhagic colitis and exacerbation of ulcerative colitis or Crohn's disease), constipation, stomatitis (including ulcerative stomatitis), glossitis, impaired esophageal function, diaphragmatic stenosis of the intestine, pancreatitis.
On the part of the liver: sometimes - increased transaminase levels; rarely - hepatitis, jaundice, impaired liver function; very rarely - fulminant hepatitis, liver necrosis, liver failure.
Skin and subcutaneous tissue disorders: often - rash; rarely - urticaria; very rarely - bullous rash, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, Lyell's syndrome (toxic epidermal necrolysis), exfoliative dermatitis, hair loss, photosensitivity, 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 and administration site conditions: rarely - irritation at the injection site, swelling.
From the reproductive system and mammary glands: very rarely - impotence.
Clinical studies and epidemiological data suggest that diclofenac, especially at high doses (150 mg/day) and with long-term use, may slightly increase the risk of arterial thromboembolism (e.g. myocardial infarction or stroke).
Special instructions
General: To minimize side effects, the lowest effective dose should be used for the shortest possible period of time.
The concomitant use of Voltaren with systemic NSAIDs such as selective COX-2 inhibitors should be avoided due to the lack of any evidence of a synergistic effect and due to the potential for additive side effects. Caution is required in elderly patients. In particular, it is recommended to use the lowest effective dose in frail elderly patients with low body weight.
In rare cases, as with other non-steroidal anti-inflammatory drugs, allergic reactions, including anaphylactic/anaphylactoid reactions, may occur, even without prior exposure to diclofenac.
Due to its pharmacodynamic properties, Voltaren, like other NSAIDs, may mask the signs and symptoms of infection.
Gastrointestinal effects: Gastrointestinal bleeding (hemorrhage, melena), ulceration or perforation, which can be fatal, have been reported with all NSAIDs, including diclofenac, and may 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, medical supervision and special caution are required in patients with symptoms suggestive of gastrointestinal disorders. The risk of gastrointestinal bleeding, ulceration or perforation increases with increasing dose of NSAIDs, including diclofenac, and in patients with a history of ulcer, especially complicated by bleeding or perforation, and in the elderly.
For such patients, as well as those requiring concomitant use of low-dose ASA-containing medicinal products (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. acetylsalicylic acid) or selective serotonin reuptake inhibitors.
Hepatic effects: Close medical supervision is necessary when Voltaren is prescribed to patients with impaired liver function, as their condition may worsen. As with other non-steroidal anti-inflammatory drugs, including diclofenac, the level of one or more liver enzymes may increase.
During long-term treatment with Voltaren, regular monitoring of liver function is prescribed 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 are observed (e.g. eosinophilia, rash), Voltaren should be discontinued. Diseases such as hepatitis may occur without prodromal symptoms. Caution is required when Voltaren is used in patients with hepatic porphyria, as it may precipitate an attack.
Renal effects: Since fluid retention and oedema have been reported with NSAIDs, including diclofenac, special care should be taken in 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 of which were fatal) have been reported very rarely with NSAIDs, including Voltaren, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis. 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. Voltaren should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.
Systemic lupus erythematosus (SLE) and mixed connective tissue diseases: Patients with SLE and mixed connective tissue diseases may be at increased risk of developing aseptic meningitis.
Cardiovascular and cerebrovascular effects. Appropriate monitoring and advice should be given to 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. Clinical trial and epidemiological data suggest that the use of diclofenac, particularly at high doses (150 mg/day) and in long-term treatment, may be associated with a small increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke).
Patients with uncontrolled hypertension, mild to moderate congestive heart failure, stable coronary artery disease, peripheral arterial disease and/or cerebrovascular disease should be treated with diclofenac only after careful evaluation. A similar evaluation should be performed before initiating long-term treatment in patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidemia, diabetes mellitus and patients who smoke).
Effect on hematological parameters. With prolonged use of this drug, as with other NSAIDs, monitoring of complete blood counts is recommended.
History of asthma. Patients with asthma, seasonal allergic rhinitis, nasal mucosal edema (i.e. nasal polyps), COPD or chronic respiratory 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, 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, urticaria.
Like other drugs that inhibit prostaglandin synthetase activity, diclofenac sodium and other nonsteroidal anti-inflammatory drugs can provoke the development of bronchospasm when used in patients with bronchial asthma or patients with a history of bronchial asthma.
Use during pregnancy and breastfeeding. Pregnancy. In the I and II trimesters of pregnancy, Voltaren can be prescribed only when the expected benefit to the mother outweighs the potential risk to the fetus, and only in the minimum effective dose, the duration of treatment should be as short as possible. As with other nonsteroidal anti-inflammatory drugs, the drug is contraindicated in the last trimester of pregnancy (possible inhibition of uterine contractility and premature closure of the ductus arteriosus in the fetus).
Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryo/foetal development. Epidemiological studies have shown an increased risk of miscarriage and/or heart defects and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk of cardiovascular defects was increased from 1% to ≈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 increase 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, has been reported. If Voltaren is used by a woman planning a pregnancy, 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.
In the third trimester of pregnancy, all prostaglandin synthesis inhibitors can 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.
Effects 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 a delay or increase in the period of labor.
Therefore, Voltaren is contraindicated in the third trimester of pregnancy.
Breastfeeding. Like other non-steroidal anti-inflammatory drugs, diclofenac passes into breast milk in small amounts. In this regard, Voltaren suppositories should not be used by women during breastfeeding in order to avoid undesirable effects on the infant.
Female fertility. Like other nonsteroidal anti-inflammatory drugs, Voltaren may have a negative effect on female fertility and is therefore not recommended for use in women attempting to conceive. For women who have difficulty conceiving or are undergoing investigation of infertility, discontinuation of Voltaren should be considered.
Children. Voltaren is not prescribed to children under 1 year of age. Children aged 1-14 years with juvenile chronic arthritis are prescribed suppositories only in a dose of 25 mg. Children aged 6-14 years with acute postoperative pain are prescribed suppositories only in a dose of 25 mg. Adolescents aged 14 and older can be prescribed suppositories of 50 mg. Voltaren suppositories in a dose of 100 mg are not used to treat children and adolescents due to the high content of the active substance.
Ability to influence the reaction rate when driving vehicles or operating machinery. Patients who experience visual disturbances, dizziness, vertigo, drowsiness, CNS disorders, lethargy or fatigue during therapy with Voltaren should not drive vehicles or operate other machinery.
Interactions
Interactions observed with the use of diclofenac in the form of enteric-coated tablets and/or in other dosage forms have been noted.
Lithium: Diclofenac may increase plasma lithium concentrations when used concomitantly. Monitoring of plasma lithium levels is recommended.
Diuretics and antihypertensives. As with other NSAIDs, concomitant use of diclofenac with diuretics and antihypertensives (e.g. β-blockers, ACE inhibitors) may lead to a reduction in their antihypertensive effect due to inhibition of 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, ciclosporin, tacrolimus or trimethoprim may be associated with increases in plasma potassium levels, therefore patients should be monitored more frequently.
Anticoagulants and antithrombotic agents. Concomitant use may increase the risk of bleeding, therefore caution is advised. Although clinical studies 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 these drugs in combination. Therefore, careful monitoring of such patients is recommended to ensure that no changes in the dosage of anticoagulants are necessary. As with other non-steroidal anti-inflammatory drugs, diclofenac in high doses may temporarily inhibit platelet aggregation.
Other NSAIDs, including selective COX-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 ≥2 NSAIDs should be avoided.
Selective serotonin reuptake inhibitors (SSRIs): Concomitant use of NSAIDs and SSRIs may increase the risk of gastrointestinal bleeding.
Antidiabetic drugs. Clinical studies have shown that diclofenac can be used together with oral antidiabetic drugs without changing their therapeutic effect. However, there are some reports of the development in such cases of both hypoglycemia and hyperglycemia, which necessitated the need to change the dose of antidiabetic drugs when using diclofenac. For this reason, it is recommended to monitor blood glucose levels during combination therapy.
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 within 24 hours of methotrexate administration, 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: The use of NSAIDs with tacrolimus may increase the risk of nephrotoxicity, which may be mediated through the renal antiprostaglandin effects of the NSAID and the calcineurin inhibitor.
Quinolone antibacterials. There are isolated reports of seizures in patients receiving 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 quinolones in patients already receiving NSAIDs.
Phenytoin: When using phenytoin simultaneously with diclofenac, it is recommended to monitor the concentration of phenytoin in the blood plasma due to the expected increase in the exposure of phenytoin.
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 in patients may exacerbate heart failure, reduce glomerular filtration rate, 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 recommended when using diclofenac with potent CYP2C9 inhibitors (e.g. voriconazole), which may lead to a significant increase in plasma Cmax and exapposition of diclofenac due to inhibition of diclofenac metabolism.
Symptoms. There is no typical clinical picture characteristic 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 forms of the disease.
Treatment. If necessary, symptomatic treatment. 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.
Storage conditions
At a temperature not exceeding 30 °C.
