Description of the drug VOLTAREN® for systemic use
The dose is selected individually; it is recommended to use the drug in the minimum effective dose, with the shortest possible treatment period.
For oral and rectal use
Adults
When taken orally in the form of tablets of regular duration or rectally in the form of suppositories, the recommended initial dose is 100-150 mg/day. In relatively mild cases of the disease, as well as for long-term therapy, 75-100 mg/day is sufficient. The daily dose should be divided into several doses.
When taken in the form of extended-release tablets, the recommended initial dose is 100 mg 1 time / day. The same daily dose is used for moderately severe symptoms, as well as for long-term therapy. In cases where the symptoms of the disease are most pronounced at night or in the morning, it is advisable to take extended-release tablets at night.
To relieve night pain or morning stiffness
in addition to taking the drug during the day, diclofenac is prescribed in the form of rectal suppositories before bedtime; in this case, the total daily dose should not exceed 150 mg.
With primary dysmenorrhea
the daily dose is selected individually; usually it is 50-150 mg. The initial dose should be 50-100 mg; if necessary, over several menstrual cycles it can be increased to 150 mg/day. The drug should be started when the first symptoms appear. Depending on the dynamics of clinical symptoms, treatment can be continued for several days.
In elderly patients (65 years and older)
no adjustment of the initial dose is required.
In weakened patients, patients with low body weight
It is recommended to adhere to the minimum dose.
The drug should be used with particular caution in patients with diseases of the cardiovascular system (including uncontrolled arterial hypertension) or a high risk of developing cardiovascular diseases
. If long-term therapy (more than 4 weeks) is necessary in such patients, the drug should be used in a daily dose not exceeding 100 mg.
Children aged 1 year and older
The drug is prescribed in a dose of 0.5-2 mg/kg body weight/day (in 2-3 doses, depending on the severity of the disease). For the treatment of rheumatoid arthritis
the daily dose can be maximally increased to 3 mg/kg (in several doses). The maximum daily dose is 150 mg.
The drug in the form of extended-release tablets should not be used in children and adolescents under the age of 18 years.
For parenteral use
Adults
Injected deep into the / m. Single dose - 75 mg. If necessary, repeated administration is possible, but not earlier than after 12 hours.
Duration of use is no more than 2 days, if necessary, then switch to oral or rectal use of diclofenac.
In severe cases (for example, with colic), as an exception, 2 injections of 75 mg each can be given, with an interval of several hours (the second injection should be carried out in the opposite gluteal region). Alternatively, IM administration once a day (75 mg) can be combined with diclofenac in other dosage forms (tablets, rectal suppositories), and the total daily dose should not exceed 150 mg.
For migraine attacks
Diclofenac is recommended to be administered as early as possible after the onset of an attack, IM at a dose of 75 mg, followed by the use of suppositories at a dose of up to 100 mg on the same day, if required. The total daily dose should not exceed 175 mg on the first day.
In elderly patients (65 years and older)
no adjustment of the initial dose is required. In weakened patients and patients with low body weight, it is recommended to adhere to the minimum dose.
The drug should be used with particular caution in patients with diseases of the cardiovascular system (including uncontrolled arterial hypertension) or a high risk of developing cardiovascular diseases
. If long-term therapy (more than 4 weeks) is necessary in such patients, the drug should be used in a daily dose not exceeding 100 mg.
Children and teenagers under 18 years of age
Diclofenac should not be used intramuscularly in children and adolescents under 18 years of age due to the difficulty of dosing the drug.
Voltaren retard tablets p/o prolonged action 75 mg No. 10x2
Name
Voltaren retard.
Release forms
Pills.
INN
Diclofenac
FTG
Npvp.
Compound
active ingredient: diclofenac sodium; Each tablet contains diclofenac sodium 75 mg; excipients: tablet core - magnesium stearate, anhydrous colloidal silicon dioxide, povidone, cetyl alcohol, sucrose; tablet coating - hypromellose, red iron oxide (E 172), polysorbate 80, talc, titanium dioxide (E 171), macrogol 8000, sucrose, black ink (shellac, isopropyl alcohol, black iron oxide E172, butyl alcohol, propylene glycol, ammonium hydroxide ).
Pharmacotherapeutic group
Nonsteroidal anti-inflammatory and antirheumatic drugs. Derivatives of acetic acid. ATS code M01A B05. Clinical characteristics
Indications for use
Inflammatory and degenerative rheumatic diseases: rheumatoid arthritis, ankylosing spondylitis; arthrosis; extra-articular rheumatism. Pain and inflammation of non-rheumatic or post-traumatic origin. Symptomatic treatment of primary dysmenorrhea.
Contraindications
Known hypersensitivity to the active substance or other components of the drug, to other analgesics, antipyretics, non-steroidal anti-inflammatory drugs (NSAIDs) and, in particular, to acetylsalicylic acid; Active stomach or intestinal ulcer, bleeding or perforation. Inflammatory bowel diseases (such as Crohn's disease or ulcerative colitis); Last trimester of pregnancy; Liver failure; Renal failure (GFR
Directions for use and doses
The tablets should be taken whole, without chewing or breaking, with liquid, preferably with meals. The dose should be selected individually. Side effects can be minimized by using the lowest effective dose for the minimum period necessary to control symptoms (see Precautions). The recommended initial dose of the drug for adults is 75 - 150 mg per day (1-2 tablets of Voltaren Retard 75 mg), depending on the severity of the symptoms of the disease. For long-term therapy, as a rule, the use of 1 tablet of Voltaren Retard 75 mg per day is sufficient. If the symptoms of the disease are most pronounced at night or in the morning, Voltaren Retard should be taken in the evening. Use in special groups of patients. Children (under 18 years of age) Voltaren retard tablets, film-coated, prolonged action 75 mg are not recommended for use in children due to the high content of the active substance. Elderly patients (65 years and older). For elderly patients, no adjustment of the starting dose is usually required. However, based on generally accepted approaches, caution is required when prescribing the drug, especially in weakened or low-weight elderly patients. Patients with congestive heart failure (NYHA-I) or significant cardiovascular risk factors In patients with congestive heart failure (NYHA-I) or uncontrolled hypertension, therapy with Voltaren is generally not recommended. If necessary, the drug is prescribed to patients with cardiovascular diseases or with significant risk factors for their development only after a thorough assessment, and for a duration of therapy of more than 4 weeks - only in doses
Side effects
Adverse reactions to the drug, depending on the frequency, are described in the following order: very often (> 1/10); often (> 1/100, 1/1000, 1/10000,
Overdose
There is no typical clinical picture of diclofenac overdose. Symptoms of a diclofenac overdose may include vomiting, gastrointestinal bleeding, diarrhea, dizziness, tinnitus, and convulsions. In case of significant poisoning, acute renal failure and liver damage are possible. Treatment of acute NSAID poisoning consists of the use of supportive and symptomatic therapy. Supportive and symptomatic treatment is indicated for complications such as hypotension, renal failure, seizures, gastrointestinal disorders and respiratory depression. It is unlikely that specific therapeutic measures such as forced diuresis, dialysis or hemoperfusion will be useful for the elimination of NSAIDs, since the active substances of these drugs are largely bound to blood proteins and undergo intensive metabolism. Activated charcoal may be used after a potentially toxic overdose, as well as gastric decontamination (eg, vomiting, gastric lavage) after a potentially life-threatening overdose. Women of childbearing age, pregnancy, breastfeeding, fertility There are no data to support any recommendations for women of childbearing age. Suppression of prostaglandin synthesis can adversely affect the course of pregnancy and intrauterine development of the fetus. Epidemiological studies suggest an increased risk of miscarriage and/or fetal heart defects and gastroschisis after taking prostaglandin synthesis inhibitors in early pregnancy, but aggregated data are inconclusive. The absolute risk of cardiovascular defects increased from less than 1% to 1.5%. The risk is believed to increase with increasing dose and duration of therapy. It has been shown that in animals, the administration of prostaglandin synthesis inhibitors leads to disruption of embryo implantation. In addition, in animals receiving a prostaglandin synthesis inhibitor during the period of organogenesis, the incidence of various malformations, including developmental disorders of the cardiovascular system, increased. The use of diclofenac in pregnant women has not been studied. Therefore, Voltaren Retard should not be prescribed during the first two trimesters of pregnancy, unless the benefits of its use outweigh the risks to the fetus. As with other NSAIDs, use of the drug during the third trimester of pregnancy is contraindicated. When taking prostaglandin synthesis inhibitors in the third trimester of pregnancy, the fetus may experience: premature closure of the ductus arteriosus and pulmonary hypertension, renal dysfunction, with the progression of which renal failure with oligohydroamnion develops. When taking diclofenac at the end of pregnancy, labor weakness may develop and the duration of labor may increase. In the mother and in the fetus/newborn, bleeding time may be prolonged; the antiplatelet effect may occur even after taking very low doses of diclofenac. Thus, diclofenac is contraindicated in the third trimester of pregnancy. Like other NSAIDs, diclofenac is excreted in small quantities into breast milk. Thus, Voltaren Retard should not be used during breastfeeding in order to prevent unwanted reactions in the child. Like other NSAIDs, Voltaren Retard can adversely affect female fertility, so it is not recommended to prescribe the drug to women planning a pregnancy. In women who have difficulty conceiving or are undergoing examination for infertility, the advisability of discontinuing the drug should be considered.
Children
Voltaren Retard is not recommended for the treatment of children aged 14-18 years due to the high content of the active substance in the tablet. The drug is contraindicated in children under 14 years of age. Precautions Gastrointestinal effects With all NSAIDs, gastrointestinal bleeding, ulceration and perforation are possible, which can be fatal and occur during treatment with or without a history of warning symptoms or serious gastrointestinal disorders. In general, such phenomena are most dangerous for elderly patients. In isolated cases, when patients taking Voltaren Retard develop these complications, treatment with this drug should be discontinued. While taking the drug Voltaren Retard, medical supervision is necessary for patients who have diseases of the gastrointestinal tract or a history of gastric or intestinal ulcers, ulcerative colitis or Crohn's disease. The risk of gastrointestinal bleeding increases with increasing doses of NSAIDs and in patients with a history of ulcers, especially if the ulcer was complicated by bleeding or perforation or occurred in the elderly. To reduce the risk of toxic effects on the gastrointestinal tract in patients with a history of peptic ulcer, in particular, complicated by bleeding and perforation, as well as in elderly patients, treatment should be started with the lowest effective dose and maintained thereafter. In the above patients and patients requiring concomitant use of low doses of acetylsalicylic acid or other drugs that may increase the risk of developing adverse reactions from the gastrointestinal tract, combination therapy in combination with protective drugs (for example, proton pump inhibitors or misoprostol) should be considered. . Caution is advised in patients receiving concomitant therapy with systemic corticosteroids, anticoagulants, antiplatelet agents, or selective serotonin reuptake inhibitors. Cardiovascular Effects: Clinical studies and epidemiological data strongly suggest an increased risk of arterial thrombotic events (eg, myocardial infarction or stroke) that may be associated with the use of diclofenac, particularly when used in high doses (150 mg daily) and with long-term use. In patients with significant risk factors for cardiovascular complications (eg, hypertension, hyperlipidemia, diabetes mellitus, smoking), diclofenac should be prescribed only after careful consideration of this possibility. Due to the possible increased risk of cardiovascular events with long-term use or high doses of the drug, patients should be prescribed diclofenac at the minimum effective dose and take it for the shortest time necessary to reduce the severity of symptoms. The need for symptom relief and response to treatment should be periodically re-evaluated. In patients with congestive heart failure (NYHA-I) or significant risk factors for cardiovascular events (eg, hypertension, hyperlipidemia, diabetes mellitus, smoking), diclofenac should be used only after careful evaluation, and if the duration of therapy is more than 4 weeks - only in doses
Impact on the ability to drive vehicles and operate machinery
Patients who experience dizziness or other unpleasant sensations from the central nervous system, including visual disturbances, while taking Voltaren Retard, are not recommended to drive a car or operate machinery.
Interaction with other drugs
Caution is recommended when co-administering Voltaren Retard with CYP2C9 inhibitors (such as voriconazole), which may lead to a significant increase in peak plasma concentrations and exposure of diclofenac. Voltaren Retard may increase plasma concentrations of lithium and digoxin. It is recommended to monitor serum lithium and digoxin levels. Voltaren Retard, like other NSAIDs, may inhibit the activity of diuretics or antihypertensive drugs (for example, beta blockers, angiotensin-converting enzyme (ACE) inhibitors). Therefore, the combination should be used with caution and the blood pressure of patients, especially the elderly, should be monitored periodically. Patients should receive adequate fluid intake, and monitoring of renal function is recommended upon initiation of concomitant therapy and on a regular basis thereafter, especially when using diuretics and ACE inhibitors due to the increased risk of nephrotoxicity. Concomitant use of potassium-sparing diuretics, cyclosporine, tacrolimus or trimethoprim may lead to an increase in serum potassium levels (this indicator should be regularly monitored). Concomitant use with other systemic NSAIDs or corticosteroids may increase the incidence of adverse reactions of Voltaren Retard from the gastrointestinal tract. Concomitant use of systemic NSAIDs and SSRIs may increase the risk of bleeding in the digestive tract. Although clinical studies have not established the effect of Voltaren Retard on the action of anticoagulants, there are isolated reports of an increased risk of bleeding in patients taking Voltaren Retard and anticoagulants simultaneously. Therefore, close monitoring of such patients is recommended. Clinical studies have shown that Voltaren Retard can be used in conjunction with oral antidiabetic agents and does not change their therapeutic effect. However, there are isolated reports of the development in such cases of both hypoglycemia and hyperglycemia, which led to changes in the dose of glucose-lowering drugs during the use of Voltaren Retard. For this reason, monitoring of blood glucose levels is recommended as a precaution during concomitant therapy. Caution should be exercised when prescribing NSAIDs less than 24 hours before or after taking methotrexate, as in such cases the concentration of methotrexate in the blood may increase and its toxic effect may increase. The effect of NSAIDs, including Voltaren Retard, on the synthesis of prostaglandins in the kidneys may enhance the nephrotoxicity of cyclosporine. In this regard, Voltaren Retard should be used in lower doses than in patients who do not receive cyclosporine. When using phenytoin together with Voltaren Retard, it is recommended to monitor the concentration of phenytoin in the blood plasma due to a possible increase in phenytoin exposure. Colestipol and cholestyramine may delay or reduce the absorption of diclofenac. It is recommended to take diclofenac at least one hour before or 4-6 hours after colestipol/cholestyramine. There are isolated reports of the development of seizures in patients receiving concomitant quinolone derivatives and NSAIDs.
Pharmacological properties
Pharmacodynamics. Diclofenac, the active substance of Voltaren Retard, is a non-steroidal compound with pronounced antirheumatic, anti-inflammatory, analgesic and antipyretic effects. The main mechanism of action of diclofenac, established under experimental conditions, is considered to be inhibition of prostaglandin biosynthesis. Prostaglandins play an important role in the genesis of inflammation, pain and fever. In vitro, diclofenac sodium in concentrations equivalent to those achieved in the treatment of patients does not suppress the biosynthesis of proteoglycans in cartilage tissue. Voltaren Retard is suitable for patients in whom a daily dose of 75 mg is appropriate, taking into account the clinical picture. The ability to prescribe a drug that allows for a single dose of the entire daily dose greatly simplifies long-term treatment and helps avoid possible dosage errors. Voltaren Retard allows the use of a maximum daily dose of 150 mg in a balanced regimen twice a day. In rheumatic diseases, the anti-inflammatory and analgesic properties of Voltaren Retard provide a significant reduction in the severity of pain (both at rest and during movement), morning stiffness, swelling of the joints and, thus, improving the functional state of the patient. In the presence of inflammation caused by injury or surgery, Voltaren Retard quickly eliminates both spontaneous pain and pain during movement, and also reduces inflammatory tissue swelling and swelling at the site of the surgical wound. In clinical studies, it was found that Voltaren Retard also exhibits a strong analgesic effect in moderate and severe pain of non-rheumatic origin. Pharmacokinetics. Analysis of unchanged diclofenac and its hydroxylated metabolites excreted in urine showed that the amount of diclofenac released and absorbed was the same as when taking an equivalent dose of diclofenac sodium in the form of enteric-coated tablets. However, the systemic bioavailability of diclofenac (released from Voltaren Retard) is, on average, 82% of that after oral administration of Voltaren enteric tablets at the same dose. Due to the prolonged release of the active substance from Voltaren Retard, the maximum drug concentrations achieved in plasma are lower than after taking enteric-coated tablets. The average peak concentration of 0.4 mcg/ml or 0.5 mcg/ml (1.25 or 1.6 μmol/L) is achieved, on average, 4 hours after taking the 75 mg or 100 mg tablet. Eating does not clinically affect the absorption and systemic bioavailability of Voltaren Retard. On the other hand, a mean plasma concentration of 13 ng/mL (40 nmol/L) may be observed 24 hours (16 hours) after taking Voltaren Retard 75 mg. The amount of absorbed active substance is linearly dependent on the dose of the drug. Since about half of diclofenac is metabolized during the first passage through the liver (“first pass effect”), the area under the concentration/time curve (AUC) after taking Voltaren Retard tablet is almost half that of parenteral administration of an equivalent dose of the drug. After repeated administration of Voltaren Retard, the pharmacokinetics do not change. If the recommended intervals between doses of the drug are observed, no accumulation is observed. The corresponding concentrations are 22 ng/ml or 25 ng/ml (70 nmol/l or 80 nmol/l) when taking Voltaren Retard 75 mg 2 times a day. Pharmacokinetic behavior does not change after repeated use. There is no accumulation provided that the recommended intervals between applications are observed. Distribution. 99.7% of diclofenac is bound to serum proteins, mainly albumin (99.4%). The volume of distribution is 0.12-0.17 l/kg. Diclofenac penetrates into the synovial fluid, where its maximum concentration is reached 2-4 hours later than in plasma. The apparent half-life from synovial fluid is 3-6 hours. 2 hours after reaching maximum plasma concentrations, the concentration of the active substance in the synovial fluid is higher than in the plasma, and remains higher for 12 hours. Diclofenac was detected at low concentrations (100 ng/ml) in the breast milk of one breastfeeding woman. The amount consumed by the infant through breast milk is equivalent to a dose of 0.03 mg/kg/day. Biotransformation. Biotransformation of diclofenac occurs partly through glucuronidation of the unchanged molecule, but mainly through 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′-methoxydiclofenac), most of which are conjugated with glucuronic acid. Two of these phenolic metabolites are pharmacologically active, but to a significantly lesser extent than diclofenac. Excretion. The total systemic plasma clearance of diclofenac is 263 ± 56 ml/min. The terminal half-life in plasma is 1-2 hours. The half-life of 4 metabolites, including 2 pharmacologically active ones, is also short and amounts to 1-3 hours. One of the metabolites, 3′-hydroxy-4′-methoxydiclofenac, has a longer half-life. However, this metabolite is completely inactive pharmacologically. About 60% of the applied dose of the drug is excreted in the urine in the form of glucuronic conjugates of the intact molecule of the active substance, as well as in the form of metabolites, most of which are also converted into glucuronic conjugates. Less than 1% of diclofenac is excreted unchanged. The remainder of the applied dose of the drug is excreted in the form of metabolites through bile and feces. Linearity. The amount absorbed is linearly related to the dosage. Special groups of patents. No age-related differences in drug absorption, metabolism or excretion were identified. However, in several elderly patients, a 15-minute intravenous infusion resulted in plasma concentrations 50% higher than expected based on data obtained in young healthy subjects. In patients with impaired renal function, no accumulation of unchanged active substance was detected based on single-dose kinetics data using the usual dosage regimen. When creatinine clearance is less than 10 ml/min, the calculated equilibrium levels of hydroxymetabolites in blood plasma are approximately 4 times higher than in healthy individuals. Metabolites are finally excreted in bile. In patients with chronic hepatitis or uncompensated cirrhosis, the kinetics and metabolism of diclofenac are the same as in patients without liver disease.
Pharmaceutical characteristics
Basic physical and chemical properties: tablets are pale pink, triangular, biconvex, with beveled edges, with the inscription “ID” on one side and “CG” on the other in black ink.
Best before date
3 years. Do not use after the expiration date stated on the package.
Storage conditions
Store at a temperature not exceeding 30°C, in the original packaging to protect from moisture. Keep out of the reach of children.
Package
10 tablets in a blister, 2 blisters in a cardboard box along with an insert.
Conditions for dispensing from pharmacies
On prescription.
Buy Voltaren retard tablet p/o extended d-i 75 mg in blister pack No. 10x2 in the pharmacy
Price for Voltaren retard tablet p/o extended d-i 75 mg in sheets in pack No. 10x2
Instructions for use for Voltaren retard tablet p/o extended d-ya 75 mg in sheets in pack No. 10x2
Voltaren as a standard NSAID in modern rheumatology
The NSAID class includes a large number of drugs that are characterized by common and distinctive features. They differ from each other in the severity of analgesic and anti-inflammatory activity, the range of adverse events, routes of administration of the drug into the body, area of application and category of cyclooxygenase (COX) inhibition - the main mechanism of action of these pharmacological agents. Thus, according to the severity of inhibition of two COX isoforms, they are all divided into drugs with selective inhibition of COX-1, COX-2 non-selective, COX-2 selective and COX-2 specific. The range of adverse events when taking NSAIDs is largely associated with the preferential inhibition of one or another COX isoform. The most studied COX-2 non-selective NSAID is Voltaren (diclofenac sodium), which is most often used compared to other drugs in this group of drugs [2,3]. Despite the significant advances in modern anti-inflammatory therapy for rheumatic diseases, some drugs that were introduced into clinical practice in the 20–30s have not lost their importance. last century and later - in the 60–70s. As is known, gold salts, D-penicillamine and aminoquinoline derivatives were proposed for the treatment of rheumatoid arthritis long before the need for basic or slow-acting therapy for this disease was justified. Later, NSAIDs were developed and became widely used, which are now considered “standard” or “classic”. These drugs include, first of all, Voltaren. The history of Voltaren began in 1964, when the Geigy company synthesized a new NSAID, codenamed GP 45840. Subsequent preclinical studies revealed high therapeutic efficacy and good tolerability of GP 45840, named Voltaren. Since 1974, the widespread introduction of this drug into clinical practice began. Already in 1976, the results of 166 clinical trials in 21 countries were summarized, clearly showing the high effectiveness of Voltaren with relatively rare and mild adverse reactions. In the same year, domestic rheumatologists presented the results of testing Voltaren for rheumatoid arthritis, ankylosing spondylitis, osteoarthritis and rheumatism, noting its fairly high therapeutic potential and quite satisfactory tolerability [4]. Voltaren (diclofenac sodium) is a phenylacetic acid derivative. 95.7% of the drug binds to serum proteins. The peculiarities of its pharmacodynamics include a short half-life, which, in turn, helps reduce the number of undesirable effects due to rapid elimination from the body. The maximum concentration of Voltaren in plasma reaches 1180 ng/ml. In the body, it is transformed into inactive metabolites, which are excreted in urine and bile [5]. It does not accumulate with prolonged use. A positive property of Voltaren is its sufficient full compatibility with a number of drugs. However, it should be borne in mind that when combined with oral anticoagulants, it can lead to prolongation of prothrombin time and an increased risk of bleeding, and with hypoglycemic drugs - to the development of hypo- or hyperglycemia [6]. In some patients, Voltaren increases the toxicity of methotrexate due to prolongation of its half-life, which leads to a decrease in the excretion of methotrexate and endogenous creatinine. However, this phenomenon occurs when prescribing medium and high doses of methotrexate, and when prescribing 7.5–10 mg/week. Impairment of renal excretory function is usually not observed. When Voltaren is taken orally, its absorption occurs in the duodenum, since the tablets are produced with a coating resistant to the action of gastric juice. This coating helps reduce the frequency and severity of gastrointestinal toxicity. After 30 min. after administration, the maximum level of Voltaren in plasma is reached. Adsorption of Voltaren and its distribution in the body do not depend on food intake. There is no significant difference in its content between young and elderly people [5]. All NSAIDs are conventionally divided into short- and long-lived. However, there is no clear relationship between the half-life of the drug and its clinical effectiveness. Short-lived drugs can accumulate in high concentrations at the site of inflammation. In Voltaren, although it is a short-lived drug, the duration of the anti-inflammatory effect exceeds the circulation time in the blood plasma due to its redistribution and accumulation in inflamed tissues. When taken orally, its half-life does not exceed 2 hours and is approximately the same as that of ketoprofen and ibuprofen, while for many other NSAIDs (in particular, indomethacin and ketorolac) this period is 2.5–3 times more. Naturally, medications with a short half-life pose less risk to patients due to their rapid elimination from the body. In synovial fluid, the maximum concentration of Voltaren after a single intramuscular injection appears after 4 hours, and its half-life from joint tissue is 8 hours. Thus, the drug persists significantly longer in the synovium and joint fluid than in plasma, while the concentration in tissues is 4–5 times higher than the concentration in blood [7]. These data are of great importance for the treatment of rheumatic diseases in general and, in particular, joint diseases. The main mechanism of action of Voltaren (diclofenac sodium), like other NSAIDs, is inhibition of cyclooxygenase (COX) activity [8]. This enzyme is involved in the synthesis of prostaglandins, including PGE2. Prostaglandins are of great importance for the development of inflammation, pain and fever (Table 1). As is known, blockade of COX-2 plays a decisive role in the fight against inflammation and pain. One of the powerful COX-2 inhibitors is Voltaren [9,10,11]. It was shown that five days after the start of therapy with Voltaren at a dose of 150 mg/day. blockade of PGE2, by which one can judge the inhibition of COX-2, is 93.9%, while with the use of other NSAIDs (ibuprofen, naproxen, rofecoxib, meloxicam) this figure ranges from 66.7 to 77.0%. Suppression of PGE2 in synovial fluid lasts from 8 to 12 hours after administration of a single dose. Voltaren inhibits the release of intracellular arachidonic acid without affecting the expression of lipoxygenase [11]. The experiment established that it is a potential inhibitor of platelet aggregation. However, in clinical settings, its effect on platelet aggregation and adhesion, as well as on the activation of prothrombin time, has not been revealed [5]. The pharmacological activity of Voltaren is not limited only to the suppression of prostaglandin synthesis. In addition, it inhibits the synthesis of leukotrienes, the formation of superoxide radicals and the release of lysosomal enzymes, affects the activation of cell membranes, the aggregation and adhesion of neutrophils, and the functions of lymphocytes. When choosing an NSAID, the following factors must be taken into account: the severity of the anti-inflammatory and analgesic effect, the presence and nature of risk factors for adverse events, as well as their possible spectrum, the presence of concomitant diseases, the nature of interactions with other drugs and, of course, cost. According to these parameters, Voltaren (diclofenac sodium) has established itself as one of the most acceptable NSAIDs and continues to be considered as the “gold standard” for inflammatory and degenerative diseases of the joints and spine, especially since it is superior to most NSAIDs in its anti-inflammatory and analgesic activity [12 ]. In the treatment of rheumatoid arthritis, Voltaren (diclofenac) is considered the drug of choice. According to a double-blind study that compared Voltaren and indomethacin in patients with rheumatoid arthritis, it turned out that both drugs significantly reduced the number of inflamed joints and increased hand grip strength [13]. However, such a significant indicator of a truly anti-inflammatory effect as the dynamics of the total circumference of the proximal interphalangeal joints reliably underwent reverse dynamics only during treatment with Voltaren. It is believed that anti-inflammatory therapy for rheumatoid arthritis should begin with the prescription of Voltaren, because it has a significant anti-inflammatory effect [14]. In the presence of high activity of the inflammatory process, accompanied by severe pain, it is advisable to prescribe Voltaren in the form of intramuscular injections, which accelerates the onset of the therapeutic effect. Parenteral or rectal administration of the drug significantly reduces the risk of gastroenterological complications, but does not eliminate them completely. Voltaren is no less important in the treatment of ankylosing spondylitis (Bechterew's disease). Symptom-modifying therapy for this disease primarily includes NSAIDs, which are considered first-line drugs and a necessary component of combination therapy for ankylosing spondylitis. Patients with this diagnosis take NSAIDs almost continuously for many months and even years. These drugs are the basis of drug therapy, especially since in case of ankylosing spondylitis, effective basic therapy is limited only to sulfasalazine, which has a positive effect on the manifestations of peripheral arthritis and has virtually no effect on the symptoms of spondylitis. As for NSAIDs, they are effective not only in suppressing the inflammatory process in the joints, but also in the axial skeleton, while they significantly reduce the intensity of pain in the spine and its mobility, as well as the severity and duration of morning rigidity. Phenylbutazone and indomethacin have long been considered as the most effective NSAIDs in the treatment of ankylosing spondylitis. However, this point of view is not obvious. In controlled double-blind studies, diclofenac showed the same effectiveness as these drugs, with better tolerability of the latter. In another randomized controlled trial of piroxicam, naproxen, and Voltaren at equivalent doses, they were found to have approximately the same symptom-modifying effect. However, when assessing adverse events, the majority of patients preferred Voltaren [15]. The possibility of an active influence of NSAIDs on the prognosis of ankylosing spondylitis requires clarification. For a long time it was generally accepted that they have only a symptomatic effect in this disease, without controlling the progression of structural changes in the spine, including those patients who have a clear clinical (anti-inflammatory) effect. However, there have been recent reports implicating NSAIDs as agents that may reduce the rate of radiographic progression of ankylosing spondylitis. In this regard, they can be considered as disease-modifying agents [16]. The clear positive effect of NSAIDs on the symptoms of spondylitis during the first 48 hours after their administration is considered as one of the diagnostic criteria for ankylosing spondylitis. In a study of 741 patients with spinal pain, it turned out that this symptom occurred in the vast majority of patients with ankylosing spondylitis and only in 15% of spinal pain caused by other pathological conditions [17]. In ankylosing spondylitis, the sensitivity of this symptom is 77% and the specificity is 85%. Interestingly, if the intensity of back pain does not decrease from taking NSAIDs in the first 48 hours of treatment, then the probability of this disease is only 3%. The presented data emphasize the importance of this group of drugs in the treatment of ankylosing spondylitis. Another indication for Voltaren is acute gouty arthritis. To suppress it, not only NSAIDs are used, but colchicine, corticosteroids and some other drugs. The bright and rapid (within 48 hours) effect of colchicine was considered as one of the diagnostic signs of this disease. However, the effectiveness of NSAIDs and colchicine appears to be similar. These drugs can prevent the further development of an acute attack of gout if they are prescribed in a timely manner, i.e. for 30–60 minutes. from the start of the attack. In Europe, rheumatologists prefer to use colchicine or a combination of colchicine and NSAIDs, while in North America they prefer NSAIDs. NSAIDs are used for gout not only to relieve an acute attack, but also to treat chronic arthritis. Among NSAIDs, preference is given to indomethacin and Voltaren. Controlled studies have not revealed a higher effectiveness of traditional NSAIDs compared to selective COX-2 inhibitors (for example, coxibs). Carrying out effective therapy for osteoarthritis is a difficult task, which is associated with its chronic and steadily progressing course, which is so typical for this disease. One of the most important areas of drug therapy for osteoarthritis is the suppression of persistent inflammation of joint tissues with its localization in cartilage, bone, entheses and synovium. This effect involves the prescription of anti-inflammatory therapy, and primarily NSAIDs. As is known, NSAIDs occupy a central place among symptom-modifying drugs for osteoarthritis. For this disease, NSAIDs are prescribed, predominantly rapidly absorbed and short-lived, with a pronounced analgesic effect. At the same time, these drugs should not have a chondronegative effect in the prescribed doses. The effect of NSAIDs on cartilage metabolism appears to be multifaceted. Some NSAIDs have a negative effect on the synthesis of the cartilage matrix and thereby contribute to the progression of osteoarthritis, others have a chondroneutral effect, and others have a chondroprotective effect. Thus, indomethacin inhibits the synthesis of proteoglycans, type II collagen and hyaluronic acid by chondrocytes, and also promotes premature death of chondrocytes [18]. Huskisson EC et al. in a randomized controlled trial, joint space width was assessed in 812 patients with knee osteoarthritis [19]. While taking indomethacin, narrowing of the gap was observed in 47% of patients and only in 22% on placebo. There are observations that the use of indomethacin in patients with osteoarthritis leads to rapid and significant impairment of the function of the hip joint and its subsequent replacement compared to those patients who were treated only with simple analgesics. However, not all NSAIDs contribute to the progression of osteoarthritis. It has been shown that some of them stimulate the anabolic function of cartilage tissue by inhibiting the production of interleukin (IL)-1 and the expression of the receptor for this cytokine, promote the intensification of the synthesis of growth factors, including transforming growth factor-1, inhibit the degradation of aggrecan, inhibit the catabolism of cartilage, and neutralize the action of metalloproteinases and reduce the intensity of chondrocyte apoptosis [20]. Such drugs include diclofenac, meloxicam, ketoprofen, aceclofenac. It has been shown that diclofenac in vitro does not suppress the biosynthesis of proteoglycans at concentrations equivalent to those in humans, and in vivo it suppresses the activity of costal cartilage chondrocytes, but stimulates articular cartilage chondrocytes [21]. Great importance is attached to NSAIDs in the treatment of a large group of diseases accompanied by pain in the lower back. The literature presents the results of studying the effect of NSAIDs on the central mechanisms of pain that are not associated with inhibition of prostaglandin synthesis, although inhibition of their production seems to be one of the main mechanisms of analgesic action. In this regard, of particular interest are data on the presence of dissociation between the anti-inflammatory (COX-dependent) and analgesic (antinoceptive) effects of NSAIDs [1]. Activation of prostaglandin synthesis in the central nervous system (including the spinal cord) occurs with any peripheral stimulus and inflammation. Voltaren, by suppressing the activity of COX-2, promotes the development of a pronounced analgesic effect, which is of pathogenetic significance for pain in the lower back. When managing such patients, Voltaren is first prescribed parenterally, and only when the pain subsides should one switch to taking this drug orally. The doctor has a large number of different forms of Voltaren at his disposal. It can be used as oral tablets, suppositories, parenteral solution, topical gel and eye drops. The drug is available in various concentrations, which creates certain convenience in the treatment of patients. The maximum daily dose of Voltaren is 0.15 g. This dose is divided into 2–4 doses. Voltaren Emulgel is a means for external use. It gives a high concentration of the drug in subcutaneously located target tissues, which is of particular value to improve the tolerance of the drug. Thus, the concentration of diclofenac in the affected structures of the joint and periarticular tissues after the re -use of Voltaren Emulgel is 770 ng/ml (110–2960) in the synovial fluid, and only 27.6 ng/ml in plasma. These new dosage forms contain special modifications of diclofenac. The tolerance of Voltaren (sodium diclofenac) was studied in a large number of controlled studies, in which it was compared with other non -election and selective TSOG -2 inhibitors. In terms of tolerance, Voltaren surpasses most non -election NSAIDs and takes 2nd place after Ibuprofen. Voltaren and Indomethacin showed the same therapeutic potential in patients with rheumatoid arthritis of 36 months. study [22]. However, the best tolerance was observed in the treatment of Voltaren. In particular, after 12 months. Treatment in the Indomethacin group ceased to treat 41% of patients, and only 19% in the voltaren group. The risk of developing the undesirable phenomena of Voltaren is inaccurately higher than when taking placebo [23]. In general, the manifestations of drug intolerance to this drug are close to similar manifestations of other NSAIDs. However, it should be borne in mind that the frequency of the occurrence of undesirable phenomena and their severity is reliably distinguished by Voltaren and numerous generics, and this applies not only to complaints that are actively presented to patients, or complaints identified during questioning, but also objective symptoms of drug intolerance. So, according to the Institute of Rheumatology, for 2002–2005, in patients taking voltaren, the frequency of detection of single erosions was 7.1% and multiple erosions and ulcers - 11.1%, while the treatment with generics of diclofenac 13, 3 and 14.9%, respectively. A comparative study of the effectiveness and tolerance of Voltaren (diclofenac) and selective TSOG -2 inhibitors, for example, rofecoxib and celloxib, showed that in patients with osteoarthritis, diclofenac was more effective, while there were no reliable differences in the frequency of unwanted reactions. An interesting study is RL Dreiser C COVAVT. (2000). The authors reported the results of a randomized double blind study, in which they evaluated the tolerance of sodium diclofenac 150 mg/day. and two doses of meloxicam - 7.5 and 15 mg/day. In 489 patients with acute pain in the lower back. The duration of therapy was 14 days. According to the doctors, the good and satisfactory tolerance of the selective inhibitor of the COO -2 and the diclofenac, which is not such, turned out to be the same and corresponded to 96 and 95%. Similar assessment was received according to patients. In another placebo -controlled, randomized, double blind examination, 150 mg/day diclofenac was compared in patients with osteoarthritis. (1 group) and celloxib 200 mg/day. (Group 2) [24]. Gastrointestinal complications were often found in patients of group 1, as well as an increase in serum aminotransferases and anemia. In the 2nd group, on the contrary, peripheral edema was 2 times more likely, also almost 2 times - dizziness, 3 times - infection of the upper respiratory tract, 5 times - pain in the lower back. In general, it can be noted that Voltaren demonstrates good tolerance with fairly high doses (150 mg) and prolonged use (up to 8 months or more). Thus, Diclofenac at the beginning of the 21st century did not lose its relevance and continues to be considered as a standard in the treatment of joint diseases and spine. It has an optimal combination of anti -inflammatory and analgesic effects, has a large arsenal of various dosage forms, allows optimizing therapy and conducting effective monitoring of treatment safety.
Literature 1. Nasonov E.L. Non-steroidal anti-inflammatory drugs. M, 2000, 143 p. 2. Thompson PW et al. Rheumatology 2005; 44:1308–1310. 3. Zeider H et al. Rheumatology 2006; 45:494–496. 4. Nasonova V.A. RMJ 2004; 6: 392– 395. 5. Brogden RN, Heel R, Pakes GE et al. Drugs 1980; 20: 24. 6. Liauw HL, Moscaritola JD, Bucher J. Diclofenac sodium (Voltaren). New York, Marcel Dekker, 1987. 7. Abberger H, Korbonits M. Das Markewzeichen in der Rheumatherapie aus Novartis. 2000, 2. 8. Ku EC, Lee W, Kohari HV et al. Semin Arthritis Rheum 1985; 15: 36. 9. Patrignari P, Panara VR, Sciulli VG et al. J Physiol Pharmacol 1997; 48:623–631. 10. Gottesdiener K, Schnitzer T, Fisher C. et al. Arthritis Rheum 1999; 42 (Suppl 9): 144. 11. Schwartz JI, Van Hecken A, De Leperieri I et al. Ann Rheum Dis 1999; 206: abstract 857. 12. Nasonova V.A. Difficult Patient 2004; 2 (3): 6–10. 13. Tsvetkova E.S. Ter. archive 1978; 9:26–30. 14. Sididin Ya.A., Guseva N.G., Ivanova M.M. Diffuse connective tissue diseases. M., 2004, 638 p. 15. Calin A, Eastmond JJ Rheumatol 1990; 17:801–803. 16. Wanders A et al. Arthritis Rheum 2005;52:1756–1765. 17. Dougados M., Dijrmans B., Khan M. et al. Ann. Rheum. Dis. 2002; 61(Suppl III): 40–50. 18. Ding C. Inflammation 2002; 26: 139. 19. Huskinsson EC, Berry P, Gishen P. J Rheumatol 1995; 22: 1941–1946. 20. HenrotinY, Reginster T. Osteoarthritis Cartilage 1999; 7: 355–357. 21. Knokher VA, Jasani MK, Dandona P. Clin Sci 1993; 84(3). 13P, abstract 46. 22. Wyjnand SM, van Riel P et al. J Rheumatol 1991; 18: 184–187. 23. Maeda T, Yoshida A. et al. Jap J Inalammation 1990. 10, 213–226. 24. Mc Kenna F., Borenstein D., Wendt H. et al. Scand. J. Rheumatol, 2001; 30: 11–18.
Voltaren®
When using the drug Voltaren® and other NSAIDs, careful medical monitoring is necessary for patients who have symptoms/signs indicating gastrointestinal lesions/diseases or ulcerative lesions of the stomach or intestines, bleeding or perforation, a history of Helicobacter pylori infection, ulcerative colitis, Crohn's disease , a history of liver dysfunction, or patients presenting with complaints indicating gastrointestinal diseases. The risk of developing gastrointestinal bleeding increases with increasing doses of NSAIDs or with a history of ulcers, especially bleeding and perforation of the ulcer and in elderly patients.
When using diclofenac, phenomena such as bleeding or ulceration/perforation of the gastrointestinal tract, in some cases with fatal outcome, were observed. These events may occur at any time when using drugs in patients with or without previous symptoms and a history of serious gastrointestinal diseases. In elderly patients, such complications can have serious consequences. If bleeding or gastrointestinal ulceration develops in patients receiving Voltaren®, the drug should be discontinued.
To reduce the risk of toxic effects on the gastrointestinal tract, patients with gastrointestinal ulcers, especially those complicated by bleeding or a history of perforation, as well as elderly patients, should be prescribed the drug in the minimum effective dose.
Patients with an increased risk of developing gastrointestinal complications, as well as patients receiving therapy with low doses of acetylsalicylic acid, should take gastroprotectors (proton pump inhibitors or misoprostol). Or other medications to reduce the risk of unwanted effects on the gastrointestinal tract.
Patients with a history of gastrointestinal lesions, especially the elderly, should report all abdominal symptoms to the doctor.
Particular caution should be exercised when using the drug Voltaren® in patients receiving drugs that increase the risk of gastrointestinal bleeding: systemic corticosteroids (including prednisolone), anticoagulants (including warfarin), antiplatelet agents (including clopidogrel, acetylsalicylic acid) or selective serotonin reuptake inhibitors (including citalopram, fluoxetine, paroxetine, sertraline).
Particular caution is required when treating patients with cardiovascular diseases (including ischemic heart disease, cerebrovascular diseases, compensated heart failure, peripheral vascular disease), impaired renal function (including chronic renal failure, CC 30-60 ml/min), with dyslipidemia/hyperlipidemia, diabetes mellitus, arterial hypertension, patients receiving diuretics or other drugs that affect renal function, as well as patients with a significant decrease in blood volume of any etiology, for example, in the periods before and after major surgical interventions; when treating smoking patients or patients who abuse alcohol.
NSAID therapy, incl. Diclofenac, particularly long-term and high-dose therapy, may be associated with a small increase in the risk of serious cardiovascular thrombotic complications (including myocardial infarction and stroke). To reduce the risk of these complications, especially in patients with cardiovascular disease, NSAIDs should be taken at the lowest effective dose for the shortest possible duration of treatment.
During therapy with Voltaren®, it is recommended to monitor renal function in patients with arterial hypertension, impaired cardiac or renal function, elderly patients, patients receiving diuretics or other drugs that affect renal function, as well as in patients with a significant decrease in blood volume of any etiology, for example, in the period before and after major surgical interventions. After cessation of drug therapy, normalization of renal function indicators to baseline levels is usually observed.
Caution should be exercised when using the drug Voltaren® in elderly patients, especially in weakened or low-weight elderly people (in such cases, the drug should be prescribed in the minimum effective dose).
Serious dermatological reactions such as exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, in some cases fatal, have been reported very rarely with the use of diclofenac. The highest risk and incidence of severe dermatological reactions were observed in the first month of treatment with diclofenac. If patients receiving Voltaren® develop the first signs of skin rash, damage to the mucous membranes or other symptoms of hypersensitivity, the drug should be discontinued.
Since during the period of use of the drug Voltaren® there may be an increase in the activity of one or more liver enzymes, during long-term therapy with the drug, monitoring of liver function is indicated as a precaution. If liver dysfunction persists or progresses or signs of liver disease or other symptoms (eg, eosinophilia, rash) occur, the drug should be discontinued. It should be borne in mind that hepatitis during the use of the drug Voltaren® can develop without prodromal phenomena.
Caution is necessary when using the drug Voltaren® in patients with mild to moderate liver dysfunction, as well as in patients with hepatic porphyria, because the drug can provoke attacks of porphyria.
Voltaren® may temporarily inhibit platelet aggregation. Therefore, in patients with hemostasis disorders, it is necessary to carefully monitor relevant laboratory parameters.
With long-term use of the drug Voltaren®, it is recommended to conduct regular clinical tests of peripheral blood.
In rare cases, anaphylactic/anaphylactoid reactions have been observed in patients who are not allergic to diclofenac when using Voltaren®.
Exacerbation of asthma (NSAID intolerance/NSAID-induced asthma), angioedema, and urticaria are most common in patients with asthma, seasonal allergic rhinitis, nasal polyps, COPD, or chronic respiratory infections (especially those associated with allergic rhinitis-like symptoms) . In this group of patients, as well as in patients with allergies to other drugs (rash, itching or urticaria), special caution (preparedness for resuscitation measures) should be taken when prescribing Voltaren®.
The anti-inflammatory effect of the drug Voltaren® may complicate the diagnosis of infectious processes.
Voltaren® should not be prescribed together with other NSAIDs, including selective COX-2 inhibitors, due to the risk of increased adverse reactions.
Impact on the ability to drive vehicles and operate machinery
Patients who experience visual disturbances, dizziness, drowsiness, vertigo or other disorders of the central nervous system while using the drug Voltaren® should not drive vehicles or operate machinery.
