Diclofenac-LF solution for injections 75mg/3ml №5×1

Name:
Diclofenac-LF solution for and 75mg/3ml in amp. No. 5х1
Description:
Transparent colorless, slightly yellowish or slightly brownish liquid. The main active ingredient Diclofenac Release form Solution for injection. Dosage 75 mg / 3 ml Pharmacological properties Pharmacodynamics Diclofenac sodium is a non-steroidal compound with pronounced antirheumatic, anti-inflammatory, analgesic and antipyretic properties. Inhibition of prostaglandin biosynthesis, demonstrated in experiments, is considered the main mechanism of its action. Prostaglandins play an important role in causing inflammation, pain, and fever. In vitro, diclofenac sodium at concentrations equivalent to those achieved in the treatment of patients does not inhibit the biosynthesis of cartilage proteoglycans. In rheumatic diseases, the anti-inflammatory and analgesic properties of diclofenac cause a clinical response, which is characterized by a significant reduction in the signs and symptoms of the disease: pain at rest and during movement, morning stiffness and swelling of the joints, as well as a marked improvement in joint function. Diclofenac-LF has a pronounced analgesic effect in moderate and severe pain of non-rheumatic origin, the analgesic effect begins to appear 15-30 minutes after application. The drug has also shown a significant effect on migraine attacks. In post-traumatic and postoperative conditions in the presence of inflammation, diclofenac quickly relieves spontaneous pain and pain during movement and reduces swelling caused by inflammation and wounds. If the drug is used simultaneously with opioid painkillers to relieve postoperative pain, diclofenac sodium significantly reduces the need for them. Solution for injection Diclofenac-LF is especially necessary to start the treatment of inflammatory and degenerative rheumatic diseases and pain syndrome due to inflammation of non-rheumatic origin. Pharmacokinetics Absorption After intramuscular administration of 75 mg of diclofenac sodium, absorption begins immediately, and the average maximum plasma concentrations of 2.5 μg / ml (8 μmol / ml) are reached after about 20 minutes. In the case of intravenous infusion of 75 mg of diclofenac over 2 hours, the average maximum plasma concentrations are approximately 1.9 μg / ml (5.9 μmol / ml). Shorter infusion times lead to higher peak plasma concentrations, while longer infusions produce plateau concentrations proportional to the infusion rate at 3-4 hours. Following intramuscular injection or administration of enteric tablets or suppositories, plasma concentrations decline rapidly immediately after peak levels are reached. The area under the concentration curve (AUC) after intramuscular or intravenous administration is approximately twice that after oral or rectal administration, since approximately half of the active substance is metabolized during the first pass through the liver (the “first pass” effect) when the drug is administered orally or rectally. Distribution 99.7% of diclofenac binds to serum proteins, mainly albumin (99.4%). The apparent volume of distribution is 0.12-0.17 l / kg. Diclofenac penetrates into the synovial fluid, where the maximum concentration is established 2-4 hours after the time of reaching the peak value in the blood plasma. The apparent elimination half-life from synovial fluid is 3 to 6 hours. 2 hours after reaching the peak plasma level, the concentration of diclofenac in the synovial fluid exceeds this indicator in the blood plasma and remains higher for 12 hours. Diclofenac was found at low concentration (100 ng/mL) in the breast milk of one breastfeeding woman. The amount consumed by an infant with breast milk is equivalent to a dose of 0.03 mg/kg/day. Biotransformation Biotransformation of diclofenac occurs partly by glucuronidation of the unchanged molecule, but mainly by single and multiple hydroxylation and methoxylation, resulting in the formation of several phenolic metabolites (3′-hydroxy-, 4′-hydroxy-, 5-hydroxy-, 4′, 5-dihydroxy- and 3′-hydroxy-4′-methoxydiclofenac), most of which are converted to glucuronic acid conjugates. Two of these phenolic metabolites are biologically active, but their action is much less pronounced than that of diclofenac. Withdrawal The total systemic clearance of diclofenac in plasma is 263 ± 56 ml / min (mean ± SD). The terminal half-life in plasma is 1-2 hours. Four metabolites, including two active ones, also have a short plasma half-life of 1-3 hours. One metabolite, 3′-hydroxy-4′-methoxydiclofenac, has a much longer plasma half-life. However, this metabolite is practically inactive. About 60% of the administered dose is excreted in the urine as the unchanged molecule glucuronic conjugate and as metabolites, most of which are also converted to glucuronic conjugates. Less than 1% is excreted unchanged. The rest is eliminated in the form of metabolites through bile with faeces. Special groups of patients No differences in relation to age dependence in absorption, metabolism or excretion of the drug were observed. However, in some elderly patients, a 15-minute intravenous infusion resulted in a 50% increase in plasma concentrations compared with young healthy patients. In patients with impaired renal function, if the usual dosing regimen is observed, no accumulation of the active substance can be expected. With creatinine clearance less than 10 ml/min, steady state plasma levels of hydroxymetabolites are approximately 4 times higher than in healthy individuals. However, the metabolites are eventually excreted in the bile. In patients with chronic hepatitis or compensated cirrhosis of the liver, the parameters of the kinetics and metabolism of diclofenac are the same as in patients without liver disease. Indications for use When administered intramuscularly The drug is intended for the treatment of: – inflammatory and degenerative forms of rheumatism, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, spondyloarthritis, vertebral pain syndrome, extra-articular rheumatism; – acute attacks of gout; – renal and hepatic colic; – inflammation, pain and swelling after injuries and operations; – severe migraine attacks. In the form of intravenous infusion The drug is intended for the treatment or prevention of postoperative pain in a hospital setting. Route of administration and doses The dose should be selected individually. Side effects can be minimized by using the minimum effective dose for the minimum period necessary to control symptoms (see “Precautions”). Diclofenac-LF, solution for injection, should not be used for more than 2 days. If necessary, treatment can be continued with other dosage forms of diclofenac sodium (eg, tablets, suppositories). Each ampoule is for single use only. The solution should be used immediately after opening the ampoule. Any unused content must be disposed of. Intramuscular injection In order to prevent damage to nerve or other tissues at the site of intramuscular injection (which can lead to muscle weakness, muscle paralysis and hypoesthesia), the following rules must be observed. The dose is usually one ampoule of 75 mg per day, administered by deep injection into the upper outer quadrant of the gluteus maximus using asepsis. In severe cases (eg, colic), the daily dose can be increased to two injections of 75 mg, between which an interval of several hours is observed (one injection in each buttock). Alternatively, 1 ampoule (75 mg) may be combined with other dosage forms of diclofenac sodium (eg tablets, suppositories) up to a total maximum daily dose of 150 mg. For migraine attacks, the available clinical experience is limited to the use as follows: treatment is started as early as possible with the appointment of 1 ampoule (75 mg), if necessary, treatment is continued with suppositories on the same day at a dose of up to 100 mg. The total dose on the first day should not exceed 175 mg. There are no data on the use of diclofenac for more than 1 day for migraine. If it is necessary to continue treatment in the following days, it should be limited to the use of suppositories in a daily dose of up to 150 mg, divided into several single doses. Intravenous infusion The solution for injection should not be administered as an intravenous bolus injection. Immediately before the start of intravenous infusion, depending on its required duration, the contents of one ampoule of Diclofenac-LF should be diluted in 100-500 ml of 0.9% sodium chloride solution or 5% glucose solution. The solution used for dilution should be buffered with sodium bicarbonate solution for injection (0.5 ml of 8.4% solution or 1 ml of 4.2%) taken from a freshly opened container. Only clear solutions can be used. If there are crystals or sediment in the solution, then it cannot be used for infusion. Prepared solutions for infusion should be used immediately. Two alternative dosing regimens are recommended: For the treatment of moderate to severe postoperative pain, 75 mg should be administered continuously for 30 minutes to 2 hours. If necessary, the treatment can be repeated after a few hours, but the dose should not exceed the maximum dose of 150 mg per day. For the prevention of postoperative pain after surgery, a loading dose of 25-50 mg should be administered by infusion lasting 15 minutes – 1 hour, after which it is necessary to apply a continuous infusion at a dose of about 5 mg / hour up to a maximum daily dose of 150 mg. Special patient groups Children (under 18 years of age) The dosage of diclofenac injection solution is not suitable for use in children under 18 years of age. Elderly patients (aged 65 years and older) For elderly patients, adjustment of the initial dose is usually not required. However, based on generally accepted approaches, caution is necessary when prescribing the drug, especially in debilitated or low body 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, Diclofenac-LF therapy 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 careful evaluation. In cases where treatment started with an injection solution is continued with tablets or suppositories containing diclofenac sodium as an active substance for more than 4 weeks, only at doses of ≥100 mg per day. Patients with impaired renal function The drug is contraindicated in patients with renal insufficiency (GFR <15 ml / min / 1.73 m2) (see "Contraindications"). Since special studies have not been conducted in patients with impaired renal function, specific recommendations for dose adjustment cannot be made. Caution is advised when using the drug in patients with impaired renal function (see "Precautions"). Patients with impaired liver function The drug is contraindicated in patients with hepatic impairment (see "Contraindications"). Since special studies have not been conducted in patients with impaired liver function, specific recommendations for dose adjustment cannot be made. Caution is advised when using the drug in patients with mild to moderate hepatic impairment (see "Precautions"). Women of childbearing potential, pregnancy, breastfeeding, fertility There are no data to support any recommendation for women of childbearing potential. Pregnancy Suppression of prostaglandin synthesis can adversely affect the course of pregnancy and intrauterine development of the fetus. Data from epidemiological studies indicate an increased risk of spontaneous abortion and / or the development of heart defects and gastroschisis in the fetus after taking prostaglandin synthesis inhibitors in early pregnancy. It is believed that the risk increases with increasing dose and duration of therapy. It has been shown that in animals, the administration of prostaglandin synthesis inhibitors leads to fetal loss in the pre- and post-implantation period of embryo development. In addition, in animals treated with a prostaglandin synthesis inhibitor during 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, Diclofenac-LF should not be used during the first two trimesters of pregnancy unless the benefits outweigh the risks to the fetus. As with other NSAIDs, the use of the drug during the third trimester of pregnancy is contraindicated. When taking inhibitors of prostaglandin synthesis in the third trimester of pregnancy in the fetus, the following are possible: 1) premature closure of the arterial duct and pulmonary hypertension; 2) renal dysfunction, with the progression of which develops renal failure with oligohydroamnios. In the mother and fetus / newborn, bleeding time may be prolonged, and an antiplatelet effect may occur even after taking very low doses of diclofenac. When taking diclofenac at the end of pregnancy, it is possible to develop weakness in labor and increase the duration of labor. Breastfeeding Like other NSAIDs, diclofenac passes into breast milk in small quantities. Diclofenac-LF should not be used during breastfeeding to prevent adverse reactions in the child. Fertility As with other NSAIDs, diclofenac may affect a woman's fertility and is not recommended for women planning a pregnancy. Women who have difficulty conceiving or who have been tested for infertility should stop taking Diclofenac-LF. Preclinical animal studies have shown that the use of NSAIDs (including diclofenac) inhibits ovulation in rabbits and implantation and placentation in rats, and also leads to premature closure of the ductus arteriosus in pregnant rats. Maternally toxic doses of diclofenac have been associated with dystocia, prolonged pregnancy, poor fetal survival, and intrauterine growth retardation in rats. The slight effect of diclofenac on reproductive parameters and childbirth, as well as intrauterine narrowing of the ductus arteriosus, are pharmacological effects of the prostaglandin synthesis inhibitor class. In animals, on the basis of relevant data, an impairment of male fertility cannot be excluded. The relevance of these findings to humans is uncertain. Additional studies show that at repeated oral doses in rats (>1mg/kg body weight), diclofenac causes effects that affect fertility (lower testosterone levels, as well as reduced epididymal and testicular mass in combination with histopathological changes). Similar effects were also observed in the F1 generation at doses >1.25 mg/kg in a two-generation study. In dogs, daily subcutaneous doses of diclofenac sodium 2 mg/kg resulted in an increase in spermatid count. Subsequent studies describe a reduced mating frequency in female rats following a repeated dose of ≥0.5 mg/kg diclofenac. For this reason, an impact on both male and female fertility cannot be ruled out. The ability to influence the reaction rate when driving vehicles or operating other mechanisms Patients who experience visual impairment, dizziness, vertigo, drowsiness or other disorders of the central nervous system during treatment with Diclofenac-LF should refrain from driving vehicles and working with mechanisms. Interaction with other medicinal products and other forms of interaction The interactions that were observed with the use of diclofenac in the form of a solution for injection and / or other dosage forms of diclofenac are listed below. CYP2C9 inhibitors: Caution is advised when diclofenac is co-administered with potent CYP2C9 inhibitors (such as voriconazole), which can lead to a significant increase in peak plasma concentration and exposure of diclofenac due to inhibition of diclofenac metabolism. Lithium: under conditions of simultaneous use, diclofenac can increase the concentration of lithium in the blood plasma. Monitoring of plasma lithium levels is recommended. Digoxin: under conditions of simultaneous use, diclofenac can increase the concentration of digoxin in the blood serum. Monitoring of serum digoxin levels is recommended. Diuretics and antihypertensive agents: As with other NSAIDs, concomitant use of diclofenac with diuretics and antihypertensive agents (eg, beta-blockers, angiotensin converting enzyme (ACE) inhibitors) may lead to a decrease in their antihypertensive effect. Thus, such a combination should be used with caution, and patients, especially the elderly, should be carefully monitored for blood pressure. Patients should be adequately hydrated, and monitoring of renal function is also recommended after initiation of concomitant therapy and regularly thereafter, especially when diuretics and ACE inhibitors are used due to an increased risk of nephrotoxicity. Drugs that cause hyperkalemia: the simultaneous use of potassium-sparing diuretics, cyclosporine, tacrolimus or trimethoprim can lead to an increase in the level of potassium in the blood serum (this indicator should be monitored regularly). Other NSAIDs and corticosteroids: The concomitant use of diclofenac and other systemic NSAIDs or corticosteroids may increase the incidence of adverse reactions from the gastrointestinal tract. Anticoagulants and antiplatelet agents: Precautionary measures are recommended as the combination of these drugs with diclofenac may increase the risk of bleeding. Although clinical studies do not indicate an effect of diclofenac on the activity of anticoagulants, there are reports of an increased risk of bleeding in patients receiving diclofenac and anticoagulants at the same time. Therefore, careful monitoring of such patients is recommended. Selective serotonin reuptake inhibitors (SSRIs): Co-administration of systemic NSAIDs and SSRIs may increase the risk of bleeding in the digestive tract. Antidiabetic drugs: Clinical studies have shown that diclofenac can be used together with oral antidiabetic agents without affecting their clinical effect. However, isolated cases of the development of both hypoglycemia and hyperglycemia are known, in which dose adjustment of antidiabetic agents is required during treatment with diclofenac. Such conditions require monitoring of blood glucose levels, which is a precautionary measure during concomitant therapy. There are also separate reports of the development of metabolic acidosis while taking diclofenac and metformin, especially in patients with pre-existing renal disorders. Phenytoin: When phenytoin is co-administered with diclofenac, it is recommended to monitor plasma concentrations of phenytoin due to a possible increase in phenytoin exposure. Methotrexate: When NSAIDs are administered less than 24 hours before or after treatment with methotrexate, caution is advised, as blood concentrations of methotrexate and its toxicity may increase. Cycloporine and tacrolimus: Diclofenac, like other NSAIDs, may increase the nephrotoxicity of cyclosporine and tacrolimus due to its effect on renal prostaglandins. In this regard, diclofenac should be used at lower doses than in patients not taking cyclosporine or tacrolimus. Antibacterial quinolones: There are isolated reports of the development of seizures, which may be the result of the simultaneous use of quinolones and NSAIDs. CYP2C9 inducers: Caution is advised when co-administering diclofenac with CYP2C9 inducers (eg, rifampicin), which can lead to a significant decrease in plasma concentrations and exposure of diclofenac. PrecautionsGastrointestinal effects With all NSAIDs, gastrointestinal bleeding, ulceration, or perforation can be fatal and may occur at any time during treatment, regardless of the presence or absence of warning symptoms or a history of serious gastrointestinal events. In elderly patients, these phenomena are usually more serious consequences. In the event of gastrointestinal bleeding in patients receiving diclofenac, treatment with this drug should be discontinued. As with all NSAIDs, including diclofenac, careful medical supervision and special care is necessary when prescribing Diclofenac-LF to patients with symptoms of gastrointestinal disorders or with a history of gastric or intestinal ulceration, bleeding or perforation (see “Side effect” ). The risk of gastrointestinal bleeding increases with increasing dose 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 ulcers, especially those complicated by bleeding and perforation, as well as in elderly patients, treatment should be started with the lowest effective dose and followed 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 adverse reactions from the gastrointestinal tract, combination therapy in combination with protective drugs (for example, 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 medicinal products that may increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants, antiplatelet agents, or selective serotonin reuptake inhibitors. During drug therapy, close medical supervision is necessary and caution should be exercised in patients with ulcerative colitis or Crohn’s disease, as their condition may worsen. 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, in particular when used at high doses (150 mg per day) and with prolonged use. Patients with significant risk factors for cardiovascular events (eg, hypertension, hyperlipidemia, diabetes mellitus, smoking) should only be given diclofenac after careful consideration. Due to the possible increased risk of cardiovascular events with long-term use or at high doses of the drug, patients should be prescribed diclofenac at the lowest effective dose and take the shortest possible time necessary to reduce the severity of symptoms. The need for symptomatic relief and response to treatment should be re-evaluated periodically. In patients with congestive heart failure (NYHA-I) or significant risk factors for cardiovascular events (eg, arterial hypertension, hyperlipidemia, diabetes mellitus, smoking), diclofenac should be used only after careful evaluation, and in cases where treatment started with a solution for Diclofenac-LF injection, continues with tablets or suppositories containing diclofenac sodium as an active ingredient, for more than 4 weeks – only at doses of ? 100 mg per day. Patients should be alert for signs and symptoms of severe arteriothrombotic events (eg, chest pain, dyspnoea, weakness, slurred speech), which may occur suddenly. Patients should be instructed to seek immediate medical attention in such cases. Hematological effects With long-term use of the drug, it is recommended, as with long-term use of other NSAIDs, to monitor the blood test. Diclofenac-LF, like other NSAIDs, can temporarily inhibit platelet aggregation. Therefore, patients with impaired hemostasis require careful monitoring. Respiratory effects (history of asthma) In patients with asthma, allergic rhinitis, swelling of the nasal mucosa (nasal polyps), chronic obstructive pulmonary disease, or chronic respiratory tract infections (especially if associated with rhinitis-like allergic symptoms), reactions to NSAIDs, such as provocation asthma, angioedema or urticaria, is more common. Therefore, such patients are advised to exercise caution (preparedness for an emergency). This also applies to patients who are allergic to other substances, such as skin reactions, itching or hives. Hepatobiliary effects Careful monitoring is necessary when prescribing diclofenac to patients with impaired liver function, as their condition may worsen. While taking the drug, as in the treatment of other NSAIDs, the level of one or more liver enzymes may increase. Therefore, during long-term therapy with diclofenac (for example, in the form of tablets), a regular study of liver function is indicated as a precautionary measure. If violations of liver function parameters persist or increase, or if complaints or symptoms develop that indicate liver disease, as well as if other side effects occur (for example, eosinophilia, rash, etc.), diclofenac should be discontinued . It must be borne in mind that hepatitis while taking the drug can occur without prodromal phenomena. Caution is necessary when prescribing diclofenac to patients with hepatic porphyria, as the drug can provoke attacks of acute porphyria. Skin reactions In connection with the use of NSAIDs, including diclofenac, very rarely reported severe, up to fatal, skin reactions, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis (see “Side effect”). The highest risk of these reactions exists at the beginning of therapy, and the development of these reactions is noted in most cases in the first month of treatment. The drug should be discontinued at the first manifestation of skin rash, mucosal ulcers or any other manifestations of hypersensitivity. In patients who have not previously taken diclofenac, during the period of drug treatment, as well as during therapy with other NSAIDs, allergic reactions, including anaphylactic and anaphylactoid reactions, may develop in rare cases. Renal effects NSAID therapy, including diclofenac, may be associated with fluid retention or edema. Particular care is required in the treatment of patients with impaired cardiac or renal function, elderly patients, patients receiving diuretics, as well as patients who have a significant decrease in circulating plasma volume of any etiology, for example, before and after massive surgical interventions. In such cases, during the use of diclofenac, as a precautionary measure, regular monitoring of renal function is recommended. After discontinuation of the drug, kidney function usually returns to baseline. Elderly patients Based on generally accepted approaches, caution is necessary when prescribing the drug, especially in debilitated or low body weight elderly patients. Interaction with NSAIDs It is necessary to avoid the simultaneous appointment of diclofenac and other NSAIDs, including cyclooxygenase-2 inhibitors, to reduce the risk of additional side effects (see “Interaction with other medicinal products and other forms of interaction”). Excipients Sodium metabisulphite in solution for injection may lead to some severe hypersensitivity reactions and bronchospasm. Infection masking Diclofenac, like other NSAIDs, due to its pharmacodynamic properties, can mask the symptoms characteristic of infectious and inflammatory diseases. Interactions with other drugs The following are the interactions that were observed with the use of diclofenac in the form of a solution for injection and / or other dosage forms of diclofenac. CYP2C9 inhibitors: Caution is advised when diclofenac is co-administered with potent CYP2C9 inhibitors (such as voriconazole), which can lead to a significant increase in peak plasma concentration and exposure of diclofenac due to inhibition of diclofenac metabolism. Lithium: under conditions of simultaneous use, diclofenac can increase the concentration of lithium in the blood plasma. Monitoring of plasma lithium levels is recommended. Digoxin: under conditions of simultaneous use, diclofenac can increase the concentration of digoxin in the blood serum. Monitoring of serum digoxin levels is recommended. Diuretics and antihypertensive agents: As with other NSAIDs, concomitant use of diclofenac with diuretics and antihypertensive agents (eg, beta-blockers, angiotensin converting enzyme (ACE) inhibitors) may lead to a decrease in their antihypertensive effect. Thus, such a combination should be used with caution, and patients, especially the elderly, should be carefully monitored for blood pressure. Patients should be adequately hydrated, and monitoring of renal function is also recommended after initiation of concomitant therapy and regularly thereafter, especially when diuretics and ACE inhibitors are used due to an increased risk of nephrotoxicity. Drugs that cause hyperkalemia: the simultaneous use of potassium-sparing diuretics, cyclosporine, tacrolimus or trimethoprim can lead to an increase in the level of potassium in the blood serum (this indicator should be monitored regularly). Other NSAIDs and corticosteroids: The concomitant use of diclofenac and other systemic NSAIDs or corticosteroids may increase the incidence of adverse reactions from the gastrointestinal tract. Anticoagulants and antiplatelet agents: Precautionary measures are recommended as the combination of these drugs with diclofenac may increase the risk of bleeding. Although clinical studies do not indicate an effect of diclofenac on the activity of anticoagulants, there are reports of an increased risk of bleeding in patients receiving diclofenac and anticoagulants at the same time. Therefore, careful monitoring of such patients is recommended. Selective serotonin reuptake inhibitors (SSRIs): Co-administration of systemic NSAIDs and SSRIs may increase the risk of bleeding in the digestive tract. Antidiabetic drugs: Clinical studies have shown that diclofenac can be used together with oral antidiabetic agents without affecting their clinical effect. However, isolated cases of the development of both hypoglycemia and hyperglycemia are known, in which dose adjustment of antidiabetic agents is required during treatment with diclofenac. Such conditions require monitoring of blood glucose levels, which is a precautionary measure during concomitant therapy. There are also separate reports of the development of metabolic acidosis while taking diclofenac and metformin, especially in patients with pre-existing renal disorders. Phenytoin: When phenytoin is co-administered with diclofenac, it is recommended to monitor plasma concentrations of phenytoin due to a possible increase in phenytoin exposure. Methotrexate: When NSAIDs are administered less than 24 hours before or after treatment with methotrexate, caution is advised, as blood concentrations of methotrexate and its toxicity may increase. Cycloporine and tacrolimus: Diclofenac, like other NSAIDs, may increase the nephrotoxicity of cyclosporine and tacrolimus due to its effect on renal prostaglandins. In this regard, diclofenac should be used at lower doses than in patients not taking cyclosporine or tacrolimus. Antibacterial quinolones: There are isolated reports of the development of seizures, which may be the result of the simultaneous use of quinolones and NSAIDs. CYP2C9 inducers: Caution is advised when co-administering diclofenac with CYP2C9 inducers (eg, rifampicin), which can lead to a significant decrease in plasma concentrations and exposure of diclofenac. Contraindications known hypersensitivity to the active substance, sodium metabisulphite or any other component of the drug; like other non-steroidal anti-inflammatory drugs (NSAIDs), Diclofenac-LF is contraindicated in patients in whom asthma attacks, urticaria or acute rhinitis are provoked by taking acetylsalicylic acid or other drugs that have the ability to inhibit prostaglandin synthetase; active gastric or intestinal ulcer, bleeding or perforation; inflammatory bowel disease (eg, Crohn’s disease, ulcerative colitis); liver failure; renal failure (GFR<15 ml/min/1.73 m2 ); established congestive heart failure (NYHA II-IV), ischemic heart disease, peripheral arterial disease or cerebrovascular disease; in patients with a high risk of postoperative bleeding, anticoagulation, incomplete hemostasis, hematopoietic disorders for or cerebrovascular bleeding; treatment of postoperative pain after coronary artery bypass surgery (or using a heart-lung machine); III trimester of pregnancy. Composition 3 ml of the solution contains: Active ingredient: diclofenac sodium - 75 mg (25 mg / ml); Excipients: mannitol (E 421), sodium metabisulphite (E 223), benzyl alcohol, propylene glycol, sodium hydroxide, water for injection. OverdoseSymptoms.Typical clinical presentation