Diclofenac-zdorovya

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DICOLOFENAC-ZDOROV'YA (DICLOFENAC-ZDOROV'YA)

Composition:

Active substance: diclofenac;

1 ml of solution contains 25 mg of sodium diclofenac;

Excipients: sodium metabisulfite (E 223), mannitol (E 421), propylene glycol, benzyl alcohol, sodium hydroxide, water for injections.

Medicinal form: Solution for injection.

Main physico-chemical properties: clear, colorless or slightly yellowish solution.

Pharmacotherapeutic group: Non-steroidal anti-inflammatory and antirheumatic drugs. Acetic acid derivatives and related substances. ATC code M01A B05.

Pharmacological Properties.

Pharmacodynamics. Sodium diclofenac is a non-steroidal compound with pronounced analgesic and anti-inflammatory properties. It is an inhibitor of prostaglandin synthetase (cyclooxygenase). In vitro, sodium diclofenac at concentrations equivalent to those achieved in humans does not suppress proteoglycan biosynthesis in cartilage tissue. When administered concomitantly with opioids for postoperative pain relief, it significantly reduces the need for opioids.

Pharmacokinetics. After intramuscular injection of 75 mg diclofenac, absorption begins immediately, and the mean peak plasma concentration (Cmax) of approximately 2,558±0,968 µg/mL (2.5 µg/mL = 8 µmol/L) is reached within about 20 minutes. The extent of absorption is linearly proportional to the dose.

When 75 mg of diclofenac is administered by intravenous infusion over 2 hours, the mean Cmax in plasma is approximately 1,875±0,436 µg/mL (1.9 µg/mL = 5.9 µmol/L). A shorter infusion period results in a higher Cmax, whereas longer infusions lead to a concentration plateau proportional to the infusion rate after 3–4 hours. In contrast to the results observed with oral administration, when the drug is administered as suppositories or by intramuscular injection, plasma concentrations decline rapidly immediately after reaching peak levels.

The area under the concentration-time curve (AUC) after intramuscular or intravenous administration is approximately twice as high as after oral or rectal administration, because these parenteral routes avoid first-pass hepatic metabolism.

99.7% of diclofenac is protein-bound, primarily to albumin (99.4%).

Diclofenac penetrates into synovial fluid, where Cmax is reached 2–4 hours after the peak plasma concentration. The expected half-life (T½) in synovial fluid is 3 to 6 hours. Two hours after the peak plasma concentration, the concentration of diclofenac in synovial fluid exceeds that in plasma and remains higher for up to 12 hours.

Diclofenac has been detected at low concentrations (100 ng/mL) in breast milk in one lactating woman. The estimated amount of drug transferred to the infant via breast milk is equivalent to 0.03 mg/kg/day.

Biotransformation of diclofenac occurs partially through glucuronidation of the intact molecule, but primarily via mono- and poly-hydroxylation and methoxylation, leading to the formation of several phenolic metabolites, most of which are further converted into glucuronide conjugates. Two of these phenolic metabolites are biologically active, although their activity is significantly less than that of diclofenac.

The total systemic clearance of diclofenac in plasma is 263±56 mL/min (mean ± SD). The terminal half-life (T½) in plasma is 1–2 hours. Four metabolites, including two active ones, also have short plasma elimination half-lives of 1–3 hours. Approximately 60% of the administered dose is excreted in urine as the glucuronide conjugate of the intact molecule and as metabolites, most of which are also converted into glucuronide conjugates. Less than 1% is excreted unchanged. The remainder of the dose is eliminated as metabolites via bile in feces.

Elderly patients. No age-related differences in absorption, metabolism, or excretion of the drug have been observed, except that in elderly patients, a 15-minute intravenous infusion resulted in plasma concentrations 50% higher than those observed in young healthy volunteers.

Patients with renal impairment. Based on the pharmacokinetics after single-dose administration, accumulation of unchanged active substance is not expected in patients with renal impairment when following the standard dosing regimen. With creatinine clearance less than 10 mL/min, plasma levels of hydroxymetabolites are approximately four times higher than in patients with normal renal function. However, metabolites are ultimately eliminated via bile.

Patients with hepatic disease. In patients with chronic hepatitis or compensated cirrhosis of the liver, the kinetics and metabolism of diclofenac are similar to those in patients without liver disease.

Clinical characteristics.

Indications. The drug is indicated for intramuscular administration for the treatment of:

• inflammatory and degenerative forms of rheumatism, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, spondyloarthritis, vertebral pain syndrome, non-articular rheumatism;
• acute gout attacks;
• renal and biliary colic;
• pain and swelling following trauma and surgery;
• severe migraine attacks.

The drug is indicated for intravenous infusion for the treatment or prophylaxis of postoperative pain.

Contraindications.

• Hypersensitivity to the components of the drug, sodium metabisulfite.

• Bleeding or gastrointestinal tract perforation in medical history associated with previous treatment with nonsteroidal anti-inflammatory drugs (NSAIDs).

• Active peptic ulcer disease/bleeding or recurrent peptic ulcer disease/bleeding in medical history (two or more separate episodes of confirmed ulcer or bleeding).

• Third trimester of pregnancy.

• As with other NSAIDs, diclofenac is contraindicated in patients in whom administration of ibuprofen, acetylsalicylic acid, or other NSAIDs provokes attacks of bronchial asthma, angioedema, urticaria, or acute rhinitis.

• Inflammatory bowel diseases (e.g., Crohn’s disease or ulcerative colitis).

• Hepatic failure.

• Renal failure (creatinine clearance <15 ml/min/1.73 m²).

• Congestive heart failure (NYHA II-IV).

• High risk of postoperative bleeding, coagulation disorders, hemostasis disorders, hematopoietic disorders, or cerebrovascular hemorrhage.

• Treatment of perioperative pain in aortocoronary bypass surgery (or use of cardiopulmonary bypass apparatus).

• Ischemic heart disease in patients with angina pectoris or history of myocardial infarction.

• Cerebrovascular diseases in patients with history of stroke or transient ischemic attacks.

• Peripheral arterial diseases.

For intravenous use only.

• Concomitant use of NSAIDs or anticoagulants (including low-dose heparin).
• History of hemorrhagic diathesis, confirmed or suspected cerebrovascular hemorrhage in medical history.
• Surgeries associated with high risk of bleeding.
• History of bronchial asthma.
• Moderate or severe renal function impairment (serum creatinine >160 µmol/L).
• Hypovolemia or dehydration from any cause.

Interaction with other medicinal products and other forms of interaction. The interactions listed below have been observed with the use of sodium diclofenac solution for injection and/or other dosage forms of diclofenac.

Lithium, digoxin. Diclofenac may increase plasma concentrations of lithium and digoxin when used concomitantly; therefore, monitoring of their serum levels is recommended.

Diuretics and antihypertensive agents. As with other NSAIDs, concomitant use of diclofenac with diuretics or antihypertensive agents (β-blockers, angiotensin-converting enzyme [ACE] inhibitors) may reduce their antihypertensive effect due to inhibition of vasodilatory prostaglandin synthesis. Therefore, such combinations should be used with caution, and patients, especially elderly patients, should be under close monitoring for arterial pressure. Adequate hydration should be maintained, and renal function should be monitored after initiation and regularly during concomitant therapy, particularly with diuretics and ACE inhibitors due to increased risk of nephrotoxicity.

Agents causing hyperkalemia. Concomitant therapy with potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may be associated with increased serum potassium levels; therefore, more frequent monitoring of patients is recommended.

Anticoagulants and antithrombotic agents. Precautions are recommended, as concomitant administration may increase the risk of bleeding. Although there are no data on the effect of diclofenac on anticoagulant activity, isolated reports indicate an increased risk of bleeding in patients receiving diclofenac and anticoagulants simultaneously.

Therefore, to ensure no dosage adjustments of anticoagulants are needed, careful monitoring of such patients is recommended. As with other NSAIDs, high-dose diclofenac may temporarily inhibit platelet aggregation.

Other NSAIDs, including selective COX-2 inhibitors, and corticosteroids. Concomitant administration of diclofenac with other systemic NSAIDs or corticosteroids may increase the risk of gastrointestinal bleeding or ulceration. Concomitant use of two or more NSAIDs should be avoided.

Selective serotonin reuptake inhibitors (SSRIs). Concomitant administration of systemic NSAIDs and SSRIs may increase the risk of gastrointestinal bleeding.

Antidiabetic agents. Data indicate that diclofenac can be used with oral antidiabetic agents without affecting their clinical efficacy. However, isolated cases of both hypoglycemic and hyperglycemic effects have been reported, requiring dosage adjustments of antidiabetic agents during diclofenac treatment. In such cases, blood glucose monitoring is necessary as a precaution during concomitant therapy.

Isolated reports also exist of cases of metabolic acidosis when used concomitantly with diclofenac, particularly in patients with pre-existing renal function impairment.

Methotrexate. Diclofenac may inhibit methotrexate clearance in renal tubules, leading to elevated methotrexate levels. Caution is recommended when administering NSAIDs, including diclofenac, less than 24 hours before methotrexate treatment, as this may increase methotrexate concentration in blood and enhance its toxicity. Serious toxicity cases have been reported when methotrexate and NSAIDs, including diclofenac, were administered within 24 hours of each other. This interaction is mediated by methotrexate accumulation due to impaired renal excretion in the presence of NSAIDs.

Cyclosporine. Diclofenac, like other NSAIDs, may increase cyclosporine nephrotoxicity due to effects on renal prostaglandins. Therefore, it should be used at lower doses than in patients not receiving cyclosporine.

Tacrolimus. Concomitant use of NSAIDs with tacrolimus may increase the risk of nephrotoxicity, possibly mediated by renal anti-prostaglandin effects of NSAIDs and calcineurin inhibitors.

Quinolone antibacterial agents. Isolated reports exist of seizures that may result from concomitant use of quinolones and NSAIDs. This may occur in patients both with and without a history of epilepsy or seizures. Therefore, caution should be exercised when considering the use of quinolones in patients already receiving NSAIDs.

Phenytoin. When phenytoin is administered concomitantly with diclofenac, monitoring of phenytoin plasma concentration is recommended due to expected increased phenytoin exposure.

Cholestyramine and colestipol. These agents may cause delayed or reduced absorption of diclofenac. Therefore, diclofenac should be administered at least 1 hour before or 4–6 hours after administration of cholestyramine/colestipol.

Cardiac glycosides. Concomitant use of cardiac glycosides and NSAIDs may exacerbate heart failure, reduce glomerular filtration rate, and increase glycoside levels in plasma.

Mifepristone. NSAIDs should not be used within 8–12 days after mifepristone administration, as NSAIDs may reduce its effect.

CYP2C9 inhibitors. Caution is recommended when co-administering diclofenac with CYP2C9 inhibitors (e.g., voriconazole), as this may lead to significant increases in diclofenac Cmax and AUC due to inhibition of its metabolism.

CYP2C9 inducers. Caution is necessary when co-administering diclofenac with CYP2C9 inducers (e.g., rifampicin). This may lead to significant increases in plasma concentration and AUC of diclofenac.

Special precautions for use. Adverse effects can be minimized by using the lowest effective dose for the shortest possible duration necessary to control symptoms.

Avoid concomitant use of the drug with systemic NSAIDs, including selective COX-2 inhibitors, due to lack of synergistic benefit and potential for additional adverse effects.

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, may occur even without prior exposure to diclofenac. Hypersensitivity reactions may progress to Kounis syndrome, a serious allergic reaction that may cause myocardial infarction. Symptoms of such reactions may include chest pain occurring in combination with an allergic reaction to diclofenac.

As with other NSAIDs, the drug, due to its pharmacodynamic properties, may mask signs and symptoms of infection.

Gastrointestinal effects. With use of all NSAIDs, including diclofenac, cases of gastrointestinal bleeding (hematemesis, melena), ulceration, or perforation, which may be fatal, have been reported, occurring at any time during treatment, with or without warning symptoms, and in patients with history of serious gastrointestinal events. These events usually have more serious consequences in elderly patients. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the drug should be discontinued.

Use of NSAIDs, including diclofenac, may be associated with increased risk of "anastomotic failure." Careful medical monitoring and caution are required when using diclofenac, as with all NSAIDs, after surgical procedures on gastrointestinal organs. Particular caution should be exercised when prescribing diclofenac to patients with symptoms indicating gastrointestinal disturbances or with history of gastric or intestinal ulcer, bleeding, or perforation. The risk of gastrointestinal bleeding, ulceration, or perforation is higher with increased NSAID doses, including diclofenac, and in patients with history of ulcers, especially complicated by bleeding or perforation.

Elderly patients have an increased frequency of adverse reactions when using NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal.

To reduce the risk of gastrointestinal toxicity in patients with history of ulcers, especially complicated by bleeding or perforation, and in elderly patients, treatment should be initiated and maintained at the lowest effective doses.

For such patients, as well as for patients requiring concomitant use of drugs containing low-dose acetylsalicylic acid or other drugs likely to increase the risk of gastrointestinal adverse effects, consideration should be given to combined therapy with protective agents (e.g., proton pump inhibitors or misoprostol).

Patients with history of gastrointestinal toxicity, especially elderly patients, should report any unusual abdominal symptoms (particularly gastrointestinal bleeding). Caution is also required for patients receiving concomitant drugs that may increase the risk of ulcer or bleeding, such as systemic corticosteroids, anticoagulants (e.g., warfarin), antiplatelet agents (e.g., acetylsalicylic acid), or SSRIs.

Hepatic effects. Close medical supervision is required if the drug is prescribed to patients with impaired liver function, as their condition may worsen.

As with other NSAIDs, including diclofenac, levels of one or more liver enzymes may increase. During long-term treatment with the drug, regular monitoring of liver function is required as a precaution.

If liver function abnormalities persist or worsen, if clinical signs or symptoms may be related to progressive liver disease, or if other manifestations occur (e.g., eosinophilia, rash), the drug should be discontinued.

The course of diseases such as hepatitis may occur without prodromal symptoms.

Caution is required if the drug is used in patients with hepatic porphyria, due to the potential risk of provoking an attack.

Renal effects. Since fluid retention and edema have been reported with NSAID treatment, including diclofenac, particular attention should be paid to patients with cardiac or renal dysfunction, history of arterial hypertension, elderly patients, patients receiving concomitant diuretic therapy or drugs significantly affecting renal function, and patients with significant reduction in extracellular fluid volume from any cause, e.g., before or after major surgery. In such cases, monitoring of renal function is recommended as a precaution. Discontinuation of therapy usually leads to return to the pre-treatment state.

Skin effects. Serious skin reactions (some of which were fatal), including exfoliative dermatitis, Stevens-Johnson syndrome, Lyell’s syndrome, and generalized bullous fixed drug eruption, have very rarely been reported with diclofenac use. The highest risk of these reactions appears to occur early in the treatment course, mostly within the first month of therapy. The drug should be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity.

Injection site reactions. Injection site reactions have been reported after intramuscular administration of diclofenac, including injection site necrosis and medicinal embolism, also known as Nicolau syndrome (especially after accidental subcutaneous injection). Appropriate needle selection and injection technique should be followed when administering diclofenac intramuscularly.

Systemic lupus erythematosus (SLE) and mixed connective tissue diseases. Patients with SLE and mixed connective tissue diseases may have an increased risk of developing aseptic meningitis.

Cardiovascular and cerebrovascular effects. Diclofenac may be prescribed to patients with significant cardiovascular risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful clinical evaluation. Since cardiovascular risks of diclofenac may increase with dose and duration of treatment, it should be used for as short a period as possible and at the lowest effective dose. Patient needs for diclofenac use for symptom relief and response to therapy should be periodically reviewed. Use with caution in patients aged 65 years and older.

Patients with history of arterial hypertension and/or mild to moderate congestive heart failure require appropriate monitoring and recommendations, as fluid retention and edema have been reported with diclofenac use.

Data indicate that use of diclofenac, especially at high doses (150 mg daily) and for prolonged periods, may be associated with a slight increase in the risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

Diclofenac should be prescribed to patients with uncontrolled arterial hypertension, congestive heart failure, stable ischemic heart disease, peripheral arterial diseases, and/or cerebrovascular disease only after careful risk-benefit assessment and at a dose not exceeding 100 mg daily. A similar assessment should be conducted before initiating long-term treatment in patients with risk factors for cardiovascular events (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking).

Patients should be informed about the possibility of serious events (chest pain, dyspnea, weakness, speech disturbances) that may occur at any time. In such cases, immediate medical attention is required.

Hematological parameters. Monitoring of blood tests is recommended during prolonged use of the drug.

As with other NSAIDs, diclofenac may temporarily inhibit platelet aggregation. Close monitoring is required in patients with hemostasis disorders, hemorrhagic diathesis, or hematological disorders.

History of asthma. Patients with bronchial asthma, seasonal allergic rhinitis, nasal mucosal edema (nasal polyps), chronic obstructive pulmonary diseases, or chronic respiratory tract infections (especially associated with allergic, rhinitis-like symptoms) more frequently than others experience reactions to NSAIDs resembling asthma exacerbation (so-called analgesic intolerance/analgesic asthma), angioedema, or urticaria. Therefore, special precautions (readiness for emergency care) are recommended for such patients. This also applies to patients with allergy to other substances manifesting as skin reactions, pruritus, or urticaria.

As with other drugs that inhibit prostaglandin synthetase activity, diclofenac may provoke bronchospasm in patients with bronchial asthma or history of bronchial asthma.

Female fertility. Use of the drug may impair fertility in women; therefore, it is not recommended for women wishing to become pregnant. Consider discontinuation of the drug in women who may have difficulty conceiving or who are undergoing infertility evaluation.

Sodium metabisulfite (E 223), included in the drug formulation, may rarely cause hypersensitivity reactions and bronchospasm.

Use during pregnancy or breastfeeding.

Pregnancy. From the 20th week of pregnancy, use of diclofenac may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation of treatment. In the first and second trimesters of pregnancy, the drug may be prescribed only if the expected benefit to the mother outweighs the potential risk to the fetus and only at the lowest effective dose. The duration of treatment should be as short as possible. Prenatal monitoring for oligohydramnios should be considered after diclofenac exposure for several days starting from the 20th week of pregnancy. Diclofenac use should be discontinued if oligohydramnios is detected.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Data indicate an increased risk of miscarriage and/or risk of cardiac defects and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular defects increased from less than 1% to approximately 1.5%.

The risk may increase with increasing dose and duration of treatment. In animal studies, administration of prostaglandin synthesis inhibitors has been shown to increase pre- and post-implantation losses and embryonic/fetal mortality.

Furthermore, in animals receiving prostaglandin synthesis inhibitors during organogenesis, an increased frequency of various developmental abnormalities, including cardiovascular, has been observed. If the drug is used in women wishing to become pregnant or during the first trimester of pregnancy, the drug dose should be as low as possible, and the treatment duration as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may affect the fetus as follows:

• cardiopulmonary toxicity (with premature closure of the arterial duct and pulmonary hypertension);
• impaired renal function, which may progress to renal failure with oligohydramnios (see above).

On the mother and newborn, especially near the end of pregnancy:

• possible prolonged bleeding time, anti-aggregatory effect, which may occur even at very low doses;
• inhibition of uterine contractions, leading to delayed or prolonged labor.

Therefore, the drug is contraindicated during the third trimester of pregnancy.

Breastfeeding. As with other NSAIDs, diclofenac passes into breast milk in small amounts. Therefore, to avoid adverse effects on the infant, the drug should not be used during breastfeeding.

Fertility. As with other NSAIDs, the drug may affect female fertility. The drug is not recommended for women planning to become pregnant. Women experiencing difficulties with conception or undergoing evaluation for infertility should discontinue use of the drug.

Ability to affect reaction speed when driving vehicles or operating machinery. Patients who experience visual disturbances, dizziness, vertigo, somnolence, or other nervous system disturbances during diclofenac treatment should refrain from driving vehicles or operating machinery.

Administration and dosage. The dose should be individually adjusted, starting with the lowest effective dose, and the drug should be used at the lowest effective dose for as short a duration as possible, considering the treatment goals for each individual patient. Do not use for more than 2 days. If further treatment is needed, it may be continued with other dosage forms containing diclofenac.

One ampoule is intended for single use only. The solution should be used immediately after opening the ampoule. Any unused content must be discarded.

Intramuscular injection. To prevent nerve or other tissue damage at the site of intramuscular injection, the following rules should be followed. Such damage may lead to muscle weakness, muscle paralysis, and paresthesia.

The usual dose is 1 ampoule of 75 mg daily by deep injection into the upper outer quadrant of the gluteal muscle. In severe cases (e.g., colic), the daily dose may be increased to two injections of 75 mg, with several hours between injections (one injection in each buttock). Alternatively, 1 ampoule of 75 mg may be combined with other dosage forms of the drug (e.g., tablets, suppositories) up to a total maximum daily dose of 150 mg.

In migraine attacks, clinical experience is limited to cases starting with 1 ampoule of 75 mg, with the dose administered, if possible, immediately after using 100 mg suppositories on the same day (if necessary). The total daily dose should not exceed 175 mg on the first day. No data are available on use of the drug for migraine treatment for more than one day.

Intravenous infusions. The drug should not be administered as an intravenous bolus injection.

Immediately before starting intravenous infusion of diclofenac, depending on the required duration, the contents of 1 ampoule should be diluted in 100–500 ml of 0.9% sodium chloride solution or 5% glucose solution buffered with sodium bicarbonate injection solution (0.5 ml of 8.4% solution or 1 ml of 4.2% solution, or corresponding volume of another concentration) taken from a freshly opened container. Only clear solutions should be used. If crystals or precipitate are present in the solution, it should not be used for infusion.

Two alternative dosing regimens are recommended. For treatment of moderate to severe postoperative pain, 75 mg should be administered continuously over 30 minutes to 2 hours. If necessary, treatment may be repeated after several hours, but the dose should not exceed 150 mg within any 24-hour period.

For prophylaxis of postoperative pain, a loading dose of 25–50 mg should be administered 15 minutes to 1 hour after surgery, followed by continuous infusion at approximately 5 mg/hour up to a maximum daily dose of 150 mg.

Elderly patients (aged 65 years and older). Although pharmacokinetics of the drug in elderly patients is not clinically significantly impaired, NSAIDs should be used with particular caution in such patients, who are generally more susceptible to adverse reactions. In particular, for frail elderly patients or patients with low body weight, the lowest effective doses of the drug are recommended (see also section "Special precautions for use"). Patients should also be evaluated for gastrointestinal bleeding during NSAID treatment.

Children. The drug in this dosage form should not be used in children.

Overdose.

Symptoms. The typical clinical picture of diclofenac overdose is absent. Overdose may cause symptoms such as headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, diarrhea, dizziness, disorientation, excitement, coma, somnolence, tinnitus, loss of consciousness, or seizures. In severe poisoning, acute renal failure and liver damage may occur.

Treatment. Within one hour after ingestion of a potentially toxic amount of the drug, consider administration of activated charcoal orally. Additionally, in adults, consider gastric lavage within 1 hour after ingestion of a potentially toxic amount of the drug. Intravenous diazepam should be administered for frequent or prolonged seizures. Other measures may be indicated depending on the patient's clinical condition. Treatment is symptomatic.

Adverse reactions. The adverse effects listed below include those associated with administration of sodium diclofenac during short- and long-term use.

Blood and lymphatic system: thrombocytopenia, leukopenia, anemia (including hemolytic and aplastic), agranulocytosis.

Immune system: hypersensitivity, anaphylactic and anaphylactoid reactions (including arterial hypotension and shock), angioedema (including facial swelling).

Psychiatric disorders: disorientation, depression, insomnia, night terrors, irritability, and other psychiatric disorders.

Nervous system: headache, dizziness, somnolence, fatigue, paresthesia, memory impairment, seizures, anxiety, tremor, aseptic meningitis, taste disturbance, stroke, confusion, hallucinations, sensory disturbances, malaise.

Eye disorders: visual disturbances, blurred vision, diplopia, optic neuritis.

Ear and labyrinth disorders: vertigo, tinnitus, hearing disturbances.

Cardiac disorders: palpitations, chest pain, heart failure, myocardial infarction, Kounis syndrome.

Vascular disorders: arterial hypertension, arterial hypotension, vasculitis.

Respiratory, thoracic and mediastinal disorders: asthma (including dyspnea), pneumonitis.

Gastrointestinal disorders: nausea, vomiting, diarrhea, dyspepsia, abdominal pain, flatulence, anorexia, gastritis, gastrointestinal bleeding, hematemesis, hemorrhagic diarrhea, melena, gastric or intestinal ulcer with bleeding, gastrointestinal stenosis with perforation (sometimes fatal, especially in elderly patients), which may lead to peritonitis; colitis (including hemorrhagic colitis and exacerbation of ulcerative colitis or Crohn’s disease), constipation, stomatitis (including ulcerative stomatitis), glossitis, esophageal disorders, membranous intestinal strictures, pancreatitis.

Hepatobiliary disorders: increased transaminase levels, hepatitis, jaundice, liver function impairment, fulminant hepatitis, hepatonecrosis, liver failure.

Skin and subcutaneous tissue disorders: skin rashes (including with "unknown" frequency: fixed drug eruption, generalized bullous fixed drug eruption), urticaria, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, Lyell’s syndrome, exfoliative dermatitis, alopecia, photosensitivity reaction, purpura, allergic purpura, pruritus.

Renal and urinary disorders: acute kidney injury (acute renal failure), hematuria, proteinuria, nephrotic syndrome, interstitial nephritis, renal papillary necrosis.

General disorders and administration site conditions: injection site reaction, pain, induration, swelling, medicinal embolism (Nicolau syndrome), injection site necrosis, injection site abscess.

Reproductive system and breast disorders: impotence.

Data exist on the possible increased risk of thrombotic complications (e.g., myocardial infarction or stroke) associated with diclofenac use, particularly at high therapeutic doses (150 mg daily) and with prolonged use.

Visual disturbances. Visual disturbances such as visual disturbances, worsening vision, and diplopia are class effects of NSAIDs and are usually reversible after discontinuation of the drug. The most likely mechanism of visual disturbances is inhibition of prostaglandin and other related compound synthesis, which, by disrupting retinal blood flow regulation, contributes to the development of visual disturbances. If such symptoms occur during diclofenac treatment, ophthalmological examination should be performed to exclude other possible causes.

Shelf life. 5 years.

Storage conditions. Store in original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Incompatibility. Do not mix the drug with other injection solutions.

0.9% sodium chloride solution and 5% glucose solution without sodium bicarbonate as additive pose a risk of supersaturation, which may lead to crystal or precipitate formation. Other infusion solutions should not be used.

Packaging. 3 ml in ampoules, 5 in a box, 5 in a blister pack in a box.

Prescription category. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROV'YA".

Manufacturer's location and address of business activity. Ukraine, 61013, Kharkiv region, Kharkiv, Shevchenko Street, 22.