Diclofenac sodium

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DICLOFENAC SODIUM (Diclofenac sodium)

Composition:

Active ingredient: diclofenac;

1 ml of solution contains 25 mg of sodium diclofenac;

Excipients: mannite, sodium metabisulfite (E 223), benzyl alcohol, propylene glycol, 1 M solution of sodium hydroxide, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless or slightly yellowish solution with a faint characteristic odor of benzyl alcohol, practically free from particles.

Pharmacotherapeutic group.

Nonsteroidal anti-inflammatory and antirheumatic agents. Acetic acid derivatives and related compounds. ATC code M01A B05.

Pharmacological Properties.

Pharmacodynamics.

Diclofenac sodium is a non-steroidal compound with pronounced anti-rheumatic, anti-inflammatory, analgesic, and antipyretic properties. Inhibition of prostaglandin biosynthesis, demonstrated in experimental studies, is considered the primary mechanism of its action. Prostaglandins play a key role in the development of inflammation, pain, and fever.

In rheumatic diseases, the anti-inflammatory and analgesic properties of the drug produce a clinical response characterized by marked relief of signs and symptoms: pain at rest and during movement, morning stiffness, and joint swelling, along with noticeable improvement in function.

Diclofenac is capable of producing a pronounced analgesic effect on moderate to severe non-rheumatic pain within 15–30 minutes.

Diclofenac has also demonstrated a significant effect on migraine attacks.

In post-traumatic and postoperative conditions associated with inflammation, diclofenac rapidly relieves spontaneous pain and pain during movement, and reduces swelling caused by inflammation and injury.

When the drug is used concomitantly with opioid analgesics for postoperative pain relief, diclofenac significantly reduces their required dosage.

Diclofenac Sodium Injection Solution in ampoules is particularly indicated for initiating treatment of inflammatory and degenerative rheumatic diseases and for pain conditions due to non-rheumatic inflammation.

Pharmacokinetics.

Absorption. After intramuscular injection of 75 mg diclofenac, absorption begins immediately, and mean peak plasma concentrations of approximately 2.5 µg/mL (8 µmol/L) are reached within about 20 minutes. The extent of absorption may be linearly dependent on the dose administered.

When 75 mg of diclofenac is administered by intravenous infusion over 2 hours, mean peak plasma concentrations are approximately 1.9 µg/mL (5.9 µmol/L). Shorter infusion durations lead to higher peak plasma concentrations, while longer infusions result in plasma concentrations proportional to the infusion rate after 3–4 hours. After intramuscular injection or oral administration of enteric-coated tablets or rectal suppositories, plasma concentrations decline rapidly immediately after peak levels are reached.

The area under the concentration-time curve (AUC) following intramuscular or intravenous administration is approximately twice that observed after oral or rectal administration, because about half of the active substance undergoes metabolism during its first pass through the liver (first-pass effect) when administered orally or rectally.

Pharmacokinetic properties do not change after repeated administration. With adherence to recommended dosing intervals, accumulation of the drug does not occur.

Distribution. 99.7% of diclofenac is bound to plasma proteins, primarily to albumin (99.4%). The apparent volume of distribution is 0.12–0.17 L/kg.

Diclofenac penetrates into synovial fluid, where maximum concentrations are reached 2–4 hours after peak plasma levels. The half-life in synovial fluid ranges from 3 to 6 hours. Two hours after peak plasma concentration is achieved, diclofenac concentrations in synovial fluid exceed those in plasma and remain higher for up to 12 hours.

Biological Transformation. Diclofenac undergoes biotransformation partly via glucuronidation of the intact molecule, but primarily through single and multiple hydroxylations and methoxylations, 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.

Elimination. The total systemic clearance of diclofenac from plasma is 263 ± 56 mL/min (mean value ± SD). The terminal half-life in plasma is 1–2 hours. Four metabolites, including two active ones, also have short plasma half-lives of 1–3 hours. One metabolite has a much longer plasma half-life; however, this metabolite is practically inactive.

Approximately 60% of the administered dose is excreted in urine as glucuronide conjugates 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 via bile into feces as metabolites.

Special Patient Groups.

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

In patients with impaired renal function, accumulation of the active substance is not expected when standard dosing regimens are followed. With creatinine clearance < 10 mL/min, steady-state plasma levels of hydroxy-metabolites are approximately four times higher than in healthy patients.

Thus, metabolites are ultimately eliminated via bile.

In patients with chronic hepatitis or decompensated cirrhosis, the kinetics and metabolism of diclofenac are similar to those in healthy subjects.

Clinical characteristics.

Indications.

The drug is indicated for intramuscular administration in 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 in the treatment or prevention of postoperative pain.

Contraindications.

• Hypersensitivity to diclofenac, sodium metabisulfite, or any other component of the drug.
• History of gastrointestinal bleeding or perforation related to previous treatment with nonsteroidal anti-inflammatory drugs (NSAIDs).
• Active peptic ulcer/hemorrhage or recurrent peptic ulcer/hemorrhage in history (two or more separate episodes of confirmed ulcer or bleeding).
  • As with other NSAIDs, diclofenac is contraindicated in patients in whom administration of ibuprofen, acetylsalicylic acid, or other nonsteroidal anti-inflammatory agents triggers attacks of bronchial asthma, angioneurotic edema, urticaria, acute rhinitis/nasal polyps, bronchospasm, or other allergic reactions.
• Inflammatory bowel diseases (e.g., Crohn’s disease or ulcerative colitis).
• Active gastric or intestinal ulcer; gastrointestinal hemorrhage or perforation.
• Hepatic insufficiency (Child–Pugh class C, liver cirrhosis and ascites).
• Renal insufficiency (creatinine clearance < 30 ml/min).
• Congestive heart failure (NYHA II–IV).
• High risk of postoperative bleeding, coagulation disorders, hemostatic disorders, hematopoietic disorders, or cerebrovascular hemorrhage.
• Treatment of perioperative pain associated with coronary artery bypass grafting (CABG) (or use of cardiopulmonary bypass).
• 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 disease.
• This medicinal form is contraindicated in children.
• Third trimester of pregnancy.

Specifically regarding intravenous administration.

• Concomitant use of NSAIDs or anticoagulants (including low-dose heparin).
• History of hemorrhagic diathesis, confirmed or suspected history of cerebrovascular hemorrhage.
• 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. When used concomitantly, diclofenac may increase plasma lithium concentrations. Monitoring of serum lithium levels is recommended.

Digoxin. When used concomitantly, diclofenac may increase plasma digoxin concentrations. Monitoring of serum digoxin levels is recommended.

Diuretics and antihypertensive agents. As with other NSAIDs, concomitant use of diclofenac with diuretics or antihypertensive agents (e.g., 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 closely monitored for blood pressure. Adequate hydration should be ensured, and renal function should be monitored after initiation and on a regular basis during concomitant therapy, particularly when diuretics or ACE inhibitors are used, due to increased risk of nephrotoxicity.

Medicinal products known to cause hyperkalemia. Concomitant treatment with potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may lead to increased serum potassium levels; therefore, more frequent monitoring of patients is recommended.

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

Anticoagulants and antithrombotic agents. Caution is advised, as concomitant use may increase the risk of bleeding. Although clinical studies do not indicate a direct effect of diclofenac on anticoagulant activity, isolated reports suggest an increased risk of bleeding in patients receiving diclofenac and anticoagulants simultaneously. Therefore, careful monitoring of patients receiving both diclofenac and anticoagulants is recommended, with dose adjustment of anticoagulants if necessary. Like other NSAIDs, high-dose diclofenac may transiently inhibit platelet aggregation.

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

Antidiabetic agents. Clinical studies have shown that diclofenac can be used concomitantly with oral antidiabetic agents without affecting their clinical efficacy. However, isolated cases of both hypoglycemic and hyperglycemic effects have been reported, requiring dose adjustments of antidiabetic agents during diclofenac therapy. In such cases, blood glucose monitoring is necessary as a precautionary measure during concomitant therapy.

There have also been isolated reports of metabolic acidosis with concomitant use of diclofenac, particularly in patients with pre-existing renal impairment.

Cholestyramine and colestipol. Concomitant use of diclofenac with cholestyramine or colestipol may delay or reduce diclofenac absorption by approximately 30% and 60%, respectively. Therefore, diclofenac should be administered at least 1 hour before or 4–6 hours after cholestyramine/colestipol.

Agents stimulating drug-metabolizing enzymes. Agents that induce enzymes, such as rifampicin, carbamazepine, phenytoin, and St. John’s wort (Hypericum perforatum), may theoretically reduce plasma concentrations of diclofenac.

Methotrexate. Diclofenac may inhibit renal tubular clearance of methotrexate, leading to elevated methotrexate levels. Caution is recommended when using NSAIDs, including diclofenac, within 24 hours before or after methotrexate therapy, as this may increase methotrexate blood concentrations and enhance its toxicity. Serious cases of toxicity 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 administered at lower doses than in patients not receiving cyclosporine.

Tacrolimus. Concomitant use of NSAIDs with tacrolimus increases the risk of nephrotoxicity, possibly mediated by renal anti-prostaglandin effects of NSAIDs and calcineurin inhibitors. Therefore, diclofenac should be used at lower doses in patients receiving tacrolimus.

Quinolone antibiotics. Isolated reports suggest an increased risk of seizures with 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 quinolone use in patients already receiving NSAIDs.

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

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

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

Strong CYP2C9 inhibitors. Caution is required when using diclofenac concomitantly with strong CYP2C9 inhibitors (e.g., voriconazole), which may lead to a significant increase in diclofenac’s maximum plasma concentration and exposure due to inhibition of its metabolism.

Probenecid. Medicinal products containing probenecid may delay the elimination of diclofenac.

Special precautions for use.

Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control (alleviate) symptoms.

Concomitant use of this medicinal product with systemic NSAIDs, including selective COX-2 inhibitors, should be avoided due to the absence of any synergistic benefit and the potential for additional adverse effects.

Caution is advised when prescribing the drug to patients aged 65 years and older. In particular, for elderly patients with poor general health and those with low body weight, the lowest effective doses are recommended.

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, may occur rarely 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.

The use of NSAIDs, including diclofenac, is associated with an increased risk of gastrointestinal anastomotic bleeding. Careful medical monitoring and caution are recommended when prescribing diclofenac after gastrointestinal surgery.

Effects of NSAIDs on the kidneys include fluid retention with edema and/or arterial hypertension. Therefore, diclofenac should be used with caution in patients with cardiac dysfunction and other conditions predisposing to fluid retention. Caution is also required when treating patients receiving concomitant diuretics or ACE inhibitors or those prone to hypovolemia.

Like other NSAIDs, diclofenac may mask signs of infection.

Injection site reactions

Injection site reactions have been reported following intramuscular administration of diclofenac, including injection site necrosis and medication embolism, also known as Nicolau syndrome (particularly after inadvertent subcutaneous injection). Strict adherence to intramuscular injection instructions is essential to avoid adverse reactions at the injection site, which may lead to muscle weakness, paralysis, hypoesthesia, medication embolism (Nicolau syndrome), and injection site necrosis. An appropriate needle and injection technique should be used when administering diclofenac intramuscularly (see section "Dosage and administration").

Gastrointestinal effects

When using all NSAIDs, including diclofenac, cases of gastrointestinal bleeding (hematemesis, melena), ulceration, or perforation have been reported, which may be fatal and may occur at any time during treatment, with or without warning symptoms, and even in patients with a history of serious gastrointestinal events. In elderly patients, these events usually have more serious consequences. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the drug should be discontinued.

As with all NSAIDs, including diclofenac, careful medical supervision is required; particular caution should be exercised when prescribing diclofenac to patients with symptoms indicating gastrointestinal disorders or with a history of peptic ulcer, gastrointestinal bleeding, or perforation. The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, including diclofenac, and in patients with a history of peptic 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 a history of peptic ulcer, 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 those requiring concomitant use of low-dose acetylsalicylic acid (ASA) or other drugs likely to increase gastrointestinal adverse effects, consideration should be given to combined therapy with protective agents (e.g., proton pump inhibitors or misoprostol).

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

Diclofenac should be prescribed with caution to patients with inflammatory bowel diseases in their medical history, such as Crohn's disease or ulcerative colitis, and careful medical monitoring and appropriate precautions should be implemented, as their condition may worsen.

Hepatic effects

Careful medical monitoring is required when diclofenac is prescribed to patients with impaired liver function, as their condition may worsen.

As with other NSAIDs, levels of one or more liver enzymes may increase. During long-term treatment with the drug (tablets or suppositories), regular monitoring of liver function should be performed as a precautionary measure. If liver function abnormalities persist or worsen, if clinical 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 proceed without prodromal symptoms.

In addition to elevated liver enzyme levels, rare cases of severe hepatic reactions have been reported, including jaundice and fulminant hepatitis, liver necrosis, and liver failure, which in some cases resulted in fatal outcomes.

Caution is required when diclofenac 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 during NSAID therapy, particular attention should be paid to patients with impaired cardiac or renal function (including functional renal insufficiency due to hypovolemia, nephrotic syndrome, lupus nephropathy, and decompensated liver cirrhosis), a 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 for any reason, such as before or after major surgery. In such cases, monitoring of renal function is recommended as a precautionary measure. Discontinuation of therapy usually results in return to the pre-treatment state.

Due to the importance of prostaglandins in maintaining renal blood flow, prolonged treatment with high doses of NSAIDs, including diclofenac, often leads to edema and arterial hypertension.

Skin effects

Very rarely, serious skin reactions, some of which are fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been observed in association with the use of NSAIDs, including diclofenac. The highest risk of these reactions occurs early in the treatment course, with most cases appearing within the first month of treatment. The drug should be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity.

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 higher doses and longer treatment duration, it should be used for the shortest possible duration and at the lowest effective dose. The patient's need for diclofenac to alleviate symptoms and response to therapy should be periodically reviewed. Use with caution in patients aged 65 years and older.

For patients with a history of arterial hypertension and/or mild to moderate congestive heart failure, appropriate monitoring and recommendations are required, as fluid retention and edema have been reported with the use of NSAIDs, including diclofenac.

Clinical data indicate that the use of diclofenac, particularly at high doses (150 mg/day) and for prolonged periods, is associated with a certain increased risk of arterial thrombotic complications (e.g., myocardial infarction or stroke). The patient's need for diclofenac to alleviate symptoms and response to therapy should be periodically reviewed, especially if therapy exceeds 4 weeks.

Diclofenac is not recommended for patients with uncontrolled arterial hypertension, congestive heart failure, stable ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. If use is necessary, it should only be considered after careful risk-benefit assessment at a dosage not exceeding 100 mg per day. 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, and smoking).

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

Studies have shown an increased risk of thrombotic cardiovascular and cerebrovascular complications with certain selective COX-2 inhibitors. It is currently unknown whether this risk is directly related to the COX-1/COX-2 selectivity of individual NSAIDs. There are no study data on long-term treatment with the maximum dose of diclofenac. Until such data are available, careful assessment of the risk-benefit ratio of using diclofenac is required in patients with clinically confirmed ischemic heart disease, cerebrovascular disorders, peripheral arterial occlusive diseases, or significant risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking). Due to the risk, the lowest effective dose should be used for the shortest possible treatment duration.

Hematological effects

With prolonged use of the drug, as with other NSAIDs, monitoring of complete blood count is recommended.

Like other NSAIDs, diclofenac may temporarily inhibit platelet aggregation. Careful monitoring is required for patients with hemostasis disorders.

History of asthma

Patients with bronchial asthma, seasonal allergic rhinitis, nasal mucosal edema (e.g., nasal polyps), chronic obstructive pulmonary diseases, or chronic respiratory tract infections (especially those associated with allergic, rhinitis-like symptoms) are more likely to experience NSAID-related reactions resembling asthma exacerbations (also related to analgesic intolerance/analgesic-induced asthma), Quincke's edema, or urticaria. Therefore, special precautions (readiness for emergency intervention) are recommended for such patients. This also applies to patients with allergies to other substances, e.g., skin reactions, pruritus, or urticaria.

Like other drugs that inhibit prostaglandin synthetase activity, sodium diclofenac and other NSAIDs may provoke bronchospasm in patients with bronchial asthma or with a history of bronchial asthma.

Special warnings regarding inactive ingredients

Benzyl alcohol: Do not use in premature infants and newborns. May cause toxic and allergic reactions in infants and children under 3 years of age.

Metabisulfites may cause allergic-type reactions, including anaphylactic symptoms and bronchospasm in sensitive individuals, particularly those with a history of asthma or allergy.

Sodium: Contains less than 1 mmol (23 mg) of sodium per dose, i.e., practically sodium-free.

Use during pregnancy or breastfeeding.

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

Like other NSAIDs, the drug is contraindicated in the third trimester of pregnancy (possible inhibition of uterine contractility and premature closure of the fetal ductus arteriosus).

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Study 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%.

An increased risk with higher doses and longer treatment duration cannot be excluded.

If diclofenac is used in women planning pregnancy or during the first trimester of pregnancy, the drug dose should be as low as possible, and treatment duration should be 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 ductus arteriosus and pulmonary hypertension);
• impaired kidney function, which may progress to renal failure with oligohydramnios;

and in the mother towards the end of pregnancy and in the newborn:

• 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 in the third trimester of pregnancy.

Breastfeeding period. Like other NSAIDs, diclofenac passes into breast milk in small amounts. Therefore, to avoid adverse effects on the infant, diclofenac should not be used during breastfeeding. If treatment is essential, breastfeeding should be discontinued.

Fertility. Like other NSAIDs, diclofenac may affect female fertility. The drug is not recommended for women planning pregnancy. Women experiencing conception difficulties or undergoing infertility investigations should discontinue the drug.

Ability to affect reaction speed when driving or operating machinery.

Patients who experience visual disturbances, dizziness, vertigo, somnolence, or other central nervous system disorders, lethargy, or fatigue during treatment with diclofenac should refrain from driving or operating machinery.

Method of Administration and Dosage

The dose should be individually adjusted, starting with the lowest effective dose, and should be administered for the shortest possible duration.

Adults

Sodium diclofenac, solution for injection, should not be used for longer than 2 days. If continued treatment is necessary, therapy may be continued with diclofenac tablets or suppositories.

Each 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 guidelines should be observed.

The usual dose is 75 mg (1 ampoule) daily administered as a 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 each, administered several hours apart (one injection into each buttock). As an alternative to the 75 mg injection, the drug may be combined with other dosage forms (e.g., tablets, suppositories) up to a total maximum daily dose of 150 mg of sodium diclofenac.

In the treatment of migraine attacks, clinical experience is limited to cases where an initial dose of 1 ampoule (75 mg) is administered, preferably immediately after administration of a 100 mg suppository on the same day (if necessary). The total daily dose should not exceed 175 mg on the first day.

There are no available data on the use of diclofenac for the treatment of migraine attacks beyond one day.

Intravenous Infusion

Sodium diclofenac, solution for injection, should not be administered as an intravenous bolus injection.

Immediately before starting intravenous infusion, diclofenac should be diluted depending on the required duration of infusion 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; then add the contents of 1 ampoule of the drug. Only clear solutions should be used. If crystals or precipitate are present in the solution, it must 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 4–6 hours, but the dose should not exceed 150 mg per day;
• 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.

The drug should be used at the lowest effective dose for the shortest possible duration, taking into account the individual treatment needs of each patient.

Elderly Patients

Although the pharmacokinetics of diclofenac in elderly patients is not impaired to any clinically significant extent, nonsteroidal anti-inflammatory drugs should be used with particular caution in this population, who are generally more susceptible to adverse reactions. In particular, the lowest effective doses are recommended for frail elderly patients or those with low body weight (see section "Special Warnings and Precautions for Use"). Patients should also be monitored for gastrointestinal bleeding during NSAID therapy.

The recommended maximum daily dose of the drug is 150 mg.

Cardiovascular Diseases or Significant Risk Factors

Diclofenac is contraindicated in patients with established congestive heart failure, ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease (see section "Contraindications").

Diclofenac should be prescribed to patients with congestive heart failure or significant cardiovascular risk factors only after careful clinical evaluation. Since cardiovascular risks of diclofenac increase with higher doses and longer duration of treatment, it should be used for the shortest possible duration and at the lowest effective dose (see section "Special Warnings and Precautions for Use").

Children. This medicinal product in the given pharmaceutical form is not used in children.

Overdose.

There is no typical clinical picture of diclofenac overdose.

Symptoms: nausea, vomiting, epigastric pain, gastrointestinal bleeding, diarrhea, dizziness, headache, disorientation, restlessness, coma, drowsiness, tinnitus, loss of consciousness, or convulsions. In severe poisoning, acute renal failure and liver damage may occur.

Treatment. Management of acute NSAID poisoning primarily involves supportive and symptomatic treatment. Supportive measures and symptomatic therapy are necessary to manage complications such as arterial hypotension, renal failure, convulsions, gastrointestinal disturbances, and respiratory depression.

Within 1 hour after ingestion of a potentially toxic amount of the drug, administration of activated charcoal should be considered. Additionally, in adults, gastric lavage should be considered within 1 hour after ingestion of a potentially toxic amount. In cases of frequent or prolonged convulsions, diazepam should be administered intravenously.

Specific interventions such as forced diuresis, dialysis, or hemoperfusion cannot reliably eliminate NSAIDs due to their high plasma protein binding and extensive metabolism.

Adverse Reactions

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

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

Psychiatric disorders: confusion, depression, insomnia, insomnia, nightmares, irritability, and other psychiatric disorders.

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

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

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

Cardiovascular system disorders: palpitations, chest pain, heart failure, myocardial infarction, arterial hypertension/hypotension, vasculitis, Kounis syndrome.

Respiratory system disorders: asthma (including dyspnea), bronchospasm; pneumonitis.

Gastrointestinal disorders: nausea, vomiting, diarrhea, dyspepsia, abdominal pain, flatulence, anorexia, gastritis, gastrointestinal bleeding, vomiting of blood, hemorrhagic diarrhea, melena; gastric or intestinal ulcer with or without bleeding or 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; diaphragm-like stricture of intestinal structures; esophageal disorders, membranous intestinal strictures, pancreatitis; ischemic colitis.

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

Skin and subcutaneous tissue disorders: rash, urticaria, bullous rash, eczema, erythema, erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), exfoliative dermatitis, alopecia, photosensitivity reaction, purpura, allergic purpura, pruritus, Schönlein–Henoch purpura.

Renal and urinary system disorders: fluid retention, edema, arterial hypertension, acute renal failure, hematuria, proteinuria, nephrotic syndrome, tubulointerstitial nephritis, renal papillary necrosis.

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

Reproductive system and breast disorders: impotence.

Clinical studies and epidemiological data suggest an increased risk of thrombotic complications (e.g., myocardial infarction or stroke) associated with the use of diclofenac, particularly at high therapeutic doses (150 mg per day) and with prolonged use.

Visual disturbances.

Visual disorders such as visual disturbances, worsening of vision, and diplopia are class effects of NSAIDs and are generally reversible after discontinuation of the drug. The most likely mechanism of visual disturbances is inhibition of prostaglandin synthesis and other related compounds, which may disrupt retinal blood flow regulation and contribute to the development of visual disorders. If such symptoms occur during diclofenac treatment, an ophthalmological examination should be performed to rule out other possible causes.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all cases of suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Reconstituted infusion solutions must be used immediately.

Storage conditions.

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

Keep out of reach of children.

Incompatibilities.

Generally, Diclofenac Sodium injection solution should not be mixed with other injectable solutions.

Infusion solutions of 0.9% sodium chloride or 5% glucose without sodium bicarbonate as an 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 a vial; 5 vials in a blister; 1, 2, 3, 4, or 20 blisters in a cardboard box.

3 ml in a vial; 5 or 10 vials in a partitioned cardboard box.

Prescription category.

Prescription only.

Manufacturer.

JSC "Lubnipharm".

Manufacturer's address and location of its business activities.

16, Barvinkova Street, Lubny, Poltava region, 37500, Ukraine.