Diclofenac sodium

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DICLOFENAC SODIUM

Composition:

Active substance: diclofenac sodium;

1 ml of solution contains 25 mg of sodium diclofenac;

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

Pharmaceutical form. Solution for injection.

Main physicochemical properties: colorless to slightly yellow solution.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic drugs. Acetic acid derivatives and related substances. ATC code M01AB05.

Pharmacological Properties

Pharmacodynamics

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

Pharmacokinetics

Absorption

After intramuscular administration of 75 mg diclofenac, absorption begins immediately, and mean peak plasma concentrations of approximately 2.558±0.968 µg/mL (2.5 µg/mL = 8 µmol/L) are reached within approximately 20 minutes. The extent of absorption is linearly proportional to the dose administered.

When 75 mg of diclofenac is administered by intravenous infusion over 2 hours, the mean peak plasma concentration is approximately 1.875±0.436 µg/mL (1.9 µg/mL = 5.9 µmol/L). Shorter infusion durations lead to higher peak plasma concentrations, whereas longer infusions result in plasma concentrations proportional to the infusion rate after 3–4 hours. In contrast to the corresponding results after oral administration, when the drug is administered as suppositories or by intramuscular injection, plasma concentration decreases rapidly immediately after peak levels are achieved.

Bioavailability

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 routes avoid first-pass hepatic metabolism.

Distribution

Approximately 99.7% of diclofenac is protein-bound, primarily to albumin (99.4%). Diclofenac distributes into synovial fluid, where maximum concentrations are achieved 2–4 hours after peak plasma levels. The expected half-life in synovial fluid is 3 to 6 hours. Two hours after peak plasma concentration, diclofenac concentrations in synovial fluid exceed those in plasma and remain higher for up to 12 hours.

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

Metabolism

Biotransformation of diclofenac occurs partially via glucuronidation of the intact molecule, but primarily through single and multiple hydroxylation and methoxylation reactions, 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 considerably less than that of diclofenac.

Excretion

Total systemic clearance of diclofenac in plasma is 263±56 mL/min (mean ± SD). The terminal elimination half-life in plasma is 1–2 hours. Four metabolites, including two active ones, also have short plasma half-lives of 1–3 hours.

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 as metabolites via bile in feces.

Special Patient Populations

Elderly Patients. No differences related to age in absorption, metabolism, or excretion of the drug have been observed, except that in five 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 standard dosing regimens are followed. However, when creatinine clearance is less than 10 mL/min, plasma levels of hydroxymetabolites are approximately four times higher than in healthy volunteers. Nevertheless, metabolites are ultimately eliminated via bile.

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

Clinical characteristics.

Indications.

The drug, administered intramuscularly, is indicated 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 hepatic colic;

− pain and swelling following trauma and surgery;

− severe migraine attacks.

The drug, administered as intravenous infusions, is indicated for the treatment or prevention of postoperative pain.

Contraindications.

Known hypersensitivity to the active substance, sodium metabisulfite, or any other components of the drug.

History of gastrointestinal tract bleeding or perforation associated with 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 established 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 nonsteroidal anti-inflammatory agents triggers attacks of bronchial asthma, angioneurotic edema, 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 disturbances, hematopoietic disorders, or cerebrovascular hemorrhage.

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

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

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

Peripheral arterial disease.

This pharmaceutical form is contraindicated in children.

Only regarding intravenous use.

Concomitant use of NSAIDs or anticoagulants (including low-dose heparin).

History of hemorrhagic diathesis, confirmed or suspected history of cerebrovascular hemorrhage.

Surgical procedures associated with high risk of bleeding.

History of bronchial asthma.

Moderate or severe renal impairment (serum creatinine >160 μmol/L).

Hypovolemia or dehydration of any etiology.

Interaction with other medicinal products and other forms of interaction.

Below are interactions observed during administration of sodium diclofenac injection solution and/or other diclofenac formulations.

Lithium. Diclofenac may increase plasma lithium concentrations when used concomitantly. Monitoring of serum lithium levels is recommended.

Digoxin. Diclofenac may increase plasma digoxin concentrations when used concomitantly. Monitoring of serum digoxin levels is recommended.

Diuretics and antihypertensive agents. As with other NSAIDs, concomitant use of diclofenac with diuretics and antihypertensive agents (e.g., beta-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 of concomitant therapy and regularly thereafter, particularly when using diuretics and ACE inhibitors, due to increased risk of nephrotoxicity.

Medicinal products known to cause hyperkalemia. Concomitant use with potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may lead to 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 clinical studies have not demonstrated an effect of diclofenac on anticoagulant activity, isolated reports indicate an increased risk of bleeding in patients receiving diclofenac and anticoagulants simultaneously.

Therefore, to ensure that no dosage adjustments of anticoagulants are required, careful monitoring of such patients is recommended. Like other nonsteroidal anti-inflammatory drugs, diclofenac at high doses may transiently inhibit platelet aggregation.

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

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

Antidiabetic agents. Clinical studies have shown that diclofenac can be used together 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 precautionary measure during concomitant therapy.

Isolated reports also exist of metabolic acidosis during concomitant use with diclofenac, particularly in patients with pre-existing renal impairment.

Methotrexate. Diclofenac may inhibit renal tubular clearance of methotrexate, leading to elevated methotrexate levels. Caution is recommended when administering NSAIDs, including diclofenac, less than 24 hours before or after methotrexate therapy, as this may increase methotrexate blood concentration and enhance its toxicity. Cases of severe 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 may increase the risk of nephrotoxicity, possibly mediated by renal anti-prostaglandin effects of NSAIDs and calcineurin inhibition.

Quinolone antibacterials. Isolated reports suggest seizures may occur with concomitant use of quinolones and NSAIDs. This may occur in patients both with and without 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.

Colestipol and cholestyramine. 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 colestipol/cholestyramine administration.

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

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

Potent CYP2C9 inhibitors. Caution is recommended when co-administering diclofenac with potent CYP2C9 inhibitors (e.g., voriconazole), which may lead to a significant increase in diclofenac plasma maximum concentration and exposure due to inhibition of its metabolism.

CYP2C9 inducers. Caution is required when co-administering diclofenac with CYP2C9 inducers (e.g., rifampicin). This may lead to a significant increase in plasma concentration and exposure of diclofenac.

Special precautions for use.

General.

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

Concomitant use of sodium diclofenac with systemic NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided due to lack of any synergistic benefit and the potential for increased adverse effects.

Caution should be exercised when prescribing the drug to elderly patients. In particular, for frail elderly patients and those with low body weight, the lowest effective doses are recommended.

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, may occur even in the absence of prior exposure to diclofenac. Hypersensitivity reactions may progress to Kounis syndrome, a serious allergic reaction that may lead to myocardial infarction. Symptoms of such reactions may include chest pain occurring in combination with an allergic reaction to diclofenac.

Like other NSAIDs, sodium diclofenac, due to its pharmacodynamic properties, may mask signs and symptoms of infection.

Sodium metabisulfite in the injectable solution may also cause rare but severe hypersensitivity reactions and bronchospasm.

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 can occur at any time during treatment, with or without warning symptoms, and in patients with or without a 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.

As with all NSAIDs, including diclofenac, careful medical monitoring is required; particular caution should be exercised when prescribing diclofenac to patients with symptoms suggesting gastrointestinal disorders or with a history of peptic ulcer, intestinal ulcer, gastrointestinal bleeding, or perforation. The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher doses of NSAIDs, including diclofenac, and in patients with a history of peptic ulcer, especially complicated by bleeding or perforation.

NSAIDs, including diclofenac, may be associated with an increased risk of gastrointestinal anastomotic dehiscence. Close monitoring and caution are recommended when using diclofenac after gastrointestinal surgery.

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 dose.

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

Patients with a history of gastrointestinal toxicity, especially elderly patients, should be advised to 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.

Hepatic effects.

Careful medical monitoring is required if sodium diclofenac 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 sodium diclofenac, periodic monitoring of liver function is recommended as a precautionary measure.

If liver function abnormalities persist or worsen, if clinical signs or symptoms suggest progressive liver disease, or if other manifestations occur (e.g., eosinophilia, rash), sodium diclofenac should be discontinued.

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

Caution is required when sodium diclofenac is used in patients with hepatic porphyria due to the potential to provoke an attack.

Renal effects.

Since fluid retention and edema have been reported during treatment with NSAIDs, including diclofenac, particular attention should be paid to patients with impaired cardiac or renal function, a history of arterial hypertension, elderly patients, those receiving concomitant diuretic therapy or drugs that significantly affect renal function, and patients with significant extracellular fluid volume depletion from any cause (e.g., before or after major surgery). In such cases, monitoring of renal function is recommended as a precautionary measure. Discontinuation of therapy usually leads to return to the pre-treatment state.

Skin effects.

Serious skin reactions (some of which have been fatal), including exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and generalized bullous fixed drug eruption, have been very rarely reported in association with diclofenac. The highest risk of these reactions appears to occur early in treatment, most often within the first month. Sodium diclofenac therapy should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Systemic lupus erythematosus (SLE) and mixed connective tissue diseases.

Patients with SLE and mixed connective tissue diseases may 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, smoking) only after careful clinical assessment. Since cardiovascular risks of diclofenac may increase with higher doses and longer duration of treatment, it should be used for the shortest possible duration and at the lowest effective dose. The patient's need for diclofenac 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 advice are necessary, as fluid retention and edema have been reported with NSAIDs, including diclofenac.

Clinical trial data and epidemiological evidence suggest that diclofenac use, particularly at high doses (150 mg/day) and over long durations, may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

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 and at a dose 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, 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.

Hematological effects.

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

Like other NSAIDs, sodium diclofenac may temporarily inhibit platelet aggregation. Careful monitoring is required in patients with coagulation disorders, hemorrhagic diathesis, or hematological disorders.

History of asthma.

Patients with bronchial asthma, seasonal allergic rhinitis, nasal mucosal swelling (nasal polyps), chronic obstructive pulmonary diseases, or chronic respiratory infections (especially those associated with allergic, rhinitis-like symptoms) are more likely than others to experience NSAID-related reactions resembling asthma exacerbations (so-called analgesic intolerance/analgesic asthma), Quincke's edema, or urticaria. Therefore, special precautions (readiness for emergency intervention) are recommended for these patients. This also applies to patients with allergies to other substances manifesting as 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 a history of bronchial asthma.

Injection site reactions.

Injection site reactions have been reported after intramuscular administration of diclofenac, including injection site necrosis and medication embolism, also known as Nicolau syndrome (particularly after inadvertent subcutaneous injection). Appropriate needle selection and injection technique should be followed when administering diclofenac intramuscularly (see section "Administration and dosage").

Fertility in women.

Sodium diclofenac may impair fertility in women and is not recommended for women wishing to become pregnant. For women experiencing difficulties conceiving or undergoing infertility evaluation, discontinuation of sodium diclofenac should be considered.

Use during pregnancy or breastfeeding.

Pregnancy

Sodium diclofenac may be prescribed during the first and second trimesters of pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus, at the lowest effective dose, and for the shortest possible duration. Like other NSAIDs, the drug is contraindicated in the third trimester of pregnancy (due to 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. Epidemiological data suggest an increased risk of miscarriage and/or congenital heart defects and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increased from less than 1% to approximately 1.5%.

The risk may increase with higher doses and longer duration of treatment. Animal studies have shown that prostaglandin synthesis inhibitors increase pre- and post-implantation loss and embryonic/fetal mortality.

In addition, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular malformations, has been observed.

From the 20th week of pregnancy, use of sodium diclofenac may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation. If sodium diclofenac is used by a woman planning pregnancy or during the first trimester, the dose should be as low as possible and the duration of treatment as short as possible. Fetal monitoring for oligohydramnios should be considered after exposure to sodium diclofenac for several days starting from the 20th week of pregnancy. Sodium diclofenac should be discontinued if oligohydramnios is detected.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may have the following effects:

on the fetus:

− cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);

− impaired renal function (see above).

on the mother and newborn, and on women near term:

− possible prolongation of bleeding time, antiaggregatory effect, which may occur even with very low doses;

− inhibition of uterine contractions, leading to delayed or prolonged labor.

Therefore, sodium diclofenac is contraindicated during the third trimester of pregnancy.

Breastfeeding period

Like other nonsteroidal anti-inflammatory drugs, diclofenac passes into breast milk in small amounts. Therefore, to avoid potential adverse effects on the infant, sodium diclofenac should not be used during breastfeeding.

Fertility

Like other nonsteroidal anti-inflammatory drugs, sodium diclofenac may affect female fertility. The drug is not recommended for women planning pregnancy. Women experiencing difficulties with conception or undergoing evaluation for infertility should discontinue use of sodium diclofenac.

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

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

Adults.

Sodium diclofenac, solution for injection, should not be administered for more than two days. If continued treatment is necessary, therapy may be continued with sodium diclofenac tablets or suppositories.

Intramuscular injection.

To prevent nerve or other tissue damage at the site of intramuscular injection, the following precautions must be observed. Such injuries may lead to muscle weakness, muscle paralysis, and paresthesia.

The usual dose is 75 mg (1 ampoule), administered by deep injection into the upper outer quadrant of the gluteus maximus muscle using an aseptic technique. 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, the 75 mg injection solution may be combined with other dosage forms of sodium diclofenac (e.g., tablets, suppositories) up to a maximum total daily dose of 150 mg of sodium diclofenac.

In acute migraine attacks, clinical experience is limited to cases where an initial dose of 1 ampoule (75 mg) is administered as soon as possible, optionally followed on the same day by a 100 mg suppository (if necessary). The total daily dose should not exceed 175 mg on the first day.

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

Intravenous infusion.

Immediately before starting intravenous infusion, sodium diclofenac should be diluted in 100–500 mL of 0.9% sodium chloride solution or 5% glucose solution. Both solutions must be buffered with sodium bicarbonate solution (0.5 mL of 8.4% solution or 1 mL of 4.2%). Only clear solutions should be used.

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

Recommended alternative dosing regimens for sodium diclofenac solution for injection:

− For the 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 must not exceed 150 mg per day;

− For the prevention of postoperative pain: 15 minutes to 1 hour after surgery, a loading dose of 25–50 mg should be administered, 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 the pharmacokinetics of sodium diclofenac are not significantly altered to a clinically relevant extent in elderly patients, nonsteroidal anti-inflammatory drugs (NSAIDs) 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 also section "Special precautions"); patients should also be monitored for gastrointestinal bleeding during NSAID therapy.

The recommended maximum daily dose of sodium diclofenac is 150 mg.

Children.

Children (under 18 years of age). Sodium diclofenac in the form of solution for injection is contraindicated for use in children.

Overdose.

Symptoms. A typical clinical picture of diclofenac overdose is not well established. Overdose may cause symptoms such as headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, diarrhea, dizziness, disorientation, agitation, coma, drowsiness, tinnitus, loss of consciousness, or seizures. In severe poisoning, acute renal failure and hepatic injury may occur.

Treatment. 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. For frequent or prolonged seizures, diazepam should be administered intravenously. Other supportive measures may be indicated depending on the patient's clinical condition. Treatment is symptomatic.

Adverse Reactions

Adverse reactions to the drug are listed according to frequency: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1,000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).

The adverse effects listed below are associated with sodium diclofenac administration, observed during both short-term and long-term use.

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

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

Psychiatric disorders: very rare – disorientation, depression, insomnia, nightmares, irritability, and other psychiatric disorders.

Nervous system disorders: common – headache, dizziness; rare – somnolence, fatigue; very rare – paresthesia, memory impairment, convulsions, anxiety, tremor, aseptic meningitis, taste disturbances, stroke; frequency not known – confusion, hallucinations, sensory disturbances, malaise.

Eye disorders: very rare – visual disturbances, blurred vision, diplopia; frequency not known – optic neuritis.

Ear and labyrinth disorders: common – vertigo; very rare – tinnitus, hearing disturbances.

Cardiac disorders: very rare – palpitations, chest pain, heart failure, myocardial infarction; frequency not known – Kounis syndrome.

Vascular disorders: very rare – arterial hypertension, arterial hypotension, vasculitis.

Respiratory, thoracic and mediastinal disorders: rare – asthma (including dyspnea); very rare – pneumonitis.

Gastrointestinal disorders: common – nausea, vomiting, diarrhea, dyspepsia, abdominal pain, flatulence, anorexia; rare – gastritis, gastrointestinal hemorrhage, vomiting of blood, hemorrhagic diarrhea, melena, gastric or intestinal ulcer with bleeding, gastrointestinal stenosis with perforation (sometimes fatal, especially in elderly patients); very rare – colitis (including hemorrhagic colitis, ischemic colitis, and exacerbation of ulcerative colitis or Crohn’s disease), constipation, stomatitis (including ulcerative stomatitis), glossitis, esophageal disorders, intestinal membrane strictures, pancreatitis.

Hepatobiliary disorders: common – increased transaminase levels; rare – hepatitis, jaundice, liver function disorders; very rare – fulminant hepatitis, hepatonecrosis, liver failure.

Skin and subcutaneous tissue disorders: common – rash; rare – urticaria; very rare – bullous rash, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), exfoliative dermatitis, alopecia, photosensitivity reaction, purpura, allergic purpura, pruritus; frequency not known – fixed drug eruption, generalized bullous fixed drug eruption.

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

General disorders and administration site conditions: common – injection site reaction, pain, induration; rare – swelling, necrosis at injection site; very rare – abscess at injection site; frequency not known – medication embolism (Nicolau syndrome).

Reproductive system and breast disorders: very rare – impotence.

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

Visual disturbances

Visual disturbances such as blurred vision, visual impairment, and diplopia are class effects of NSAIDs and are usually reversible upon 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.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 3 ml in ampoules. 5 ampoules in a partitioned pack or 5 ampoules in a single-sided blister, 1 blister per pack, or 100 ampoules in a partitioned box.

Prescription status. Prescription only.

Manufacturer. Private Joint-Stock Company "Lekhim-Kharkiv".

Manufacturer's address and place of business.
Ukraine, 61115, Kharkiv region, Kharkiv, Severin Pototskogo Street, 36.