INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DICLODEV® (DICLODEV®)

Composition:

Active substance: diclofenac;

3 ml of solution contain 75 mg of sodium diclofenac (25 mg/ml);

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

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear solution, free from visible particles.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic agents.

Acetic acid derivatives and related substances. ATC code M01A B05.

Pharmacological properties.

Pharmacodynamics.

A non-steroidal agent with pronounced analgesic and anti-inflammatory properties. It is an inhibitor of prostaglandin synthetase (cyclooxygenase). Prostaglandins play a key role in the development of inflammation, pain, and fever. In vitro, at concentrations equivalent to those achieved in humans, sodium diclofenac does not inhibit proteoglycan synthesis in cartilage tissue. When used concomitantly with opioids for postoperative pain relief, the need for opioids is significantly reduced.

Pharmacokinetics.

Absorption

After administration of 75 mg diclofenac by intramuscular injection, absorption begins immediately, and the mean peak plasma concentration 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 peak plasma concentration is approximately 1.875±0.436 µg/mL (1.9 µg/mL = 5.9 µmol/L). Shorter infusion durations result in higher peak plasma concentrations, whereas longer infusions lead to a concentration plateau proportional to the infusion rate after 3–4 hours. After intramuscular injection or oral administration of enteric-coated tablets or rectal suppositories, plasma diclofenac concentrations decline rapidly immediately after peak levels are achieved. Following oral or rectal administration, approximately half of the absorbed diclofenac undergoes first-pass metabolism in the liver (first-pass effect). The area under the concentration-time curve (AUC) after intramuscular or intravenous administration is approximately twice that after oral or rectal administration.

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

Bioavailability

The AUC after intramuscular or intravenous administration is approximately twice that after oral or rectal administration, due to avoidance of first-pass hepatic metabolism.

Distribution

99.7% of diclofenac is bound to plasma proteins, primarily to albumin (99.4%).

The apparent volume of distribution is calculated to be 0.12–0.17 L/kg.

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

Diclofenac was 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 corresponds to 0.03 mg/kg/day.

Metabolism

Biotransformation of diclofenac occurs partially via glucuronidation of the intact molecule, but primarily via single and multiple hydroxylations and methoxylation, leading to the formation of several phenolic metabolites (3'-hydroxy-, 4'-hydroxy-, 5-hydroxy-, 4',5-dihydroxy-, and 3'-hydroxy-4'-methoxy-diclofenac), most of which are further converted into glucuronide conjugates. Two of these phenolic metabolites are pharmacologically active, although their activity is significantly less than that of diclofenac.

Elimination

Total systemic clearance of diclofenac in plasma is 263±56 mL/min (mean ± SD). The terminal half-life in plasma is 1–2 hours. Four metabolites, including two active ones, also have short plasma half-lives of 1–3 hours. One metabolite, 3'-hydroxy-4'-methoxy-diclofenac, has a much longer half-life but 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 is eliminated as metabolites via bile into feces.

Linearity/non-linearity

Plasma concentrations show a linear relationship with dose.

Special patient groups

Elderly patients. No age-related differences 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. In patients with impaired renal function, accumulation of unchanged active substance is not expected with standard dosing regimens, based on the drug's kinetics after single administration. With creatinine clearance less than 10 mL/min, theoretical steady-state plasma levels of hydroxyl metabolites are approximately four times higher than in healthy volunteers.

However, 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 medicinal product 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 injuries and surgeries;
Severe migraine attacks.

The medicinal product is indicated for intravenous infusion in the treatment or prophylaxis of postoperative pain.

Contraindications.

Known hypersensitivity to the active substance, sodium metabisulfite, or to any other components of the medicinal product.
History of gastrointestinal bleeding or perforation related to previous treatment with non-steroidal 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).
Active gastric and/or duodenal ulcer, gastrointestinal bleeding, or perforation.
As with other NSAIDs, diclofenac is contraindicated in patients in whom administration of ibuprofen, acetylsalicylic acid, or other NSAIDs induces attacks of bronchial asthma, bronchospasm, angioedema, urticaria, or allergic-type symptoms, or nasal polyps.
Inflammatory bowel diseases (e.g., Crohn’s disease or ulcerative colitis).
Hepatic failure.
Renal failure (glomerular filtration rate (GFR) < 15 mL/min/1.73 m²).
Congestive heart failure (NYHA II–IV).
High risk of postoperative bleeding, coagulation disorders, hemostatic disturbances, hematopoietic disorders, or cerebrovascular hemorrhage.
Treatment of postoperative pain following coronary artery bypass grafting (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.
Third trimester of pregnancy.

This medicinal form is contraindicated in children (under 18 years of age).

For intravenous use only

Concomitant use of NSAIDs or anticoagulants (including low-dose heparin).
History of hemorrhagic diathesis, confirmed or suspected cerebrovascular hemorrhage.
Surgeries 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 cause.

Interaction with other medicinal products and other forms of interaction.

The interactions listed below have been observed during administration of this medicinal product, injection solution, and/or other diclofenac formulations.

Litium. 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. Concomitant use of diclofenac (as with other NSAIDs) with diuretics and antihypertensive agents (e.g., β-blockers, angiotensin-converting enzyme (ACE) inhibitors) may reduce their antihypertensive effect. 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 regularly during concomitant therapy, particularly with diuretics and ACE inhibitors due to increased risk of nephrotoxicity (see section "Special precautions for use").

Medicinal products causing hyperkalemia. Concomitant therapy with potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may lead to increased serum potassium levels; thus, more frequent monitoring is recommended (see section "Special precautions for use").

Anticoagulants and antithrombotic agents. Precautions are recommended, as concomitant administration may increase the risk of bleeding (see section "Special precautions for use"). Although clinical studies have not demonstrated an effect of diclofenac on anticoagulant activity, there are individual reports of increased bleeding risk in patients receiving diclofenac and anticoagulants simultaneously. Therefore, to ensure no dosage adjustments of anticoagulants are needed, careful monitoring of such patients is recommended. Like other NSAIDs, high-dose diclofenac may transiently inhibit platelet aggregation.

Other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, and corticosteroids. Concomitant administration of diclofenac with other systemic NSAIDs or corticosteroids may increase the frequency of gastrointestinal adverse effects. Concurrent use of two or more NSAIDs should be avoided (see section "Special precautions for use").

Selective serotonin reuptake inhibitors (SSRIs). Concomitant administration of systemic NSAIDs and SSRIs may increase the risk of gastrointestinal bleeding (see section "Special precautions for use").

Antidiabetic agents. Studies have shown 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 after diclofenac administration, requiring dosage adjustments of antidiabetic agents during diclofenac therapy. In such cases, blood glucose monitoring is necessary as a precaution during concomitant therapy. There are also isolated reports of metabolic acidosis with concomitant use of diclofenac, particularly in patients with impaired renal function.

Methotrexate. Diclofenac may inhibit renal tubular clearance of methotrexate, leading to elevated methotrexate levels. Caution is recommended when administering NSAIDs, including diclofenac, within 24 hours before methotrexate therapy, as this may increase methotrexate blood concentration and 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 by affecting 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 NSAID-induced anti-prostaglandin effects in the kidneys and calcineurin inhibition.

Antibacterial quinolones. There are isolated reports of seizures possibly resulting from concomitant use of quinolones and NSAIDs. This may occur in patients both with and without a history of epilepsy or seizures. Therefore, caution is advised when prescribing quinolones to 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.

Cholestyramine and colestipol. These agents may delay or reduce diclofenac absorption. Therefore, diclofenac should be administered at least one hour before or 4–6 hours after cholestyramine/colestipol.

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.

CYP2C9 inhibitors. Caution is recommended when co-prescribing diclofenac with strong 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), as this may lead to a significant increase in plasma concentration and exposure of diclofenac.

Special precautions for use.

General

Gastrointestinal ulcers, bleeding, or perforation may occur at any time during NSAID therapy, regardless of COX-2 selectivity, even in the absence of warning signs or predisposing history. Concomitant use of systemic NSAIDs, including selective COX-2 inhibitors, should be avoided due to the potential for additional adverse reactions (see section "Interaction with other medicinal products and other forms of interaction").

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

Placebo-controlled trials have shown an increased risk of thrombotic cardiovascular and cerebrovascular complications with certain selective COX-2 inhibitors. A direct correlation between this risk and the COX-1/COX-2 selectivity of individual NSAIDs has not yet been established. Due to the lack of comparative clinical data on long-term treatment with maximum doses of diclofenac, the possibility of a similar increased risk cannot be excluded. In the absence of such data, a careful benefit-risk assessment should be performed before initiating diclofenac in patients with clinically confirmed ischemic heart disease, cerebrovascular disorders, peripheral arterial disease, or significant risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking). Given this risk, the lowest effective dose should be used for the shortest possible duration.

The effect of NSAIDs on the kidneys includes fluid retention with edema and/or arterial hypertension. Therefore, diclofenac should be used with caution in patients with impaired cardiac function and other conditions causing fluid retention. Caution is also advised in patients receiving concomitant diuretics or angiotensin-converting enzyme (ACE) inhibitors, or those at risk of hypovolemia.

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.

Consequences are generally more severe in elderly patients. Caution should be exercised when prescribing the drug to elderly patients. Particularly in frail elderly patients and those with low body weight, the lowest effective doses are recommended. If gastrointestinal bleeding or ulceration occurs in patients receiving the drug, treatment should be discontinued.

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

Sodium metabisulfite in the injectable solution may also cause severe hypersensitivity reactions.

Effects on the gastrointestinal tract

When using all NSAIDs, including diclofenac, cases of gastrointestinal bleeding (hematemesis, melena), ulceration, or perforation—potentially fatal—have been reported, occurring at any time during treatment, with or without warning symptoms, and in patients with a history of serious gastrointestinal events. These events generally 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, careful medical monitoring is required during diclofenac use. Particular caution should be exercised when prescribing diclofenac to patients with symptoms indicating gastrointestinal disorders or with a history of gastric or intestinal ulcers, bleeding, or perforation (see section "Adverse reactions"). The risk of gastrointestinal bleeding increases with higher NSAID doses, including diclofenac, and in patients with a history of ulcers, especially complicated by bleeding or perforation, and in elderly patients.

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 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 those requiring concomitant use of low-dose acetylsalicylic acid or other drugs likely to increase 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 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 SSRIs (see section "Interaction with other medicinal products and other forms of interaction").

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

Effects on the liver

Close medical supervision is required when administering the drug to patients with impaired liver function, as their condition may worsen (see section "Adverse reactions").

As with other NSAIDs, during diclofenac use, one or more liver enzymes may increase. This has been very commonly observed in clinical trials with diclofenac (approximately 15% of patients), but rarely associated with clinical symptoms. Most cases involve borderline elevations. Moderate increases (≥ 3 to < 8 times the upper normal limit) have been frequently observed (in 2.5% of cases), while marked increases (≥ 8 times the upper normal limit) occur in approximately 1% of cases. Elevated liver enzymes were associated with clinically evident liver injury in 0.5% of cases in the aforementioned clinical trials. Increased enzyme concentrations were usually reversible after discontinuation of the drug. In patients receiving diclofenac, conditions such as hepatitis may progress without prodromal symptoms.

Caution is necessary when administering the drug to patients with hepatic porphyria due to the potential to provoke an attack.

Effects on the kidneys

Due to the importance of prostaglandins in maintaining renal blood flow, prolonged high-dose NSAID therapy, including diclofenac, often (1–10%) leads to edema and arterial hypertension.

Since fluid retention and edema have been reported with NSAID therapy, 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 significantly affecting renal function, and patients with significant extracellular fluid volume depletion from any cause, e.g., before or after major surgery (see section "Contraindications"). 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.

Effects on the skin

Serious skin reactions (some of which have been fatal), including exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and cutaneous drug embolism, also known as Nicolau syndrome (especially after improper subcutaneous injection), have very rarely been reported with NSAIDs, including diclofenac. Appropriate recommendations regarding needle selection and injection technique should be followed when administering this medicinal product (see section "Method of administration and dosage"). The highest risk of these reactions appears to occur early in treatment, mostly within the first month. The drug should be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity. As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, may rarely occur even without prior exposure to diclofenac.

Systemic lupus erythematosus (SLE) and mixed connective tissue diseases

Patients with SLE and mixed connective tissue diseases may have an increased risk of 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.

NSAID therapy, including diclofenac, especially at high doses and for prolonged periods, may be associated with a slightly increased risk of serious cardiovascular thrombotic events (including myocardial infarction and stroke).

Treatment with Diclodev® is generally not recommended for patients with diagnosed cardiovascular diseases (heart failure, ischemic heart disease, peripheral arterial disease) or uncontrolled arterial hypertension. If such treatment is necessary for patients with diagnosed cardiovascular diseases, uncontrolled hypertension, or significant cardiovascular risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking), Diclodev® should only be prescribed after careful evaluation and only at doses up to 100 mg daily for treatment courses exceeding 4 weeks.

Since cardiovascular risks of diclofenac may increase with dose and 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, especially when treatment exceeds 4 weeks. Use with caution in patients aged 65 years and older.

Appropriate monitoring and advice are necessary for patients with a history of arterial hypertension and/or mild to moderate congestive heart failure, as fluid retention and edema have been reported with NSAIDs, including diclofenac.

Clinical and epidemiological data indicate that diclofenac use, 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 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 may be considered only after careful benefit-risk assessment and at a dosage not exceeding 100 mg daily. A similar assessment should be performed before initiating long-term treatment in patients with risk factors for cardiovascular disease (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smokers).

Patients should be informed about signs and symptoms of serious arterial thromboembolic events (e.g., chest pain, dyspnea, weakness, speech disturbances), which may occur without warning symptoms. In such cases, immediate medical attention should be sought.

Effects on hematological parameters

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

The drug may temporarily inhibit platelet aggregation. Close monitoring is required in patients with coagulation disorders, hemorrhagic diathesis, or hematological disorders.

Effects on the respiratory system (asthma history)

Patients with bronchial asthma, seasonal allergic rhinitis, nasal mucosal edema (nasal polyps), chronic obstructive lung diseases, or chronic respiratory infections (especially those associated with allergic, rhinitis-like symptoms) more frequently experience NSAID-related reactions resembling asthma exacerbation (so-called analgesic intolerance/analgesic-induced asthma), Quincke's edema, or urticaria compared to others. Therefore, special precautionary measures (readiness for emergency intervention) are recommended for such patients. This also applies to patients with allergies to other substances manifesting as skin reactions, pruritus, or urticaria.

Particular caution is advised when parenterally administering Diclodev® to patients with bronchial asthma, as symptoms may worsen.

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

Fertility in women

The use of the drug may impair fertility in women and is not recommended for women wishing to become pregnant. The possibility of discontinuing the drug should be considered in women experiencing difficulties with conception or undergoing infertility evaluation.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, 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 may occur shortly after starting treatment and is usually reversible upon discontinuation. Additionally, there are reports of arterial duct constriction after second-trimester treatment, most of which resolved after stopping treatment. Therefore, the drug should not be prescribed during the first and second trimesters unless necessary. If the drug is used by a woman trying to conceive or during the first and second trimesters of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible. Prenatal monitoring for oligohydramnios and arterial duct constriction should be considered after exposure to diclofenac for several days starting from the 20th gestational week. The drug should be discontinued if oligohydramnios or arterial duct constriction is detected.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage and/or congenital heart defects and gastroschisis after 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.

Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular defects, was observed.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors cause:

Risks to the fetus:

Cardio-pulmonary toxicity (with premature closure of the arterial duct and pulmonary hypertension);
Impaired renal function (see above);

Risks to the mother at the end of pregnancy and to the newborn:

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

The drug is contraindicated during the third trimester of pregnancy (see section "Contraindications").

Breastfeeding period

Like other NSAIDs, diclofenac passes into breast milk in small amounts. Therefore, to avoid undesirable effects on the infant, the drug should not be used during breastfeeding. If treatment is considered necessary, the infant should be switched to artificial feeding.

Fertility

Like 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 infertility evaluation should discontinue the drug. Based on relevant animal studies, impairment of male reproductive function cannot be excluded. The relevance of these findings to humans has not been established.

Ability to affect reaction speed when driving or operating machinery.

Patients experiencing visual disturbances, dizziness, vertigo, somnolence, or other central nervous system disorders during treatment with the drug should refrain from driving or operating machinery.

Dosage and Administration

The general recommendation is individual dose determination. Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

Adults

The drug should not be used for more than 2 days. If further treatment is needed, therapy may be continued with diclofenac tablets or suppositories.

Intramuscular Injection

To prevent nerve or other tissue damage at the site of intramuscular injection, the following guidelines must be followed. Such damage may lead to muscle weakness, muscle paralysis, hypoesthesia, and cutaneous medicamentous embolism (Nicolau syndrome).

The usual dose is 75 mg (1 ampoule) daily, 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 75 mg injections, 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 the drug (e.g., tablets or 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 one 75 mg ampoule 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 the drug for the treatment of migraine attacks for more than 1 day. If further therapy is required in subsequent days, the maximum daily dose should be up to 150 mg (as divided doses administered in suppository form).

Intravenous Infusion

Immediately before starting intravenous infusion, the drug 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. If crystals or precipitate are present, the solution must not be used.

The injection solution must not be administered as an intravenous bolus injection.

Recommended alternative dosing regimens for the injection solution:

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 several hours, but the dose must not exceed 150 mg per day;
For the prevention 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.

When administering intramuscular diclofenac, appropriate needle selection and injection technique must be observed.

Special Patient Groups

Elderly Patients (aged 65 years and older)

Dose adjustment is generally not required for elderly patients. However, caution is recommended based on the patient's condition, especially in frail elderly patients or those with low body weight (see section "Special Warnings and Precautions for Use").

Established Cardiovascular Disease or Serious Cardiovascular Risk Factors

Diclofenac treatment is generally not recommended for patients with cardiovascular disease or uncontrolled arterial hypertension. If necessary, patients with cardiovascular disease, uncontrolled arterial hypertension, or significant cardiovascular risk factors should only be treated with diclofenac after careful assessment and only at doses up to 100 mg per day for treatment courses exceeding 4 weeks (see section "Special Warnings and Precautions for Use").

Renal Impairment

Diclofenac is contraindicated in patients with renal impairment (GFR < 15 mL/min/1.73 m²; see section "Contraindications").

No specific studies have been conducted in patients with impaired renal function; therefore, dose adjustment recommendations cannot be made. Diclofenac should be used with caution in patients with renal dysfunction (see section "Special Warnings and Precautions for Use").

Hepatic Impairment

Diclofenac is contraindicated in patients with hepatic impairment (see section "Contraindications").

No specific studies have been conducted in patients with impaired liver function; therefore, dose adjustment recommendations cannot be made. Diclofenac should be used with caution in patients with mild to moderate hepatic dysfunction (see section "Special Warnings and Precautions for Use").

Children

The drug in the form of injection solution is contraindicated for use in children and adolescents.

Overdose

Symptoms. There is no typical clinical picture of diclofenac overdose. Overdose may cause symptoms such as headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, diarrhea, dizziness, disorientation, agitation, coma, drowsiness, tinnitus, loss of consciousness, or convulsions. In severe poisoning, acute renal failure and liver damage may occur.

Treatment

Management of acute poisoning with NSAIDs, including diclofenac, consists primarily of supportive measures and symptomatic treatment. Supportive care and symptomatic treatment are necessary to manage complications such as hypotension, renal failure, seizures, gastrointestinal disturbances, and respiratory depression.

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

Adverse Reactions

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

The adverse reactions listed below include those associated with both short-term and long-term use of the medicinal product.

Infections and infestations: very rare – injection site abscess.

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 – confusion, 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: uncommon* – palpitations, chest pain, heart failure, myocardial infarction; frequency not known – Kounis syndrome.

*Frequency reflects data from long-term treatment with high doses (150 mg per day).

Vascular disorders: common – arterial hypertension; very rare – 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, decreased appetite; rare – gastritis, gastrointestinal hemorrhage, vomiting with blood, hemorrhagic diarrhea, melena, gastric or intestinal ulcer (with or without bleeding, gastrointestinal stenosis or perforation (sometimes fatal, especially in elderly patients), which may lead to peritonitis); very rare – colitis (including hemorrhagic colitis, ischemic colitis, and exacerbation of ulcerative colitis or Crohn’s disease), constipation, stomatitis, glossitis, esophageal disorders, intestinal membrane strictures, pancreatitis.

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

Skin and subcutaneous tissue disorders: common – skin rashes; rare – urticaria; very rare – bullous eruptions, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), exfoliative dermatitis, alopecia, photosensitivity reaction, purpura, Henoch-Schönlein purpura, pruritus.

Renal and urinary disorders: common – fluid retention, edema; very rare – acute kidney injury (acute renal failure), hematuria, proteinuria, nephrotic syndrome, tubulointerstitial nephritis, renal papillary necrosis.

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

Reproductive system and breast disorders: very rare – impotence.

Clinical studies and pharmacoepidemiological data indicate an increased risk of arterial 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 (see section "Special precautions for use").

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 lead to visual disturbances. If such symptoms occur during treatment with diclofenac, an ophthalmological examination should be performed to rule out other possible causes.

Shelf life. 3 years.

Storage conditions.

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

Keep out of the reach of children.

Incompatibilities.

The medicinal product, solution for injection, should generally not be mixed with other injectable solutions.

Solutions of 0.9% sodium chloride or 5% glucose for infusion without sodium bicarbonate as an additive carry a risk of supersaturation, which may lead to crystal or precipitate formation. Other infusion solutions besides those recommended must not be used.

Packaging.

3 ml of solution in a vial; 5 vials in a blister pack in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

DEMO S.A. Pharmaceutical Industry.

Manufacturer's address and place of business.

21st km National Road Athens-Lamia, Kryoneri Attica, 14568, Greece.