DICLOBENE® N 75

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DICLOBERL® N75 (DICLOBERL® N75)

Composition:

Active substance: sodium diclofenac;

1 ml of injection solution contains 25 mg of sodium diclofenac (1 ampoule contains 3 ml of injection solution, equivalent to 75 mg of sodium diclofenac);

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

Pharmaceutical form. Injection solution.

Main physicochemical characteristics: clear solution, colorless to almost colorless, free from visible particles.

pH: 8.0 – 9.0.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Acetic acid derivatives and related compounds. ATC code M01A B05.

Pharmacological properties.

Pharmacodynamics.

Diclobel® N75 is a non-steroidal agent with pronounced analgesic and anti-inflammatory properties. It is an inhibitor of prostaglandin synthetase (cyclooxygenase). In vitro, diclofenac sodium at concentrations equivalent to those achieved in humans does not suppress proteoglycan biosynthesis in cartilage tissue. When the medicinal product is used concomitantly with opioids for postoperative pain relief, Diclobel® N75 often reduces the need for opioids.

Pharmacokinetics.

Absorption.

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

In contrast to the results observed after oral administration, when the medicinal product is administered as suppositories or by intramuscular injection, plasma concentration rapidly decreases immediately after reaching peak levels.

Bioavailability.

The area under the concentration-time curve (AUC) after intramuscular or intravenous administration is approximately twice as high as that after oral or rectal administration, because this route avoids first-pass hepatic metabolism.

Distribution.

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

Diclofenac penetrates into synovial fluid, where maximum concentration is achieved 2–4 hours after peak plasma levels are reached. The expected half-life in synovial fluid is 3 to 6 hours. Two hours after peak plasma concentration is achieved, the concentration of the active substance in synovial fluid exceeds that in plasma and remains higher for up to 12 hours.

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

Metabolism.

Biotransformation of diclofenac occurs partially 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 phenolic metabolites are biologically 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 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.

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 as unchanged drug. The remainder of the dose is eliminated as metabolites via bile into feces.

Special patient groups.

Elderly patients. No age-related differences in absorption, metabolism, or excretion of the drug have been observed. However, 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. When creatinine clearance is less than 10 mL/min, plasma levels of hydroxymetabolites 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 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 injuries and surgeries;
• Severe migraine attacks.

Dylobel® N 75 is indicated for adults.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients listed in the section “Composition”;
• History of gastrointestinal bleeding or perforation related to previous treatment with nonsteroidal anti-inflammatory drugs (NSAIDs);
• Active gastric or intestinal ulcer, bleeding, or perforation;
• Known history of bronchospasm, asthma, rhinitis, or urticaria after taking acetylsalicylic acid or other NSAIDs;
• Unspecified disorders of blood coagulation;
• Active peptic ulcer/bleeding or recurrent peptic ulcer/bleeding in history (two or more separate episodes of confirmed ulcer or bleeding);
• Third trimester of pregnancy;
• As with other NSAIDs, diclofenac is contraindicated in patients in whom administration of ibuprofen, acetylsalicylic acid, or other nonsteroidal anti-inflammatory agents has triggered attacks of bronchial asthma, angioedema, urticaria, or acute rhinitis;
• Inflammatory bowel diseases (e.g., Crohn’s disease or ulcerative colitis);
• Hepatic failure;
• Renal failure (creatinine clearance < 15 mL/min/1.73 m²);
• Peripheral arterial disease;
• Cerebrovascular disorders in patients who have suffered a stroke or have episodes of transient ischemic attacks;
• Ischemic heart disease in patients with angina pectoris or history of myocardial infarction;
• Congestive heart failure (NYHA II–IV);
• High risk of postoperative bleeding, blood coagulation disorders, hemostatic disorders, hematopoietic disorders, or cerebrovascular bleeding;
• Treatment of postoperative pain following coronary artery bypass grafting (CABG) (or use of cardiopulmonary bypass);
• Use in children and adolescents under 18 years of age, as the content of the active substance is too high.

Interaction with other medicinal products and other forms of interaction.

The interactions listed below have been observed during the use of Dylobel® N75, solution for injection, and/or other dosage forms of diclofenac.

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.

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

Diuretics and antihypertensive agents. NSAIDs may reduce the antihypertensive efficacy of diuretics and other antihypertensive agents (such as beta-blockers, angiotensin-converting enzyme (ACE) inhibitors) due to inhibition of vasodilatory prostaglandin synthesis. Therefore, such combinations should be used with caution, and patients, especially elderly ones, should be closely monitored for blood pressure. Adequate hydration should be ensured, and renal function should be monitored after initiation of concomitant therapy and periodically thereafter, particularly with diuretics and ACE inhibitors, due to the increased risk of nephrotoxicity.

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

Anticoagulants and antithrombotic agents. Precautions should be taken, as concomitant administration increases the risk of bleeding. Although clinical studies do not indicate an effect of diclofenac on anticoagulant activity, data suggest an increased risk of bleeding in patients receiving diclofenac and anticoagulants simultaneously. Therefore, careful monitoring of such patients is recommended to ensure no dosage adjustments of anticoagulants are needed.

Like other NSAIDs, diclofenac at high doses may reversibly inhibit platelet aggregation.

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

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

Antidiabetic agents. Clinical studies have shown that diclofenac can be used together with oral antidiabetic agents (e.g., sulfonylureas) without affecting their clinical efficacy. However, isolated reports of both hypoglycemic and hyperglycemic effects requiring dosage adjustments of antidiabetic agents during diclofenac treatment have been documented. For this reason, monitoring of blood glucose levels is necessary as a precaution during concomitant therapy.

There are also isolated reports of metabolic acidosis when used concomitantly with diclofenac, particularly in patients with pre-existing renal function impairment.

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

Metotrexate. 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 methotrexate treatment, 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 accumulation of methotrexate due to impaired renal excretion in the presence of NSAIDs.

Cyclosporine. Nonsteroidal anti-inflammatory agents (such as sodium diclofenac) may increase the nephrotoxicity of cyclosporine due to effects on renal prostaglandins. Therefore, it should be used at lower doses than in patients not receiving cyclosporine.

Tacrolimus. When NSAIDs are used with tacrolimus, there may be an increased risk of nephrotoxicity. This may be mediated via renal anti-prostaglandin effects of NSAIDs and calcineurin inhibitors.

Antibacterial quinolones. There are isolated data on seizures that may result from concomitant use of quinolones and NSAIDs. This may occur in patients with or without a history of epilepsy or seizures. Therefore, caution should be exercised when prescribing quinolones to patients already receiving NSAIDs.

Colestipol and cholestyramine. These agents may delay or reduce the absorption of diclofenac. Therefore, it is recommended to administer diclofenac at least 1 hour before or 4–6 hours after colestipol/chlorestyramine.

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

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

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

Tenofovir. Concomitant use with NSAIDs may lead to increased plasma urea nitrogen and creatinine levels; renal function should be monitored to control potential synergistic effects on renal function.

Deferasirox. Concomitant use with NSAIDs may increase the risk of gastrointestinal toxicity. Close clinical monitoring is required when deferasirox is used concomitantly with these agents.

Mifepristone. Due to the theoretical risk that prostaglandin synthetase inhibitors may alter the efficacy of mifepristone, NSAIDs should not be used within 8–12 days after mifepristone administration.

Limited data suggest that concomitant use of NSAIDs on the day of prostaglandin administration does not negatively affect the effect of mifepristone or prostaglandin on cervical ripening or uterine contractility, nor does it reduce the clinical efficacy of medical termination of pregnancy.

Pemetrexed. Concomitant use with NSAIDs may reduce pemetrexed elimination; therefore, caution should be exercised when prescribing high-dose NSAIDs. Patients with mild to moderate renal impairment (creatinine clearance 45–79 mL/min) should avoid concomitant use of pemetrexed with NSAIDs for 2 days before and 2 days after pemetrexed administration.

Special precautions for use

General

Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Dosage and administration", as well as gastrointestinal and cardiovascular risks below).

Concomitant use of Diclobene® N75 with systemic NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided due to lack of any synergistic benefit and the potential for additional adverse effects.

As with other NSAIDs, allergic reactions including anaphylactic/anaphylactoid reactions may occur even in the absence of prior exposure to diclofenac.

Like other NSAIDs, Diclobene® N75, due to its pharmacodynamic properties, may mask signs and symptoms of infection. Rare cases of worsening of infectious inflammatory conditions (e.g., development of necrotizing fasciitis) have been reported with systemic NSAID use. This may be related to the mechanism of action of nonsteroidal anti-inflammatory agents.

If signs of infection appear or worsen during treatment with Diclobene® N75, patients should be advised to seek immediate medical attention. Evaluation for the need of anti-infective/antibiotic therapy should be considered.

Gastrointestinal effects

When using all NSAIDs, including diclofenac, cases of gastrointestinal bleeding (hematemesis, melena), ulceration or perforation, sometimes fatal, have been reported. These events may occur at any time during treatment, without preceding symptoms or history of serious gastrointestinal events. These events are usually more severe in elderly patients. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the drug should be discontinued. In case of severe upper abdominal pain, melena or bloody vomiting, patients should stop taking the medication and seek immediate medical advice.

Careful medical monitoring is required when using all NSAIDs, including diclofenac; 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. The risk of gastrointestinal bleeding, ulceration or perforation increases with higher NSAID doses, including diclofenac, and in patients with a history of ulcers, especially complicated by bleeding or perforation.

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

Elderly patients

Use with caution in elderly individuals due to comorbid conditions. In particular, for frail elderly patients or those with low body weight, the lowest effective dose should be used.

Adverse reactions occur more frequently in elderly patients receiving NSAIDs, especially gastrointestinal bleeding and perforation, which may be fatal.

To reduce the risk of gastrointestinal toxicity in patients with a history of ulcers, particularly 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 medications containing low-dose acetylsalicylic acid (ASA) or other drugs increasing 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 informed about any unusual abdominal symptoms (particularly gastrointestinal bleeding). Caution is also recommended in patients receiving concomitant medications that 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 (SSRIs).

Hepatic effects

Caution should be exercised before initiating treatment in patients with hepatic impairment, as their condition may worsen during diclofenac therapy.

As with other NSAIDs, including diclofenac, levels of one or more liver enzymes may increase. Regular monitoring of liver function should be performed as a precautionary measure during prolonged or repeated diclofenac therapy.

Diclofenac should be discontinued immediately if clinical signs of liver disease occur.

Hepatitis without preceding symptoms may occur during diclofenac use. Caution is required when using diclofenac in patients with hepatic porphyria, due to the potential to provoke an attack.

Renal effects

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, 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 due to any cause (e.g., pre- or post-major surgery). In such cases, monitoring of renal function is recommended as a precautionary measure during diclofenac use. Discontinuation of therapy usually leads to return to the pre-treatment state.

Skin reactions

Serious skin reactions, some of which were fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis (Lyell’s syndrome), have been very rarely reported with NSAID use. The highest risk of these reactions occurs early in the course of treatment, mostly within the first month. Diclobene® N75 should be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity. In such cases, patients should be advised to seek immediate medical attention and should not take Diclobene® N75 again.

Systemic lupus erythematosus (SLE) and mixed connective tissue diseases

Diclobene® N75 should be used in patients with autoimmune diseases such as systemic lupus erythematosus (SLE) and mixed connective tissue diseases only after careful benefit-risk assessment, as these patients may be predisposed to certain adverse effects, e.g., aseptic meningitis (see section "Adverse reactions").

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 duration of treatment, it should be used for the shortest possible duration and at the lowest effective daily dose. The need for diclofenac therapy for symptom relief and the patient’s response to treatment should be reviewed periodically. 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 NSAID use, including diclofenac.

Clinical and epidemiological data indicate that diclofenac use, especially at high doses (150 mg/day) and for prolonged periods, increases 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 should only be considered after careful benefit-risk assessment and at a dose not exceeding 100 mg per day. Treatment with diclofenac in patients with significant risk factors for cardiovascular events (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) should only be initiated after careful evaluation. Patients should be informed about signs and symptoms of serious thrombotic events (e.g., chest pain, dyspnea, weakness, speech disturbances), which may occur without warning. In such cases, patients should seek immediate medical attention.

Hypersensitivity reactions may also lead to Kounis syndrome, a serious allergic reaction that may result in myocardial infarction. Symptoms may include chest pain occurring during an allergic reaction to diclofenac.

Injection site reactions

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

Hematological effects

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

Like other NSAIDs, Diclobene® N75 may reversibly inhibit platelet aggregation. Patients with coagulation disorders, hemorrhagic diathesis, or hematological disorders should be carefully monitored.

History of asthma

In patients with bronchial asthma, seasonal allergic rhinitis, nasal mucosal edema (nasal polyps), chronic obstructive pulmonary disease, or chronic respiratory infections (especially those associated with allergic, rhinitis-like symptoms), reactions to NSAIDs resembling asthma exacerbation (so-called analgesic intolerance/analgesic-induced asthma), Quincke's edema, or urticaria occur more frequently than in other patients. Therefore, special precautions (readiness for emergency treatment) are recommended for such 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.

Female fertility

Use of Diclobene® N75 may impair fertility in women and is not recommended for women wishing to become pregnant. If a woman experiences difficulty conceiving or is undergoing infertility evaluation, discontinuation of Diclobene® N75 should be considered.

Other precautions

Benzyl alcohol may cause toxic and anaphylactic reactions in infants under 3 years of age.

This medicinal product contains 105 mg of benzyl alcohol per injection. Benzyl alcohol may cause allergic reactions.

This medicinal product contains 200 mg of propylene glycol per ml, equivalent to 600 mg per injection.

This medicinal product contains less than 1 mmol of sodium (23 mg) per injection, i.e., essentially "sodium-free".

Strict adherence to the instructions for intramuscular administration is necessary to avoid adverse reactions at the injection site, which may lead to muscle weakness, paralysis, paresthesia, medication embolism (Nicolau syndrome), and injection site necrosis.

With prolonged use of diclofenac, regular monitoring of liver and kidney function and blood counts is required.

Use during pregnancy or breastfeeding

Pregnancy

From the 20th week of pregnancy, use of diclofenac may cause oligohydramnios due to fetal renal dysfunction. This disorder may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, there have been reports of fetal arterial duct constriction after NSAID treatment in the second trimester, which mostly resolved after stopping treatment. Therefore, Diclobene® N75 should not be used during the first and second trimesters of pregnancy, except when the expected benefit to the mother outweighs the potential risk to the fetus. In such cases, it is recommended to use the lowest effective dose for the shortest possible duration. Prenatal monitoring for oligohydramnios and arterial duct constriction may be appropriate if diclofenac exposure occurred for several days starting from the 20th gestational week. Diclofenac should be discontinued if oligohydramnios or arterial duct constriction is detected. Like other NSAIDs, the drug is contraindicated during the third trimester of pregnancy (possible inhibition of uterine contractility and premature closure of the fetal arterial duct).

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data suggest an increased risk of miscarriage and/or cardiac defects and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular defects increased from less than 1% to approximately 1.5%. The risk may increase with higher doses and longer duration of treatment.

Animal studies have shown that administration of prostaglandin synthesis inhibitors leads to increased pre- and post-implantation loss and embryotoxic/fetotoxic effects.

Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of various malformations, including cardiovascular defects, has been observed. If Diclobene® N75 is used in women planning pregnancy or during the first trimester of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible.

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

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

effects on the mother at the end of pregnancy and on the newborn:

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

Therefore, diclofenac is contraindicated during the third trimester of pregnancy (see section "Contraindications").

Breastfeeding

Like other NSAIDs, diclofenac passes into breast milk in small amounts. Therefore, to avoid undesirable effects on the infant, diclofenac should not be used during breastfeeding.

Fertility

As with other nonsteroidal anti-inflammatory drugs, use of Diclobene® N75 may affect female fertility and is therefore not recommended for women wishing to become pregnant. Women experiencing difficulty conceiving or undergoing infertility evaluation should discontinue use of Diclobene® N75.

Ability to affect reaction speed when driving or operating machinery

Patients who experience visual disturbances, dizziness, vertigo, somnolence, or other central nervous system disorders during treatment with Diclobene® N75 should refrain from driving or operating machinery. This is particularly important when used concomitantly with alcohol.

Warning

Propylene glycol contained in Diclobene® N75 may cause symptoms resembling those after alcohol consumption.

Method of Administration and Dosage

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

Adults

Treatment with Diclobene® N75 should be administered as a single injection (75 mg of sodium diclofenac). If necessary, treatment may be continued using oral or rectal dosage forms. The total daily dose must not exceed 150 mg, even on the day of injection.

Intramuscular Injection

To prevent nerve or other tissue damage at the site of intramuscular injection, the following instructions must be followed, as such damage may lead to muscle weakness, paralysis, and paresthesia.

The usual dose is 75 mg (1 ampoule) per day, administered by deep injection into the upper outer quadrant of the gluteal 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 Diclobene® (e.g., tablets or suppositories) up to a maximum total daily dose of 150 mg of sodium diclofenac.

In the case of a migraine attack, clinical experience is limited to cases where an initial dose of 75 mg of diclofenac was used; the injection dose may be administered as soon as possible after the use of 100 mg suppositories on the same day (if necessary). The total daily dose must not exceed 175 mg on the first day.

There are no available data on the use of Diclobene® N75 for the treatment of migraine attacks for more than one day.

Special Patient Groups

Elderly Patients

Although the pharmacokinetics of Diclobene® N75 are not significantly impaired in elderly patients, nonsteroidal anti-inflammatory drugs (NSAIDs) should be used with particular caution in this population, as they 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 Diclobene® N75 is 150 mg.

Renal Impairment

Dose reduction is not required in patients with mild to moderate renal impairment (for patients with severe renal impairment, see section «Special Precautions»).

Hepatic Impairment

Dose reduction is not required in patients with mild to moderate hepatic impairment (for patients with severe hepatic impairment, see section «Special Precautions»).

Handling of OPC (one-point-cut) Ampoules

Filing of the ampoule is not required!

Turn the colored dot upward.

Allow the solution to flow from the top to the bottom of the ampoule by tapping or shaking.

Turn the colored dot upward again.

Snap off the tip of the ampoule downward.

The product should be used immediately after the first opening of the ampoule.

Children

Diclobene® N75 in the form of injection solution is contraindicated for use in children.

Overdose

Symptoms of Overdose

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. Hypotension, respiratory distress, and cyanosis may also occur. In cases of severe poisoning, acute renal failure and hepatic injury are possible.

Therapeutic Measures in Overdose

Within 1 hour after accidental ingestion of a potentially toxic amount of the drug, administration of activated charcoal may be beneficial. Alternatively, gastric lavage may be necessary in adults within 1 hour after ingestion of a potentially toxic amount. For frequent or prolonged convulsions, diazepam should be administered intravenously. Other measures may be indicated depending on the patient's clinical condition. Treatment is symptomatic.

Side effects

The following frequency categories are used to assess side effects: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data).

Regarding the side effects listed below, it should be noted that they are predominantly dose-dependent and may vary individually. The adverse reactions listed below include those associated with administration of Diclobene® N75 under conditions of short-term or long-term use.

Immune system side effects

If any of the listed symptoms develop, even after the first administration, Dicloberl® N75 must be discontinued immediately and the patient should receive urgent medical attention.

Reproductive system and mammary gland side effects

Clinical study data and epidemiological evidence indicate an increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke) associated with the use of diclofenac, particularly at high doses (150 mg daily) and during long-term treatment.

Visual disturbances

Visual disturbances such as blurred vision, visual blurring, and diplopia are class effects of NSAIDs and are generally reversible upon discontinuation of the drug. The most likely mechanism of visual disturbances is inhibition of prostaglandin and other related compound synthesis, which disrupts retinal blood flow regulation and contributes to the development of visual disturbances. If such symptoms occur during treatment with diclofenac, an ophthalmological examination should be performed to rule out other possible causes.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all 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.

Storage conditions. Store at a temperature not exceeding 30 °C!

To protect from light, ampoules should be stored in the original packaging. Keep out of reach and sight of children!

Incompatibility.

In general, Dicloberl® N75, injection solution, should not be mixed with other injectable solutions.

Packaging. 3 mL in a clear glass ampoule, 5 ampoules per blister pack in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

A. Menarini Manufacturing Logistics and Services S.r.l.

Manufacturer's address and location of operations.

Via Sette Santi 3, 50131 Florence (FI), Italy