INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CLODIFEN (CLODIFEN)

Composition:

Active substance: diclofenac;

1 ml of injection solution contains 25 mg sodium diclofenac;

1 ampoule (3 ml) of injection solution contains 75 mg sodium diclofenac;

Excipients: propylene glycol; sodium metabisulfite (E 223); benzyl alcohol; mannitol (E 421); sodium hydroxide or hydrochloric acid diluted; water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, light yellow solution.

Pharmacotherapeutic group.

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

Pharmacological Properties

Pharmacodynamics

The active substance of the medicinal product, diclofenac, is 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, sodium diclofenac at concentrations equivalent to those achieved in humans does not inhibit proteoglycan synthesis in cartilage tissue.

When diclofenac is administered concomitantly with opioids for postoperative pain relief, it significantly reduces the need for opioids.

Pharmacokinetics

Absorption

After intramuscular injection of 75 mg diclofenac, absorption begins immediately, and the mean peak plasma concentration (C_max) of approximately 2.5 μg/mL is reached within about 20 minutes.

When 75 mg of diclofenac is administered by intravenous infusion over 2 hours, the C_max is approximately 1.9 μg/mL. Shorter infusion durations result in higher C_max values, 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 reaching peak levels. 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 plasma concentration-time curve (AUC) after intramuscular or intravenous administration is approximately twice as high as after oral or rectal administration, because these parenteral routes avoid first-pass hepatic metabolism.

Pharmacokinetic properties do not change following repeated administration. With adherence to recommended dosing intervals, accumulation of diclofenac does not occur.

Distribution

Approximately 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 penetrates into synovial fluid, where maximum concentration is achieved 2–4 hours after peak plasma levels. The expected half-life (t_1/2) in synovial fluid is 3 to 6 hours. Two hours after peak plasma concentration, the concentration of diclofenac in synovial fluid exceeds that in plasma and remains higher for up to 12 hours.

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

Metabolism

Biotransformation of diclofenac occurs in the liver, partly via glucuronidation of the intact molecule, but mainly through single and multiple hydroxylations and methoxylations, 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 biologically active, although their activity is significantly less than that of diclofenac.

Elimination

Total systemic clearance of diclofenac from plasma is 263 ± 56 mL/min (mean value ± SD). The terminal t_1/2 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 t_1/2, but is practically inactive. Approximately 60% of the administered dose is excreted in urine as the glucuronide conjugate of the intact molecule and as metabolites, most of which are also converted into glucuronide conjugates. Less than 1% is excreted unchanged. The remainder of the dose is eliminated via bile into the intestine as metabolites.

Linearity/Non-linearity

Plasma concentrations demonstrate a linear relationship with dose.

Special Patient Groups

Elderly Patients

No age-related differences in absorption, metabolism, or excretion of diclofenac have been observed, except that in elderly patients, a 15-minute intravenous infusion resulted in a 50% higher plasma concentration of diclofenac compared to young healthy volunteers.

Patients with Renal Impairment

Based on the pharmacokinetics of diclofenac 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 hydroxylated metabolites are approximately four times higher than in healthy volunteers. However, these metabolites are ultimately eliminated via bile.

Patients with Hepatic Impairment

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, when administered intramuscularly, is indicated for the treatment of:

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

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

Contraindications.

Hypersensitivity to the active substance, sodium metabisulfite, or any other component of the medicinal product;
history of gastrointestinal bleeding or perforation related to previous treatment with nonsteroidal anti-inflammatory drugs (NSAIDs);
active gastric and/or duodenal ulcer, gastrointestinal hemorrhage, or perforation;
active or recurrent peptic ulcer disease/bleeding in history (two or more separate episodes of confirmed ulcer or bleeding);
in patients in whom administration of ibuprofen, acetylsalicylic acid, or other NSAIDs induces asthma attacks, bronchospasm, angioedema, urticaria, or rhinitis/nasal polyps, or allergy-like symptoms;
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);
heart failure (NYHA II–IV);
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;
high risk of postoperative bleeding, coagulation disorders, hemostatic disturbances, hematopoietic disorders, or cerebrovascular hemorrhage;
treatment of perioperative pain in coronary artery bypass grafting (CABG) (or use of cardiopulmonary bypass);
third trimester of pregnancy;
breastfeeding period;
pediatric age (under 18 years).

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 (plasma creatinine >160 µmol/L);
hypovolemia or dehydration of any cause.

Interaction with other medicinal products and other forms of interaction.

Potential interactions may occur when used concomitantly with other medicinal products.

Lithium. Possible increase in plasma lithium concentration. Monitoring of plasma lithium levels is recommended.

Digoxin. Possible increase in plasma digoxin concentration. Monitoring of plasma digoxin levels is recommended.

Diuretics and antihypertensive agents (e.g., beta-blockers, angiotensin-converting enzyme (ACE) inhibitors). Possible reduction in antihypertensive effect due to inhibition of vasodilatory prostaglandin synthesis. This combination should be used with caution, and patients, especially elderly, should be closely monitored for blood pressure. Adequate hydration is recommended, 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 known to cause hyperkalemia (e.g., potassium-sparing diuretics, cyclosporine, tacrolimus, trimethoprim). Possible increase in plasma potassium levels. If such combination is used, patient monitoring should be intensified (see section "Special precautions for use").

Anticoagulants and antiplatelet agents. Possible increased risk of bleeding. This combination should be used with caution. Although clinical studies do not indicate an effect of diclofenac on anticoagulant activity, isolated reports suggest an increased risk of bleeding in patients receiving diclofenac and anticoagulants simultaneously. Therefore, careful monitoring of such patients is recommended to ensure no dosage adjustments of anticoagulants are needed. Like other NSAIDs, high-dose diclofenac may transiently inhibit platelet aggregation.

Other NSAIDs (including selective cyclooxygenase-2 (COX-2) inhibitors) and corticosteroids. Possible increased risk of gastrointestinal bleeding and ulcers. Concomitant use of two or more NSAIDs should be avoided (see section "Special precautions for use").

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

Antidiabetic agents. Clinical 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, requiring dosage adjustments of antidiabetic agents during diclofenac treatment. Blood glucose monitoring is recommended as a precaution during concomitant therapy. Isolated reports of metabolic acidosis with concomitant use of diclofenac, particularly in patients with pre-existing renal impairment, have also been reported.

Methotrexate. Possible inhibition of methotrexate renal tubular clearance, leading to elevated methotrexate levels. Caution is recommended when using NSAIDs, including diclofenac, within 24 hours before or after methotrexate administration, as this may increase plasma methotrexate concentration and its toxicity. Serious toxicity cases have been reported when methotrexate and NSAIDs, including diclofenac, were administered within 24 hours of each other. This interaction is mediated by methotrexate accumulation due to impaired renal excretion in the presence of NSAIDs.

Cyclosporine. Possible increased nephrotoxicity of cyclosporine due to effects on renal prostaglandins. Therefore, it should be administered at lower doses than in patients not receiving cyclosporine.

Tacrolimus. Possible increased risk of nephrotoxicity, potentially mediated by renal anti-prostaglandin effects of NSAIDs and calcineurin inhibitors.

Quinolone antibiotics. Isolated reports of seizures in patients with and without history of epilepsy or seizures. Caution should be exercised when considering quinolone use in patients already receiving NSAIDs.

Phenytoin. Possible increased phenytoin exposure. Monitoring of plasma phenytoin levels is recommended.

Colestipol and cholestyramine. Possible delay or reduction in diclofenac absorption. Therefore, diclofenac should be administered at least 1 hour before or 4–6 hours after colestipol/cholestyramine administration.

Cardiac glycosides. Possible exacerbation of heart failure, decreased glomerular filtration rate, and increased plasma glycoside levels.

Mifepristone. Possible reduction in its efficacy. NSAIDs, including diclofenac, should not be used within 8–12 days after mifepristone administration.

CYP2C9 inhibitors (e.g., voriconazole). Possible significant increase in diclofenac plasma maximum concentration and exposure due to inhibition of its metabolism. This combination should be used with caution.

CYP2C9 inducers (e.g., rifampicin). Possible significant decrease in diclofenac plasma maximum concentration and exposure due to enhanced metabolism. This combination should be used with caution.

Special precautions for use.

General

Gastrointestinal ulcers, bleeding or perforation may occur at any time during therapy with NSAIDs, regardless of COX-2 selectivity, even in the absence of warning symptoms or predisposing history.

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

Concomitant use of this medicinal product with systemic NSAIDs, including selective COX-2 inhibitors, should be avoided due to lack of any synergistic benefit and the potential for additional adverse reactions (see section "Interaction with other medicinal products and other forms of interaction").

Placebo-controlled studies 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 comparable 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 treatment in patients with clinically confirmed ischemic heart disease, cerebrovascular disorders, peripheral arterial occlusive disease, or significant risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking). Because of this risk, the lowest effective dose should be used for the shortest possible duration of treatment.

NSAIDs may affect renal function, causing fluid retention with edema and/or arterial hypertension. Therefore, the medicinal product should be used with caution in patients with cardiac dysfunction and other conditions predisposing to fluid retention. Caution should also be exercised when administering the medicinal product to patients receiving concomitant diuretics or angiotensin-converting enzyme (ACE) inhibitors, or those prone to hypovolemia.

Adverse effects are usually more serious in elderly patients. The medicinal product should be used with caution in elderly patients. In particular, for frail elderly patients and those with low body weight, the lowest effective doses of diclofenac are recommended. If gastrointestinal bleeding or ulceration occurs, treatment with the medicinal product should be discontinued.

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

Like other NSAIDs, diclofenac may cause allergic reactions (including anaphylactic/anaphylactoid reactions), even without prior exposure (see section "Adverse reactions"). In cases of progressive hypersensitivity reactions, Kounis syndrome—a severe allergic reaction that may lead to myocardial infarction—may also develop. Symptoms of such reactions may include chest pain associated with an allergic reaction to diclofenac.

To avoid adverse reactions at the injection site—including muscle weakness, muscle paralysis, paresthesia, medication embolism (Nicolau syndrome), and tissue necrosis—appropriate instructions for intramuscular administration of the medicinal product must be strictly followed.

Gastrointestinal effects

Gastrointestinal bleeding (hematemesis, melena), ulceration, or perforation have been reported with all NSAIDs, including diclofenac, and may be fatal. These events may occur at any time during treatment, with or without warning symptoms, and in patients with or without gastrointestinal history. These events are usually more serious in elderly patients. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the medicinal product should be discontinued.

As with all NSAIDs, including diclofenac, careful monitoring is required, and the medicinal product should be used with particular caution in patients with symptoms suggesting gastrointestinal disorders, or in patients with a history of gastric or intestinal ulcers, bleeding, or perforation (see section "Adverse reactions"). 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—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 medicinal products that may 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 report any unusual abdominal symptoms (particularly gastrointestinal bleeding).

The medicinal product should be used with caution in patients receiving concomitant medicinal products 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").

Use of NSAIDs, including diclofenac, may be associated with an increased risk of gastrointestinal anastomosis failure. The medicinal product should be used with caution and under close medical supervision in patients following gastrointestinal surgery.

Hepatic effects

As with other NSAIDs, including diclofenac, levels of one or more liver enzymes may increase. This has been very frequently 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) occurred in approximately 1% of cases. Elevated liver enzyme levels 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 diclofenac. During long-term treatment, regular 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), the medicinal product should be discontinued.

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

Careful monitoring is required when administering the medicinal product to patients with hepatic impairment, as their condition may worsen (see section "Adverse reactions").

The medicinal product should be used with caution in patients with hepatic porphyria due to the potential to provoke an attack.

Renal effects

Due to the importance of prostaglandins in maintaining renal blood flow, prolonged use of high doses of NSAIDs, including diclofenac, frequently (1–10%) leads to edema and arterial hypertension. Since fluid retention and edema have been reported during treatment with NSAIDs, including diclofenac, the medicinal product should be used with particular caution in patients with cardiac or renal impairment, history of arterial hypertension, elderly patients, patients receiving concomitant diuretic therapy or drugs significantly affecting renal function, and patients with significant extracellular fluid volume depletion due to any cause, e.g., before or after major surgery (see section "Contraindications"). Renal function should be monitored in such cases.

Discontinuation of therapy usually results in return to the pre-treatment state.

Skin effects

Serious skin reactions (some of which were fatal), including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been very rarely reported during use of NSAIDs, including diclofenac. The highest risk appears to be during the initial phase of treatment, most often within the first month of therapy. At the first sign of skin rash, mucosal lesions, or any other signs of hypersensitivity, the medicinal product should be discontinued.

Cardiovascular and cerebrovascular effects

The medicinal product may be used in patients with significant cardiovascular risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful clinical evaluation.

Use of 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).

The medicinal product is generally not recommended for patients with diagnosed cardiovascular diseases (heart failure, ischemic heart disease, peripheral arterial disease) or uncontrolled arterial hypertension. If treatment is necessary in patients with diagnosed cardiovascular diseases, uncontrolled hypertension, or significant cardiovascular risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking), the medicinal product should be used only after careful evaluation and at doses not exceeding 100 mg daily for treatment courses longer than 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 need for diclofenac and the patient's response to therapy should be periodically reviewed, especially when treatment exceeds 4 weeks.

The medicinal product should be used with caution in elderly patients (aged 65 years and older).

Patients with a history of arterial hypertension and/or mild to moderate congestive heart failure should be monitored and advised, as fluid retention and edema have been reported with use of NSAIDs, including diclofenac.

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

Diclofenac is not recommended for patients with uncontrolled arterial hypertension, congestive heart failure, stable ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. Use of the medicinal product, if necessary, 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, smoking).

Patients should be informed about the possibility of developing symptoms of serious arterial thromboembolic events (e.g., chest pain, dyspnea, weakness, speech disturbances), which may occur without warning symptoms. Such symptoms may develop at any time. In such cases, immediate medical attention is required.

Hematological effects

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

With long-term treatment, as with other NSAIDs, blood monitoring is recommended.

Use in patients with asthma history

In patients with bronchial asthma, seasonal allergic rhinitis, nasal mucosal edema (nasal polyps), chronic obstructive lung diseases, or chronic respiratory tract 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 others. Therefore, special precautionary measures (emergency readiness) are recommended for such patients. This also applies to patients with allergies to other substances manifesting as skin reactions, pruritus, or urticaria.

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

Use in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders

An increased risk of aseptic meningitis may occur in such patients.

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 strictly followed when administering the medicinal product intramuscularly (see section "Method of administration and dosage").

Effect on female fertility

Use of diclofenac may impair female fertility and is not recommended for women attempting to conceive. For women experiencing difficulties with conception or undergoing infertility investigations, discontinuation of the medicinal product should be considered.

Based on relevant animal studies, impairment of male reproductive function cannot be excluded. The relevance of these findings to humans has not been established.

Precautions regarding excipients

Sodium metabisulfite in the injectable solution may cause severe hypersensitivity reactions, including anaphylactoid reactions and bronchospasm.

The medicinal product contains less than 1 mmol/dose of sodium, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

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 administration of prostaglandin synthesis inhibitors leads to increased 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, has been observed.

From the 20th week of pregnancy, use of diclofenac may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation.

The medicinal product should not be used during the first and second trimesters of pregnancy, except in cases of extreme necessity.

If the medicinal product is used by women attempting 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 should be considered after exposure to the medicinal product for several days starting from the 20th week of pregnancy. The medicinal product should be discontinued if oligohydramnios is detected.

During the third trimester, all prostaglandin synthesis inhibitors cause:

Risks to the fetus:

Cardio-pulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
Renal dysfunction (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 with very low doses;
Inhibition of uterine contractions, leading to delayed or prolonged labor.

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

Breastfeeding

Like other NSAIDs, diclofenac passes into breast milk in small amounts. The medicinal product should not be used during breastfeeding.

Effect on fertility

Like other NSAIDs, diclofenac may affect female fertility. The medicinal product Clodifen is not recommended for women planning to become pregnant. Women experiencing difficulties with conception or who have undergone infertility evaluation should discontinue use of the medicinal product.

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 influence reaction speed when driving vehicles or operating machinery.

If visual disturbances, dizziness, vertigo, somnolence, or other central nervous system disturbances occur during NSAID treatment, patients should refrain from driving vehicles or operating machinery.

Method of Administration and Dosage

The general recommendation is to determine the dose individually.

The medicinal product Clofen should be used at the lowest effective doses for the shortest duration necessary, taking into account the treatment objectives for each individual patient.

Adults

The medicinal product should be administered for no more than two days. If further treatment is required, it may be continued with diclofenac tablets or suppositories.

Intramuscular administration

To prevent nerve or other tissue damage at the site of intramuscular injection, the following rules must be observed, as such injuries may lead to muscle weakness, muscle paralysis, hyposthesia, medication embolism (Nicolau syndrome), and necrosis at the injection site.

The medicinal product Clofen should be administered by deep injection into the upper outer quadrant of the gluteus maximus muscle, using an aseptic technique. The usual dose is 75 mg (1 ampoule) once daily. 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 diclofenac formulations (e.g., tablets or suppositories) up to a maximum total daily dose of 150 mg.

Severe migraine attacks

In the setting of a migraine attack, clinical experience is limited to cases where an initial dose of 1 ampoule (75 mg) is administered. The dose may be given, if possible, immediately after administration of a 75 mg suppository on the same day (if necessary). The total daily dose should not exceed 150 mg on the first day.

There are no available data on the use of diclofenac for the treatment of migraine attacks beyond 1 day. If further therapy is required in subsequent days, the maximum daily dose should be up to 150 mg (in the form of divided doses administered as suppositories).

Intravenous administration

The medicinal product should be administered as an intravenous infusion. Immediately before starting the intravenous infusion, the contents of the ampoule should be diluted in 100–500 ml of 0.9% sodium chloride solution or 5% glucose solution. Both solutions should 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.

The medicinal product must not be administered as an intravenous bolus injection.

Recommended alternative dosing regimens:

For the treatment of moderate to severe postoperative pain, 75 mg of the medicinal product should be administered continuously over 30 minutes to 2 hours; if necessary, treatment may be repeated after 4–6 hours, but the dose should not exceed 150 mg per day;
For the prevention of postoperative pain, a loading dose of 25–50 mg of the medicinal product 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.

Special patient categories

Elderly patients (aged 65 years and older)

Dose adjustment of the medicinal product is generally not required in elderly patients. However, caution is recommended based on the patient's condition, particularly in frail elderly patients or those with low body weight (see section "Special precautions for use").

Children (under 18 years of age)

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

Patients with confirmed cardiovascular disease or serious cardiovascular risk factors

In general, the use of the medicinal product is not recommended in patients with cardiovascular disease or uncontrolled arterial hypertension. If necessary, the medicinal product may be used in patients with cardiovascular disease, uncontrolled arterial hypertension, or significant cardiovascular risk factors only after careful assessment and only at doses up to 100 mg per day for treatment courses longer than 4 weeks (see section "Special precautions for use").

Patients with renal impairment

The medicinal product is contraindicated in patients with renal impairment (GFR < 15 ml/min/1.73 m²; see section "Contraindications").

Specific studies in patients with renal dysfunction have not been conducted; therefore, no dosage recommendations can be made. The medicinal product should be used with caution in patients with renal dysfunction (see section "Special precautions for use").

Patients with hepatic impairment

The medicinal product is contraindicated in patients with hepatic impairment (see section "Contraindications").

Specific studies in patients with hepatic dysfunction have not been conducted; therefore, no dosage recommendations can be made. The medicinal product should be used with caution in patients with mild to moderate hepatic dysfunction (see section "Special precautions for use").

Children

The medicinal product in the form of injection solution is contraindicated for use in children.

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, excitement, coma, drowsiness, tinnitus, loss of consciousness, or convulsions. In severe poisoning, acute renal failure and liver damage may occur.

Treatment

Treatment of acute poisoning with NSAIDs, including diclofenac, consists primarily of supportive measures and symptomatic therapy. Supportive care and symptomatic treatment are necessary to manage complications such as arterial 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

The adverse reactions listed below are those associated with diclofenac administration under both short-term and long-term use.

Adverse reactions are listed by frequency: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from available data).

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:

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

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 bleeding, vomiting of blood, hemorrhagic diarrhea, melena, gastric or intestinal ulcer with bleeding, gastrointestinal stenosis with 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 (including ulcerative 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 – 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, pruritus, Henoch-Schönlein purpura.

Renal and urinary disorders:

common – fluid retention, edema; 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.

Published clinical trial data and epidemiological evidence indicate an increased risk of thrombotic complications (e.g., myocardial infarction or stroke) associated with diclofenac use, particularly at high therapeutic doses (150 mg daily) and with prolonged use (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 diclofenac. The most likely mechanism of visual disturbances is inhibition of prostaglandin synthesis and other related compounds, which disrupt retinal blood flow regulation and lead to visual disturbances. If such symptoms occur during treatment, ophthalmological examination should be performed to exclude other possible causes.

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine registration is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in a place inaccessible to children.

Incompatibilities.

The injectable solution 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 not recommended must not be used.

Packaging.

3 ml of injectable solution in glass ampoules; 5 ampoules in a blister pack;

1 blister pack in a cardboard box.

Prescription status.

Prescription only.

Marketing Authorization Holder.

WORLD MEDICINE, LLC, Ukraine.

Manufacturer.

WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and place of business.

Lot No. 30, 6th Street, G.O. Pasha District, Cerkezkoy/Tekirdag, Turkey.