INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EWINOPON (EVINOPON)

Composition:

Active substance: diclofenac sodium;

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

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

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, almost colorless solution.

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

Pharmacological Properties

Pharmacodynamics.

Evinopon 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 inhibit proteoglycan synthesis in cartilage tissue. When administered concomitantly with opioids for postoperative pain relief, Evinopon significantly reduces the need for opioids.

Pharmacokinetics.

Absorption.

After administration of 75 mg diclofenac by intramuscular injection, absorption begins immediately, and the mean peak plasma concentration (Cmax) 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 administered.

When 75 mg of diclofenac is administered by intravenous infusion over 2 hours, the mean peak plasma concentration is approximately 1,875 ± 0,436 mg/mL (1.9 µg/mL ≡ 5.9 µmol/L). Shorter infusion durations result in higher peak plasma concentrations, while longer infusions lead to a concentration plateau proportional to the infusion rate after 3–4 hours. In contrast to the corresponding results after oral administration, when the drug is administered as suppositories or by intramuscular injection, plasma concentration decreases rapidly immediately after reaching peak levels.

Bioavailability.

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

Distribution.

99.7% of diclofenac is protein-bound, primarily to albumin (99.4%).

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

Diclofenac has been detected at low concentrations (100 ng/mL) in breast milk in one breastfeeding woman. The estimated amount of diclofenac 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 mainly through mono- and poly-hydroxylation and methoxylation, leading to the formation of several phenolic metabolites, most of which are subsequently converted into glucuronide conjugates. Two of these phenolic metabolites are biologically active, although their activity is considerably weaker than that of diclofenac.

Elimination.

Total systemic clearance of diclofenac from plasma is 263 ± 56 mL/min (mean value ± standard deviation). 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 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 in feces as metabolites.

Special patient groups.

Elderly patients. No age-related differences in absorption, metabolism, or excretion of diclofenac have been observed, except that in some 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 under normal dosing regimens, based on the drug's kinetics after single administration. However, in patients with creatinine clearance less than 10 mL/min, plasma levels of hydroxymetabolites are approximately four times higher than in healthy volunteers.

Nevertheless, metabolites are ultimately eliminated via bile.

Patients with liver 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 for intramuscular administration is indicated for the treatment of:

Inflammatory and degenerative forms of rheumatism, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, spondyloarthritis, vertebral pain syndrome, non-articular rheumatism;
Acute gout attacks;
Renal and biliary colic;
Pain and swelling following trauma and surgery;
Severe migraine attacks.

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

Contraindications.

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 nonsteroidal anti-inflammatory drugs (NSAIDs).
Active peptic ulcer/hemorrhage or recurrent peptic ulcer/hemorrhage in history (two or more separate episodes of confirmed ulcer or bleeding).

− Active gastric and/or duodenal ulcer, gastrointestinal bleeding, or perforation.

Third trimester of pregnancy.
As with other NSAIDs, diclofenac is contraindicated in patients in whom administration of ibuprofen, acetylsalicylic acid, or other nonsteroidal anti-inflammatory agents triggers attacks of bronchial asthma, bronchospasm, angioneurotic edema, urticaria, acute rhinitis/nasal polyps, or allergy-like symptoms.
Inflammatory bowel diseases (e.g., Crohn’s disease or ulcerative colitis).
Hepatic insufficiency (Child-Pugh class C), liver cirrhosis, and ascites.

− Heart failure (functional class II–IV according to NYHA — New York Heart Association).

Renal insufficiency (glomerular filtration rate (GFR) < 15 mL/min/1.73m²).
High risk of postoperative bleeding, coagulation disorders, hemostatic disorders, hematopoietic disorders, or cerebrovascular hemorrhage.
Should not be used for treatment of postoperative pain following coronary artery bypass grafting (or when using cardiopulmonary bypass).
Ischemic heart disease in patients with angina pectoris or history of myocardial infarction.
Cerebrovascular diseases in patients with history of stroke or transient ischemic attacks.
Peripheral arterial disease.
This medicinal form is contraindicated in children.

Contraindications for intravenous use.

Concomitant use of NSAIDs or anticoagulants (including low-dose heparin).
History of hemorrhagic diathesis, confirmed or suspected history of cerebrovascular hemorrhage.
Surgeries associated with high risk of bleeding.
History of bronchial asthma.
Moderate or severe renal function impairment (serum creatinine > 160 µmol/L).
Hypovolemia or dehydration of any cause.

Interaction with other medicinal products and other types of interactions.

The interactions listed below have been observed during administration of the drug Evinopon, injection solution, and/or other diclofenac formulations.

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

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

Diuretics and antihypertensive agents. As with other NSAIDs, concomitant use of diclofenac with diuretics and antihypertensive agents [e.g., β-blockers, angiotensin-converting enzyme (ACE) inhibitors] may reduce their antihypertensive effect due to inhibition of vasodilatory prostaglandin synthesis. Therefore, such combinations should be used with caution, and patients, especially elderly ones, should be closely monitored for blood pressure. Adequate hydration should be ensured, and monitoring of renal function is recommended both after initiation and on a regular basis 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 be associated with increased serum potassium levels; therefore, more frequent monitoring of patients is advised (see section "Special precautions for use").

Anticoagulants and antithrombotic agents. Precautions are recommended, as concomitant administration increases the risk of bleeding (see section "Special precautions for use"). Although clinical studies have not demonstrated an effect of diclofenac on anticoagulant activity, isolated reports indicate an increased risk of bleeding in patients receiving diclofenac and anticoagulants simultaneously. Therefore, careful monitoring of patients receiving diclofenac and anticoagulants is recommended, and dose adjustment of anticoagulants may be necessary if needed. As with other nonsteroidal anti-inflammatory drugs, high-dose diclofenac may temporarily inhibit platelet aggregation.

Other NSAIDs, including selective cyclooxygenase-2 inhibitors, and corticosteroids. Concomitant administration of diclofenac with other systemic NSAIDs or corticosteroids increases the frequency of gastrointestinal adverse effects (see section "Special precautions for use").

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

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

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

Methotrexate. Diclofenac may inhibit methotrexate clearance in renal tubules, leading to elevated methotrexate levels. Caution is advised when administering NSAIDs, including diclofenac, less than 24 hours before methotrexate treatment, as this may increase methotrexate blood concentration and enhance 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 and tacrolimus. Diclofenac, like other NSAIDs, may increase the nephrotoxicity of cyclosporine and tacrolimus due to effects on renal prostaglandins. Therefore, it should be administered at lower doses than in patients not receiving cyclosporine or tacrolimus.

Quinolone antibiotics. 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 should be exercised when considering quinolone use in patients already receiving NSAIDs.

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

Colestipol and cholestyramine. These agents may cause delayed or reduced absorption of diclofenac. Therefore, diclofenac should be administered at least one hour before or 4–6 hours after colestipol/cholestyramine administration.

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

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

Inhibitors of CYP2C9. Caution is required when co-prescribing diclofenac with CYP2C9 inhibitors (e.g., voriconazole). This may lead to a significant increase in maximum plasma concentration and exposure to diclofenac.

Inducers of CYP2C9. Caution is required when co-prescribing diclofenac with CYP2C9 inducers (e.g., rifampicin). This may lead to a significant decrease in plasma concentration and reduced efficacy of diclofenac.

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

Special precautions for use.

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

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

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 been established. Due to the absence of comparable clinical data on long-term treatment with maximum doses of diclofenac, a similar increased risk cannot be excluded. Before initiating diclofenac, a careful benefit-risk assessment should be performed 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). Given this risk, the lowest effective dose should be used for the shortest possible duration.

NSAIDs may affect kidney function, causing fluid retention with edema and/or arterial hypertension. Therefore, diclofenac should be used with caution in patients with cardiac dysfunction and other conditions predisposing to fluid retention. Caution is also advised when treating patients receiving diuretics or ACE inhibitors, or those prone to hypovolemia.

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

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

Like other NSAIDs, Evipan may mask signs and symptoms of infection.

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

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

Reactions at the injection site

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

Gastrointestinal effects

With the use of all NSAIDs, including diclofenac, cases of gastrointestinal bleeding (hematemesis, melena), ulceration, or perforation have been reported, which may be fatal and can occur at any time during treatment, regardless of prior warning 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.

The use of NSAIDs, including diclofenac, may be associated with an increased risk of "anastomotic failure." Careful medical monitoring and caution are required when using diclofenac, as with all NSAIDs, following surgical procedures on the gastrointestinal tract.

Careful medical monitoring is necessary 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 peptic ulcer, gastrointestinal bleeding, or perforation (see section "Adverse reactions"). The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher doses of NSAIDs, including diclofenac, and in patients with a history of peptic ulcer, especially with complications such as 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 peptic ulcer, especially with complications such as 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 medications containing low-dose acetylsalicylic acid (ASA) or other drugs likely to increase the risk of gastrointestinal adverse effects, consideration should be given to combination therapy with protective agents (e.g., proton pump inhibitors or misoprostol).

Patients with a history of gastrointestinal toxicity, especially elderly patients, should report any unusual abdominal symptoms (particularly gastrointestinal bleeding). Caution is also required for 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 (see section "Interaction with other medicinal products and other forms of interaction").

Hepatic effects

Close medical monitoring is required if Evipan is prescribed to patients with impaired liver function, as their condition may worsen (see section "Adverse reactions").

With the use of NSAIDs, including diclofenac, liver enzyme levels may increase. This phenomenon was very frequently observed in clinical trials with diclofenac (approximately 15% of patients), but rarely accompanied by clinical symptoms. Most increases in liver enzymes were within the normal range. Moderate increases (≥3 to <8 times the upper limit of normal) were observed in 2.5% of cases, while the frequency of marked increases (≥8 times the upper limit of normal) remained around 1%. Elevated liver enzymes were associated with clinically evident liver damage 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, diseases such as hepatitis may progress without prodromal symptoms.

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), Evipan should be discontinued.

Caution is required when Evipan is used 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 treatment with high doses of NSAIDs, including diclofenac, often (1–10%) leads to edema and arterial hypertension.

Since fluid retention and edema have been reported with NSAID treatment, 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 reduction in extracellular fluid volume for any reason, such as before or after major surgery (see section "Contraindications"). In such cases, monitoring of renal function is recommended as a precaution when using Evipan. Discontinuation of therapy usually leads to 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 in association with NSAIDs, including Evipan. The highest risk of these reactions appears to be at the beginning of treatment, mostly within the first month of therapy. Treatment with Evipan should be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity.

Systemic lupus erythematosus (SLE) and mixed connective tissue diseases

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

Cardiovascular and cerebrovascular effects

Treatment with NSAIDs, including diclofenac, especially at high doses and for prolonged periods, slightly increases the risk of serious cardiovascular thrombotic events (including myocardial infarction and stroke).

Treatment with Evipan is 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), Evipan should be prescribed only after careful evaluation and at doses up to 100 mg daily if treatment duration exceeds 4 weeks.

Since cardiovascular risks of diclofenac may increase with dose and duration of treatment, it should be used for the shortest possible period and at the lowest effective dose. The patient's need for diclofenac and response to therapy should be periodically reviewed, especially when treatment lasts longer than 4 weeks. Use with caution in patients aged 65 years and older.

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

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

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 is required.

Effects on hematological parameters

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

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

Respiratory effects

In 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), 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 precautions (readiness for emergency care) 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 with a history of bronchial asthma.

Fertility in women

Use of Evipan may impair fertility in women and is not recommended for women wishing to become pregnant. For women who may have difficulty conceiving or undergoing infertility evaluation, discontinuation of Evipan should be considered.

Special warnings regarding inactive ingredients

Benzyl alcohol

With prolonged use in high doses, benzyl alcohol may accumulate in the body and cause adverse reactions (so-called "metabolic acidosis"). Benzyl alcohol may cause mild irritation.

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

Propylene glycol

Due to reported adverse reactions associated with propylene glycol, medical monitoring is required for patients with impaired renal or hepatic function.

Sodium

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

Use during pregnancy or breastfeeding.

Pregnancy

Use of Evipan from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible after discontinuation of the drug.

In the first and second trimesters of pregnancy, Evipan may be prescribed only if the expected benefit to the mother outweighs the potential risk to the fetus, at the lowest effective dose, and for the shortest possible duration. Like other NSAIDs, the drug is contraindicated in the third trimester of pregnancy (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 indicate an increased risk of miscarriage and/or risk of cardiac defects and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy.

The absolute risk of cardiovascular malformations increases from less than 1% to approximately 1.5%.

The risk increases 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 losses and embryonic/fetal mortality.

Furthermore, in animals treated with a prostaglandin synthesis inhibitor during organogenesis, an increased frequency of various developmental abnormalities, including cardiovascular defects, has been observed. If Evipan is used in women wishing to become pregnant or during the first or second trimester of pregnancy, the dose should be as low as possible and the treatment duration as short as possible.

Antenatal monitoring for oligohydramnios should be considered after exposure to Evipan for several days starting from the 20th week of pregnancy. Evipan should be discontinued if oligohydramnios is detected.

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

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

On the mother and newborn, especially near the end of pregnancy:

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, Evipan is contraindicated during the third trimester of pregnancy.

Breastfeeding period

Like other nonsteroidal anti-inflammatory drugs, diclofenac passes into breast milk in small amounts. Therefore, to avoid adverse effects on the infant, Evipan should not be used during breastfeeding. If treatment is considered necessary, the infant should be switched to artificial feeding.

Fertility

Evipan 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 Evipan.

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 vehicles or operating machinery.

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

Dosage and Administration

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

Adults

The medicinal product Evinopon, injection solution, should not be administered for more than 2 days. If continued treatment is necessary, therapy may be continued with diclofenac in another pharmaceutical form, for example, tablets or suppositories.

Intramuscular injection

To prevent nerve or other tissue injury at the site of intramuscular injection, the following instructions must be followed. Such injuries may lead to muscle weakness, paralysis, hypoesthesia, medication embolism (Nicolau syndrome), and necrosis at the injection site.

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

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

There are no available data on the use of diclofenac for migraine treatment beyond one day. If further therapy is required on subsequent days, the daily dose should not exceed 150 mg (administered as divided doses in suppository form).

Intravenous infusion

Immediately before starting intravenous infusion, Evinopon injection solution should be diluted in 100–500 mL of 0.9% sodium chloride solution or 5% glucose solution. Both solutions should first 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 in the solution, it must not be used.

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

Recommended alternative dosing regimens for Evinopon injection solution:

For treatment of moderate to severe postoperative pain: 75 mg should be administered continuously over 30 minutes to 2 hours; if necessary, treatment may be repeated after 4–6 hours, but the daily dose must not exceed 150 mg;
For prophylaxis of postoperative pain: a loading dose of 25–50 mg should be administered 15 minutes to 1 hour after surgery, followed by continuous infusion at approximately 5 mg/hour up to a maximum daily dose of 150 mg.

Special patient groups

Elderly patients (aged 65 years and older)

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

The recommended maximum daily dose of Evinopon is 150 mg.

Established cardiovascular disease or serious cardiovascular risk factors

Evinopon is generally not recommended for patients with cardiovascular disease or uncontrolled arterial hypertension. If necessary, Evinopon may be prescribed to patients with cardiovascular disease, uncontrolled arterial hypertension, or significant cardiovascular risk factors only after careful assessment and at doses not exceeding 100 mg per day if the duration of treatment exceeds 4 weeks (see section "Special warnings and precautions for use").

Renal impairment

Evinopon 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 renal dysfunction; therefore, no dosage recommendations can be made. Evinopon should be used with caution in patients with impaired renal function (see section "Special warnings and precautions for use").

Hepatic impairment

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

No specific studies have been conducted in patients with hepatic dysfunction; therefore, no dosage recommendations can be made. Evinopon should be used with caution in patients with mild to moderate hepatic impairment (see section "Special warnings and precautions for use").

Children

Evinopon 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, excitation, coma, somnolence, tinnitus, loss of consciousness, or seizures. In severe poisoning, acute renal failure and hepatic injury may occur.

Treatment. Management of acute NSAID poisoning is primarily supportive and symptomatic, aimed at treating 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

Adverse reactions to the medicinal product are listed by frequency as follows: 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 available data).

The adverse effects listed below are associated with administration of the medicinal product Evipan, both during short-term and long-term use.

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 – angioneurotic edema (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 impairment.

Cardiovascular disorders: very rare – palpitations, chest pain, heart failure, myocardial infarction; common – arterial hypertension; very rare – arterial hypotension, vasculitis; frequency not known – Kounis syndrome.

Respiratory system disorders: rare – asthma (including dyspnea); very rare – pneumonitis.

Gastrointestinal disorders: common – nausea, vomiting, diarrhea, dyspepsia, abdominal pain, flatulence, anorexia; rare – gastritis, gastrointestinal bleeding, 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 (including ulcerative stomatitis), glossitis, esophageal disorders, membranous intestinal 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, allergic purpura, pruritus, Schönlein-Henoch purpura.

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, pain, induration; rare – swelling, necrosis at injection site; very rare – injection site abscess; frequency not known – medication embolism (Nicolau syndrome).

Reproductive system 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 blurring, and diplopia are class effects of NSAIDs and are usually reversible upon discontinuation of the drug. The most likely mechanism of visual disturbances is inhibition of prostaglandin synthesis and other related compounds, which may disrupt retinal blood flow regulation and contribute to the development of visual 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 a medicinal product has been authorized is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life. 5 years.

Reconstituted infusion solutions should be used immediately.

Storage conditions.

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

Keep out of the reach of children.

Incompatibilities.

Evipan, injection solution, should generally not be mixed with other injection solutions.

Infusion solutions of 0.9% sodium chloride or 5% glucose without sodium bicarbonate as an additive pose a risk of oversaturation, which may lead to crystal or precipitate formation. Other infusion solutions should not be used except those recommended.

Packaging.

Injection solution, 25 mg/mL, 3 mL (75 mg) in vials, pack of 5, in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

BROS LTD / BROS LTD.

Manufacturer's address and place of business.

Augis & Galinis 15, Nea Kifisia (Attiki) 145 64, Greece.

Evipon