Evinopon-vf

Ukraine
Brand name Evinopon-vf
Form solution for injection
Active substance / Dosage
diclofenac · 25 mg/ml
Prescription type prescription only
ATC code
M01AB05
Registration number UA/19439/01/01
Manufacturer PJSC "Lekhim-Kharkiv"

Table of Contents

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT EVINOPON-VPh (EVINOPON-VPh)

Composition:

Active substance: sodium diclofenac;

1 ml of solution contains sodium diclofenac, calculated as 100% substance – 25 mg;

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

Pharmaceutical form. Solution for injection.

Main physicochemical properties: colorless to slightly yellow solution.

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

Pharmacological Properties

Pharmacodynamics

Evinopon-VF 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 suppress proteoglycan biosynthesis in cartilage tissue.

When administered concomitantly with opioids for postoperative pain relief, Evinopon-VF significantly reduces the need for opioids.

Pharmacokinetics

Absorption

After intramuscular administration of 75 mg of diclofenac, the mean peak plasma concentration of approximately 2.5 µg/mL is reached within about 20 minutes. When 75 mg of diclofenac is administered via intravenous infusion over 2 hours, the mean peak plasma concentration is approximately 1.9 µg/mL. 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. After intramuscular injection or oral administration of enteric-coated tablets or rectal suppositories, plasma 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 that observed after oral or rectal administration.

Pharmacokinetic properties do not change following repeated administration. With adherence to recommended dosing intervals, drug accumulation 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 its maximum concentration is achieved 2–4 hours after peak plasma concentration. The expected half-life (t1/2) in synovial fluid is 3–6 hours. Two hours after peak plasma concentration, diclofenac concentration 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 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 via single and multiple hydroxylation and methoxylation reactions, resulting in several phenolic metabolites (3’-hydroxy-, 4’-hydroxy-, 5-hydroxy-, 4’,5-dihydroxy-, and 3’-hydroxy-4’-methoxy-diclofenac), most of which are converted into glucuronide conjugates. Two of these phenolic metabolites are pharmacologically active, although their activity is significantly less than that of diclofenac.

Excretion

Total systemic clearance of diclofenac from plasma is 263 ± 56 mL/min (mean ± SD). The terminal elimination half-life (t1/2) from plasma is 1–2 hours. Four metabolites, including two active ones, also have short plasma t1/2 values of 1–3 hours. One metabolite, 3’-hydroxy-4’-methoxy-diclofenac, has a much longer t1/2 but is essentially inactive. Approximately 60% of the administered dose is excreted in urine as metabolites. Less than 1% is excreted unchanged. The remainder is eliminated as metabolites via bile in feces.

Linearity/Non-linearity

Plasma concentrations of the drug demonstrate a linear relationship with dose.

Special Patient Groups

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

Patients with renal impairment. Based on the pharmacokinetics after single-dose administration, accumulation of unchanged active substance is not expected in patients with renal impairment when standard dosing regimens are followed. However, with creatinine clearance less than 10 mL/min, theoretical steady-state plasma levels of metabolites are approximately four times higher than in healthy volunteers.

Nevertheless, metabolites are ultimately eliminated via bile.

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

Clinical characteristics.

Indications.

The drug 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 prevention and treatment of postoperative pain.

Contraindications.

  • Known hypersensitivity to the active substance, sodium metabisulfite, or to any other components of the drug.
  • History of gastrointestinal bleeding or perforation associated with previous treatment with non-steroidal anti-inflammatory drugs (NSAIDs).
  • Active peptic ulcer/hemorrhage or recurrent peptic ulcer/hemorrhage in history (two or more separate episodes of established 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 NSAIDs induces attacks of bronchial asthma, bronchospasm, angioneurotic edema, 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).
  • High risk of postoperative bleeding, coagulation disorders, hemostasis disorders, hematopoietic disorders, or cerebrovascular hemorrhage.
  • Treatment of postoperative pain following coronary artery bypass grafting (or use of cardiopulmonary bypass machine).
  • 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.

For intravenous use only

  • 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.

Below are interactions observed during the use of the medicinal product Evipon-VF, solution for injection, and/or other medicinal 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.

Diuretics and antihypertensive agents. As with other NSAIDs, concomitant use of diclofenac with diuretics and antihypertensive agents (e.g., beta-blockers, angiotensin-converting enzyme (ACE) inhibitors) may reduce their antihypertensive effect. Therefore, such combinations should be used with caution, and blood pressure should be closely monitored, especially in elderly patients. Adequate hydration is recommended, and renal function should also be monitored 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 treatment with potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may lead to increased serum potassium levels; therefore, more frequent monitoring of patients is recommended (see section "Special precautions for use").

Anticoagulants and antithrombotic agents. Precautions are recommended, as concomitant administration may increase the risk of bleeding (see section "Special precautions for use"). Although clinical studies have not shown an effect of diclofenac on anticoagulant activity, there are individual reports of increased bleeding risk in patients receiving diclofenac and anticoagulants simultaneously. Therefore, careful monitoring of such patients is recommended.

Other NSAIDs and corticosteroids. Concomitant administration of diclofenac with other systemic NSAIDs or corticosteroids may increase the frequency of gastrointestinal adverse effects (see section "Special precautions for use").

Selective serotonin reuptake inhibitors (SSRIs). Concomitant use of systemic NSAIDs and SSRIs may increase 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, individual cases of both hypoglycemic and hyperglycemic effects have been reported after diclofenac administration, requiring dosage adjustments of antidiabetic agents during diclofenac treatment. Monitoring of blood glucose levels is necessary in such cases, as a precaution during concomitant therapy.

Isolated reports of metabolic acidosis have also been reported with concomitant use of diclofenac, particularly in patients with pre-existing renal function impairment.

Methotrexate. 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.

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 antibacterials. There are isolated reports of seizures that may result from concomitant use of quinolones and NSAIDs.

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

Cholestyramine and colestipol. These agents may cause delayed or reduced absorption of diclofenac. Therefore, diclofenac should be administered at least 1 hour before or 4–6 hours after cholestyramine/colestipol administration.

Cardiac glycosides. Concomitant use of cardiac glycosides and NSAIDs may exacerbate heart failure, reduce GFR, 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.

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

CYP2C9 inducers. Caution is required when co-prescribing diclofenac with CYP2C9 inducers (e.g., rifampicin), as their combined use may lead to a significant increase in diclofenac plasma concentration and exposure.

Special precautions for use.

General

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

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

Placebo-controlled studies have revealed 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 diclofenac in patients with clinically confirmed ischemic heart disease, cerebrovascular disorders, peripheral arterial disease, or significant risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking). Given this risk, the lowest effective dose should be administered for the shortest possible duration.

The effect of NSAIDs on the kidneys includes fluid retention with edema and/or arterial hypertension. Therefore, diclofenac should be used with caution in patients with cardiac dysfunction and other conditions causing fluid retention. Caution is also advised when administering the drug to patients taking concomitant diuretics or ACE inhibitors, or those prone to hypovolemia.

Consequences are usually more serious in elderly patients. Caution should be exercised when prescribing the drug to elderly individuals. In particular, the lowest effective doses are recommended for frail elderly patients and those with low body weight. If gastrointestinal bleeding or ulcers occur in patients receiving Evipon-VF, treatment should be discontinued.

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

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

Gastrointestinal effects

Cases of gastrointestinal bleeding (hematemesis, melena), ulceration, or perforation have been reported with diclofenac use. These events may occur at any time during treatment, with or without warning symptoms, and may be associated with a history of serious gastrointestinal events; they can lead to fatal outcomes. These events usually have more serious consequences in elderly patients. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the drug should be discontinued.

As with all NSAIDs, careful medical monitoring is required when using diclofenac; particular caution should be exercised when prescribing diclofenac to patients with symptoms indicating gastrointestinal tract disorders, or with a history of peptic ulcer, gastrointestinal bleeding, or perforation (see section "Adverse reactions"). The risk of gastrointestinal bleeding increases with higher NSAID doses, in patients with a history of ulcers (especially complicated by bleeding or perforation), and in elderly patients.

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

Elderly patients have an increased frequency of adverse reactions when using diclofenac, 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, diclofenac should be administered at the lowest effective dose.

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

Patients with a history of gastrointestinal toxicity, especially elderly patients, should report any unusual abdominal symptoms (particularly gastrointestinal bleeding). Caution is also required for patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants (e.g., warfarin), antiplatelet agents (e.g., acetylsalicylic acid), or SSRIs (see section "Interaction with other medicinal products and other forms of interaction").

Hepatic effects

Close medical monitoring is required when administering Evipon-VF to patients with hepatic impairment, as their condition may worsen (see section "Adverse reactions").

As with other NSAIDs, during diclofenac use, levels of one or more liver enzymes may increase. This has been very commonly observed in clinical trials with diclofenac (approximately 15% of patients), but rarely accompanied by clinical symptoms. Most of these cases involve borderline elevations. Moderate increases (≥3 to <8 times the upper limit of normal [ULN]) have been commonly observed (in 2.5% of cases), while the frequency of marked increases (≥8 times ULN) remains around 1%. 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 upon discontinuation of the drug. In patients receiving diclofenac, conditions such as hepatitis may progress without prodromal symptoms.

Caution is necessary if Evipon-VF is administered to patients with hepatic porphyria, due to the potential for provoking an attack.

Renal effects

Due to the importance of prostaglandins in maintaining renal blood flow, prolonged treatment with high doses of diclofenac often (1–10%) leads to edema and arterial hypertension.

Since fluid retention and edema have been reported with diclofenac use, particular attention should be paid to patients with cardiac or renal impairment, a history of arterial hypertension, elderly patients, those receiving concomitant diuretic therapy or drugs significantly affecting renal function, and patients with substantial extracellular fluid volume depletion due to any cause, e.g., before or after major surgery (see section "Contraindications"). As a precautionary measure, monitoring of renal function is recommended when using Evipon-VF. 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, toxic epidermal necrolysis, and generalized bullous fixed drug eruption, have been very rarely reported with diclofenac. The highest risk of these reactions appears to occur early in the course of treatment, in most cases within the first month of therapy. Treatment with Evipon-VF must be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity.

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, may rarely occur even without prior exposure to diclofenac.

Hypersensitivity reactions may also progress to Kounis syndrome, a serious allergic reaction that may cause myocardial infarction. Symptoms of such reactions may include chest pain occurring in combination with an allergic reaction to diclofenac.

Systemic lupus erythematosus (SLE) and mixed connective tissue diseases

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

Cardiovascular and cerebrovascular effects

Diclofenac should be prescribed to patients with significant cardiovascular risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful clinical evaluation.

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

The use of Evipon-VF is generally not recommended in patients with diagnosed cardiovascular diseases (heart failure, ischemic heart disease, peripheral arterial disease) or uncontrolled arterial hypertension. If such treatment is necessary in patients with diagnosed cardiovascular diseases, uncontrolled hypertension, or significant cardiovascular risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking), Evipon-VF should be prescribed only after careful evaluation and only at doses up to 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 period and at the lowest effective dose. The patient's need for diclofenac and response to therapy should be periodically reviewed, especially when treatment exceeds 4 weeks. Use with caution in patients aged 65 years and older.

Patients with a history of arterial hypertension and/or mild to moderate congestive heart failure require appropriate monitoring and advice, as fluid retention and edema have been reported with diclofenac use.

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

Diclofenac is not recommended for patients with uncontrolled arterial hypertension, congestive heart failure, stable ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. If use is necessary, it should only be considered after careful 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 events (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking).

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

Hematological effects

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

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

Respiratory effects (asthma history)

In patients with bronchial asthma, seasonal allergic rhinitis, nasal mucosal edema (nasal polyps), chronic obstructive pulmonary 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.

Particular caution is recommended when administering Evipon-VF parenterally to patients with bronchial asthma, as symptoms may worsen.

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

Injection site reactions

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

Fertility in women

Use of Evipon-VF may impair fertility in women and is not recommended for women wishing to conceive. For women who may have difficulty conceiving or undergoing infertility evaluation, discontinuation of Evipon-VF 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.

Use during pregnancy or breastfeeding.

Pregnancy

Evipon-VF may be prescribed during the first and second trimesters of pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus, and only at the lowest effective dose. The duration of treatment should be as short as possible. Like other NSAIDs, the drug is contraindicated in the third trimester of pregnancy (possible inhibition of uterine contractility and premature closure of the fetal ductus arteriosus).

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

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

The risk increases with higher doses and longer duration of treatment. In animal studies, administration of a prostaglandin synthesis inhibitor has been shown to increase pre- and post-implantation loss and embryonic/fetal mortality.

Furthermore, in animals receiving a prostaglandin synthesis inhibitor during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular defects, has been observed.

Starting from the 20th week of pregnancy, use of Evipon-VF may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation of therapy. If Evipon-VF is used in women wishing to conceive or in pregnant women during the first or second trimester, the dose should be as low as possible and the duration of treatment as short as possible. Fetal monitoring for oligohydramnios should be considered after several days of Evipon-VF exposure starting from the 20th week of pregnancy. Evipon-VF should be discontinued if oligohydramnios is detected.

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

on the fetus:

  • cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
  • renal dysfunction (see above).

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

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

Therefore, Evipon-VF is contraindicated during the third trimester of pregnancy.

Lactation

Like other NSAIDs, diclofenac passes into breast milk in small amounts. To avoid potential adverse effects on the infant, Evipon-VF should not be used during breastfeeding. If treatment is considered necessary, the infant should be switched to artificial feeding.

Fertility

Evipon-VF may affect female fertility. The drug is not recommended for women planning pregnancy. Women experiencing conception difficulties or undergoing infertility evaluation should discontinue use of Evipon-VF.

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 rate when driving or operating machinery.

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

Method of Administration and Dosage

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

Adults

Evipan-VF, solution for injection, should not be used for more than 2 days. If continued treatment is necessary, therapy may be continued with gastro-resistant tablets or suppositories of Evipan-VF.

Intramuscular Injection

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

The usual dose is 75 mg (one ampoule) daily, administered by deep injection into the upper outer quadrant of the gluteus maximus muscle, using an aseptic technique. In severe cases (e.g., colic), the daily dose may be increased to two 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 Evipan-VF (e.g., tablets or suppositories) up to a maximum total daily dose of 150 mg of sodium diclofenac.

In the management of 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 Evipan-VF for the treatment of migraine attacks beyond one day. If further therapy is required on subsequent days, the maximum daily dose should be up to 150 mg (in divided doses administered as suppositories).

Intravenous Infusion

Immediately before starting intravenous infusion, Evipan-VF 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% solution). Only clear solutions should be used. If crystals or precipitate are present in the solution, it must not be used.

Evipan-VF, solution for injection, must not be administered as an intravenous bolus injection.

Recommended alternative dosing regimens for Evipan-VF, solution for injection:

  • 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 several hours, but the dose should not exceed 150 mg per day;
  • 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 of approximately 5 mg/hour up to a maximum daily dose of 150 mg.

Special Patient Groups

Elderly Patients (aged 65 years and older)

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

Paediatric Population (children under 18 years of age)

Evipan-VF in the form of injection solution is contraindicated for use in children and adolescents.

Established Cardiovascular Disease or Serious Cardiovascular Risk Factors

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

Renal Impairment

Evipan-VF 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 dose adjustment recommendations can be made. Evipan-VF should be used with caution in patients with renal dysfunction (see section "Special Warnings and Precautions for Use").

Hepatic Impairment

Evipan-VF is contraindicated in patients with hepatic impairment (see section "Contraindications").

Specific studies in patients with hepatic dysfunction have not been conducted; therefore, no dose adjustment recommendations can be made. Evipan-VF should be used with caution in patients with mild to moderate hepatic impairment (see section "Special Warnings and Precautions for Use").

Children

Evipan-VF in the form of injection solution is contraindicated for use in children and adolescents.

Overdose.

Symptoms

There is no typical clinical picture of diclofenac overdose. Overdose may cause symptoms such as vomiting, gastrointestinal bleeding, diarrhea, dizziness, tinnitus, or convulsions. In severe poisoning, acute renal failure and liver damage may occur.

Treatment

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

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

Adverse Reactions

Adverse reactions to the drug are listed by frequency: 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 undesirable effects listed below are associated with administration of Evipon-VF under both short-term and long-term use.

Infections and infestations: very rare – abscess at injection site; not known – medicamentous embolism (Nicolau syndrome).

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 disturbance, stroke; frequency not known – confusion, hallucinations, sensory disturbance, 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.

Cardiac disorders: uncommon* – palpitations, chest pain, heart failure, myocardial infarction (*frequency reflects data from long-term treatment with high doses (150 mg per day)); 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 or without bleeding, gastrointestinal stenosis or perforation (sometimes fatal, especially in elderly patients), which may lead to peritonitis); very rare – colitis (including hemorrhagic colitis, ischemic colitis, and exacerbation of ulcerative colitis or Crohn’s disease), constipation, stomatitis, glossitis, esophageal disorders, 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 rash, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), exfoliative dermatitis, alopecia, photosensitivity reaction, purpura, allergic purpura (Schönlein-Henoch), pruritus; frequency not known – fixed drug eruption, generalized bullous fixed drug eruption.

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

General disorders and administration site conditions: common – injection site reaction, injection site pain, induration; rare – swelling, necrosis at injection site; very rare – abscess at injection site.

Reproductive system and breast disorders: very rare – impotence.

Meta-analysis of clinical trial data and pharmacoepidemiological evidence indicate an increased risk of arterial thrombotic complications (e.g., myocardial infarction or stroke) associated with the use of diclofenac, particularly at high therapeutic doses (150 mg per day) and with prolonged use (see section "Special precautions for use").

Visual disturbances

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

Shelf life. 2 years.

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

Keep out of reach of children.

Packaging. 3 ml in an ampoule, 5 ampoules in a blister, 1 blister in a carton.

Prescription status. Prescription only.

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

Manufacturer's address and location of business activity.
36 Severyna Pototskoho Street, Kharkiv, Kharkiv Oblast, 61115, Ukraine.