Raptene 75

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RAPTEN 75 (RAPTEN 75)

Composition:

Active substance: diclofenac;

1 ml of solution contains 25 mg of diclofenac sodium;

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

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless or pale yellow solution with a characteristic odor.

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

Pharmacological Properties

Pharmacodynamics

The medicinal product contains sodium diclofenac, a non-steroidal compound with pronounced anti-rheumatic, anti-inflammatory, analgesic, and antipyretic properties. Inhibition of prostaglandin biosynthesis, demonstrated in experimental studies, is considered the primary mechanism of its action. Prostaglandins play a key role in the development of inflammation, pain, and fever.

In rheumatic diseases, the anti-inflammatory and analgesic properties of the medicinal product produce a clinical response characterized by a marked reduction in signs and symptoms: pain at rest and during movement, morning stiffness, and joint swelling, as well as noticeable improvement in function.

Diclofenac is capable of producing a pronounced analgesic effect on moderate to severe non-rheumatic pain within 15–30 minutes.

Diclofenac has also demonstrated a significant effect on migraine attacks.

In post-traumatic and postoperative conditions associated with inflammation, diclofenac rapidly relieves spontaneous pain and pain during movement and reduces swelling caused by inflammation and injury.

The use of diclofenac for postoperative pain relief significantly reduces the need for concomitant use of opioid analgesics.

Rapten 75, solution for injection in ampoules, is particularly indicated at the beginning of treatment for inflammatory and degenerative rheumatic diseases and for pain states due to non-rheumatic inflammation.

Pharmacokinetics

Absorption

After administration of 75 mg diclofenac by intramuscular injection, absorption begins immediately, and mean peak plasma concentrations of approximately 2.5 µg/mL (8 µmol/L) are reached after about 20 minutes. The extent of absorption may be linearly dependent on the dose administered.

When 75 mg of diclofenac is administered by intravenous infusion over 2 hours, mean peak plasma concentrations are approximately 1.9 µg/mL (5.9 µmol/L). Shorter infusion durations result in higher peak plasma concentrations, while longer infusions lead to concentrations 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 peak levels are achieved.

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 about half of the active substance is metabolized during the first pass through the liver when the medicinal product is administered orally or rectally.

Pharmacokinetic properties do not change after repeated administration. With adherence to recommended dosing intervals, no accumulation of the medicinal product occurs.

Distribution

99.7% of diclofenac is bound to plasma proteins, primarily to albumin (99.4%). The apparent volume of distribution is 0.12–0.17 L/kg.

Diclofenac penetrates into synovial fluid, where maximum concentrations are achieved 2–4 hours after peak plasma levels. The apparent half-life in synovial fluid is 3–6 hours. Two hours after peak plasma concentrations are reached, diclofenac concentrations in synovial fluid exceed those in plasma and remain higher for up to 12 hours.

Biological Transformation

Biological transformation of diclofenac occurs partially via glucuronidation of the intact molecule, but primarily through single and multiple hydroxylations and methoxylations, leading to the formation of several phenolic metabolites (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 considerably less than that of diclofenac.

Elimination

Total systemic clearance of diclofenac from plasma is 263 ± 56 mL/min (mean ± SD). The terminal half-life in plasma is 1–2 hours. Four of the metabolites, including two active ones, also have short plasma half-lives (1–3 hours). One metabolite, 3'-hydroxy-4'-methoxy-diclofenac, has a much longer plasma half-life. However, this metabolite is practically inactive.

Approximately 60% of the administered dose is excreted in urine as glucuronide conjugate of the intact molecule and as metabolites, most of which are also converted into glucuronide conjugates. Less than 1% is excreted as unchanged substance. The remainder of the dose is eliminated via bile as metabolites in feces.

Special Patient Groups

No age-related differences in absorption, metabolism, or excretion of the medicinal product have been observed. However, in some elderly patients, a 15-minute intravenous infusion resulted in plasma concentrations 50% higher than those observed in young healthy volunteers.

In patients with impaired renal function, accumulation of the active substance is not expected when standard dosing regimens are followed. With creatinine clearance less than 10 mL/min, plasma levels of hydroxymetabolites at steady state are approximately four times higher than in normal subjects.

Thus, metabolites are ultimately eliminated via bile.

In patients with chronic hepatitis or decompensated cirrhosis, the kinetics and metabolism of diclofenac are similar to those in patients without liver disease.

Clinical characteristics.

Indications.

The medicinal product is indicated for intramuscular administration in the treatment of:

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

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

Contraindications.

Known hypersensitivity to the active substance, sodium metabisulfite, or to any other components of the medicinal product.

History of gastrointestinal bleeding or perforation related to previous treatment with nonsteroidal anti-inflammatory drugs (NSAIDs).

Active peptic ulcer disease/bleeding or recurrent peptic ulcer disease/bleeding in history (two or more separate episodes of confirmed ulcer or bleeding).

Third trimester of pregnancy.

As with other NSAIDs, diclofenac is contraindicated in patients in whom administration of ibuprofen, acetylsalicylic acid, or other NSAIDs induces attacks of bronchial asthma, angioneurotic edema, urticaria, or acute rhinitis.

Inflammatory bowel diseases (e.g., Crohn’s disease or ulcerative colitis).

Hepatic failure.

Renal failure (creatinine clearance <15 mL/min/1.73 m²).

Congestive heart failure (NYHA II–IV).

High risk of postoperative bleeding, coagulation disorders, hemostatic disturbances, hematopoietic disorders, or cerebrovascular hemorrhage.

Treatment of perioperative pain in coronary artery bypass graft (CABG) surgery (or use of cardiopulmonary bypass).

Ischemic heart disease in patients with angina pectoris or history of myocardial infarction.

Cerebrovascular disorders in patients with history of stroke or transient ischemic attacks.

Peripheral arterial disease.

This medicinal form is contraindicated in children.

Only regarding intravenous use.

Concomitant use of NSAIDs or anticoagulants (including low-dose heparin).

History of hemorrhagic diathesis, confirmed or suspected history of cerebrovascular hemorrhage.

Surgical procedures associated with high risk of bleeding.

History of bronchial asthma.

Moderate or severe renal impairment (serum creatinine >160 μmol/L).

Hypovolemia or dehydration of any cause.

Interaction with other medicinal products and other forms of interaction.

The interactions listed below have been observed during the use of Rapten 75, 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 or antihypertensive agents (e.g., beta-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 patients—should be closely monitored for blood pressure. Adequate hydration is recommended, and monitoring of renal function is advised both at initiation and on a regular basis during concomitant therapy, particularly with diuretics and ACE inhibitors due to increased risk of nephrotoxicity.

Medicinal products causing hyperkalemia. Concomitant use of potassium supplements may lead to increased serum potassium levels, requiring continuous monitoring of patients.

Anticoagulants and antithrombotic agents. Precautions are recommended, as concomitant administration may increase the risk of bleeding. Although clinical studies have not demonstrated an effect of diclofenac on anticoagulant activity, there are individual reports of increased bleeding risk in patients receiving diclofenac and anticoagulants simultaneously. Therefore, careful monitoring of such patients is recommended. As with other NSAIDs, high-dose diclofenac may transiently inhibit platelet aggregation.

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

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

Antidiabetic agents. Clinical studies have shown that diclofenac can be used concomitantly with oral antidiabetic agents without affecting their clinical efficacy. However, isolated cases of both hypoglycemic and hyperglycemic effects have been reported, requiring dose adjustments of antidiabetic agents during diclofenac treatment. These conditions require monitoring of blood glucose levels as a precaution during concomitant therapy.

Metabolic acidosis has also been reported with concomitant use of diclofenac, particularly in patients with pre-existing renal impairment.

Methotrexate. Diclofenac may inhibit renal tubular clearance of methotrexate, leading to elevated methotrexate levels. Caution is recommended when administering NSAIDs, including diclofenac, within 24 hours before or after methotrexate therapy, as this may increase methotrexate blood concentrations 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. Diclofenac, as with other NSAIDs, may increase cyclosporine nephrotoxicity via effects on renal prostaglandins. Therefore, it should be administered at lower doses in patients receiving cyclosporine compared to those not receiving cyclosporine.

Tacrolimus. Concomitant use of NSAIDs with tacrolimus may increase the risk of nephrotoxicity, possibly mediated by renal anti-prostaglandin effects of NSAIDs and the calcineurin inhibitor.

Quinolone antibacterials. Isolated reports of seizures have been associated with 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 delay or reduce absorption of diclofenac. Therefore, diclofenac should be administered at least 1 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 plasma glycoside levels.

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

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

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

Special precautions for use.

General.

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

Concomitant use of Rapten 75 with systemic NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided due to lack of any synergistic benefit and the potential for additional adverse effects.

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

Like other NSAIDs, Rapten 75, 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 and bronchospasm.

Gastrointestinal effects.

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

As with all NSAIDs, including diclofenac, careful medical monitoring is required; particular caution should be exercised when prescribing diclofenac to patients with symptoms indicating gastrointestinal disturbances or with a history of peptic ulcer, gastrointestinal bleeding, or perforation. The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher doses of NSAIDs, including diclofenac, and in patients with a history of ulcers, especially those complicated by bleeding or perforation.

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 those complicated by bleeding or perforation, and in elderly patients, treatment should be initiated and maintained at the lowest effective dose.

For such patients, as well as those requiring concomitant use of medications containing low-dose acetylsalicylic acid 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, particularly elderly patients, should report any unusual abdominal symptoms (especially gastrointestinal bleeding). Caution is also required in 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.

Hepatic effects.

Careful medical monitoring is required if Rapten 75 is prescribed to patients with impaired liver function, as their condition may worsen.

As with other NSAIDs, including diclofenac, levels of one or more liver enzymes may increase. During long-term treatment with Rapten 75, 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), Rapten 75 should be discontinued.

Diseases such as hepatitis may progress without prodromal symptoms.

Caution is necessary when Rapten 75 is used in patients with hepatic porphyria due to the potential to provoke an attack.

Renal effects.

Since fluid retention and edema have been reported during treatment with NSAIDs, including diclofenac, particular attention should be paid to patients with impaired cardiac or renal function, a history of arterial hypertension, elderly patients, patients receiving concomitant diuretic therapy or drugs that significantly affect renal function, and patients with significant extracellular fluid volume depletion due to any cause, such as before or after major surgery. In such cases, monitoring of renal function is recommended as a precautionary measure. Discontinuation of therapy usually results in reversal to the pre-treatment state.

Skin reactions.

Serious skin reactions (some of which have been fatal), including exfoliative dermatitis, Stevens–Johnson syndrome, and toxic epidermal necrolysis, have very rarely been reported with the use of NSAIDs, including Rapten 75. The highest risk of these reactions appears to occur early in the course of therapy, mostly within the first month of treatment. Rapten 75 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 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. Since cardiovascular risks associated with diclofenac may increase with higher doses and longer duration of treatment, it should be used for the shortest possible duration and at the lowest effective dose. The patient's need for diclofenac and response to therapy should be periodically reviewed. 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 NSAID use, including diclofenac.

Clinical trial data and epidemiological evidence suggest that the use of diclofenac, particularly at high doses (150 mg daily) and over long durations, 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 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 risk-benefit assessment and at a daily dose not exceeding 100 mg. A similar evaluation 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 the possibility of serious events (chest pain, shortness of breath, weakness, speech disturbances) at any time. In such cases, immediate medical attention is required.

Hematological effects.

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

History of asthma.

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 exacerbations (so-called analgesic intolerance/analgesic-induced asthma), Quincke's edema, or urticaria occur more frequently than in others. Therefore, special precautionary measures (readiness for emergency intervention) are recommended for such patients. This also applies to patients with allergies to other substances manifesting as skin reactions, pruritus, or urticaria.

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

Fertility in women.

Use of Rapten 75 may impair fertility in women and is therefore not recommended for women wishing to become pregnant. Consider discontinuation of Rapten 75 in women experiencing difficulty conceiving or undergoing infertility investigations.

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 needles and injection technique should be used for intramuscular administration of diclofenac (see section "Dosage and administration").

Use during pregnancy or breastfeeding.

Pregnancy. From the 20th week of pregnancy, use of Rapten 75 may cause oligohydramnios due to fetal renal dysfunction. This disorder may occur soon after starting treatment and is usually reversible upon discontinuation of therapy.

During the first and second trimesters of pregnancy, Rapten 75 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.

Prenatal monitoring for oligohydramnios may be advisable after exposure to Rapten 75 for several days starting from the 20th week of pregnancy. Treatment should be discontinued if oligohydramnios is detected.

Like other NSAIDs, the drug is contraindicated during the third trimester of pregnancy (due to 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 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 embryotoxicity/fetotoxicity.

Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular defects, has been observed. If Rapten 75 is used in women attempting to conceive or during the first trimester of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible.

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

• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction, 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, Rapten 75 is contraindicated during the third trimester of pregnancy.

Lactation. Like other NSAIDs, diclofenac passes into breast milk in small amounts. Therefore, to avoid potential adverse effects on the infant, Rapten 75 should not be used during breastfeeding.

Fertility. Like other NSAIDs, Rapten 75 may affect female fertility. The drug is not recommended for women attempting to conceive. Women experiencing difficulties with conception or undergoing infertility evaluation should discontinue use of Rapten 75.

Ability to influence reaction speed when driving or operating machinery.

Patients who experience visual disturbances, dizziness, vertigo, somnolence, or other central nervous system disorders during treatment with Rapten 75 should refrain from driving or operating machinery.

Method of Administration and Dosage.

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

Adults

Rapten 75, solution for injection, should not be used for more than 2 consecutive days. If continued treatment is necessary, other dosage forms of diclofenac (tablets or suppositories) may be used.

Intramuscular injection

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

The usual dose is 1 ampoule of 75 mg (1 ampoule) per day 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 solution may be combined with other dosage forms up to a maximum total daily dose of 150 mg of sodium diclofenac.

For migraine attacks, clinical experience is limited to cases where an initial dose of one 75 mg ampoule is administered, preferably immediately after the use of 100 mg suppositories on the same day (if necessary). The total daily dose of diclofenac should not exceed 175 mg on the first day.

There are no available data on the use of Rapten 75 for the treatment of migraine attacks for more than one day.

Intravenous infusion

Immediately before starting intravenous infusion, Rapten 75 should be diluted in 100–500 mL of 0.9% sodium chloride solution or 5% glucose solution. Both solutions must 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.

Rapten 75, solution for injection, must not be administered as an intravenous bolus injection.

Recommended alternative dosing regimens:

• 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 dose must 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 at approximately 5 mg/hour up to a maximum daily dose of 150 mg.

Elderly patients (aged 65 years and older)

Although the pharmacokinetics of Rapten 75 are not significantly altered in elderly patients to a clinically relevant extent, NSAIDs should be used with particular caution in this population, as they are generally more susceptible to adverse reactions. Specifically, 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 Rapten 75 is 150 mg.

Children

Rapten 75, solution for injection, is contraindicated for use in children.

Overdose.

Symptoms. A typical clinical picture of diclofenac overdose has not been established. Overdose may cause symptoms such as headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, diarrhea, dizziness, disorientation, excitement, coma, somnolence, tinnitus, loss of consciousness, or convulsions. In cases of severe poisoning, acute renal failure and hepatic injury may occur.

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

Adverse reactions.

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

The undesirable effects listed below are associated with administration of Rapten 75 during both short-term and long-term use.

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 – paraesthesia, memory impairment, convulsions, anxiety, tremor, aseptic meningitis, taste disturbance, stroke; frequency not known – confusion, hallucinations, sensory disturbances, malaise.

Eye disorders: very rare – visual disturbance, blurred vision, diplopia; frequency not known – optic neuritis.

Ear and labyrinth disorders: common – vertigo; very rare – tinnitus, hearing impairment.

Cardiac disorders: very rare – palpitations, chest pain, heart failure, myocardial infarction.

Vascular disorders: very rare – arterial hypertension, 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, anorexia; rare – gastritis, gastrointestinal hemorrhage, 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, membranous intestinal strictures, pancreatitis.

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

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

Renal and urinary disorders: 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.

Clinical studies and epidemiological data indicate an increased risk of thrombotic events (e.g., myocardial infarction or stroke) associated with the use of diclofenac, particularly at high therapeutic doses (150 mg per day) and during prolonged treatment.

Visual disturbances.

Visual disturbances such as blurred vision, impaired vision, and diplopia have been reported with NSAIDs and are usually reversible upon discontinuation of the drug. The most likely mechanism involves inhibition of prostaglandin and related compound synthesis, which may disrupt retinal blood flow regulation and lead to visual disturbances. If such symptoms occur during diclofenac therapy, an ophthalmological examination should be performed to rule out other potential causes.

Shelf life. 3 years. The solution must be used immediately after opening the ampoule.

Storage conditions.

Store at temperatures not exceeding 25 °C.

Keep out of the reach and sight of children.

Incompatibilities.

Rapten 75, solution for injection, must not be mixed with other injectable solutions.

Packaging.

3 ml (75 mg) in an ampoule; 5 ampoules in a blister pack; 1 blister pack in a cardboard box.

Prescription status. Prescription only.

Manufacturer. «Hemofarm» AD / «Hemofarm» AD.

Manufacturer's address and place of business.

Beogradski put bb, 26300, Vrsac, Serbia.