Diclofenac-darnitsa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DICLOFENAC-DARNITSA (DICLOFENAC-DARNITSA)

Composition:

active substance: diclofenac;

1 ml of solution contains sodium diclofenac 25 mg;

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

Pharmaceutical form. Solution for injection.

Main physico-chemical properties: clear, colorless or slightly yellowish liquid with a mild specific odor.

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

Pharmacological Properties.

Pharmacodynamics.

Diclofenac-Darnitsya contains diclofenac sodium, a non-steroidal compound with pronounced anti-rheumatic, anti-inflammatory, analgesic, and antipyretic properties. Inhibition of prostaglandin biosynthesis, which plays a key role in the development of inflammation, pain, and fever, is considered the primary mechanism of action of the drug. In rheumatic diseases, the anti-inflammatory and analgesic effects of the drug result in a clinical response characterized by the disappearance of signs and symptoms: pain at rest and during movement, morning stiffness, and joint swelling; a noticeable improvement in motor function is also observed.

Diclofenac exerts 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 movement-related pain and reduces edema caused by inflammation and injury.

When the drug is used concomitantly with opioid analgesics for postoperative pain relief, diclofenac significantly reduces the need for opioids.

In vitro, diclofenac sodium at concentrations equivalent to those achieved in humans does not inhibit proteoglycan synthesis in cartilage tissue.

Diclofenac-Darnitsya, solution for injection in ampoules, is particularly necessary for initiating treatment of inflammatory and degenerative rheumatic diseases and pain syndrome due to non-rheumatic inflammation.

Pharmacokinetics.

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

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 times lead to higher peak plasma concentrations, whereas longer infusions result in concentrations proportional to the infusion rate after 3–4 hours. After intramuscular injection or administration of enteric-coated tablets or suppositories, plasma concentrations decline rapidly once peak levels are achieved.

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 about half of the active substance is metabolized during the first pass through the liver (first-pass effect) when the drug is administered orally or rectally.

Pharmacokinetic properties do not change after repeated administration. With adherence to recommended dosing intervals, drug accumulation does not occur.

Distribution. 99.7% of diclofenac is bound to plasma proteins, primarily to albumin (99.4%). The 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 expected half-life in synovial fluid is 3 to 6 hours. Two hours after peak plasma concentration, diclofenac concentrations in synovial fluid exceed those in plasma and remain higher for up to 12 hours.

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

Biotransformation. Biotransformation of diclofenac occurs partially via glucuronidation of the intact molecule, but primarily via single and multiple hydroxylation and methoxylation, 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 converted into glucuronide conjugates. Two of these phenolic metabolites are biologically active, although their activity is significantly less than that of diclofenac.

Elimination. Total systemic clearance of diclofenac from plasma is 263 ± 56 mL/min (mean ± 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. 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 conjugates 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 as metabolites via bile in feces.

Special patient groups.

Elderly patients. No age-related differences in absorption, metabolism, or excretion of the drug 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 subjects.

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

Thus, metabolites are ultimately eliminated via bile.

Patients with liver disease. In patients with chronic hepatitis or compensated cirrhosis, the kinetics and metabolism of diclofenac are the same as in healthy volunteers.

Clinical characteristics.

Indications.

The medicinal product, when administered intramuscularly, is indicated for the treatment of:

− inflammatory and degenerative forms of rheumatism, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, spondyloarthritis, vertebral pain syndrome, non-articular rheumatism;

− acute gout attacks;

− renal and biliary colic;

− pain and swelling following trauma and surgery;

− severe migraine attacks.

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

Contraindications.

− Hypersensitivity to the active substance, sodium metabisulfite, or to any other components of the medicinal product.

− As with other non-steroidal anti-inflammatory drugs (NSAIDs), diclofenac is contraindicated in patients in whom the use of ibuprofen, acetylsalicylic acid, or other NSAIDs induces an attack of bronchial asthma, angioneurotic edema, urticaria, acute rhinitis, nasal polyps, or allergy-like symptoms.

− History of gastrointestinal bleeding or perforation related to previous NSAID therapy.

− Active peptic ulcer/hemorrhage or recurrent peptic ulcer/hemorrhage (two or more separate episodes of confirmed ulcer or bleeding).

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

− Hepatic failure.

− Renal failure.

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

− Ischemic heart disease in patients (angina pectoris, history of myocardial infarction).

− Cerebrovascular diseases in patients with a history of stroke or transient ischemic attacks.

− Peripheral arterial disease.

− Treatment of perioperative pain in patients undergoing coronary artery bypass grafting (or use of cardiopulmonary bypass).

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

− Third trimester of pregnancy.

This medicinal product is contraindicated in children in this pharmaceutical form.

Intravenous infusions are contraindicated in:

− concomitant use of NSAIDs or anticoagulants (including low-dose heparin);

− history of hemorrhagic diathesis or confirmed/suspected history of cerebrovascular hemorrhage;

− surgical procedures with high risk of bleeding;

− history of bronchospasm or bronchial asthma;

− moderate or severe renal impairment (serum creatinine level > 160 mmol/L);

− hypovolemia or dehydration of any origin.

Interaction with other medicinal products and other types of interactions.

The interactions listed below have been observed during the use of diclofenac preparations in injectable solution form and/or other pharmaceutical forms.

Lithium. Diclofenac may increase plasma lithium concentrations when used concomitantly. Monitoring of lithium levels in serum is recommended.

Digoxin. Diclofenac may increase plasma digoxin concentrations when used concomitantly. Monitoring of digoxin levels in serum is recommended.

Diuretics and antihypertensive agents. As with other NSAIDs, concomitant use of diclofenac with diuretics or antihypertensive agents [e.g., β-blockers, angiotensin-converting enzyme (ACE) inhibitors] may reduce their antihypertensive effect due to inhibition of the synthesis of vasodilatory prostaglandins. Therefore, such combinations should be used with caution, and patients, especially elderly patients, should be closely monitored for blood pressure. Adequate hydration should be ensured, and renal function should be monitored after initiation of concomitant therapy and regularly thereafter, particularly when using diuretics and ACE inhibitors due to increased risk of nephrotoxicity.

Medicinal products causing hyperkalemia. Concomitant treatment with potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may be associated with increased serum potassium levels; therefore, more frequent monitoring of patients is required.

Other NSAIDs and corticosteroids. Concomitant use of diclofenac with other systemic NSAIDs or corticosteroids may increase the frequency of gastrointestinal adverse reactions. Concomitant use of two or more NSAIDs should be avoided.

Anticoagulants and antithrombotic agents. Precautions are recommended, as concomitant use increases the risk of bleeding. Although clinical studies do not indicate an effect of diclofenac on anticoagulant activity, isolated data suggest an increased risk of bleeding in patients receiving diclofenac and anticoagulants simultaneously. Therefore, careful monitoring of such patients is recommended. Like other NSAIDs, high-dose diclofenac may transiently inhibit platelet aggregation.

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

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

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

Cholestyramine and colestipol. Concomitant use of diclofenac with cholestyramine or colestipol reduces diclofenac absorption by approximately 30% and 60%, respectively.

Therefore, diclofenac should be administered at least 1 hour before or 4–6 hours after cholestyramine/colestipol administration.

Medicinal products stimulating drug-metabolizing enzymes. Medicinal products that stimulate enzymes, such as rifampicin, carbamazepine, phenytoin, and St. John’s wort (Hypericum perforatum), are theoretically capable of reducing plasma concentrations of diclofenac.

Methotrexate. Caution is recommended when NSAIDs are administered less than 24 hours before or after methotrexate, as this may increase methotrexate blood concentrations and enhance its toxicity. Diclofenac may inhibit renal tubular clearance of methotrexate, leading to elevated methotrexate levels. This interaction is mediated by methotrexate accumulation due to impaired renal excretion caused by NSAID use.

Cyclosporine and tacrolimus. Diclofenac, like other NSAIDs, may increase the nephrotoxicity of cyclosporine due to effects on renal prostaglandins. A similar risk exists during treatment with tacrolimus. Therefore, it should be used at lower doses than in patients not receiving cyclosporine or tacrolimus.

Quinolone antibacterial agents. Seizures may occur in patients receiving quinolone derivatives and NSAIDs concomitantly, regardless of the presence or absence of epilepsy or seizure history. 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.

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 effect.

Strong CYP2C9 inhibitors. Caution is recommended when diclofenac is co-administered with strong CYP2C9 inhibitors (e.g., voriconazole), which may lead to a significant increase in maximum plasma concentration and exposure to diclofenac due to inhibition of its metabolism.

CYC2C9 inducers. Caution is required when diclofenac is co-administered with CYP2C9 inducers (e.g., rifampicin), which may lead to a significant decrease in plasma concentration and exposure to diclofenac.

Special precautions for use.

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

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

Caution should be exercised when prescribing the medicinal product to elderly patients. In particular, the lowest effective doses should be used in elderly patients with frail health or those with a low body mass index.

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, may occur during treatment with diclofenac. Hypersensitivity reactions may also progress to Kounis syndrome, a serious allergic reaction that may lead to myocardial infarction. A symptom of such a reaction may be chest pain occurring in combination with an allergic reaction to diclofenac.

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

Gastrointestinal effects

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

Careful medical monitoring is required when using all NSAIDs, including diclofenac. Particular caution is advised when prescribing diclofenac to patients with symptoms indicating gastrointestinal disorders or with a history of gastric or intestinal ulcers, bleeding, or perforation. The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher 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 low-dose acetylsalicylic acid or other drugs that may increase the risk of gastrointestinal adverse effects, consideration should be given to combination therapy with protective agents (e.g., proton pump inhibitors or misoprostol).

Patients with a history of gastrointestinal toxicity, especially elderly patients, should report any unusual abdominal symptoms (particularly gastrointestinal bleeding). 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.

The use of NSAIDs, including diclofenac, may be associated with an increased risk of anastomotic failure. Close monitoring and caution are recommended when administering the drug after surgical procedures on gastrointestinal organs.

Hepatic effects

Close medical monitoring is required when diclofenac is prescribed to patients with liver disease, as their condition may worsen.

As with other NSAIDs, levels of one or more liver enzymes may increase. Liver function should be monitored regularly during long-term treatment.

If liver function abnormalities persist or worsen, if clinical signs or symptoms suggest progressive liver disease, or if other manifestations occur (e.g., eosinophilia, rash), the drug should be discontinued.

Hepatitis during treatment with sodium diclofenac may occur without prodromal symptoms.

Caution is necessary when the drug is used in patients with hepatic porphyria, due to the potential for provoking 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 hypertension, elderly patients, those receiving concomitant diuretic therapy or drugs significantly affecting 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. 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 in association with the use of NSAIDs, including diclofenac. The highest risk of these reactions appears to occur early in treatment, mostly within the first month. Diclofenac 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 have an increased risk of developing aseptic meningitis.

Cardiovascular and cerebrovascular effects

Diclofenac may be prescribed to patients with significant cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes, smoking) only after careful clinical evaluation. Since cardiovascular risks of diclofenac may increase with higher doses and longer duration of treatment, it should be used for the shortest possible duration and at the lowest effective 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 hypertension and/or mild to moderate congestive heart failure require appropriate monitoring and advice, as fluid retention and edema have been reported with the use of NSAIDs, including diclofenac.

Clinical and epidemiological data suggest that the use of diclofenac, especially at high doses (150 mg/day) 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 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 a careful benefit-risk assessment and at a dose not exceeding 100 mg per day. A similar assessment should be performed before initiating long-term treatment in patients with risk factors for cardiovascular events (e.g., hypertension, hyperlipidemia, diabetes, smoking).

Patients should be informed about the possibility of serious complications (chest pain, dyspnea, weakness, speech disturbances), which may occur at any time. In such cases, immediate medical attention is required.

Hematological effects

Monitoring of blood parameters is recommended during prolonged use of the drug.

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

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) are more likely than others to experience NSAID-related reactions resembling asthma exacerbations (so-called analgesic intolerance/analgesic-induced asthma), Quincke's edema, or urticaria. Therefore, special precautions (preparedness 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 may provoke bronchospasm in patients with bronchial asthma or a history of bronchial asthma.

Injection site reactions

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

Important information about excipients.

The medicinal product contains sodium metabisulfite (E 223), which may rarely cause hypersensitivity reactions and bronchospasm.

Use during pregnancy or breastfeeding.

Pregnancy. Diclofenac-Darnitsia 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 (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 the 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 may increase with higher doses and longer duration of treatment. In animal studies, administration of prostaglandin synthesis inhibitors has been shown to increase pre- and post-implantation losses and embryonic/fetal mortality.

Furthermore, in animals receiving prostaglandin synthesis inhibitors during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular defects, has been observed. Starting from the 20th week of pregnancy, the use of diclofenac may cause oligohydramnios due to impaired fetal kidney function. This may occur shortly after initiation of treatment and is usually reversible upon discontinuation. Oligohydramnios monitoring should be considered after diclofenac exposure for several days starting from the 20th week of pregnancy. Diclofenac 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 ductus arteriosus and pulmonary hypertension);

• renal dysfunction (see above).

Effects on the mother and newborn, and reactions at the end of pregnancy:

− possible prolongation of bleeding time, anti-aggregatory effect, which may occur even at very low doses;

− inhibition of uterine contractions, leading to delayed or prolonged labor.

Therefore, Diclofenac-Darnitsia is contraindicated during the third trimester of pregnancy.

Lactation. Like other NSAIDs, diclofenac passes into breast milk in small amounts. To avoid undesirable effects on the infant, Diclofenac-Darnitsia should not be used during breastfeeding.

Fertility. Like other NSAIDs, Diclofenac-Darnitsia may affect female fertility. The drug should not be used in women planning to become pregnant. If a woman experiences difficulties in conceiving or is undergoing infertility investigations, use of Diclofenac-Darnitsia should be discontinued.

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 Diclofenac-Darnitsia should refrain from driving vehicles or operating machinery.

Method of Administration and Dosage.

The medicinal product should be used at the lowest recommended doses for the shortest duration necessary, taking into account the individual therapeutic goal for each patient.

Do not use for more than 2 days. If further treatment is needed, therapy may be continued with Diclofenac-Darnitsya tablets.

Intramuscular injection.

To prevent damage to nerves or other tissues at the site of intramuscular injection, the following recommendations must be followed.

The usual dose is 75 mg (1 ampoule) per day, administered by deep injection into the upper outer quadrant of the gluteus maximus muscle. In severe cases, the daily dose may be increased to two injections of 75 mg each, administered several hours apart (one injection into each buttock). Alternatively, 75 mg may be combined with other dosage forms of Diclofenac-Darnitsya (e.g., tablets) up to a total maximum daily dose of 150 mg.

In the treatment of migraine attacks, clinical experience is limited to cases where an initial dose of 1 ampoule of 75 mg was administered. The total daily dose should not exceed 175 mg on the first day. There are no available data on the use of the drug for the treatment of migraine attacks for more than 1 day.

Intravenous infusions.

Diclofenac-Darnitsya, solution for injection, must not be administered as an intravenous bolus injection.

Immediately before starting intravenous infusion of Diclofenac-Darnitsya, depending on the required duration, one ampoule of the drug should be diluted in 100–500 ml of 0.9% sodium chloride solution or 5% glucose solution, buffered with sodium bicarbonate injection solution (0.5 ml of 8.4% solution or 1 ml of 4.2% solution, or equivalent volume of another concentration), taken from a freshly opened container. Only clear solutions should be used. If crystals or precipitate are present in the solution, it must not be used for infusion.

Two alternative dosage regimens for Diclofenac-Darnitsya solution for injection are recommended:

• For the 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 total daily dose must not exceed 150 mg.
• For the prevention 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 per hour, up to a maximum daily dose of 150 mg.

Elderly patients.

Although the pharmacokinetics of the drug are not clinically significantly impaired in elderly patients, 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 Diclofenac-Darnitsya is 150 mg.

Each ampoule is intended for single use only. The solution should be used immediately after opening the ampoule. Any unused portion must be discarded.

Children.

Diclofenac-Darnitsya in the form of injection solution is contraindicated for use in children.

Overdose.

Symptoms. There is no typical clinical picture of diclofenac overdose. Overdose may cause symptoms such as headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, diarrhea, dizziness, disorientation, excitement, coma, drowsiness, tinnitus, loss of consciousness, or seizures. In cases of severe poisoning, acute renal failure and hepatic injury may occur.

Treatment. Administration of activated charcoal may be beneficial within 1 hour of ingestion of a potentially toxic dose. In addition, gastric lavage should be considered for adults within 1 hour of ingestion of a potentially toxic dose. For frequent or prolonged seizures, intravenous diazepam should be administered. Other measures may be indicated depending on the patient's clinical condition. Treatment is symptomatic.

Adverse Reactions.

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

The adverse effects listed below include events associated with the use of Diclofenac-Darnytsia, solution for injection, and/or other dosage forms of diclofenac, during both short-term and long-term treatment.

Adverse reactions are listed by organ systems and 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 the available data).

Eye disorders:

very rare: visual disturbances (blurred vision and diplopia);

frequency not known: optic neuritis.

These ocular disorders are class effects of NSAIDs and are generally reversible upon discontinuation of the drug. The most likely mechanism of visual disturbances is inhibition of prostaglandin and other related compounds synthesis, which may impair retinal blood flow regulation and lead to visual disturbances. If such symptoms occur during treatment with diclofenac, ophthalmological examination should be performed to rule out other possible causes.

Ear and labyrinth disorders:

common: vertigo;

very rare: tinnitus, hearing disturbances.

Respiratory, thoracic and mediastinal disorders:

rare: asthma (including dyspnea), bronchospasm;

very rare: pneumonitis.

Gastrointestinal disorders:

common: nausea, vomiting, diarrhea, dyspepsia, abdominal pain, flatulence, decreased appetite, anorexia;

rare: gastritis, gastrointestinal bleeding, vomiting with blood, hemorrhagic diarrhea, melena, gastric or intestinal ulcer with or without bleeding, gastrointestinal stricture with perforation (sometimes fatal, especially in elderly patients), which may lead to peritonitis;

very rare: colitis (including hemorrhagic colitis and exacerbation of ulcerative colitis or Crohn’s disease), constipation, stomatitis (including ulcerative stomatitis), glossitis, dysphagia, membranous strictures of the small intestine, pancreatitis.

Hepatobiliary disorders:

common: increased transaminase levels;

uncommon: liver function abnormalities, particularly during prolonged therapy, hepatitis with or without jaundice (in rare cases, fulminant hepatitis may occur, even without prior symptoms);

very rare: fulminant hepatitis, hepatonecrosis, liver failure.

Renal and urinary disorders:

common: edema formation, particularly in patients with hypertension or renal impairment;

very rare: acute renal failure, hematuria, proteinuria, nephrotic syndrome, interstitial nephritis, renal papillary necrosis.

Nervous system disorders:

common: headache, dizziness, somnolence;

rare: fatigue;

very rare: paresthesia, taste disturbances, memory impairment, convulsions, anxiety, tremor, aseptic meningitis*, stroke;

frequency not known: sensory disturbances, tactile sensation disorders.

Psychiatric disorders:

very rare: disorientation, depression, insomnia, nightmares, irritability, psychiatric disorders, confusion, hallucinations.

Cardiovascular disorders:

very rare: palpitations, chest pain, heart failure, myocardial infarction, arterial hypertension, arterial hypotension, vasculitis;

frequency not known: Kounis syndrome.

Blood and lymphatic system disorders:

very rare: thrombocytopenia, leukopenia, anemia (including hemolytic and aplastic anemia), agranulocytosis.

Immune system disorders:

common: hypersensitivity reactions such as skin rash and pruritus;

uncommon: urticaria;

rare: anaphylactic and pseudoanaphylactic reactions (including hypotension and shock);

very rare: angioedema (including facial swelling), allergic vasculitis.

Skin and subcutaneous tissue disorders:

common: rash;

uncommon: alopecia;

rare: urticaria;

very rare: exanthema, eczema, erythema, erythema multiforme, photosensitivity reactions, purpura (including allergic Schonlein-Henoch purpura), bullous eruptions including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell’s syndrome), exfoliative dermatitis, pruritus.

Reproductive system and breast disorders:

very rare: impotence.

General disorders and administration site conditions:

common: injection site reactions, pain and/or induration at injection site, malaise;

rare: swelling, necrosis at injection site;

very rare: abscess at injection site;

frequency not known: cutaneous medication embolism (Nicolau syndrome).

*Very rare cases of worsening of infectious inflammatory processes (e.g., development of necrotizing fasciitis) have been reported with systemic use of NSAIDs. This may be related to the mechanism of action of NSAIDs. Very rare cases of aseptic meningitis with symptoms such as neck stiffness, headache, nausea, vomiting, fever, or altered consciousness have been observed during diclofenac use. Patients with autoimmune diseases (systemic lupus erythematosus, mixed connective tissue disease) may be predisposed to such events.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization is important. It allows continued 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. 3 years.

Storage conditions.

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

Keep out of reach of children.

Incompatibilities.

Diclofenac-Darnytsia, solution for injection, must not be mixed with other injectable solutions in the same container.

0.9% sodium chloride solution and 5% glucose solution without sodium bicarbonate as additive pose a risk of supersaturation, which may lead to crystal or precipitate formation.

Other infusion solutions should not be used.

Packaging.

3 ml in a vial; 5 vials in a blister pack; 1 or 2 blister packs in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and location of its business activities.

13, Boryspilska St., Kyiv, 02093, Ukraine.