Diclasel

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

Composition:

Active substances: diclofenac sodium, lidocaine hydrochloride;

1 ml contains: diclofenac sodium 37.5 mg and lidocaine hydrochloride 10 mg;

Excipients: disodium edetate, acetylcysteine, propylene glycol, polyethylene glycol 400, sodium hydroxide, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless or slightly yellowish-brown liquid.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents.

ATC code M01A B55.

Pharmacological Properties

Pharmacodynamics

The medicinal product Diklasele contains sodium diclofenac, a non-steroidal active substance with pronounced anti-rheumatic, anti-inflammatory, analgesic, and antipyretic properties. Inhibition of prostaglandin biosynthesis is considered the main mechanism of its action. Prostaglandins play a significant role in the development of inflammation, pain, and fever.

In rheumatic diseases, the anti-inflammatory and analgesic properties of the medicinal product result in a pronounced clinical response characterized by the disappearance of resting pain, movement-related pain, morning stiffness, and joint swelling, as well as improvement in joint function.

In post-traumatic or postoperative inflammation, sodium diclofenac rapidly reduces acute pain and pain during movement, and also decreases edema caused by inflammation and injury.

When used concomitantly for postoperative pain management, sodium diclofenac significantly reduces the need for opioids. The medicinal product Diklasele demonstrates a pronounced analgesic effect within 15–30 minutes after administration in moderate to severe non-rheumatic pain; it can be used for initial therapy of inflammatory and degenerative rheumatic diseases, as well as for the treatment of pain caused by non-rheumatic inflammation.

Pharmacokinetics

Absorption. After intramuscular administration, maximum plasma concentration is achieved within 10–20 minutes. The therapeutic plasma concentration of the medicinal product Diklasele ranges from 0.7 to 2.0 µg/mL. Repeated administration of the drug does not cause any renal changes. When the recommended intervals between doses are maintained, no accumulation of the drug in the body is observed.

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

The drug penetrates into synovial fluid, where its maximum concentration is reached 2–4 hours after peak plasma levels. The half-life in synovial fluid is 3–6 hours. As a result, even 4–6 hours after administration, concentrations of the active substance in synovial fluid are higher than in plasma and remain at elevated levels for up to 12 hours.

Metabolism. Approximately half of the administered dose undergoes first-pass metabolism. Consequently, the area under the concentration-time curve (AUC) after oral or rectal administration is approximately half that observed after parenteral administration of an equivalent dose.

Biotransformation of the drug occurs partially via glucuronidation and methoxylation. Two of the phenolic metabolites formed in this process are pharmacologically active, although to a lesser extent than sodium diclofenac itself.

Elimination. Sodium diclofenac is eliminated from plasma with a systemic clearance of 263 ± 56 mL/min (mean ± standard deviation). The terminal half-life of the drug is 1–2 hours. Approximately 60% of the administered dose is excreted by the kidneys as metabolites, with less than 1% excreted unchanged. The remainder of the administered dose is excreted in metabolized form via bile and subsequently in feces.

Linearity/Non-linearity. Plasma concentration demonstrates a linear relationship with dose.

Pharmacokinetics in specific patient groups. No significant differences in absorption, metabolism, and elimination of the drug have been observed in elderly patients. In patients with impaired renal function, after administration of the usual dose, no increase in the amount of unchanged active substance was observed. However, when creatinine clearance was less than 10 mL/min, plasma metabolite levels at steady state were approximately four times higher than in healthy volunteers. Despite this, metabolites were ultimately eliminated via bile. In cases of hepatic impairment (chronic hepatitis, compensated liver cirrhosis), the pharmacokinetics and metabolism of the drug do not differ from those in patients with normal liver function.

Clinical Characteristics

Indications

Administer as intramuscular injections in the following conditions:

• Inflammatory or degenerative forms of rheumatism, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, spondyloarthritis, vertebral pain syndrome, periarticular rheumatism;
• Acute gout attacks;
• Renal and hepatic colic;
• Pain, inflammation, and edema following trauma and surgical procedures;
• Severe migraine attacks.

Contraindications

• Hypersensitivity to the active substances or to any other components of the medicinal product;
• Increased individual sensitivity to lidocaine or to other amide-type local anesthetics;
• History of seizures induced by lidocaine;
• Porphyria;
• Myasthenia gravis;
• Anticoagulant therapy;
• Gastrointestinal bleeding or perforation in history related to previous treatment with nonsteroidal anti-inflammatory drugs (NSAIDs);
• Active peptic ulcer disease / bleeding or recurrent peptic ulcer / bleeding in history (two or more separate episodes of established ulcer or bleeding);
• Active gastric and/or duodenal ulcer, gastrointestinal bleeding or perforation;
• As with other NSAIDs, diclofenac is contraindicated in patients in whom administration of ibuprofen, acetylsalicylic acid, or other NSAIDs induces attacks of bronchial asthma, bronchospasm, angioneurotic edema, urticaria, acute rhinitis, nasal polyps, or allergy-like symptoms;
• Inflammatory bowel diseases (e.g., Crohn’s disease or ulcerative colitis);
• Hepatic failure (Child-Pugh class C);
• Renal failure (glomerular filtration rate [GFR] < 15 mL/min/1.73 m²);
• Congestive heart failure [NYHA (New York Heart Association) functional class II–IV];
• Ischemic heart disease in patients with angina pectoris or history of myocardial infarction;
• Cerebrovascular diseases in patients with history of stroke or transient ischemic attacks;
• Peripheral arterial disease;
• Contraindicated for treatment of perioperative pain in coronary artery bypass grafting (or when using cardiopulmonary bypass);
• Severe conduction system disorders of the heart, second- or third-degree atrioventricular block, sick sinus syndrome, Adams-Stokes syndrome, Wolff-Parkinson-White syndrome, complete transverse heart block, bradycardia, cardiogenic or hypovolemic shock, marked arterial hypotension;
• High risk of postoperative bleeding, coagulation disorders, incomplete hemostasis, hematopoietic disorders, or cerebrovascular hemorrhage.

Interaction with Other Medicinal Products and Other Forms of Interaction

The following interactions may occur with the medicinal product Diklasel or other diclofenac formulations.

Diclofenac may increase plasma concentrations of lithium and digoxin. When used concomitantly, serum levels of lithium and digoxin should be monitored.

Concomitant administration of sodium diclofenac with diuretics or antihypertensive medicinal products (e.g., β-blockers, angiotensin-converting enzyme [ACE] inhibitors) may reduce antihypertensive efficacy. Such combinations should be used with caution; blood pressure should be closely monitored, especially in elderly patients. Adequate fluid intake is recommended. Renal function should be monitored at the start of concomitant therapy and regularly thereafter, particularly when diuretics and ACE inhibitors are used, due to increased risk of nephrotoxicity.

Medicinal products causing hyperkalemia. Concomitant use of potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may increase serum potassium levels; therefore, more frequent patient monitoring is recommended.

Concomitant administration of diclofenac and other systemic NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, or corticosteroids increases the risk of gastrointestinal bleeding or ulceration. Concurrent use of two or more NSAIDs should be avoided.

Diclofenac sodium should be used with caution when administered with anticoagulants and antiplatelet agents, as their combined use increases the risk of bleeding. Although no direct evidence of diclofenac affecting anticoagulant action has been established, isolated reports of hemorrhagic complications have occurred in patients receiving diclofenac and anticoagulants simultaneously. Close monitoring of such patients is recommended, and dose adjustments of anticoagulants may be necessary. Like other NSAIDs, high-dose diclofenac may reversibly inhibit platelet aggregation.

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

Antidiabetic medicinal products. It has been established that sodium diclofenac can be co-administered with oral hypoglycemic agents without affecting their clinical efficacy. However, isolated reports of hypoglycemic and hyperglycemic reactions following sodium diclofenac administration have necessitated dose adjustments of hypoglycemic agents. Therefore, blood glucose levels should be monitored during such combination therapy. Isolated cases of metabolic acidosis have also been reported with concomitant use of diclofenac and metformin, particularly in patients with impaired renal function.

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

Diclofenac, like other NSAIDs, may increase the nephrotoxicity of cyclosporine and tacrolimus by affecting renal prostaglandins. Therefore, it should be administered at lower doses than in patients not receiving cyclosporine or tacrolimus.

Isolated reports exist of seizures possibly resulting from concomitant use of quinolone antibiotics and NSAIDs. Seizures may occur in patients both with and without a history of epilepsy or seizures. Therefore, caution is advised when considering quinolone use in patients already receiving NSAIDs.

When phenytoin is used concomitantly with diclofenac, plasma phenytoin levels should be monitored due to expected increased phenytoin exposure.

Cholestyramine and colestipol may delay or reduce diclofenac absorption; therefore, diclofenac should be administered at least 1 hour before or 4–6 hours after cholestyramine/colestipol.

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

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

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

Concomitant use of diclofenac with strong CYP2C9 inhibitors (such as sulfaphenazole and voriconazole) is not recommended, as it may result in a significant increase in peak plasma concentration and enhanced effect of diclofenac due to inhibition of its metabolism.

Alcohol. Concomitant use of NSAIDs and alcohol may potentiate adverse effects of the active substance, particularly on the gastrointestinal tract or central nervous system (CNS).

Interactions related to the presence of lidocaine hydrochloride may also occur.

When lidocaine is used in combination with antiarrhythmics, β-adrenergic blockers, or calcium antagonists, additive inhibitory effects on atrioventricular conduction, intraventricular conduction, and contractility should be considered.

β-adrenergic blockers (including propranolol), cimetidine, pethidine, bupivacaine, quinidine, disopyramide, amitriptyline, nortriptyline, chlorpromazine, imipramine increase serum lidocaine levels by reducing its hepatic metabolism.

In cases of cardiac glycoside intoxication, digitalis glycosides, lidocaine may worsen the severity of atrioventricular (AV) block. Lidocaine reduces the cardiotonic effect of cardiac glycosides.

When used concomitantly with antiarrhythmics (amiodarone, verapamil, quinidine, etc.) or anticonvulsants (hydantoin derivatives) and phenytoin, the cardiodepressant effect of lidocaine is enhanced.

Concomitant use with sedatives and hypnotics, anesthetics (hexobarbital, intravenous sodium thiopental) may enhance CNS depressant effects.

Concomitant use with procainamide may cause delirium and hallucinations. Lidocaine may potentiate the effect of neuromuscular blocking agents, as they reduce nerve impulse conduction.

Ethanol enhances the respiratory depressant effect of lidocaine.

Norepinephrine, mexiletine — increase lidocaine toxicity (reduced lidocaine clearance).

Isadrine (isoprenaline) and glucagon — increase lidocaine clearance.

Midazolam moderately increases lidocaine blood concentration.

Monoamine oxidase inhibitors, chlorpromazine, bupivacaine, amitriptyline, nortriptyline, imipramine — when used concomitantly with lidocaine, increase the risk of arterial hypotension and prolong the local anesthetic effect of lidocaine.

Narcotic analgesics (e.g., morphine) — when used concomitantly with lidocaine, enhance the analgesic effect of narcotic analgesics but also increase respiratory depression.

Prenylamine — increases the risk of ventricular arrhythmia of the "torsades de pointes" type.

Propafenone — may increase duration and severity of CNS-related adverse effects.

Rifampicin — may reduce lidocaine blood concentration.

Polymyxin B — respiratory function should be monitored.

Vasoconstrictors (epinephrine, methoxamine, phenylephrine) — when used concomitantly with lidocaine, slow lidocaine absorption and prolong its effect. Guanadrel, guanethidine, mecamylamine, trimethaphan — when used concomitantly for spinal and epidural anesthesia, increase the risk of severe hypotension and bradycardia. Acetazolamide, thiazide and loop diuretics — when used concomitantly with lidocaine, cause hypokalemia and reduce lidocaine's effect.

Anticoagulants (including ardeparin, dalteparin, danaparoid, enoxaparin, heparin, warfarin) — when used concomitantly with lidocaine, increase the risk of bleeding.

Special precautions for use

General recommendations. During treatment with NSAIDs, including selective or non-selective COX-2 inhibitors, gastrointestinal ulcers, bleeding, or perforation may occur regardless of the presence or absence of previous warning symptoms or serious gastrointestinal events in medical history. Adverse effects can be minimized by using the lowest effective dose for the shortest possible duration required to control symptoms.

Diclofenac sodium, like other NSAIDs, increases the risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke. Placebo-controlled studies have shown an increased risk of thrombotic cardiovascular and cerebrovascular complications with certain selective COX-2 inhibitors. A direct correlation between this risk and the selectivity of individual NSAIDs for COX-1/COX-2 has not yet been established. Due to the lack of comparative clinical trial data on long-term treatment with maximum doses of diclofenac, a similar increased risk cannot be excluded. In the absence of relevant data, the risk and benefit should be carefully evaluated before using diclofenac in patients with clinically confirmed ischemic heart disease, cerebrovascular disorders, peripheral arterial occlusive disease, or significant risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking). Diclofenac should be used only after careful assessment of potential risks and benefits. 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 particular caution in patients with impaired cardiac function and other conditions predisposing to fluid retention. Caution is also required in patients concurrently taking diuretics or ACE inhibitors, or those prone to hypovolemia.

Consequences are generally more serious in elderly patients. Caution should be exercised when prescribing the medicinal product to elderly patients. In particular, for frail elderly patients and those with low body weight, the lowest effective doses are recommended.

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

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, may occur during diclofenac use. Hypersensitivity reactions may also progress to Kounis syndrome, a severe allergic reaction that may cause myocardial infarction. Symptoms of such a reaction include chest pain occurring in combination with an allergic reaction to diclofenac.

Non-steroidal anti-inflammatory drugs, due to their pharmacodynamic properties, may mask signs and symptoms of infection. With prolonged use of analgesics, headache may develop, which cannot be treated by increasing the dose of these drugs.

Gastrointestinal (GI) tract effects. Gastrointestinal bleeding, ulcers, or perforation have been reported during treatment with all NSAIDs, including diclofenac, which may be fatal and may occur at any time during therapy, regardless of the presence or absence of warning symptoms or serious gastrointestinal events in history. These events generally have more serious consequences in elderly patients. Diclofenac sodium should be used under medical supervision and with caution in patients with symptoms indicating gastrointestinal disorders, or with a history of gastric or intestinal ulcers, gastrointestinal bleeding, or perforation. The risk of gastrointestinal bleeding is higher with increasing NSAID doses, in patients with a history of ulcers, especially complicated by bleeding or perforation, and in elderly individuals. If gastrointestinal bleeding or GI ulceration occurs during treatment with Diklasel, the drug should be discontinued.

Adverse reactions, especially gastrointestinal bleeding and perforation, occur more frequently in elderly patients during NSAID use and may be fatal. To reduce the risk of gastrointestinal disturbances in patients with a history of ulcers, particularly complicated by bleeding or perforation, as well as in elderly patients, frail patients, or those with low body weight, the drug should be used at the lowest effective dose for the shortest possible duration. Such patients, as well as those regularly taking low-dose acetylsalicylic acid/aspirin or other drugs increasing the risk of GI adverse effects, should be prescribed combination therapy with agents protective of gastric mucosa (e.g., proton pump inhibitors or misoprostol).

Patients with a history of gastrointestinal toxicity, especially elderly ones, should report any unusual abdominal symptoms (particularly gastrointestinal bleeding). Caution is also required in 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 SSRIs.

The use of NSAIDs, including diclofenac, increases the risk of leakage from gastrointestinal anastomoses; careful medical supervision and caution are required when using diclofenac after gastrointestinal surgery.

Hepatic effects. Patients with impaired liver function receiving diclofenac sodium require close medical monitoring, as their condition may worsen during treatment. During NSAID therapy, including diclofenac, levels of one or more liver enzymes may increase. Such changes were observed very commonly (approximately 15% of patients) in clinical trials with diclofenac, but rarely were associated with clinical symptoms. In most cases, these changes remained within borderline values. Moderately increased levels above normal (≥ 3 to < 8 × ULN [upper limit of normal]) occurred commonly (in 2.5%), while significant increases (≥ 8 × ULN) occurred in approximately 1% of patients. Clinically manifest liver injury (e.g., eosinophilia, rash) developed in 0.5% of patients, in addition to elevated liver enzymes. Elevated enzyme concentrations were usually reversible after discontinuation of the drug.

If impaired liver function persists or worsens during treatment, or if clinical signs or symptoms of liver disease (e.g., hepatitis) or other manifestations (e.g., eosinophilia, rash) occur, diclofenac sodium should be discontinued. The course of diseases such as hepatitis may occur without prodromal symptoms. The medicinal product Diklasel should be used cautiously in patients with hepatic porphyria due to the potential risk of provoking an attack.

Renal effects. Due to the importance of prostaglandins in maintaining renal blood flow, prolonged use of high doses of NSAIDs, including diclofenac, frequently (1–10%) leads to fluid retention, edema, and arterial hypertension.

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 significantly affecting renal function, and patients with significant extracellular fluid volume depletion due to any cause, e.g., before or after major surgery. In such cases, monitoring of renal function is recommended. Discontinuation of therapy usually results in return to the pre-treatment state. In general, frequent and regular use of analgesics, especially combinations of several analgesic drugs, may lead to persistent kidney damage associated with a risk of renal failure ("analgesic nephropathy").

Skin and subcutaneous tissue effects. Very rarely, severe skin reactions, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, sometimes fatal, may occur in association with NSAID use. The highest risk of such reactions occurs at the beginning of treatment; in most cases, these reactions appear within the first month of therapy. Diklasel should be discontinued at the first signs of skin rash, mucosal lesions, or any other signs of hypersensitivity. Like other NSAIDs, diclofenac may rarely cause allergic reactions, including anaphylactic/anaphylactoid reactions, even in patients who have not previously taken it.

Injection site reactions. Reactions at the injection site have been reported after intramuscular administration of diclofenac, including injection site necrosis and medication embolism, also known as Nicolau syndrome (especially after inadvertent subcutaneous injection). When administering diclofenac intramuscularly, appropriate needle selection and injection technique should be used (see section "Method of administration and dosage").

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 associated with NSAID treatment.

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

Generally, diclofenac is not recommended for patients with cardiovascular disease (heart failure, ischemic heart disease, peripheral arterial disease) or uncontrolled arterial hypertension. If diclofenac use is necessary in patients with cardiovascular disease or uncontrolled arterial hypertension, or in the presence of significant risk factors for cardiovascular disease (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking), risks and benefits must be carefully weighed, and the drug should be prescribed only at doses up to 100 mg daily if treatment exceeds 4 weeks.

Since cardiovascular risks increase with higher diclofenac doses and longer treatment duration, 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 if treatment lasts longer than 4 weeks. Use with caution in patients aged 65 years and older.

For patients with a history of arterial hypertension and/or mild to moderate congestive heart failure, appropriate monitoring and recommendations are necessary, as fluid retention and edema have been reported with NSAID use, including diclofenac. Clinical and epidemiological data indicate that diclofenac use, especially at high doses (150 mg/day) and over prolonged periods, slightly increases the risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

Diclofenac is not recommended for patients with uncontrolled arterial hypertension, congestive heart failure, stable ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. If use is necessary, it may be considered only after careful risk-benefit assessment and at a dosage not exceeding 100 mg/day. 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 prior warning symptoms. In such cases, immediate medical attention is required. The medicinal product is contraindicated in patients with congestive heart failure (NYHA functional class II–IV).

Hematological effects. Since NSAIDs may temporarily inhibit platelet aggregation, hematological parameters should be monitored during prolonged use of diclofenac sodium, as with other NSAIDs. Patients with coagulation disorders, hemorrhagic diathesis, or hematological abnormalities require close monitoring.

History of asthma. Patients with bronchial asthma, seasonal allergic rhinitis, nasal mucosal edema (nasal polyps), chronic obstructive pulmonary disease, or chronic respiratory tract infections (especially if associated with symptoms resembling allergic rhinitis) more frequently experience reactions to NSAIDs, such as asthma exacerbation (so-called analgesic intolerance, leukotriene asthma, aspirin-induced asthma), Quincke's edema, or urticaria, compared to other patients. Therefore, special precautionary measures (readiness for emergency care) are recommended for such patients. This also applies to patients with allergies to other substances manifesting as skin reactions, pruritus, or urticaria.

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

Female fertility. The medicinal product Diklasel may affect female fertility and therefore is not recommended for women planning pregnancy. Consideration should be given to discontinuing the medicinal product in women experiencing difficulties with conception and in women undergoing infertility evaluation.

Lidocaine. Lidocaine should be administered only by healthcare professionals. Like other lidocaine-containing products, Diklasel should be used cautiously in patients with epilepsy, conduction disorders, or respiratory insufficiency.

Since Diklasel contains lidocaine, local reactions such as pain and swelling may occur more frequently if the injection site is disinfected with solutions containing heavy metals. Lidocaine has a pronounced arrhythmogenic effect; therefore, the medicinal product should be used cautiously in individuals with a history of arrhythmia.

Use with caution in patients with moderate heart failure, moderate arterial hypotension, incomplete AV block, first-degree AV block, intraventricular conduction disturbances, moderate liver and kidney dysfunction (creatinine clearance 10 ml/min), respiratory function impairment, epilepsy, increased seizure susceptibility, severe myasthenia gravis, after cardiac surgery, in patients with genetic predisposition to hyperthermia, debilitated patients, elderly patients, and when injecting into inflamed (infected) areas.

ECG monitoring is mandatory during lidocaine use. If sinus node dysfunction, PQ interval prolongation, QRS complex widening, or new arrhythmia develops, the dose should be reduced or the drug discontinued. Before using lidocaine in cardiac conditions (hypokalemia reduces lidocaine efficacy), serum potassium levels should be normalized.

Other. Due to the presence of propylene glycol, Diklasel may cause symptoms similar to those induced by alcohol consumption.

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding

Pregnancy

From the 20th week of pregnancy, diclofenac use may cause oligohydramnios due to fetal renal dysfunction. This disorder may occur soon after starting treatment and is usually reversible after discontinuation of therapy. Diclofenac should not be prescribed during the first and second trimesters of pregnancy except in cases of extreme necessity. If diclofenac is used by women attempting to conceive or during the first and second trimesters of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible. Prenatal monitoring for oligohydramnios may be advisable after exposure to diclofenac for several days starting from the 20th week of pregnancy. Diclofenac use should be discontinued if oligohydramnios is detected.

During the third trimester, all prostaglandin synthesis inhibitors cause:

Risks to the fetus:

• Cardio-pulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• Renal dysfunction (see above);

Risks to the mother at the end of pregnancy and to the newborn:

• 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, diclofenac is contraindicated during the third trimester of pregnancy.

The use of the medicinal product Diklasel, like other preparations containing lidocaine hydrochloride, is contraindicated during pregnancy.

Breastfeeding

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

Fertility

Diclofenac may affect female fertility. The drug is not recommended for women planning pregnancy. Women experiencing difficulties with conception or those undergoing infertility evaluation should discontinue diclofenac use.

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

Ability to affect reaction speed when driving or operating machinery

Patients experiencing visual disturbances, dizziness, somnolence, lethargy, increased fatigue, or other central nervous system disorders should refrain from driving or operating machinery.

Method of Administration and Dosage

The dose is individually determined by a physician. The medicinal product should be used at the lowest effective doses for the shortest duration necessary, taking into account the treatment goal for each individual patient.

Due to the risk of anaphylactic reactions up to shock, after administration of the medicinal product Diclacel, the patient must remain under medical supervision for at least 1 hour, and emergency medical equipment must be readily available.

The medicinal product Diclacel is administered as intramuscular injections. To avoid nerve or tissue damage at the injection site, the instructions below must be followed. Such damage may lead to muscle weakness, paralysis, hypoesthesia, medication embolism (Nicolau syndrome), and necrosis at the injection site.

The usual single dose is 1 ampoule (i.e., 75 mg of sodium diclofenac), administered under aseptic conditions by deep intramuscular injection into the upper outer quadrant of the gluteal muscle once daily.

The solution should be used immediately after opening the ampoule. Any unused portion of the solution must be discarded.

In cases of severe pain (e.g., colic), as an exception, the medicinal product may be administered twice daily with several hours between doses, and the injection site must be alternated. Parenteral administration of Diclacel may be combined with other dosage forms of diclofenac (tablets, capsules, rectal suppositories, gel, or patch), provided that the total daily dose of sodium diclofenac does not exceed 150 mg.

In migraine attacks, clinical experience is limited to cases where one 75 mg ampoule is initially administered, followed if necessary by a 100 mg suppository on the same day as soon as possible. The total daily dose must not exceed 175 mg on the first day. There are no available data on the use of Diclacel for migraine treatment beyond 1 day. If further therapy is required on subsequent days, the daily dose of diclofenac must not exceed 150 mg (administered as divided doses in suppository form).

The duration of parenteral administration of Diclacel should not exceed 2 days.

Diclacel must not be used for intravenous injection or infusion.

Cardiovascular disease or significant cardiovascular risk factors. Diclofenac therapy is generally not recommended for patients with cardiovascular disease or uncontrolled arterial hypertension. If necessary, patients with cardiovascular disease, uncontrolled arterial hypertension, or significant cardiovascular risk factors should receive diclofenac treatment only after careful risk assessment and only at doses up to 100 mg daily if the treatment duration exceeds 4 weeks (see section "Special Warnings and Precautions for Use").

Use of diclofenac in patients with renal impairment is contraindicated (GFR < 15 mL/min/1.73 m²). Specific studies in patients with renal dysfunction have not been conducted; therefore, no specific dosage recommendations can be provided. Diclofenac should be used with caution in patients with renal dysfunction (see section "Special Warnings and Precautions for Use").

Use of diclofenac in patients with hepatic impairment is contraindicated (see section "Contraindications"). Specific studies in patients with hepatic dysfunction have not been conducted; therefore, no specific dosage recommendations can be provided. Diclofenac should be used with caution in patients with mild to moderate hepatic impairment (see section "Special Warnings and Precautions for Use").

Elderly patients. Dose adjustment of the initial dose is generally not required; however, caution is recommended, especially when prescribing for frail patients or those with low body weight.

Children. Not to be used in children (under 18 years of age).

Overdose

Diclofenac

Symptoms. The typical clinical symptoms of sodium diclofenac overdose are not well known. In case of overdose, symptoms may include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, diarrhea, dizziness, disorientation, agitation, coma, somnolence, tinnitus, confusion, loss of consciousness, or seizures. In severe poisoning, acute renal failure and liver damage may occur. Overdose may also lead to arterial hypotension, respiratory depression, and cyanosis.

Treatment. Within one hour after ingestion of a potentially toxic amount, administration of activated charcoal should be considered. In addition, gastric lavage should be considered for adults within one hour after ingestion of a potentially toxic amount. Supportive and symptomatic treatment should be provided to manage complications such as arterial hypotension, renal failure, seizures, gastrointestinal mucosal irritation, and respiratory depression. Specific therapies such as forced diuresis, dialysis, or hemoperfusion are not particularly effective in eliminating NSAIDs due to their high plasma protein binding and extensive metabolism. Intravenous diazepam should be administered in cases of frequent or prolonged seizures. Other measures may be indicated depending on the patient's clinical condition. Treatment is symptomatic.

Lidocaine

Symptoms: numbness of the tongue and lips, agitation, euphoria, anxiety, blurred vision, tremor, depression, somnolence, dizziness, confusion, respiratory depression or respiratory arrest, bradycardia, cardiac conduction disturbances, atrioventricular block, coma, dizziness, general weakness, decreased arterial pressure up to shock, tremor, tonic-clonic seizures, coma, collapse, and possible atrioventricular block. Initial symptoms of overdose in healthy individuals occur at blood lidocaine concentrations exceeding 0.006 mg/kg; seizures occur at 0.01 mg/kg.

Treatment: discontinue administration of the drug, oxygen therapy, anticonvulsants, vasoconstrictors (norepinephrine, mesaton), anticholinergics (0.5–1 mg atropine) in case of bradycardia. Endotracheal intubation, artificial ventilation of the lungs, and resuscitation measures may be necessary. Dialysis is ineffective.

Side effects

If adverse effects occur, consult a physician. The list of possible adverse effects includes data on the effects of active substances contained in the medicinal product, as well as data from other diclofenac dosage forms used for both short-term and long-term treatment.

Infections and infestations: abscesses at the injection site.

Blood and lymphatic system disorders: thrombocytopenia, leukopenia, anemia (including hemolytic and aplastic anemia), agranulocytosis.

Immune system disorders: hypersensitivity reactions (anaphylactic and anaphylactoid reactions, including arterial hypotension and shock), angioedema (including facial swelling), sensation of warmth, cold, or numbness in extremities.

Psychiatric disorders: disorientation, depression, insomnia, nightmares, irritability, restlessness, psychiatric disturbances.

Nervous system disorders: headache, dizziness, sleep disturbances, somnolence, paresthesia, memory impairment, convulsions, anxiety, tremor, aseptic meningitis, taste disturbances, stroke, sensory disturbances, increased fatigue, confusion, loss of consciousness up to coma, hallucinations, muscle twitching, motor block, dysarthria, dysphagia, nystagmus.

Eye disorders: visual disturbances, blurred vision, diplopia, optic neuritis, flickering "floaters", photophobia, conjunctivitis.

Ear and labyrinth disorders: vertigo, tinnitus, hearing disturbances, hyperacusis.

Cardiac disorders: palpitations, chest pain, myocardial infarction, heart failure, arterial hypertension, arterial hypotension, vasculitis, arrhythmia, bradycardia, impaired cardiac conduction, atrioventricular block, cardiac arrest, collapse, tachycardia, flushing, Kounis syndrome.

Respiratory, thoracic and mediastinal disorders: asthma (including dyspnea), bronchospasm, pneumonitis, respiratory depression or respiratory arrest, rhinitis.

Gastrointestinal disorders: abdominal pain, nausea, vomiting, diarrhea, abdominal cramps, dyspepsia, flatulence, anorexia, gastritis, vomiting blood, gastrointestinal bleeding, hemorrhagic diarrhea, melena, gastric and intestinal ulcers (with or without bleeding), perforation or gastrointestinal stenosis, which may lead to peritonitis (sometimes fatal, especially in elderly patients), colitis (including hemorrhagic colitis, ischemic colitis, and exacerbation of ulcerative colitis or Crohn's disease), constipation, stomatitis (including ulcerative stomatitis), glossitis, esophageal lesions, diaphragm-like intestinal strictures, pancreatitis.

Hepatobiliary disorders: elevated transaminase levels, hepatitis, jaundice, liver dysfunction, fulminant hepatitis, liver necrosis, liver failure.

Skin and subcutaneous tissue disorders: rash, urticaria, bullous rash, eczema, erythema, erythema multiforme, Stevens–Johnson syndrome, Lyell’s syndrome (toxic epidermal necrolysis), exfoliative dermatitis, alopecia, photosensitivity, purpura, allergic purpura, pruritus.

Renal and urinary disorders: fluid retention, edema, acute renal failure, hematuria, proteinuria, interstitial nephritis, nephrotic syndrome, renal papillary necrosis.

Reproductive system disorders: impotence.

General disorders and administration site conditions: malaise, malignant hyperthermia, weakness, reactions at the intramuscular injection site such as pain, mild burning sensation or tissue induration, swelling, necrosis at injection site, abscess at injection site, medication embolism (Nicolau syndrome).

An increased risk of thrombotic complications (e.g., myocardial infarction or stroke) has been reported with the use of diclofenac, particularly at high therapeutic doses (150 mg per day) and with prolonged use.

Such visual disturbances as blurred vision, visual obscurations, and diplopia may occur after use of NSAIDs and are usually reversible upon discontinuation of therapy. The most likely mechanism of visual disturbances is inhibition of prostaglandin synthesis and other related compounds, which may disrupt retinal blood flow regulation and contribute to visual impairments. If such symptoms occur during treatment with diclofenac, ophthalmological examination should be performed to rule out other possible causes.

Lidocaine. Allergic reactions such as urticaria, edema, bronchospasm or dyspnea, and circulatory reactions have been reported less frequently. Systemic reactions such as dizziness, clouding of consciousness, somnolence, convulsions, confusion, nausea, vomiting, bradycardia, arrhythmia, hypotension up to shock may occur due to rapid administration (accidental intravenous injection, injection into tissue with high blood flow) or overdose.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life: 2 years.

Storage conditions. Store in a refrigerator (at +2 °C to +8 °C). To protect from light, keep ampoules in the outer carton. Keep out of reach of children.

Incompatibility. The medicinal product must not be mixed with other injectable solutions.

Packaging. 2 ml in an ampoule. 5 or 10 ampoules per cardboard pack.

Prescription category: Prescription only.

Manufacturer: PHARMASELL LLC.

Manufacturer's address and place of business.

3 Pryrizna Street, Kvitneve, Brovary District, Kyiv Oblast, 07408, Ukraine.