DICLOFENAC-BIOLIK

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

Composition:

Active substance: diclofenac;

1 ml of solution contains 25 mg of diclofenac sodium;

Excipients: mannitol (E 421); sodium metabisulfite (E 223); benzyl alcohol; propylene glycol; 0.1 M solution of sodium hydroxide; water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless or slightly yellowish liquid with a faint specific odor.

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

Pharmacological Properties

Pharmacodynamics

Diclofenac-Biolik is a non-steroidal agent with pronounced analgesic and anti-inflammatory properties. It is an inhibitor of prostaglandin synthetase (cyclooxygenase). Prostaglandins play a key role in the development of inflammation, pain, and fever. In vitro, at concentrations equivalent to those achieved in humans, sodium diclofenac does not inhibit proteoglycan synthesis in cartilage tissue.

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

Pharmacokinetics

Absorption

After intramuscular injection of 75 mg diclofenac, the mean peak plasma concentration of approximately 2.5 µg/mL is reached within about 20 minutes. When 75 mg of diclofenac is administered by intravenous infusion over 2 hours, the mean peak plasma concentration is approximately 1.9 µg/mL. Shorter infusion durations lead to higher peak plasma concentrations, while longer infusions result in a concentration plateau proportional to the infusion rate after 3–4 hours. After intramuscular injection or oral administration of enteric-coated tablets or rectal suppositories, plasma concentrations decline rapidly immediately after peak levels are achieved. Following oral or rectal administration, approximately half of the absorbed diclofenac undergoes first-pass metabolism in the liver ("first-pass effect"). The area under the concentration-time curve (AUC) after intramuscular or intravenous administration is approximately twice that after oral or rectal administration.

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

Distribution

Approximately 99.7% of diclofenac is bound to plasma proteins, primarily to albumin (99.4%).

The apparent volume of distribution is calculated to be 0.12–0.17 L/kg.

Diclofenac penetrates into synovial fluid, where maximum concentration is reached 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 is achieved, the concentration of diclofenac in synovial fluid exceeds that in plasma and remains higher for up to 12 hours.

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

Metabolism

Biotransformation of diclofenac occurs partially via glucuronidation of the intact molecule, but primarily through single and multiple hydroxylation and methoxylation reactions, 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 pharmacologically active, although their activity is significantly less than that of diclofenac.

Excretion

Total systemic clearance of diclofenac from plasma is 263 ± 56 mL/min (mean ± SD). The terminal elimination half-life 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 half-life but is practically inactive. Approximately 60% of the administered dose is excreted in urine as metabolites. Less than 1% is excreted unchanged. The remainder is eliminated as metabolites via bile in feces.

Linearity/Non-linearity

Plasma concentration shows a linear relationship with dose.

Special Patient Groups

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

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

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

Clinical characteristics.

Indications.

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

• inflammatory and degenerative forms of rheumatism, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, spondyloarthritis, vertebral pain syndrome, non-articular rheumatism;
• acute gout attacks;
• renal and biliary colic;
• pain and swelling following trauma and surgery;
• severe migraine attacks.

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

Contraindications.

• Known hypersensitivity to the active substance, sodium metabisulfite, or any other components of the medicinal product;
• gastrointestinal bleeding or perforation in medical history associated with previous treatment with nonsteroidal anti-inflammatory drugs (NSAIDs);
• active peptic ulceration of the stomach or duodenum/bleeding, or recurrent peptic ulcer/bleeding in medical history (two or more separate episodes of confirmed ulceration or bleeding);
• third trimester of pregnancy;
• as with other NSAIDs, diclofenac is contraindicated in patients in whom administration of ibuprofen, acetylsalicylic acid, or other nonsteroidal anti-inflammatory drugs triggers attacks of bronchial asthma, bronchospasm, angioedema, urticaria, or acute rhinitis/nasal polyps, or allergy-like symptoms;
• inflammatory bowel diseases (e.g., Crohn's disease or ulcerative colitis);
• hepatic failure;
• renal failure (glomerular filtration rate (GFR) < 15 mL/min/1.73 m²);
• heart failure (NYHA II–IV);
• high risk of postoperative bleeding, coagulation disorders, hemostatic disorders, hematopoietic disorders, or cerebrovascular bleeding;
• treatment of perioperative pain in coronary artery bypass grafting (CABG) (or use of cardiopulmonary bypass);
• ischemic heart disease in patients with angina pectoris or history of myocardial infarction;
• cerebrovascular diseases in patients with history of stroke or transient ischemic attacks;
• peripheral arterial disease.

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

For intravenous use only.

• Concomitant use of NSAIDs or anticoagulants (including low-dose heparin);
• history of hemorrhagic diathesis, confirmed or suspected cerebrovascular bleeding in medical history;
• surgeries 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 types of interactions.

Below are interactions observed during the use of sodium diclofenac injection solution and/or other diclofenac formulations.

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

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

Diuretics and antihypertensive agents. As with other NSAIDs, concomitant use of diclofenac with diuretics and antihypertensive agents (e.g., beta-blockers, angiotensin-converting enzyme (ACE) inhibitors) may reduce their antihypertensive effect. 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 and regularly during concomitant therapy, particularly with diuretics and ACE inhibitors due to increased risk of nephrotoxicity (see section "Special precautions for use").

Medicinal products known to cause hyperkalemia. Concomitant use with potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may lead to increased serum potassium levels; therefore, more frequent monitoring of patients is recommended (see section "Special precautions for use").

Anticoagulants and antithrombotic agents. Precautions are recommended, as concomitant administration may increase the risk of bleeding (see section "Special precautions for use"). Although clinical studies do not indicate that diclofenac affects anticoagulant activity, isolated reports suggest an increased risk of bleeding in patients receiving diclofenac and anticoagulants simultaneously. Therefore, careful monitoring of such patients is recommended.

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

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

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

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

Methotrexate. Caution is recommended when NSAIDs, including diclofenac, are administered less than 24 hours before methotrexate treatment, as this may increase methotrexate blood concentrations and enhance its toxicity.

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

Quinolone antibacterial agents. Isolated data suggest seizures that may result from concomitant use of quinolones and NSAIDs.

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

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

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

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

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

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

Special precautions for use.

• General

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

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

Placebo-controlled studies have shown an increased risk of thrombotic cardiovascular and cerebrovascular complications with certain selective COX-2 inhibitors. A direct correlation between this risk and the COX-1/COX-2 selectivity of individual NSAIDs has not yet been established. Due to the lack of comparable clinical data on long-term treatment with maximum doses of diclofenac, the possibility of a similar increased risk cannot be excluded. In the absence of such data, a careful benefit-risk assessment should be performed before using diclofenac in patients with clinically confirmed ischemic heart disease, cerebrovascular disorders, peripheral arterial disease, or significant risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking). Because of this risk, the lowest effective dose should be administered for the shortest possible duration.

Effects of NSAIDs on the kidneys include fluid retention with edema and/or arterial hypertension. Therefore, diclofenac should be used with caution in patients with impaired cardiac function and other conditions predisposing to fluid retention. Caution is also advised in patients receiving concomitant diuretics or angiotensin-converting enzyme (ACE) inhibitors, or those prone to hypovolemia.

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

Outcomes are generally more serious in elderly patients. Caution should be exercised when prescribing the drug to elderly patients. In particular, for frail elderly patients and those with low body weight, the lowest effective doses are recommended. If gastrointestinal bleeding or ulceration occurs in patients receiving Diclofenac-Biolic, treatment should be discontinued.

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

Sodium metabisulfite in the injectable solution may also cause severe hypersensitivity reactions in susceptible individuals.

• Gastrointestinal effects

Cases of gastrointestinal bleeding (hematemesis, melena), ulceration, or perforation have been reported with all NSAIDs, including diclofenac, which may be fatal and can occur at any time during treatment, with or without warning symptoms, and in patients with or without a history of serious gastrointestinal events. These events generally have more serious outcomes 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 disorders or with a history of peptic or intestinal ulcers, gastrointestinal bleeding, or perforation (see section "Adverse reactions"). 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 patients.

Elderly patients have an increased frequency of adverse reactions when using NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal.

To reduce the risk of gastrointestinal toxicity in patients with a history of ulcers (especially 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 (ASA) or other drugs likely to increase gastrointestinal adverse effects, consideration should be given to combination therapy with protective agents (e.g., proton pump inhibitors or misoprostol).

Patients with a history of gastrointestinal toxicity, 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 selective serotonin reuptake inhibitors (SSRIs) (see section "Interaction with other medicinal products and other forms of interaction").

The use of NSAIDs, including diclofenac, may be associated with an increased risk of gastrointestinal anastomotic dehiscence. Careful medical monitoring and caution are recommended when using Diclofenac-Biolic after gastrointestinal surgery.

• Hepatic effects

Close medical supervision is required when Diclofenac-Biolic is administered to patients with impaired liver function, as their condition may worsen (see section "Adverse reactions").

As with other NSAIDs, including diclofenac, one or more liver enzymes may increase. This has been very commonly observed in clinical trials with diclofenac (approximately 15% of patients), but rarely accompanied by clinical symptoms. Most cases involve elevations at the upper limit of normal. Moderate increases (≥ 3 to < 8 times the upper limit of normal) have been frequently observed (in 2.5% of cases), while marked elevations (≥ 8 times the upper limit of normal) occurred in approximately 1% of cases. Clinically evident liver injury occurred in 0.5% of cases in the aforementioned clinical trials. Elevated enzyme concentrations were generally reversible upon discontinuation of the drug. In patients receiving diclofenac, diseases such as hepatitis may progress without prodromal symptoms.

Caution is required when Diclofenac-Biolic is used in patients with hepatic porphyria due to the potential to provoke an attack.

• Renal effects

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

Since fluid retention and edema have been reported 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 significantly affecting renal function, and patients with substantial extracellular fluid volume depletion due to any cause, such as before or after major surgery (see section "Contraindications"). As a precautionary measure, monitoring of renal function is recommended when using Diclofenac-Biolic. Discontinuation of therapy usually leads to reversal of the condition.

• Dermatological effects

Serious skin reactions (some of which were fatal), including exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, generalized bullous fixed drug eruption, and cutaneous drug embolism, also known as Nicolau syndrome (especially after inadvertent subcutaneous injection), have been very rarely reported with diclofenac (see section "Adverse reactions").

Appropriate needle selection and injection technique should be observed during administration of Diclofenac-Biolic (see section "Incompatibilities").

The highest risk of these reactions appears to occur early in treatment, mostly within the first month. Treatment with Diclofenac-Biolic should be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity.

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

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

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

Treatment with Diclofenac-Biolic is generally not recommended in patients with diagnosed cardiovascular diseases (heart failure, ischemic heart disease, peripheral arterial disease) or uncontrolled arterial hypertension. If such treatment is necessary in patients with diagnosed cardiovascular diseases, uncontrolled hypertension, or significant cardiovascular risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking), Diclofenac-Biolic should be prescribed only after careful evaluation and only at doses up to 100 mg daily for treatment courses exceeding 4 weeks.

Since cardiovascular risks of diclofenac may increase with dose and 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, especially when treatment exceeds 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 advice are necessary, as fluid retention and edema have been reported with NSAIDs, including diclofenac.

Clinical and epidemiological data suggest that diclofenac use, particularly at high doses (150 mg/day) and for prolonged periods, may be associated with a small increase in 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 should only be considered after careful benefit-risk assessment and at a dose not exceeding 100 mg daily. A similar assessment should be performed before initiating long-term treatment in patients with risk factors for cardiovascular events (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking).

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

• Hematological effects

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

• Respiratory effects (asthma history)

In patients with bronchial asthma, seasonal allergic rhinitis, nasal mucosal edema (nasal polyps), chronic obstructive pulmonary diseases, or chronic respiratory tract infections (especially those associated with allergic, rhinitis-like symptoms), reactions to NSAIDs resembling asthma exacerbation (so-called analgesic intolerance/analgesic-induced asthma), Quincke's edema, or urticaria occur more frequently than in others. Therefore, special 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.

Particular caution is advised when parenterally administering Diclofenac-Biolic to patients with bronchial asthma, as symptoms may worsen.

Like other drugs 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 Diclofenac-Biolic may impair fertility in women and is not recommended for women attempting to conceive. For women experiencing difficulties with conception or undergoing infertility evaluation, discontinuation of Diclofenac-Biolic should be considered.

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

Use during pregnancy or breastfeeding.

Pregnancy

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%.

Animal studies have shown that prostaglandin synthesis inhibitors increase pre- and post-implantation loss and embryonic/fetal mortality. In addition, increased incidence of various developmental abnormalities, including cardiovascular defects, has been observed in animals treated with prostaglandin synthesis inhibitors during organogenesis.

First/second trimester

Diclofenac-Biolic 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. If Diclofenac-Biolic is used by a woman attempting to conceive or by a pregnant woman during the first or second trimester, the dose should be as low as possible and the duration of treatment as short as possible.

Oligohydramnios / renal dysfunction in newborns / ductus arteriosus constriction

NSAID use from the 20th week of gestation may result in fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse effects are observed on average after several days or weeks of treatment, although in rare cases oligohydramnios developed within 48 hours of starting NSAID therapy. Oligohydramnios often, but not always, resolves after discontinuation of NSAID treatment. Complications of prolonged oligohydramnios may include limb contractures and pulmonary hypoplasia. In some post-marketing clinical reports, neonatal renal impairment required invasive procedures such as exchange transfusion or dialysis.

Additionally, constriction of the ductus arteriosus has been reported after second-trimester treatment, which resolves in most cases after discontinuation of therapy.

If treatment with Diclofenac-Biolic lasts more than 48 hours, ultrasound monitoring of amniotic fluid volume and fetal heart should be considered. In case of oligohydramnios or ductus arteriosus constriction, Diclofenac-Biolic should be discontinued and appropriate management initiated according to clinical practice.

Third trimester

Diclofenac-Biolic is contraindicated during the third trimester of pregnancy.

All prostaglandin synthesis inhibitors may:

• expose the fetus to the following risks:
  • cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
  • renal dysfunction, which may progress to renal failure with oligohydramnios;
• expose the mother and neonate to the following risks:
  • possible prolongation of bleeding time – due to inhibition of platelet aggregation, which may occur even with very low doses; inhibition of uterine contractions, leading to delayed or prolonged labor.

Breastfeeding

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

Fertility

Diclofenac-Biolic may affect female fertility. The drug should not be recommended to women planning pregnancy. Women experiencing conception difficulties or undergoing infertility evaluation should discontinue Diclofenac-Biolic.

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

Ability to influence reaction speed when driving or operating machinery.

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

Method of Administration and Dosage.

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

Adults

The medicinal product Diclofenac-Biolik, solution for injection, should not be used for more than 2 days. If continued treatment is required, therapy may be continued with gastro-resistant tablets or rectal forms of diclofenac.

Intramuscular injection

To prevent nerve or other tissue damage at the site of intramuscular injection, certain instructions must be followed. Such damage may lead to muscle weakness, muscle paralysis, hypoesthesia, and cutaneous drug embolism (Nicolau syndrome).

The usual dose is 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 injection solution may be combined with other diclofenac formulations (e.g., tablets or suppositories) up to a maximum total daily dose of 150 mg of sodium diclofenac.

In the setting of a migraine attack, clinical experience is limited to cases where an initial dose of one 75 mg ampoule is administered, preferably immediately after administration of a 75 mg suppository on the same day (if necessary). The total daily dose should not exceed 150 mg on the first day.

There are no available data on the use of Diclofenac-Biolik for the treatment of migraine attacks for more than one day. If the patient requires further therapy on subsequent days, the maximum daily dose should be up to 150 mg (as divided doses administered in suppository form).

Intravenous infusions

Immediately before starting intravenous infusion, Diclofenac-Biolik should be diluted in 100–500 mL of 0.9% sodium chloride solution or 5% glucose solution. Both solutions should be buffered with sodium bicarbonate solution (0.5 mL of 8.4% solution or 1 mL of 4.2%). Only clear solutions should be used. If crystals or precipitate are present in the solution, it must not be used.

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

Recommended alternative dosing regimens for Diclofenac-Biolik solution for injection:

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

Special patient groups

Elderly patients (65 years and older)

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

Paediatric population (under 18 years)

Diclofenac-Biolik in the form of solution for injection is contraindicated for use in children and adolescents.

Established cardiovascular disease or serious cardiovascular risk factors

Treatment with Diclofenac-Biolik is generally not recommended in patients with cardiovascular disease or uncontrolled arterial hypertension. If necessary, patients with cardiovascular disease, uncontrolled arterial hypertension, or significant cardiovascular risk factors should be treated with Diclofenac-Biolik only after careful assessment and only at doses up to 100 mg per day when treatment duration exceeds 4 weeks (see section "Special precautions").

Renal impairment

Diclofenac-Biolik is contraindicated in patients with renal impairment (GFR < 15 mL/min/1.73 m²; see section "Contraindications").

Specific studies in patients with renal dysfunction have not been conducted; therefore, no dose adjustment recommendations can be made. Diclofenac-Biolik should be used with caution in patients with impaired renal function (see section "Special precautions").

Hepatic impairment

Diclofenac-Biolik is contraindicated in patients with hepatic impairment (see section "Contraindications").

Specific studies in patients with hepatic dysfunction have not been conducted; therefore, no dose adjustment recommendations can be made. Diclofenac-Biolik should be used with caution in patients with mild to moderate hepatic impairment (see section "Special precautions").

Children

Diclofenac-Biolik in the form of solution for injection is contraindicated for use in children and adolescents.

Overdose.

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

Treatment.

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

Specific interventions such as forced diuresis, dialysis, or hemoperfusion cannot reliably eliminate NSAIDs, including diclofenac, due to their high plasma protein binding and extensive metabolism.

Side effects.

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 adverse effects listed below are associated with administration of Diclofenac-Biolik, both during short-term and long-term use.

Infections and infestations: very rare – injection site abscess.

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

Immune system disorders: rare – hypersensitivity, anaphylactic and anaphylactoid reactions (including arterial hypotension and shock); very rare – angioneurotic edema (including facial swelling).

Psychiatric disorders: very rare – confusion, depression, insomnia, nightmares, irritability, and other psychiatric disorders.

Nervous system disorders: common – headache, dizziness; rare – somnolence, fatigue; very rare – paresthesia, memory impairment, convulsions, anxiety, tremor, aseptic meningitis, taste disturbance, stroke; frequency not known – confusion, hallucinations, sensory disturbances, malaise.

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

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

Cardiac disorders: uncommon* – palpitations, chest pain, heart failure, myocardial infarction; frequency not known – Kounis syndrome.

*Frequency reflects data from long-term treatment with high doses (150 mg/day).

Vascular disorders: common – arterial hypertension; very rare – arterial hypotension, vasculitis.

Respiratory, thoracic and mediastinal disorders: rare – asthma (including dyspnea); very rare – pneumonitis, throat irritation, nasal congestion.

Gastrointestinal disorders: common – nausea, vomiting, diarrhea, dyspepsia, abdominal pain; rare – gastritis, gastrointestinal bleeding, vomiting of blood, hemorrhagic diarrhea, melena, gastric or intestinal ulcer (with or without bleeding, gastrointestinal stenosis or perforation (sometimes fatal, especially in elderly patients), which may lead to peritonitis); very rare – colitis (including hemorrhagic colitis, ischemic colitis, and exacerbation of ulcerative colitis or Crohn’s disease), constipation, stomatitis, glossitis, esophageal disorders, intestinal membrane strictures, pancreatitis, belching, dry mouth, epigastric pain.

Hepatobiliary disorders: common – increased transaminase levels; rare – hepatitis, jaundice, liver function abnormalities; very rare – right upper quadrant discomfort, fulminant hepatitis, hepatonecrosis, liver failure.

Skin and subcutaneous tissue disorders: common – skin rashes; rare – urticaria, hyperemia; very rare – bullous eruptions, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), exfoliative dermatitis, alopecia, photosensitivity reaction, purpura, Henoch-Schönlein purpura, pruritus; frequency not known – fixed drug eruption, generalized bullous fixed drug eruption.

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

General disorders and administration site conditions: common – injection site reaction, injection site pain, induration; rare – swelling, necrosis at injection site; very rare – abscess at injection site, hemorrhage, weakness, sweating, fever, chills, pain shock.

Reproductive system disorders: very rare – impotence.

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

Visual disturbances.

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

Adverse reactions reported during post-marketing (frequency not known)

Injection site reactions: cutaneous drug embolism (Nicolau syndrome).

Reporting of adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, or their legal representatives, should report any suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

Reconstituted infusion solutions should be used immediately.

Storage conditions.

Store in a place protected from light at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Incompatibilities.

Generally, Diclofenac-Biolik, solution for injection, should not be mixed with other injectable solutions.

Solutions of 0.9% sodium chloride or 5% glucose for infusion without sodium bicarbonate as an additive pose a risk of supersaturation, which may lead to crystal or precipitate formation. Other infusion solutions not specifically recommended must not be used.

Packaging.

3 ml in ampoules, 5 ampoules per pack.

Prescription status.

Prescription only.

Manufacturer.

LLC "BIOLIK PHARMA".

Manufacturer's address and location of business activity.

Legal entity location:

70 Pomirky, Kharkiv, Kharkiv region, 61070, Ukraine.

Address of business activity:

Pomirky-70, building without number, Kharkiv, Kharkiv region, 61070, Ukraine.