Naklofen

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

Composition:

Active substance: diclofenac;

3 ml of solution (1 ampoule) contains sodium diclofenac – 75 mg;

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

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear solution, colorless to slightly yellow, practically free from mechanical impurities.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Diclofenac. ATC code M01AB05.

Pharmacological Properties

Pharmacodynamics

Naklofen is a non-steroidal agent with pronounced analgesic and anti-inflammatory properties. It is an inhibitor of prostaglandin synthetase (cyclooxygenase). In vitro, diclofenac sodium at concentrations equivalent to those achieved in humans does not suppress proteoglycan synthesis in cartilage tissue. When used concomitantly with opioids to manage postoperative pain, Naklofen significantly reduces the need for opioids.

In rheumatic diseases, the anti-inflammatory and analgesic properties of the drug result in a clinical response characterized by marked reduction in signs and symptoms: pain at rest and during movement, morning stiffness, joint swelling, and improved joint function. In post-traumatic and postoperative conditions associated with inflammation, Naklofen also alleviates pain and swelling.

Pharmacokinetics

Absorption

After intramuscular injection of 75 mg diclofenac, absorption begins immediately, and the mean peak plasma concentration of approximately 2.558±0.968 µg/mL (2.5 µg/mL ≡ 8 µmol/L) is reached within about 20 minutes. The extent of absorption is linearly proportional to the dose administered.

When 75 mg of diclofenac is administered by intravenous infusion over 2 hours, the mean peak plasma concentration is approximately 1.875±0.436 µg/mL (1.9 µg/mL ≡ 5.9 µmol/L). 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. In contrast to oral administration, when the drug is administered as suppositories or by intramuscular injection, plasma concentration decreases rapidly immediately after reaching peak levels.

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 these parenteral routes avoid first-pass hepatic metabolism.

Distribution

Approximately 99.7% of diclofenac is protein-bound, primarily to albumin (99.4%).

Diclofenac penetrates into synovial fluid, where maximum concentration is 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, 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 breastfeeding woman. The estimated amount of drug transferred to the infant via breast milk is equivalent to 0.03 mg/kg/day.

Metabolism

Biological transformation of diclofenac occurs partially through glucuronidation of the intact molecule, but primarily via single and multiple hydroxylations and methoxylations, leading to the formation of several phenolic metabolites, most of which are subsequently converted into glucuronide conjugates. Two of these phenolic metabolites are biologically active, although their activity is considerably weaker than that of diclofenac.

Elimination

Total systemic clearance of diclofenac from plasma is 263±56 mL/min (mean ± SD). The terminal half-life in plasma is 1–2 hours. Four metabolites, including two active ones, also have short plasma half-lives of 1–3 hours. Approximately 60% of the administered dose is excreted in urine as the glucuronide conjugate of the intact molecule and as metabolites, most of which are also converted into glucuronide conjugates. Less than 1% is excreted unchanged. The remainder of the dose is eliminated as metabolites via bile into feces.

Special patient groups

Elderly patients

No differences in absorption, metabolism, or excretion of the drug have been observed related to patient age, except that in five elderly patients, a 15-minute intravenous infusion resulted in a 50% higher plasma concentration compared to 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, in patients with creatinine clearance below 10 mL/min, plasma levels of hydroxymetabolites are approximately four times higher than in healthy volunteers. Nevertheless, these metabolites are ultimately eliminated via bile.

Patients with hepatic disease

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

Clinical characteristics.

Indications.

The drug is indicated for intramuscular administration in the treatment of:

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

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

Contraindications.

• Known hypersensitivity to the active substance, sodium metabisulfite, or any other components of the drug.
• History of gastrointestinal bleeding or perforation associated with previous treatment with nonsteroidal anti-inflammatory drugs (NSAIDs).
• Active peptic ulcer disease/bleeding or recurrent peptic ulcer disease/bleeding in history (two or more separate episodes of confirmed ulcer or bleeding).
• Hepatic failure.
• Renal failure (glomerular filtration rate (GFR) < 15 mL/min/1.73 m²).
• Congestive heart failure (NYHA II–IV).
• Third trimester of pregnancy.
• As with other NSAIDs, diclofenac is contraindicated in patients in whom administration of ibuprofen, acetylsalicylic acid, or other NSAIDs induces attacks of bronchial asthma, angioedema, urticaria, or rhinitis/nasal polyps, or allergy-like symptoms.
• Inflammatory bowel diseases (e.g., Crohn’s disease or ulcerative colitis).
• Acute gastric or intestinal ulcer; gastrointestinal bleeding or perforation.
• High risk of postoperative bleeding, coagulation disorders, hemostatic disorders, hematopoietic disorders, or cerebrovascular bleeding.
• Management of perioperative pain in coronary artery bypass graft (CABG) surgery (or use of cardiopulmonary bypass).
• Ischemic heart disease in patients with angina pectoris or history of myocardial infarction.
• Cerebrovascular diseases in patients with history of stroke or transient ischemic attacks.
• Peripheral arterial disease.

This medicinal form is contraindicated in children.

For intravenous use only.

• Concomitant use of NSAIDs or anticoagulants (including low-dose heparin).
• History of hemorrhagic diathesis, confirmed or suspected cerebrovascular bleeding in 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 from any cause.

Interaction with other medicinal products and other forms of interactions.

The interactions listed below have been observed with the use of Naclofen, injection solution, and/or other medicinal forms of diclofenac.

Litium: Concurrent use of diclofenac may increase plasma lithium concentrations. Monitoring of serum lithium levels is recommended.

Digoxin: Concurrent use of 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 or antihypertensive agents (e.g., beta-blockers, angiotensin-converting enzyme (ACE) inhibitors) may reduce their antihypertensive effect due to inhibition of vasodilatory prostaglandin synthesis. Therefore, such combinations should be used with caution, and patients, especially elderly ones, should be closely monitored for blood pressure. Adequate hydration should be ensured, and monitoring of renal function is recommended at the start of concomitant therapy and regularly thereafter, 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 treatment with potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may increase serum potassium levels; therefore, more frequent monitoring of patients is recommended.

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

Anticoagulants and antithrombotic agents. Precautions are recommended, as concomitant administration may increase the risk of bleeding. Although clinical studies do not indicate an effect of diclofenac on anticoagulant activity, there are individual reports of increased bleeding risk in patients receiving diclofenac and anticoagulants simultaneously.

Therefore, careful monitoring of patients receiving diclofenac and anticoagulants is recommended, and dose adjustment of anticoagulants may be necessary if required. As with other NSAIDs, diclofenac at high doses may temporarily inhibit platelet aggregation.

Selective serotonin reuptake inhibitors (SSRIs). Concomitant administration of systemic NSAIDs and SSRIs may increase 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, individual cases of both hypoglycemic and hyperglycemic effects have been reported, requiring dose adjustments of antidiabetic agents during diclofenac treatment. Such conditions require monitoring of blood glucose levels as a precaution during concomitant therapy.

There are also isolated reports of metabolic acidosis with concomitant use of diclofenac, particularly in patients with pre-existing renal impairment.

Cholestyramine and colestipol. These agents may delay or reduce absorption of diclofenac. Therefore, it is recommended to administer diclofenac at least 1 hour before or 4–6 hours after cholestyramine/colestipol.

Methotrexate. Diclofenac may inhibit methotrexate clearance in renal tubules, leading to increased methotrexate levels. Caution is advised when prescribing NSAIDs, including diclofenac, less than 24 hours before methotrexate administration, as this may increase methotrexate blood concentration and enhance its toxicity. Serious toxicity cases have been reported when methotrexate and NSAIDs, including diclofenac, were administered within 24 hours of each other. This interaction is mediated by methotrexate accumulation due to impaired renal excretion in the presence of NSAIDs.

Cyclosporine. Diclofenac, as with other NSAIDs, may increase cyclosporine nephrotoxicity through effects on renal prostaglandins. Therefore, diclofenac should be administered at lower doses in patients receiving cyclosporine compared to those not receiving cyclosporine.

Tacrolimus. Concomitant use of NSAIDs with tacrolimus may increase the risk of nephrotoxicity, possibly mediated by renal anti-prostaglandin effects of NSAIDs and calcineurin inhibitors; therefore, diclofenac should be administered at lower doses in patients receiving tacrolimus compared to those not receiving tacrolimus.

Quinolone antibiotics. There are isolated reports of seizures possibly resulting from concomitant use of quinolones and NSAIDs. This may occur in patients both with and without history of epilepsy or seizures. Therefore, caution should be exercised when considering quinolone use in patients already receiving NSAIDs.

Phenytoin. When phenytoin is administered concurrently 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 GFR, and increase plasma glycoside levels.

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

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

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

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

Special precautions for use.

General

Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control (alleviate) symptoms (see section "Dosage and administration" and gastrointestinal and cardiovascular risks below).

Concomitant use of Naclofen with systemic NSAIDs, including selective COX-2 inhibitors, should be avoided due to lack of any synergistic benefit and the potential for additional adverse effects (see section "Interaction with other medicinal products and other forms of interaction").

Caution should be exercised when prescribing diclofenac to patients aged 65 years and older. In particular, lower effective doses are recommended for elderly patients with poor general health and those with low body weight.

Use of NSAIDs, including diclofenac, may be associated with an increased risk of gastrointestinal anastomotic bleeding. Careful medical monitoring and caution are recommended when prescribing diclofenac after gastrointestinal surgery.

Renal effects of NSAIDs include fluid retention with edema and/or hypertension. Therefore, diclofenac should be used with caution in patients with cardiac dysfunction 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.

In rare cases, as with other NSAIDs, allergic reactions including anaphylactic/anaphylactoid reactions may occur, even without prior exposure to diclofenac. Hypersensitivity reactions may also progress to Kounis syndrome, a serious allergic reaction that may lead to myocardial infarction. Symptoms of such reactions may include chest pain occurring in combination with an allergic reaction to diclofenac.

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

Injection site reactions

Strict adherence to instructions for intramuscular injection is essential to avoid adverse reactions at the injection site, which may lead to muscle weakness, paralysis, hypoesthesia, skin embolism (Nicolau syndrome), and necrosis at the injection site.

Cases of injection site reactions have been reported following intramuscular administration of diclofenac, including necrosis at the injection site and medication-induced skin embolism, also known as Nicolau syndrome (particularly after inadvertent subcutaneous injection). Appropriate needle size and injection technique should be used for intramuscular administration of diclofenac.

Gastrointestinal effects

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

As with all NSAIDs, including diclofenac, careful medical monitoring is required; particular caution should be exercised when prescribing diclofenac to patients with symptoms suggesting gastrointestinal disorders or with a history of peptic ulcer, gastrointestinal bleeding, or perforation (see section "Undesirable effects"). The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, including diclofenac, and in patients with a history of peptic ulcer, especially 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 peptic ulcer, especially complicated by bleeding or perforation, and in elderly patients, treatment should be initiated and maintained at the lowest effective doses.

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, especially elderly patients, should report any unusual abdominal symptoms (particularly gastrointestinal bleeding).

Caution is also required for patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants (e.g., warfarin), antiplatelet agents (e.g., ASA), or SSRIs (see section "Interaction with other medicinal products and other forms of interaction").

Careful medical monitoring and special caution are required when prescribing diclofenac to patients with ulcerative colitis or Crohn's disease, as their condition may worsen.

Cardiovascular and cerebrovascular effects

Appropriate monitoring and consultation are required for patients with a history of hypertension and/or moderate heart failure, as fluid retention and edema have been reported with NSAID use, including diclofenac.

Clinical trial data and epidemiological evidence suggest that the use of diclofenac, particularly at high doses (150 mg/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). The need for diclofenac use for symptom relief and response to therapy should be periodically reviewed, especially if treatment duration exceeds 4 weeks.

Diclofenac may be prescribed to patients with significant cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes, smoking) only after careful clinical assessment. 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 need for diclofenac use for symptom relief and response to therapy should be periodically reviewed. Use with caution in patients aged 65 years and older.

Diclofenac is not recommended for patients with uncontrolled hypertension, congestive heart failure, stable ischemic heart disease, peripheral artery disease, and/or cerebrovascular disease. If use is necessary, it should only be considered after careful risk/benefit assessment and at doses 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 need to monitor for symptoms of serious arterial thromboembolic events (chest pain, dyspnea, weakness, speech disturbances), which may occur without warning. In case of such an event, patients should seek immediate medical attention.

Effects on hematological parameters

With prolonged use of diclofenac, as with other NSAIDs, monitoring of complete blood count is recommended.

Like other NSAIDs, Naclofen may temporarily inhibit platelet aggregation. Careful monitoring is required in patients with coagulation disorders, hemorrhagic diathesis, or hematological disorders.

Hepatic effects

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

During NSAID use, including diclofenac, levels of one or more liver enzymes may increase. As a precautionary measure, regular monitoring of liver function is recommended 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), diclofenac should be discontinued.

In addition to elevated liver enzymes, rare cases of severe hepatic reactions have been reported, including jaundice and fulminant hepatitis, liver necrosis, and hepatic failure, some of which have resulted in fatal outcomes.

In patients receiving diclofenac, conditions such as hepatitis may progress without prodromal symptoms.

Caution is required when diclofenac 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 leads to edema and hypertension.

Since fluid retention and edema have been reported during treatment with NSAIDs, including diclofenac, special attention should be paid to patients with impaired cardiac or renal function, a history of hypertension, elderly patients, patients receiving concomitant diuretic therapy or drugs that significantly affect renal function, and patients with significant reduction in extracellular fluid volume for any reason, e.g., before or after major surgery (see section "Undesirable effects"). In such cases, monitoring of renal function is recommended as a precautionary measure. Discontinuation of therapy usually leads to return to the pre-treatment state.

Skin and subcutaneous tissue disorders

Serious skin reactions (some of which have been fatal) have been very rarely reported with diclofenac use, including exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and generalized bullous fixed drug eruption (see section "Undesirable effects"). The highest risk of these reactions appears to occur early in the course of therapy, in most cases within the first month of treatment.

Diclofenac therapy 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 disorders

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

History of asthma

Patients with 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) are more likely than others to experience NSAID reactions resembling asthma exacerbation (so-called analgesic intolerance/analgesic-induced asthma), Quincke's edema, or urticaria. Therefore, special precautionary measures (readiness for emergency intervention) are recommended for such patients. This also applies to patients with allergic reactions to other substances manifesting as skin reactions, pruritus, or urticaria.

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.

Special warnings regarding inactive ingredients

Benzyl alcohol: Do not use in premature infants and newborns. May cause toxic and allergic reactions in infants and children under 3 years of age.

Metabisulfites: May cause allergic-type reactions, including anaphylactic symptoms and bronchospasm in susceptible individuals, especially those with a history of asthma and allergy.

Sodium: Contains less than 1 mmol (23 mg) sodium per dose, i.e., practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

Diclofenac should not be used in women planning pregnancy or during the first and second trimesters of pregnancy unless absolutely necessary. From the 20th week of pregnancy, use of diclofenac may cause oligohydramnios due to fetal renal dysfunction. This condition may occur soon after initiation of treatment and is usually reversible upon discontinuation of therapy. Additionally, cases of ductus arteriosus constriction have been reported after treatment in the second trimester, most of which resolved after discontinuation of treatment. Therefore, during the first and second trimesters of pregnancy, diclofenac should be prescribed only when the expected benefit to the mother outweighs the potential risk to the fetus, and only at the lowest effective dose; treatment duration should be as short as possible.

Prenatal monitoring for oligohydramnios and ductus arteriosus constriction may be advisable after diclofenac exposure for several days starting from the 20th week of pregnancy. If oligohydramnios or ductus arteriosus constriction is detected, diclofenac should be discontinued.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage and/or risk of cardiac defects and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular defects increased from less than 1% to approximately 1.5%.

The risk may increase with dose and duration of treatment. In animal studies, administration of a prostaglandin synthesis inhibitor resulted in increased pre- and post-implantation loss and embryonic/fetal mortality.

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

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

• cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure with oligohydramnios (see above);

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

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

Therefore, Naclofen is contraindicated during the third trimester of pregnancy.

Breastfeeding period

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

Fertility

Like other NSAIDs, diclofenac may negatively affect female fertility and therefore is not recommended for women planning pregnancy. For women experiencing infertility or undergoing fertility investigations, discontinuation of diclofenac should be considered.

Based on 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, central nervous system disorders, lethargy, or fatigue during treatment with Naclofen should not drive or operate machinery.

Method of Administration and Dosage

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

Naklofen, solution for injection, should not be administered for more than 2 days. If continued treatment is necessary, it may be continued with Naklofen in another pharmaceutical form (tablets or suppositories).

Intramuscular Injection

To prevent nerve or other tissue damage at the site of intramuscular injection, the following guidelines must be observed.

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 (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 to the 75 mg injection solution, it may be combined with other pharmaceutical forms of Naklofen (e.g., tablets or suppositories) up to a maximum total daily dose of 150 mg of diclofenac.

In the treatment of migraine attacks, clinical experience is limited to cases where an initial dose of 1 ampoule of 75 mg is administered, followed, if possible, by the use of 100 mg suppositories on the same day (if necessary). The total daily dose should not exceed 175 mg on the first day.

There are no available data on the use of Naklofen for the treatment of migraine attacks for more than 1 day.

Intravenous Infusion

Immediately before starting intravenous infusion, Naklofen 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% solution). Only clear solutions should be used.

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

Two alternative dosing regimens are recommended for Naklofen, solution for injection:

• For the treatment of moderate to severe postoperative pain, administer 75 mg solution continuously over 30 minutes to 2 hours; if necessary, treatment may be repeated after 4–6 hours, but the daily dose must not exceed 150 mg;
• For prophylaxis of postoperative pain, administer a loading dose of 25–50 mg 15 minutes to 1 hour after surgery, followed by continuous infusion of approximately 5 mg/hour, up to a maximum daily dose of 150 mg.

Elderly Patients

Although the pharmacokinetics of diclofenac in elderly patients is not impaired to a clinically significant extent, NSAIDs should be used with particular caution in such patients, 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, and patients should be monitored for gastrointestinal bleeding during NSAID therapy (see section "Special Warnings and Precautions for Use").

The recommended maximum daily dose of Naklofen is 150 mg.

Cardiovascular Disease or Significant Risk Factors

Diclofenac is contraindicated in patients with established congestive heart failure, ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease (see section "Contraindications").

Diclofenac should be prescribed to patients with congestive heart failure or significant cardiovascular risk factors 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 (see section "Special Warnings and Precautions for Use").

Renal Impairment

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

No specific studies have been conducted in patients with hepatic impairment; therefore, dose adjustment recommendations cannot be provided. Diclofenac should be used with caution in patients with mild to moderate renal impairment (see section "Special Warnings and Precautions for Use").

Hepatic Impairment

The use of diclofenac is contraindicated in patients with hepatic insufficiency (see section "Contraindications").

No specific studies have been conducted in patients with hepatic impairment; therefore, dose adjustment recommendations cannot be provided. Diclofenac should be used with caution in patients with mild to moderate hepatic impairment (see section "Special Warnings and Precautions for Use").

It is not recommended to mix the drug with other medicinal products in the same syringe.

Children

Naklofen in the form of solution for injection is contraindicated for use in children.

Overdose

Symptoms. There is no typical clinical picture specific to diclofenac overdose. Overdose may cause symptoms such as headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, diarrhea, dizziness, disorientation, excitation, coma, drowsiness, tinnitus, loss of consciousness, or convulsions. In severe poisoning, acute renal failure and liver damage may occur.

Treatment. Treatment is symptomatic. Supportive measures and symptomatic therapy should be initiated for complications such as arterial hypotension, renal failure, convulsions, gastrointestinal disorders, and respiratory depression.

Specific interventions such as forced diuresis, dialysis, or hemoperfusion are unlikely to be effective in eliminating NSAIDs, including diclofenac, from the body due to their high protein binding and extensive metabolism.

Within 1 hour after ingestion of a potentially toxic amount of the drug orally, administration of activated charcoal should be considered. Additionally, in adults, gastric lavage should be considered within 1 hour after ingestion of a potentially toxic amount. In cases of frequent or prolonged convulsions, intravenous diazepam should be administered. Other measures may be indicated depending on the patient's clinical condition.

Adverse reactions.

Adverse effects that may occur during the use of diclofenac are classified into the following groups according to their frequency: very common > 1/10; common > 1/100, < 1/10; uncommon > 1/1000, < 1/100; rare > 1/10000, < 1/1000; very rare < 1/10000; frequency not known (cannot be estimated from the available data).

The undesirable effects listed below include those associated with both short-term and long-term use.

Blood and lymphatic system disorders:

• very rare: thrombocytopenia, leukopenia, anaemia (including haemolytic and aplastic anaemias), agranulocytosis.

Immune system disorders:

• rare: hypersensitivity, anaphylactic and anaphylactoid reactions (including arterial hypotension and shock);
• very rare: angioedema (including facial swelling).

Psychiatric disorders:

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

Nervous system disorders:

• common: headache, dizziness;
• rare: somnolence, fatigue;
• very rare: paraesthesia, memory impairment, convulsions, anxiety, tremor, aseptic meningitis, taste disturbances, cerebral ischaemia;
• 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 reflects data from long-term treatment with high doses (150 mg/day).

• frequency not known: Quincke's syndrome.

Vascular disorders:

• common: arterial hypertension;
• very rare: arterial hypotension, vasculitis.

Respiratory, thoracic and mediastinal disorders:

• rare: asthma (including dyspnoea);
• very rare: pneumonitis.

Gastrointestinal disorders:

• common: nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, anorexia;
• rare: gastritis, gastrointestinal haemorrhage, vomiting blood, haemorrhagic diarrhoea, melaena, peptic ulcer with or without bleeding or perforation, gastrointestinal stricture or perforation (sometimes fatal, especially in elderly patients), which may lead to peritonitis;
• very rare: colitis (including haemorrhagic colitis and exacerbation of ulcerative colitis or Crohn's disease), constipation, stomatitis, glossitis, oesophageal disorders, intestinal membrane strictures, pancreatitis;
• frequency not known: ischaemic colitis.

Hepatobiliary disorders:

• common: increased transaminase levels;
• rare: hepatitis, jaundice, liver function abnormalities;
• very rare: fulminant hepatitis, hepatonecrosis, liver failure.

Skin and subcutaneous tissue disorders:

• common: rash;
• rare: urticaria;
• very rare: bullous rash, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), exfoliative dermatitis, alopecia, photosensitivity reaction, purpura (including allergic purpura), Schönlein-Henoch purpura, pruritus;
• frequency not known: fixed drug eruption, generalized bullous fixed drug eruption.

Renal and urinary disorders:

• common: fluid retention and oedema;
• very rare: acute renal failure, haematuria, proteinuria, nephrotic syndrome, tubulointerstitial nephritis, renal papillary necrosis.

General disorders and administration site conditions:

• common: injection site reaction, pain, induration;
• rare: swelling, necrosis at injection site;
• very rare: abscess at injection site;
• frequency not known: cutaneous medication embolism (Nicolau syndrome).

Reproductive system and breast disorders:

• very rare: impotence.

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

Visual disturbances

Visual disturbances such as visual impairment, worsening of vision, 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 synthesis and other related compounds, which disrupt retinal blood flow regulation and contribute to the development of visual disturbances. If such symptoms occur during treatment with diclofenac, an ophthalmological examination should be performed to rule out other possible causes.

If serious adverse reactions occur, treatment should be discontinued.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after a medicinal product is authorised is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 5 years.

Storage conditions. Store at temperatures not exceeding 25 °C in the original packaging to protect from light. Keep out of reach of children.

Incompatibilities. It is not recommended to mix the medicinal product with other medicinal products in the same syringe.

Packaging.

3 ml in an ampoule; 5 ampoules in a blister; 1 blister in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto / KRKA, d.d., Novo mesto.

Manufacturer's address and location of operations.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.