INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ALMIRAL® (ALMIRAL)

Composition:

Active substance: diclofenac;

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

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

Pharmaceutical form. Solution for injection.

Main physicochemical characteristics: clear, colorless or slightly yellowish solution.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Acetic acid derivatives and related compounds. ATC code M01AB05.

Pharmacological properties.

Pharmacodynamics.

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

Pharmacokinetics.

Absorption.

After administration of 75 mg diclofenac by intramuscular injection, absorption begins immediately, and the mean peak plasma concentration of approximately 2.558±0.968 µg/mL (2.5 µg/mL ≡ 8 micromol/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 micromol/L). Shorter infusion durations result in higher peak plasma concentrations, while longer infusions lead to a concentration plateau proportional to the infusion rate after 3–4 hours. In contrast to the corresponding results following oral administration, when the drug is administered as suppositories or by intramuscular injection, plasma concentration declines 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 that after oral or rectal administration, because these parenteral routes avoid first-pass hepatic metabolism.

Distribution.

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

Diclofenac penetrates into synovial fluid, where maximum concentration is achieved 2–4 hours after the peak plasma level. The expected half-life in synovial fluid is 3 to 6 hours. Two hours after the peak plasma concentration is reached, 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.

Biotransformation of diclofenac occurs partially via glucuronidation of the intact molecule, but mainly through single and multiple hydroxylations and methoxylations, leading to the formation of several phenolic metabolites, most of which are further 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 value ± 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 is eliminated as metabolites via bile into feces.

Special patient groups.

Elderly patients. No differences in absorption, metabolism, or excretion of the drug related to patient age have been observed, 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. In patients with impaired renal function, accumulation of unchanged active substance is not expected under normal dosing regimens, based on the drug's kinetics after single administration. However, when creatinine clearance is less than 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 pharmacokinetics and metabolism of diclofenac are similar to those in patients without liver disease.

Clinical characteristics.

Indications.

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

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

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

Contraindications.

Known hypersensitivity to the active substance, sodium metabisulfite, or any other component of the medicinal product;
History of gastrointestinal bleeding or perforation related to previous treatment with nonsteroidal anti-inflammatory drugs (NSAIDs);
Active peptic ulcer/hemorrhage, or recurrent peptic ulcer/hemorrhage in history (two or more distinct episodes of confirmed ulcer or bleeding);
Third trimester of pregnancy;
As with other NSAIDs, diclofenac is contraindicated in patients in whom administration of ibuprofen, acetylsalicylic acid, or other nonsteroidal anti-inflammatory agents triggers attacks of bronchial asthma, angioedema, urticaria, or acute rhinitis;
Inflammatory bowel diseases (e.g., Crohn's disease or ulcerative colitis);
Hepatic failure;
Renal failure (creatinine clearance <15 mL/min/1.73 m²);
Congestive heart failure (NYHA II–IV);
High risk of postoperative bleeding, coagulation disorders, hemostatic disturbances, hematopoietic disorders, or cerebrovascular hemorrhage;
Treatment of perioperative pain in coronary artery bypass graft (CABG) surgery (or use of cardiopulmonary bypass);
Ischemic heart disease in patients with angina pectoris or history of myocardial infarction;
Cerebrovascular diseases in patients with history of stroke or transient ischemic attacks (TIAs);
Peripheral arterial disease.

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

Only regarding intravenous use.

Concomitant use of NSAIDs or anticoagulants (including low-dose heparin).
History of hemorrhagic diathesis, confirmed or suspected history of cerebrovascular hemorrhage.
Surgical procedures associated with high risk of bleeding.
History of bronchial asthma.
Moderate or severe impairment of renal function (serum creatinine >160 µmol/L).
Hypovolemia or dehydration of any etiology.

Interaction with other medicinal products and other forms of interactions.

The interactions listed below have been observed during administration of injectable solution and/or other pharmaceutical forms of diclofenac.

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

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

Diuretics and antihypertensive agents. As with other NSAIDs, concomitant use of diclofenac with diuretics and 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 renal function should be monitored after initiation of concomitant therapy and regularly thereafter, particularly when diuretics and ACE inhibitors are used, due to increased risk of nephrotoxicity.

Medicinal products known to cause hyperkalemia. Concomitant use of potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may lead to increased serum potassium levels; therefore, more frequent monitoring of patients is recommended.

Anticoagulants and antithrombotic agents. Precaution is advised, as concomitant administration may increase the risk of bleeding. Although no effect of diclofenac on anticoagulant activity has been demonstrated, there are isolated reports of increased bleeding risk in patients receiving diclofenac and anticoagulants simultaneously.

Therefore, to ensure that no dosage adjustments of anticoagulants are required, careful monitoring of such patients is recommended. Like other NSAIDs, diclofenac at high doses may transiently inhibit platelet aggregation.

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

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, isolated cases of both hypoglycemic and hyperglycemic effects have been reported, requiring dosage adjustments of antidiabetic agents during diclofenac treatment. In such cases, blood glucose monitoring is necessary as a precautionary measure during concomitant therapy.

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

Methotrexate. Diclofenac may inhibit renal tubular clearance of methotrexate, leading to elevated methotrexate levels. Caution is recommended when administering NSAIDs, including diclofenac, within 24 hours before or after methotrexate therapy, as this may increase methotrexate plasma concentrations and enhance its toxicity. Serious cases of toxicity 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, like other NSAIDs, may increase cyclosporine nephrotoxicity by affecting renal prostaglandins. Therefore, it should be administered at lower doses than in patients 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 inhibition.

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

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

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

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

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

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

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

Special precautions for use.

General.

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

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

Caution is advised when prescribing the drug to elderly patients. In particular, for elderly patients with frail health or those with low body weight, the lowest effective doses are recommended.

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

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 combination with an allergic reaction to diclofenac.

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

Sodium metabisulfite in the injectable solution may also cause rare but severe hypersensitivity reactions and bronchospasm.

Strict adherence to intramuscular injection guidelines is essential to avoid local adverse reactions that may lead to muscle weakness, muscular paralysis, hypoesthesia, medication embolism (Nicolau syndrome), and injection site necrosis.

Reactions at the injection site.

Reactions at the injection site have been reported following intramuscular administration of diclofenac, including necrosis at the injection site and medication embolism, also known as Nicolau syndrome (particularly after inadvertent subcutaneous injection). When administering diclofenac intramuscularly, appropriate needle selection and injection technique must be followed (see section "Dosage and administration").

Gastrointestinal effects.

Gastrointestinal bleeding (hematemesis, melena), ulceration, and perforation have been reported with all NSAIDs, including diclofenac, and may be fatal. These events may occur at any time during treatment, with or without warning symptoms, and have been observed in patients with or without a history of gastrointestinal disorders. These events are usually more serious 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 suggestive of gastrointestinal disorders or with a history of peptic ulcer, gastrointestinal bleeding, or perforation. The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher doses of NSAIDs, including diclofenac, and in patients with a history of 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 ulcer, 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, 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., acetylsalicylic acid), or selective serotonin reuptake inhibitors.

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

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

Hepatic effects.

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

As with other NSAIDs, including diclofenac, levels of one or more liver enzymes may increase. As a precautionary measure, regular monitoring of liver function is recommended during long-term treatment with Almiral**®**.

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), Almiral**®** should be discontinued.

Conditions such as hepatitis may progress without prodromal symptoms.

Caution is required when Almiral**®** is used in patients with hepatic porphyria due to the potential to provoke an attack.

Renal effects.

Fluid retention and edema have been reported with NSAIDs, including diclofenac. Particular attention should be paid to patients with impaired cardiac or renal function, a history of hypertension, elderly patients, those receiving concomitant diuretic therapy or drugs that significantly affect renal function, and patients with significant extracellular fluid volume depletion due to any cause (e.g., before or after major surgery). In such cases, renal function should be monitored as a precautionary measure. Discontinuation of therapy usually leads to reversal of these effects.

Skin reactions.

Serious skin reactions (some of which have been fatal), including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been very rarely reported with NSAIDs, including diclofenac. The highest risk of these reactions appears to be early in treatment, most often within the first month. Almiral**®** should be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity.

Systemic lupus erythematosus (SLE) and mixed connective tissue diseases.

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

Cardiovascular and cerebrovascular effects.

Diclofenac may be prescribed to patients with significant cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes, smoking) only after careful clinical evaluation. Since cardiovascular risks of diclofenac may increase with dose and duration of treatment, it should be used for the shortest possible duration and at the lowest effective dose. The need for diclofenac and the patient’s response to therapy should be periodically reviewed. Use with caution in patients aged 65 years and older.

Appropriate monitoring and advice are necessary for patients with a history of mild or moderate hypertension and/or congestive heart failure, as fluid retention and edema have been reported with NSAIDs, including diclofenac.

Use of diclofenac, especially at high doses (150 mg/day) and for prolonged periods, may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

Diclofenac is not recommended for patients with uncontrolled hypertension, congestive heart failure, stable ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. If use is necessary, it should only be considered after careful risk-benefit assessment and at a dose 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., hypertension, hyperlipidemia, diabetes, smoking).

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

Hematological effects.

Blood monitoring is recommended during long-term use of the drug, as with other NSAIDs.

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

History of asthma.

Patients with bronchial asthma, seasonal allergic rhinitis, nasal mucosal swelling (nasal polyps), chronic obstructive lung diseases, or chronic respiratory tract infections (especially those associated with allergic, rhinitis-like symptoms) are more likely than others to experience NSAID-related 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 allergies to other substances manifesting as skin reactions, itching, 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.

Female fertility.

Use of Almiral**®** may impair fertility in women and is not recommended for women wishing to conceive. For women experiencing difficulties with conception or undergoing infertility evaluation, discontinuation of Almiral**®** should be considered.

Use during pregnancy or breastfeeding.

Pregnancy

Almiral**®** 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, at the lowest effective dose, and for the shortest possible duration. As with other NSAIDs, the drug is contraindicated in the third trimester of pregnancy (due to possible inhibition of uterine contractility and premature closure of the fetal ductus arteriosus).

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data suggest an increased risk of miscarriage and/or congenital heart defects and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increases from less than 1% to approximately 1.5%. The risk may increase with higher doses and longer duration of treatment. Animal studies have shown that prostaglandin synthesis inhibitors increase pre- and post-implantation loss and embryonic/fetal mortality. Furthermore, increased incidence of various developmental abnormalities, including cardiovascular, has been observed in animals treated with prostaglandin synthesis inhibitors during organogenesis.

Starting from the 20th week of pregnancy, diclofenac use may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation. If diclofenac is used in women planning pregnancy or during the first trimester, the dose should be as low as possible and the duration as short as possible. Fetal monitoring for oligohydramnios should be considered after several days of diclofenac exposure starting from the 20th week of pregnancy. Diclofenac should be discontinued if oligohydramnios is detected.

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

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

In the mother and newborn, especially near term:

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, Almiral**®** is contraindicated in the third trimester of pregnancy.

Lactation. Like other NSAIDs, diclofenac passes into breast milk in small amounts. To avoid potential adverse effects on the infant, Almiral**®** should not be used during breastfeeding.

Fertility. As with other NSAIDs, Almiral**®** may affect female fertility. The drug should not be recommended to women planning pregnancy. Women experiencing difficulties with conception or undergoing infertility evaluation should discontinue use of Almiral**®**.

Ability to influence reaction rate when driving or operating machinery.

Patients who experience visual disturbances, dizziness, vertigo, somnolence, or other central nervous system effects during treatment with Almiral**®** should refrain from driving or operating machinery.

Method of Administration and Dosage.

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

Adults

Almiral**®**, solution for injection, should not be used for more than 2 days. If continued treatment is needed, it can be continued with diclofenac tablets or suppositories.

Intramuscular injection

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

The usual dose is 75 mg (1 ampoule) per day, administered by deep injection into the upper outer quadrant of the gluteal 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, 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 diclofenac sodium.

In the case of a migraine attack, clinical experience is limited to cases where an initial dose of 1 ampoule of 75 mg is administered, preferably immediately after using a 100 mg suppository 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 Almiral**®** for the treatment of migraine attacks for more than one day.

Intravenous infusions

Immediately before starting intravenous infusion, Almiral**®** should be diluted in 100–500 ml of 0.9% sodium chloride solution or 5% glucose solution. Both solutions must 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.

Almiral**®**, solution for injection, must not be administered as an intravenous bolus injection.

Recommended alternative dosing regimens for Almiral**®**, 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 4–6 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.

Elderly patients

Although the pharmacokinetics of Almiral**®** are not significantly altered in elderly patients, NSAIDs should be used with particular caution in this population, as they are generally more susceptible to adverse reactions. In particular, the lowest effective doses are recommended for frail elderly patients or those with low body weight (see also section "Special precautions"); also, patients should be monitored for gastrointestinal bleeding during NSAID therapy.

The recommended maximum daily dose of Almiral**®** is 150 mg.

Children

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

Overdose.

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

Treatment.

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, diazepam should be administered intravenously. Other measures may be indicated depending on the patient's clinical condition. Treatment is symptomatic.

Adverse Reactions

Adverse reactions to the medicinal product are listed according to 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 available data).

The adverse effects listed below are those associated with administration of Almirel**®** during both short-term and long-term use.

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

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

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

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

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

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

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

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

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, hair loss, photosensitivity reaction, purpura, allergic purpura, pruritus.

Renal and urinary disorders: very rare – acute kidney injury (acute renal failure), hematuria, proteinuria, nephrotic syndrome, interstitial nephritis, renal papillary necrosis.

General disorders and administration site conditions: common – injection site reaction, pain, induration; rare – swelling; frequency not known – necrosis at injection site; very rare – abscess at injection site; frequency not known – medication embolism (Nicolau syndrome).

Reproductive system and breast disorders: very rare – impotence.

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

Visual disturbances

Visual disturbances such as blurred vision, impaired vision, and diplopia are adverse effects associated with NSAID use and are usually reversible upon discontinuation of the drug. The most likely mechanism of visual disturbances is inhibition of prostaglandin and other related compound synthesis, which may disrupt regulation of retinal blood flow and contribute to the development of visual disorders. If such symptoms occur during diclofenac treatment, an ophthalmological examination should be performed to exclude other possible causes.

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

Shelf life. 3 years.

Storage conditions. Store at a temperature not exceeding 25 °C in the original packaging, in a place inaccessible to children.

Incompatibilities. Almirel**®**, solution for injection, must not be mixed with other injectable solutions.

Packaging. Ampoules of 75 mg/3 ml: 5 ampoules in a blister pack, 1 or 2 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Medocemie Limited / Medochemie Limited.

Manufacturer's address and place of business.
Agios Athanassios Industrial Area, Iapetou 48, Limassol, 4101, Cyprus /
Agios Athanassios Industrial Area, Iapetou 48, Limassol, 4101, Cyprus.

Almiral®