Diclofenac-pharmex

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

Composition:

Active substance: diclofenac;

1 suppository contains 100 mg of sodium diclofenac (calculated as 100% dry substance);

Excipient: hard fat.

Pharmaceutical form. Rectal suppositories.

Main physicochemical characteristics: suppositories with smooth surface, white or almost white, of uniform consistency. The presence of a funnel-shaped depression and an air channel is permissible.

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

Pharmacological Properties

Pharmacodynamics.

Diclofenac sodium is a nonsteroidal anti-inflammatory agent with pronounced analgesic and anti-inflammatory effects. It is an inhibitor of prostaglandin synthetase (cyclooxygenase).

Pharmacokinetics.

Absorption. Absorption is rapid, but slower than with enteric-coated tablets.

After administration of 50 mg diclofenac sodium suppositories, the concentration per dose unit is approximately 2/3 of that achieved after administration of enteric-coated tablets [1.95 + 0.8 μg/mL (1.9 μg/mL = 5.9 μmol/L)].

Bioavailability. As with oral dosage forms of the drug, the area under the concentration-time curve (AUC) is approximately half of that obtained after parenteral administration. After repeated administration, the pharmacokinetics of the drug do not change. No accumulation occurs under recommended dosing regimens.

Distribution. Diclofenac binding to plasma proteins is 99.7%, primarily to albumin – 99.4%.

Diclofenac penetrates into synovial fluid, where its maximum concentration is reached 2–4 hours later than in blood plasma. The apparent half-life from synovial fluid is 3–6 hours. Two hours after peak plasma concentrations are reached, diclofenac concentration in synovial fluid remains higher than in plasma; this phenomenon persists for up to 12 hours.

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

Metabolism. Diclofenac is partially metabolized via glucuronidation of the unchanged molecule, but primarily through single and multiple hydroxylation and methoxylation, leading to the formation of several phenolic metabolites, most of which form conjugates with glucuronic acid. Two of these phenolic metabolites are biologically active, but significantly less so than diclofenac.

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

Pharmacokinetics in specific patient populations. No significant effect of patient age on absorption, metabolism, or elimination of the drug has been observed, except that in five elderly patients, a 15-minute intravenous infusion resulted in a 50% higher plasma concentration of the drug than expected in young healthy volunteers.

In patients with impaired renal function receiving therapeutic doses, accumulation of unchanged active substance is not expected based on the drug's kinetics after single administration. In patients with creatinine clearance less than 10 mL/min, calculated steady-state concentrations of hydroxylated metabolites in plasma were approximately four times higher than in healthy volunteers. However, ultimately, all metabolites were excreted via bile.

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

Clinical characteristics.

Indications.

Inflammatory and degenerative forms of rheumatism: rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, including spondyloarthritis.

Spinal pain syndromes.

Rheumatic diseases of soft tissues surrounding joints.

Post-traumatic and postoperative pain syndromes associated with inflammation and edema, particularly following dental and orthopedic surgeries.

Gynecological conditions associated with pain and inflammation, e.g., primary dysmenorrhea and adnexitis.

Migraine attacks.

Acute attacks of gout.

As an adjunctive agent in severe inflammatory conditions of the ear, nose, and throat (ENT) organs accompanied by pain, e.g., pharyngotonsillitis, otitis.

According to general therapeutic principles, the underlying disease should be treated with basic therapy agents. Fever alone is not an indication for the use of this drug.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

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 (two or more distinct episodes of confirmed ulcer or bleeding).

Third trimester of pregnancy.

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

Hepatic failure.

Renal failure (glomerular filtration rate <15 mL/min/1.73 m²).

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

Not to be used for the treatment of postoperative pain following 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.

Proctitis.

Diclofenac sodium, like other NSAIDs, is contraindicated in patients who have experienced asthma attacks, urticaria, angioedema, or acute rhinitis in response to administration of acetylsalicylic acid or other NSAIDs.

Interaction with other medicinal products and other forms of interaction.

Interactions observed during the use of diclofenac in enteric-coated tablets and/or other pharmaceutical forms are indicated.

Lithium. 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. Concomitant use of diclofenac with diuretics and antihypertensive agents [e.g., β-blockers, angiotensin-converting enzyme (ACE) inhibitors] may reduce their antihypertensive effect by inhibiting the synthesis of vasodilatory prostaglandins. Therefore, such combinations should be used with caution, and patients, especially elderly ones, should be closely monitored for blood pressure. Adequate hydration is recommended, 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 causing hyperkalemia. Concomitant treatment with potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may be associated with increased serum potassium levels; therefore, more frequent patient monitoring is required.

Anticoagulants and antiplatelet agents. Concomitant use increases the risk of bleeding; therefore, precautionary measures are recommended. 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, to ensure that no dosage adjustments of anticoagulants are needed, careful monitoring of such patients is recommended. Like other nonsteroidal anti-inflammatory drugs, diclofenac at high doses may transiently inhibit platelet aggregation.

Other NSAIDs, including selective cyclooxygenase-2 inhibitors and corticosteroids. Concomitant use of diclofenac with other 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 use of 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 altering their therapeutic effect. However, there are some reports of both hypoglycemia and hyperglycemia occurring in such cases, necessitating dosage adjustments of antidiabetic agents during diclofenac use. Therefore, blood glucose monitoring is recommended during combination therapy.

There are also isolated reports of metabolic acidosis occurring 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 should be exercised when prescribing NSAIDs, including diclofenac, less than 24 hours before methotrexate administration, as this may increase methotrexate blood concentrations and enhance its toxic effects. Serious toxicity cases have been reported when the interval between methotrexate and NSAID (including diclofenac) administration was within 24 hours. This interaction is mediated via methotrexate accumulation due to impaired renal excretion in the presence of NSAIDs.

Cyclosporine. The effect of diclofenac, like other NSAIDs, on prostaglandin synthesis in the kidneys may potentiate the nephrotoxicity of cyclosporine; therefore, diclofenac should be administered at lower doses than in patients not receiving cyclosporine.

Tacrolimus. Concomitant use of NSAIDs with tacrolimus increases the risk of nephrotoxicity, possibly mediated through renal anti-prostaglandin effects of NSAIDs and calcineurin inhibition. Therefore, diclofenac should be used at lower doses than in patients not receiving tacrolimus.

Quinolone antibacterial agents. There are isolated reports of seizures in patients receiving quinolone derivatives and NSAIDs concomitantly. 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 used concomitantly with diclofenac, monitoring of plasma phenytoin concentrations is recommended due to expected increased phenytoin effects.

Colestipol and cholestyramine. 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 colestipol/cholestyramine.

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

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

CYP2C9 inhibitors. Caution is recommended when co-prescribing diclofenac with strong CYP2C9 inhibitors (e.g., voriconazole), which may lead to significantly increased plasma maximum concentrations and exposure of diclofenac due to inhibition of diclofenac metabolism.

CYP2C9 inducers. Caution is required when co-prescribing diclofenac with CYP2C9 inducers (e.g., rifampicin). This may lead to significantly reduced plasma concentrations and exposure of diclofenac.

Special precautions for use.

Gastrointestinal ulcers, bleeding, or perforation may occur at any time during treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), regardless of whether they are COX-2 selective, even in the absence of warning symptoms or predisposition in medical history. To minimize adverse effects, the lowest effective dose should be used for the shortest possible duration.

Placebo-controlled studies have revealed an increased risk of thrombotic cardiovascular and cerebrovascular complications with the use of certain selective COX-2 inhibitors. Whether this risk directly correlates with the COX-1/COX-2 selectivity of individual NSAIDs remains unknown.

Concomitant use of Diclofenac-Pharmex with systemic NSAIDs, such as selective cyclooxygenase-2 inhibitors, should be avoided due to the lack of evidence for synergistic effects and the potential for additive adverse effects.

As there are currently no comparative clinical trial data on long-term treatment with the maximum dose of diclofenac, an increased risk cannot be excluded. Therefore, a careful benefit-risk assessment should be performed before prescribing diclofenac to patients with clinically confirmed coronary heart disease, cerebrovascular disorders, peripheral arterial occlusive disease, or significant risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking). The lowest effective dose should be used for the shortest possible duration.

Caution is required when administering the drug to patients over 65 years of age. In particular, the lowest effective dose is recommended for frail elderly patients or those with low body weight.

Allergic reactions, including anaphylactic/anaphylactoid reactions, may rarely occur with NSAIDs, even without prior exposure to diclofenac. Hypersensitivity reactions may also progress to Quincke's edema, 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. Diclofenac-Pharmex, like other NSAIDs, may mask signs and symptoms of infection.

Gastrointestinal effects.

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

As with other NSAIDs, including diclofenac, medical monitoring and special caution are mandatory for patients with symptoms indicating gastrointestinal tract (GI) disorders. The risk of GI bleeding, ulceration, or perforation increases with higher NSAID doses, including diclofenac, and in patients with a history of peptic ulcer, especially with complications such as bleeding or perforation, and in elderly patients.

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

To reduce the risk of such toxic effects on the GI tract, treatment should be initiated and maintained at the lowest effective doses.

For such patients, as well as those requiring concomitant use of medications containing low-dose acetylsalicylic acid (ASA/aspirin) or other drugs that increase the risk of GI 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 GI 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.

The use of NSAIDs, including diclofenac, increases the risk of gastrointestinal anastomosis failure. Close monitoring and caution are recommended when using diclofenac after gastrointestinal surgery.

Hepatic effects.

Careful medical monitoring is required when Diclofenac-Pharmex is prescribed to patients with impaired liver function, as their condition may worsen.

As with treatment with other NSAIDs, including diclofenac, levels of one or more liver enzymes may increase. During prolonged treatment with sodium diclofenac, regular monitoring of liver function is recommended as a precautionary measure. If liver function abnormalities persist or worsen, and if clinical signs or symptoms may be related to progressive liver disease or other manifestations (e.g., eosinophilia, rash), Diclofenac-Pharmex should be discontinued. The course of diseases such as hepatitis may proceed without prodromal symptoms. Caution is required when Diclofenac-Pharmex is used in patients with hepatic porphyria due to the potential risk of provoking a porphyria attack.

Renal effects.

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

Since fluid retention and edema have been reported during treatment with NSAIDs, including diclofenac, particular attention should be paid to patients with cardiac or renal impairment, a history of arterial 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, such as before or after major surgery. In such cases, monitoring of renal function is recommended. Discontinuation of therapy usually leads to reversal to the pre-treatment state.

Skin effects.

Serious skin reactions (some of which have been fatal), including exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and generalized bullous fixed drug eruption, have very rarely been reported with the use of diclofenac. The highest risk of these reactions occurs at the beginning of treatment: most cases occur within the first month of therapy. Diclofenac-Pharmex should be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity.

Systemic lupus erythematosus and mixed connective tissue diseases.

Patients with systemic lupus erythematosus (SLE) and mixed connective tissue diseases may have an increased risk of developing aseptic meningitis.

Cardiovascular and cerebrovascular effects.

The use of the drug is generally not recommended in patients with established cardiovascular disease (e.g., heart failure, ischemic heart disease, peripheral arterial disease) or uncontrolled hypertension.

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

Clinical trial data and epidemiological evidence indicate that the use of diclofenac, especially at high doses (150 mg/day) and during prolonged treatment, may slightly increase the risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

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

Patients should be informed about the need to monitor for symptoms of serious arterial thromboembolic 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.

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

Diclofenac-Pharmex may reversibly inhibit platelet aggregation. Careful monitoring is required in patients with hemostasis disorders, hemorrhagic diathesis, or hematological disorders.

History of bronchial asthma.

Patients with bronchial asthma, seasonal allergic rhinitis, nasal mucosal swelling (i.e., nasal polyps), chronic obstructive pulmonary diseases, or chronic respiratory infections (especially those associated with rhinitis-like allergic symptoms) are more likely to experience reactions to NSAIDs, such as exacerbation of bronchial asthma (so-called analgesic intolerance/analgesic asthma), Quincke's edema, or urticaria. Therefore, special precautionary measures (readiness for emergency care) are recommended for such patients. This also applies to patients with allergic reactions to other substances, such as rash, pruritus, or urticaria.

Like other drugs that inhibit prostaglandin synthetase activity, sodium diclofenac and other NSAIDs may provoke bronchospasm when administered to patients suffering from bronchial asthma or with a history of bronchial asthma.

Use during pregnancy or breastfeeding.

Pregnancy.

From the 20th week of pregnancy, the 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. Diclofenac should not be used during the first or second trimester of pregnancy unless absolutely necessary. In the first and second trimesters, sodium diclofenac may be prescribed only if the expected benefit to the mother outweighs the potential risk to the fetus, and only at the lowest effective dose. The duration of treatment should be as short as possible. Prenatal monitoring for oligohydramnios may be appropriate if diclofenac exposure occurred over several days starting from the 20th week of pregnancy. If oligohydramnios is detected, diclofenac should be discontinued.

Like other NSAIDs, the drug is contraindicated in the third trimester of pregnancy (due to possible inhibition of uterine contractility and premature closure of the fetal arterial duct).

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of cardiac defects and gastroschisis following 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. Animal studies have shown that administration of prostaglandin synthesis inhibitors leads to increased pre- and post-implantation loss and embryonic/fetal mortality.

Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular defects, has been observed. If sodium diclofenac is used by a woman planning pregnancy or during the first trimester of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible.

During the third trimester of pregnancy, the following adverse effects may occur with the use of prostaglandin synthesis inhibitors:

in the fetus:

• cardiopulmonary toxicity (with premature closure of the arterial duct and pulmonary hypertension);
• impaired renal function (see above);

in the mother at the end of pregnancy and in the newborn:

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

Therefore, sodium diclofenac is contraindicated in the third trimester of pregnancy.

Breastfeeding.

Like other NSAIDs, diclofenac passes into breast milk in small amounts. Therefore, diclofenac suppositories should not be used during breastfeeding to avoid potential adverse effects on the infant. If treatment is essential, the infant should be switched to artificial feeding.

Female fertility.

Like other NSAIDs, sodium 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 sodium diclofenac should be considered.

Based on animal studies, impaired fertility in males cannot be excluded. The significance of these findings for humans is unclear.

Ability to influence reaction speed when driving vehicles or operating machinery.

Patients who experience visual disturbances, dizziness, vertigo, somnolence, central nervous system disorders, lethargy, or increased fatigue during treatment with sodium diclofenac should not drive vehicles or operate complex machinery.

Method of Administration and Dosage

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

Do not take orally — for rectal use only.

Suppositories should be inserted into the rectum as deeply as possible, preferably after bowel evacuation.

The initial dose of sodium diclofenac is usually 100–150 mg/day. In mild symptoms and during long-term therapy, a daily dose of 75–100 mg of sodium diclofenac is sufficient.

The daily dose should be divided into 2–3 administrations. To prevent nocturnal pain or morning stiffness, administer sodium diclofenac in the form of rectal suppositories before bedtime (daily dose must not exceed 150 mg).

For primary dysmenorrhea, the daily dose of sodium diclofenac should be individually adjusted, typically ranging from 50–150 mg/day. The initial dose may be 50–100 mg/day, but if necessary, it can be increased over several menstrual cycles up to the maximum dose of 150 mg/day.

Treatment should be initiated at the onset of the first pain symptoms and continued for several days, depending on the clinical response and symptom regression.

For the treatment of migraine attacks, begin the course with a dose of 100 mg at the first signs of an attack. If necessary, a second suppository (100 mg of diclofenac) may be administered on the same day. If needed, treatment may be continued in the following days (daily dose of sodium diclofenac must not exceed 150 mg; divide the dose into 2–3 administrations).

Elderly patients: Although the pharmacokinetics of sodium diclofenac are not significantly altered in elderly patients to a clinically relevant extent, nonsteroidal anti-inflammatory drugs (NSAIDs) should be used with particular caution in this population, as they are generally more susceptible to adverse reactions. In particular, frail elderly patients or those with low body weight should receive the lowest effective doses. Patients should also be monitored for gastrointestinal bleeding during NSAID therapy.

Renal function impairment

The use of the medicinal product Diclofenac-Pharmex is contraindicated in patients with renal insufficiency (GFR <15 mL/min/1.73 m²; see section "Contraindications").

No specific studies in patients with impaired renal function have been conducted; therefore, dosage adjustment recommendations cannot be provided. The drug should be used with caution in patients with renal impairment (see section "Special Warnings and Precautions for Use").

Hepatic function impairment

The use of the medicinal product Diclofenac-Pharmex is contraindicated in patients with hepatic insufficiency (see section "Contraindications").

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

Children

Sodium diclofenac 100 mg suppositories are not recommended for use in children.

Overdose

Symptoms. There is no typical clinical picture characteristic of diclofenac overdose. Overdose may cause symptoms such as headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, diarrhea, dizziness, disorientation, agitation, coma, drowsiness, tinnitus, and seizures. Acute renal failure and liver damage are possible in cases of severe intoxication.

Treatment. Symptomatic therapy should be administered if necessary. Supportive measures and symptomatic treatment should be provided for complications such as arterial hypotension, renal failure, seizures, gastrointestinal disturbances, 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 the drug's high protein binding and extensive metabolism. Activated charcoal should be considered within one hour after ingestion of a potentially toxic dose. In addition, gastric lavage should be considered in adults within one hour after ingestion of a potentially toxic dose. Intravenous diazepam should be administered in cases of frequent or prolonged seizures. Other measures may be indicated depending on the patient's clinical condition.

Adverse Reactions

The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders: very rare – thrombocytopenia, leukopenia, anemia (hemolytic anemia, aplastic anemia), 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, irritability, nightmares, psychotic disorders.

Nervous system disorders: common – headache, dizziness; rare – somnolence, increased fatigue; very rare – paresthesia, weakness, memory impairment, convulsions, restlessness, tremor, aseptic meningitis, taste disturbances, 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: common – arterial hypertension; uncommon* – palpitations, chest pain, heart failure, myocardial infarction, arterial hypertension, arterial hypotension, very rare – vasculitis; frequency not known – Kounis syndrome.

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

Gastrointestinal disorders: common – nausea, vomiting, diarrhea, dyspepsia, abdominal pain, flatulence, anorexia, decreased appetite; rare – gastritis, gastrointestinal hemorrhage, hematemesis, melena, hemorrhagic diarrhea, gastric and intestinal ulcers with or without bleeding, gastrointestinal stenosis or perforation (sometimes fatal, especially in elderly patients), which may lead to peritonitis, proctitis; very rare – colitis (including hemorrhagic colitis, ischemic colitis, and exacerbation of ulcerative colitis or Crohn’s disease), constipation, stomatitis (including ulcerative stomatitis), glossitis, esophageal dysfunction, diaphragm-like intestinal stricture, pancreatitis, hemorrhoidal flare-ups.

Hepatobiliary disorders: common – increased transaminase levels; rare – hepatitis, jaundice, liver disorders; very rare – fulminant hepatitis, liver necrosis, liver failure.

Skin and subcutaneous tissue disorders: common – rash; rare – urticaria; very rare – blistering rash, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, Lyell’s syndrome (toxic epidermal necrolysis), exfoliative dermatitis, alopecia, photosensitivity reactions, 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, edema; very rare – acute kidney injury (acute renal failure), hematuria, proteinuria, tubulointerstitial nephritis, nephrotic syndrome, renal papillary necrosis.

General disorders and administration site conditions: common – irritation at the site of administration; rare – swelling.

Reproductive system and breast disorders: very rare – impotence.

*Frequency data are based on long-term use at high doses (150 mg/day).

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 with prolonged use.

Visual disturbances

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

Shelf life

2 years – for packaging in strips of PVC/PVDC/PE film.

3 years – for packaging in strips of PVC/PE film.

Storage conditions

Store in original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging

5 suppositories per strip, 2 strips per cardboard pack.

Prescription status

Prescription only.

Manufacturer

PHARMEX GROUP LLC

Manufacturer's address and location of business activity

100 Shevchenka Street, Boryspil, Kyiv region, 08301, Ukraine.

All cases of adverse reactions should be reported to the manufacturer:

PHARMEX GROUP LLC, 100 Shevchenka Street, Boryspil, Kyiv region, 08301, Ukraine, tel.: +38(044)391-19-19, fax: +38(044)391-19-18;

or via the form on the website: http://www.pharmex.com.ua/kontakty/farmakonadzor