DICLOSEF®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIKLOSEYF® (DICLOSAFE®)

Composition:

Active substance: diclofenac;

1 suppository contains sodium diclofenac 50 mg;

Excipient: hard fat.

Dosage form. Suppositories.

Main physico-chemical properties: suppositories from white to light yellow, torpedo-shaped.

Pharmacotherapeutic group. Nonsteroidal anti-inflammatory and antirheumatic agents.

ATC code M01A B05.

Pharmacological Properties

Pharmacodynamics

Diclofenac sodium is a non-steroidal anti-inflammatory drug (NSAID) that exerts pronounced analgesic and anti-inflammatory effects. It is an inhibitor of prostaglandin synthetase (cyclooxygenase).

Pharmacokinetics

Absorption

Absorption is rapid, although slower compared to enteric-coated tablets.

After administration of 50 mg diclofenac sodium suppositories, maximum plasma concentration (Cmax) is reached approximately within 1 hour. However, the maximum concentration per dose unit is about two-thirds 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 plasma concentration-time curve (AUC) is approximately half of that obtained after parenteral administration. Pharmacokinetics of the drug do not change after repeated administration. No accumulation occurs when recommended dosing intervals are observed.

Distribution

Diclofenac binding to plasma proteins is 99.7%, primarily to albumin (99.4%).

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

Diclofenac was detected at low concentrations (100 ng/mL) in breast milk in one patient. The estimated amount of drug transferred to the infant via breast milk is equivalent 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 pathways, resulting in 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 from plasma is 263 ± 56 mL/min (mean + SD). The terminal half-life in plasma is 1–2 hours. The plasma half-life of four metabolites, including two pharmacologically active ones, is also short, ranging from 1 to 3 hours. Approximately 60% of the administered dose is excreted in urine as glucuronide conjugates 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

Elderly patients

No significant effect of patient age on absorption, metabolism, and elimination of the drug has been observed, except for one finding: 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.

Patients with renal impairment

In patients with impaired renal function receiving therapeutic doses, accumulation of the unchanged active substance is not expected, based on the drug's kinetics after single administration. In patients with creatinine clearance below 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 liver cirrhosis, 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 outside the joints.
• Post-traumatic and postoperative pain syndromes accompanied by inflammation and swelling, particularly following dental and orthopedic surgeries.
• Gynecological conditions associated with pain and inflammation, e.g., primary dysmenorrhea and adnexitis.
• Migraine attacks.
• Acute gout attacks.
• As an adjunctive agent in severe inflammatory ENT disorders 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 ulceration of the stomach or duodenum/bleeding, or recurrent peptic ulcer/bleeding in history (two or more distinct episodes of established 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 (GFR) <15 mL/min/1.73 m²).
• Congestive heart failure (NYHA II–IV).
• Ischemic heart disease in patients with angina pectoris or history of myocardial infarction.
• Treatment of perioperative pain in coronary artery bypass grafting (or use of cardiopulmonary bypass apparatus).
• 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 in whom administration of acetylsalicylic acid or other NSAIDs induces attacks of bronchial asthma, urticaria, angioedema, acute rhinitis, or nasal polyps.

Interaction with other medicinal products and other forms of interaction.

The interactions listed below include those observed with diclofenac administered as enteric-coated tablets and/or in other pharmaceutical forms.

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

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

Diuretics and antihypertensive agents. As with other NSAIDs, concomitant use of diclofenac with diuretics and antihypertensive agents (e.g., 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 monitoring of renal function should be performed after initiation and on a regular basis during concomitant therapy, particularly with diuretics and ACE inhibitors, due to increased risk of nephrotoxicity.

Agents causing hyperkalemia.

Concomitant use of potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may be associated with increased serum potassium levels; therefore, more frequent monitoring of patients is recommended.

Anticoagulants and antiplatelet agents. Concomitant use may increase the risk of bleeding; therefore, precautionary measures are recommended. Although clinical studies have not shown an effect of diclofenac on anticoagulant activity, there are data indicating an increased risk of bleeding 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 NSAIDs, 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 have been some reports of both hypoglycemia and hyperglycemia, necessitating dosage adjustments of antidiabetic agents during diclofenac treatment. Therefore, monitoring of blood glucose levels is recommended during combination therapy.

Isolated cases of metabolic acidosis have also been reported 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 advised when administering diclofenac less than 24 hours before or after methotrexate, as this may increase methotrexate blood concentration 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 caused by NSAIDs.

Cyclosporine. The effect of diclofenac, like other NSAIDs, on renal prostaglandin synthesis may potentiate the nephrotoxicity of cyclosporine; therefore, diclofenac should be administered at lower doses in such patients 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 inhibition. Therefore, diclofenac should be administered at lower doses in such patients compared to those not receiving tacrolimus.

Quinolone antibiotics. Isolated data suggest an increased risk of seizures in patients receiving quinolone derivatives and NSAIDs concomitantly. This may occur in patients with or without prior 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 the expected increase in phenytoin effects.

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

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

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

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

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

Special precautions for use.

General

Peptic ulcers, bleeding, or perforation may occur at any time during diclofenac therapy, regardless of whether the drug is COX-2 selective, even in the absence of warning symptoms or predisposition in medical history. To minimize adverse effects, the lowest effective dose of the medicinal product Diclosafe® should be used for the shortest possible duration.

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

Concomitant use of the medicinal product Diclosafe® with systemic NSAIDs, such as selective COX-2 inhibitors, should be avoided due to the lack of evidence for synergistic effect and the potential for additive adverse reactions.

Since comparative clinical trial data on long-term treatment using the maximum dose of diclofenac are currently lacking, the possibility of such an increased risk cannot be excluded. Until such data become available, a careful benefit-risk assessment should be performed before prescribing diclofenac to patients with clinically confirmed coronary heart disease, cerebrovascular disorders, peripheral arterial disease, or significant risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking). Due to this risk, the lowest effective dose should be used for the shortest possible duration.

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

Rarely, allergic reactions, including anaphylactic/anaphylactoid reactions, may occur during diclofenac use, as with other NSAIDs, even without prior exposure to diclofenac. Due to its pharmacodynamic properties, the medicinal product Diclosafe®, like other NSAIDs, may mask signs and symptoms of infection.

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.

Gastrointestinal effects

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

As with other NSAIDs, patients with symptoms indicating gastrointestinal disturbances require medical supervision and special caution. The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher doses of 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 gastrointestinal toxicity, treatment should be initiated and maintained at the lowest effective dose.

For these patients, as well as for those requiring concomitant use of low-dose acetylsalicylic acid (ASA/aspirin) or other drugs that may increase the risk of 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 in patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants (e.g., warfarin), antiplatelet agents (e.g., acetylsalicylic acid), or SSRIs.

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

Hepatic effects

Close medical monitoring is required if the medicinal product Diclosafe® is prescribed to patients with hepatic impairment, as their condition may worsen.

As with other NSAIDs, during diclofenac use, the levels of one or more liver enzymes may increase.

This occurred very frequently in clinical trials of diclofenac (approximately in 15% of patients), but rarely was associated with clinical symptoms. Most of these cases involved borderline elevations. Moderate increases (≥ 3 to < 8 times the upper limit of normal) were observed frequently (in 2.5% of cases), while significant elevations (≥ 8 times the upper limit of normal) occurred in approximately 1% of cases. In the aforementioned clinical trials, elevated liver enzyme levels were clinically apparent in liver injury in 0.5% of patients. After discontinuation of diclofenac, liver enzyme levels returned to baseline.

As a precautionary measure, regular monitoring of liver function is recommended during long-term diclofenac therapy. If hepatic impairment persists or worsens, and if clinical symptoms may be related to progressive liver disease or other manifestations occur (e.g., eosinophilia, rash), Diclosafe® should be discontinued.

In addition to elevated liver enzyme levels, isolated reports of severe hepatic reactions have been received, including jaundice and fulminant hepatitis, hepatic necrosis, and hepatic failure, which in some cases were fatal.

The course of diseases such as hepatitis may occur without prodromal symptoms. Caution is required if Diclosafe® is administered to patients with hepatic porphyria due to the potential for provoking an 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 and hypertension.

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

Skin effects

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

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

Systemic lupus erythematosus and mixed connective tissue diseases

In patients with systemic lupus erythematosus and mixed connective tissue diseases, there is a possible increased risk of aseptic meningitis.

Cardiovascular and cerebrovascular effects

Diclofenac is generally not recommended for patients with established cardiovascular disease (e.g., heart failure, established ischemic heart disease, peripheral arterial disease) or uncontrolled hypertension.

Diclofenac may be prescribed to patients with significant cardiovascular risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful clinical evaluation and only at doses up to 100 mg daily if the duration of therapy exceeds 4 weeks. Since cardiovascular risks of diclofenac may increase with higher doses and longer treatment duration, it should be used for the shortest possible duration and at the lowest effective dose. The patient's need for diclofenac for symptom relief and response to therapy should be periodically reviewed.

Patients with a history of arterial hypertension and/or mild to moderate congestive heart failure require appropriate monitoring and counseling, as fluid retention and edema have been reported with diclofenac use.

Clinical trial data and epidemiological evidence indicate that diclofenac use, especially at high doses (150 mg daily) and during long-term treatment, may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

The patient's need for symptom relief and response to therapy should be periodically evaluated, especially if therapy duration exceeds 4 weeks.

Patients should be informed about the necessity to monitor for symptoms of serious arterial thromboembolic events (e.g., chest pain, dyspnea, weakness, slurred speech), which may occur without warning. If such an event occurs, patients should seek immediate medical attention.

Hematological effects

With prolonged use of diclofenac, as with other NSAIDs, monitoring of all blood parameters is recommended.

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

History of bronchial asthma

Patients with bronchial asthma, seasonal allergic rhinitis, nasal mucosal edema (i.e., nasal polyps), chronic obstructive pulmonary diseases, or chronic respiratory infections (especially those associated with allergic, rhinitis-like symptoms) are more likely to experience reactions to NSAIDs, such as bronchial asthma exacerbation (so-called analgesic intolerance/analgesic-induced 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, diclofenac and other NSAIDs may provoke bronchospasm when administered to patients with bronchial asthma or a history of bronchial asthma.

Use during pregnancy or breastfeeding.

Pregnancy

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

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

First/second trimester of pregnancy

Diclofenac may be prescribed during the first and second trimesters of pregnancy only if the expected benefit to the woman outweighs the potential risk to the fetus. If diclofenac is used by a woman attempting to conceive or during the first or second trimester of pregnancy, the dose of Diclosafe® should be as low as possible and the duration of treatment as short as possible.

Oligohydramnios/renal dysfunction in newborns

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 of therapy.

Fetal monitoring for oligohydramnios should be considered after diclofenac exposure for several days starting from the 20th week of pregnancy. Diclofenac use should be discontinued if oligohydramnios is detected.

Third trimester

Diclofenac is contraindicated during the third trimester of pregnancy.

All prostaglandin synthesis inhibitors may:

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

Breastfeeding period

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

Fertility

Like other NSAIDs, diclofenac may negatively affect female fertility; therefore, it 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 significance of these findings for humans is unclear.

Ability to affect reaction speed when driving or operating machinery.

Patients who experience visual disturbances, dizziness, vertigo, somnolence, central nervous system disorders, lethargy, or fatigue during diclofenac therapy should not drive or operate machinery.

Method of Administration and Dosage.

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

Do not administer orally; for rectal use only. Suppositories should be inserted into the rectum as deeply as possible, preferably after bowel evacuation. Suppositories should not be divided, as altering the method of administration may disrupt the distribution of the active substance.

The initial dose is usually 100–150 mg per day. For mild symptoms and during long-term therapy, a daily dose of 75*–100 mg is sufficient.

Divide the daily dose into 2–3 administrations. To prevent nocturnal pain or morning stiffness, administer diclofenac as rectal suppositories before bedtime (daily dose must not exceed 150 mg).

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

Treatment should begin after the onset of the first painful symptoms and continued for several days, depending on the clinical progression and symptom regression.

For migraine attacks, initiate treatment with a dose of 100 mg at the first signs of an attack. If necessary, another suppository (100 mg diclofenac) may be used the same day. If needed, treatment may continue on subsequent days (daily dose must not exceed 150 mg; divide the dose into 2–3 administrations).

* Use in corresponding dosage strength.

For treatment of juvenile rheumatoid arthritis, the daily dose may be set up to 3 mg/kg, which is the maximum daily dose and must not exceed 150 mg per day. Children aged 14 years and older may be prescribed 50 mg suppositories.

Elderly Patients

Although the pharmacokinetics of diclofenac are not significantly altered in elderly patients to a clinically relevant extent, diclofenac should be used with particular caution in this population, as they are generally more susceptible to adverse reactions. Especially frail elderly patients or those with low body weight should receive the lowest effective doses. Patients should also be monitored for gastrointestinal bleeding during diclofenac therapy.

Renal Impairment

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

No specific studies have been conducted in patients with renal impairment; therefore, dosage 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

Diclofenac is contraindicated in patients with hepatic insufficiency (see section "Contraindications").

No specific studies have been conducted in patients with hepatic impairment; therefore, dosage 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").

Children

Diclosafe® 50 mg suppositories should not be used in children under 14 years of age due to the high content of active substance. The medicinal product may be used in children aged 14 years and older.

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, excitement, coma, drowsiness, tinnitus, or convulsions. Acute renal failure and liver injury are possible in cases of severe intoxication.

Treatment

Symptomatic treatment should be administered as needed. Supportive measures and symptomatic therapy should be provided for complications such as arterial hypotension, renal failure, convulsions, 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 extensive protein binding and intensive metabolism.

Activated charcoal should be considered within one hour after ingestion of a potentially toxic amount of the drug. In addition, gastric lavage should be considered for adult patients within one hour after ingestion of a potentially toxic amount. Intravenous diazepam should be administered in cases of frequent or prolonged convulsions. Other measures may be indicated based on the patient's clinical condition.

Adverse Reactions

The frequency category of adverse reactions is defined as follows: 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).

Blood and lymphatic system disorders: very rare – thrombocytopenia, leucopenia, anaemia (haemolytic anaemia, aplastic anaemia), 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, fatigue; very rare – paraesthesia, 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 hypotension; very rare – vasculitis; frequency not known – Kounis syndrome.

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

Gastrointestinal disorders: common – nausea, vomiting, diarrhoea, dyspepsia, epigastric pain, abdominal pain, flatulence, anorexia, decreased appetite; rare – gastritis, gastrointestinal bleeding, haematemesis, melaena, haemorrhagic diarrhoea, 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 haemorrhagic colitis, ischaemic colitis, and exacerbation of ulcerative colitis or Crohn’s disease), constipation, stomatitis (including ulcerative stomatitis), glossitis, oesophageal dysfunction, diaphragm-like stricture of the intestine, pancreatitis, haemorrhoidal flare-up.

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.

Renal and urinary disorders: common – fluid retention, oedema; very rare – acute kidney injury (acute renal failure), haematuria, proteinuria, tubulo-interstitial 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 rates are based on long-term use at high doses (150 mg per day).

Clinical 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 per day) and with prolonged use.

Visual disturbances

Visual disturbances such as visual impairment, worsening of vision, 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 the synthesis of prostaglandins and related compounds, which disrupt retinal blood flow regulation and lead 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.

Reporting of suspected adverse reactions

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

Shelf life

3 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging

5 suppositories per strip. 2 strips per cardboard package.

Prescription status

Prescription only.

Manufacturer

Kusum Healthcare Pvt Ltd.

Manufacturer's address and place of business

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.