INSTRUCTIONS for medical use of the medicinal product DICLOFENAC (diclofenac)

Composition:

Active substance: diclofenac;

1 suppository contains 100 mg (0.1 g) of sodium diclofenac;

Excipient: hard fat.

Pharmaceutical form. Rectal suppositories.

Main physicochemical properties: suppositories from white to white with yellowish or creamy hue, bullet-shaped. A surface film on the suppository may be present.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents.

ATC code M01A B05.

Pharmacological properties.

Pharmacodynamics.

Diclofenac contains diclofenac sodium – a non-steroidal compound exerting pronounced analgesic and anti-inflammatory effects. It is an inhibitor of prostaglandin synthetase (cyclooxygenase).

Pharmacokinetics.

Absorption. The plasma concentration of the drug is in linear correlation with the dose administered.

After repeated administration, the pharmacokinetics of the drug remain unchanged. No drug accumulation is observed.

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 plasma. The apparent half-life from synovial fluid is 3–6 hours. Two hours after peak plasma concentration, diclofenac concentration in synovial fluid remains higher than in plasma; this phenomenon persists for up to 12 hours.

Metabolism. Diclofenac is partially metabolized via glucuronidation of the unchanged molecule, but primarily through single and multiple hydroxylation and methoxylation pathways, 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.

Excretion. Total systemic clearance of diclofenac from plasma is 263±56 mL/min. The terminal half-life in plasma is 1–2 hours. The half-life in plasma 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 the 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 groups. Age of the patient has no observed effect on drug absorption, metabolism, or excretion.

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 plasma concentrations of hydroxylated metabolites 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 spondyloarthrosis;
Spinal pain syndromes;
Rheumatic diseases of periarticular soft tissues;
Acute gout attack;
Post-traumatic and postoperative pain syndromes associated with inflammation and edema, particularly after dental and orthopedic surgeries;
Migraine attacks;
Gynecological conditions associated with pain and inflammation, e.g. primary dysmenorrhea and adnexitis;
As an adjunctive agent in severe inflammatory conditions of the ear, nose, and throat (ENT) organs accompanied by pain, e.g. pharyngitis, tonsillitis, 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 NSAIDs;
Active peptic ulcer/hemorrhage or recurrent peptic ulcer/hemorrhage (two or more separate episodes of confirmed ulcer or bleeding);
Inflammatory bowel diseases (e.g. Crohn's disease or ulcerative colitis);
Third trimester of pregnancy;
Proctitis;
Severe hepatic, renal, or cardiac insufficiency;
Congestive heart failure (NYHA II-IV);
Ischemic heart disease in patients with angina who have suffered myocardial infarction;
Cerebrovascular diseases in patients who have had stroke or transient ischemic attacks;
Peripheral arterial disease;
Treatment of perioperative pain in coronary artery bypass grafting (CABG) (or use of cardiopulmonary bypass apparatus).

The drug is contraindicated in patients who develop attacks of bronchial asthma, urticaria, angioedema, or acute rhinitis in response to acetylsalicylic acid or other NSAIDs.

Interaction with other medicinal products and other forms of interaction.

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. 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 renal function should be monitored after initiation of concomitant therapy and regularly thereafter, particularly with diuretics and ACE inhibitors due to increased risk of nephrotoxicity.

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

Anticoagulants and antithrombotic agents. Concomitant use may increase the risk of bleeding, so precautionary measures are recommended. Although clinical studies have not shown 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 no dosage adjustment of anticoagulants is 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. Concurrent 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). Concurrent 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, necessitating dose adjustments of antidiabetic agents during diclofenac treatment. For this reason, blood glucose monitoring is recommended during combination therapy.

Methotrexate. Diclofenac may inhibit renal tubular clearance of methotrexate, leading to elevated methotrexate levels. Caution should be exercised when using NSAIDs, including diclofenac, less than 24 hours before methotrexate administration, as this may increase methotrexate plasma concentrations and enhance its toxic effects. Serious toxicity cases have been reported when methotrexate and NSAIDs, including diclofenac, were administered within 24 hours of each other. This interaction is mediated by methotrexate accumulation due to impaired renal excretion in the presence of NSAIDs.

Cyclosporine. The effect of diclofenac, as with other NSAIDs, on prostaglandin synthesis in the kidneys may enhance the nephrotoxicity of cyclosporine; therefore, diclofenac should be used 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 inhibitors.

Antibacterial quinolones. There are isolated reports of seizures in patients receiving quinolone derivatives and NSAIDs concomitantly. This may occur in patients both with and without a prior history of epilepsy or seizures. Therefore, caution should be exercised when considering the use of quinolones 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 the absorption of diclofenac. Therefore, it is recommended to administer diclofenac 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 glomerular filtration rate (GFR), and increase glycoside plasma levels.

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

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

Special precautions for use.

General.

To minimize adverse effects, the lowest effective dose should be used for the shortest possible duration.

Concomitant use of diclofenac 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.

Caution is required in elderly patients. In particular, the lowest effective dose is recommended for frail elderly patients or those with low body weight.

Rarely, as with other NSAIDs, hypersensitivity reactions including anaphylactic/anaphylactoid reactions may occur, even in the absence of 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.

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

Gastrointestinal effects.

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

As with other NSAIDs, patients presenting with symptoms suggesting gastrointestinal (GI) disturbances require medical monitoring and special caution. 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.

NSAIDs, including diclofenac, may increase the risk of gastrointestinal anastomotic dehiscence. Careful monitoring and caution are recommended when using diclofenac after gastrointestinal surgery.

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 GI toxicity, treatment should be initiated and maintained at the lowest effective dose.

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

Hepatic effects.

Careful medical monitoring is required when prescribing diclofenac to patients with impaired liver function, as their condition may worsen.

As with other NSAIDs, including diclofenac, elevation of one or more liver enzymes may occur.

During long-term treatment with diclofenac, regular monitoring of liver function is recommended as a precautionary measure. If liver function abnormalities persist or worsen, or if clinical signs or symptoms suggest progressive liver disease, or if other manifestations occur (e.g., eosinophilia, rash), diclofenac should be discontinued. Conditions such as hepatitis may progress without prodromal symptoms. Caution is required when using diclofenac in patients with hepatic porphyria, due to the potential to provoke an attack.

Renal effects.

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 hypertension, elderly patients, patients receiving concomitant diuretic therapy or drugs that significantly affect renal function, and patients with significant extracellular fluid volume depletion due to any cause, such as before or after major surgery. In such cases, monitoring of renal function is recommended as a precautionary measure. Discontinuation of therapy usually leads to reversal of the condition.

Skin effects.

Very rarely, 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 been reported in association with diclofenac. The highest risk of these reactions occurs early in the course of treatment: most cases occur within the first month of therapy. Diclofenac 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 disorders.

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

Cardiovascular and cerebrovascular effects.

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

Clinical trial data and epidemiological evidence suggest that diclofenac use, particularly at high doses (150 mg/day) and during prolonged treatment, may be associated with a small increased 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, 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 patient's need for diclofenac and response to therapy should be reviewed periodically. Use with caution in patients aged 65 years and older.

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

Hematological effects.

With long-term use of this drug, 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 asthma.

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

Like other drugs that inhibit prostaglandin synthetase activity, sodium 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.

During the first and second trimesters of pregnancy, 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. 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 ductus arteriosus). Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage and/or congenital heart defects and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increased from less than 1% to approximately 1.5%.

The risk may increase with dose and duration of treatment. In animal studies, administration of prostaglandin synthesis inhibitors has been shown to increase pre- and post-implantation loss and embryonic/fetal mortality.

Moreover, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular defects, has been observed.

Starting from the 20th week of pregnancy, use of diclofenac 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 by a woman attempting to conceive or during the first trimester of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible. Prenatal monitoring for oligohydramnios should be considered after diclofenac exposure for several days 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:

cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
renal dysfunction (see above).

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

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

Therefore, 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.

Female fertility.

Like other NSAIDs, diclofenac may adversely affect female fertility; therefore, it is not recommended for women attempting to conceive. For women experiencing infertility or undergoing fertility investigations, discontinuation of diclofenac should be considered.

Ability to influence reaction speed when driving or operating machinery.

Patients who experience visual disturbances, dizziness, vertigo, somnolence, central nervous system disorders, lethargy, or fatigue during diclofenac therapy should refrain from driving or operating complex machinery.

Method of Administration and Dosage

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

To achieve a dose different from 100 mg, use diclofenac suppositories with appropriate dosage strength.

Do not take orally; the drug is intended for rectal administration only.

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

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/day. The initial dose may be 50–100 mg/day, but if necessary, it can be increased over several menstrual cycles up to a maximum of 200 mg/day. Treatment should begin after the onset of the first painful symptoms and continue for several days, depending on the clinical response.

For the treatment of migraine attacks, initiate therapy 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 continue in the following days (daily dose must not exceed 150 mg; divide the dose into 2–3 administrations).

Elderly patients. Although the pharmacokinetics of 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, the lowest effective doses are recommended for frail elderly patients or those with low body weight. Patients should also be monitored for gastrointestinal bleeding during NSAID therapy.

Children. The drug is not recommended for use in children.

Overdose.

There is no typical clinical picture specifically characteristic of diclofenac overdose. Overdose may cause vomiting, gastrointestinal bleeding, diarrhea, dizziness, tinnitus, and seizures. Acute renal failure and hepatic injury are possible in cases of severe intoxication. Management of acute NSAID poisoning involves supportive and symptomatic therapy.

This includes treatment of manifestations such as arterial hypotension, renal failure, seizures, and respiratory depression. Specific interventions such as forced diuresis, hemodialysis, or hemoperfusion are unlikely to be effective in eliminating NSAIDs, as the active substances of these drugs are highly protein-bound and undergo extensive metabolism.

Adverse reactions.

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

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

Psychiatric disorders: disorientation, depression, insomnia, irritability, nightmares, psychotic disorders.

Nervous system disorders: headache, dizziness; somnolence, fatigue; paresthesia, memory impairment, convulsions, restlessness, tremor, aseptic meningitis, taste disturbances, stroke; confusion, hallucinations, sensory disturbances, general malaise.

Eye disorders: visual disturbances, blurred vision, diplopia; optic neuritis.

Ear and labyrinth disorders: vertigo; tinnitus, hearing disturbances.

Cardiovascular system disorders: palpitations, chest pain, heart failure, myocardial infarction, Kounis syndrome, arterial hypertension, arterial hypotension, vasculitis.

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

Gastrointestinal disorders: nausea, vomiting, diarrhea, dyspepsia, abdominal pain, flatulence, anorexia; gastritis, gastrointestinal bleeding, hematemesis, melena, hemorrhagic diarrhea, gastric and intestinal ulcers with or without bleeding or perforation (sometimes fatal, especially in elderly patients); colitis (including hemorrhagic colitis and exacerbation of ulcerative colitis or Crohn’s disease), constipation, stomatitis (including ulcerative stomatitis), glossitis, esophageal dysfunction, diaphragm-like intestinal stricture, pancreatitis.

Hepatobiliary disorders: increased transaminase levels; hepatitis, jaundice, liver dysfunction; fulminant hepatitis, liver necrosis, liver failure.

Skin and subcutaneous tissue disorders: rash; urticaria; bullous rash, eczema, erythema, erythema, multiform erythema, Stevens-Johnson syndrome, Lyell’s syndrome (toxic epidermal necrolysis), exfoliative dermatitis, hair loss, photosensitivity, purpura, including allergic purpura, pruritus; frequency unknown – fixed drug eruption, generalized bullous fixed drug eruption.

Renal and urinary system disorders: acute renal failure, hematuria, proteinuria, interstitial nephritis, nephrotic syndrome, renal papillary necrosis.

Reproductive system and breast disorders: impotence.

Clinical studies and epidemiological data indicate an increased risk of thrombotic complications (such as myocardial infarction or stroke) associated with the use of diclofenac, particularly at high therapeutic doses (150 mg per day) and with prolonged use.

Shelf life. 2 years.

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

Packaging. 5 suppositories in a blister pack, 2 blisters in a carton.

Prescription status. Prescription only.

Manufacturer: Private Joint-Stock Company "Lekhim-Kharkiv".

Manufacturer's address and place of business.
Ukraine, 61115, Kharkiv region, city of Kharkiv, Severyn Pototskoho Street, building 36.