Diclotol

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DICTOLOÒ (DICLOTOLÒ)

Composition:

Active substance: aceclofenac;

1 tablet contains 100 mg of aceclofenac;

Excipients: microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, stearic acid, Opadry-YS-1-7027 White (hydroxypropylmethylcellulose), titanium dioxide (E 171), triacetin.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex, film-coated tablets.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Acetic acid derivatives and related substances.

ATC code M01AB16.

Pharmacological properties.

Pharmacodynamics.

Aceclofenac is a non-steroidal agent with anti-inflammatory and analgesic effects. The mechanism of action of this drug is believed to be based on inhibition of prostaglandin synthesis.

Pharmacokinetics.

Absorption

After oral administration, aceclofenac is rapidly absorbed, with a bioavailability of almost 100%. Peak plasma concentration is reached approximately within 1.25–3 hours after intake. Food intake slows absorption but does not affect its extent.

Distribution

Aceclofenac is highly bound to plasma proteins (> 99.7%). It penetrates into synovial fluid, where concentrations reach approximately 60% of plasma levels. The volume of distribution is approximately 30 L.

Elimination

The mean elimination half-life is 4–4.3 hours. Clearance is 5 liters per hour. Approximately two-thirds of the administered dose is excreted in urine, primarily as conjugated hydroxylated metabolites. Only 1% of a single oral dose is excreted unchanged.

Aceclofenac is likely metabolized via CYP2C9 to its major metabolite, 4-OH-aceclofenac, which has negligible clinical activity. Diclofenac and 4-OH-diclofenac have been detected among the various metabolites.

Special patient groups

No changes in the pharmacokinetics of aceclofenac have been observed in elderly patients.

In patients with impaired liver function, slower elimination of aceclofenac was observed after a single dose. However, in multiple-dose studies of 100 mg daily, no differences in pharmacokinetic parameters were observed between patients with mild to moderate hepatic cirrhosis and healthy volunteers.

In patients with mild or moderate renal impairment, no clinically relevant differences in pharmacokinetics were observed after a single dose.

Clinical characteristics.

Indications.

Symptomatic treatment of pain and inflammation in osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, as well as other musculoskeletal disorders associated with pain (e.g., periarthritis of the shoulder or extra-articular rheumatism).

As an analgesic in conditions associated with pain (including low back pain, dental pain, and primary (functional) dysmenorrhea).

Contraindications.

Aceclofenac is contraindicated:

• in patients with hypersensitivity to aceclofenac or to any excipient of the medicinal product (see section "Composition");
• in patients in whom acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs) induce asthma attacks, acute rhinitis, angioedema, or urticaria, as well as patients with hypersensitivity to these agents;
• in patients with a history of gastrointestinal bleeding or ulcer perforation associated with previous NSAID therapy;
• in patients with active peptic ulcer or gastrointestinal bleeding, including history of such conditions (two or more distinct documented episodes of ulcer development or bleeding);
• in patients with active bleeding or bleeding disorders (e.g., hemophilia or coagulation disorders);
• in patients with congestive heart failure (NYHA functional class II–IV), ischemic heart disease, peripheral arterial disease, or cerebrovascular disorders;
• in patients with cerebrovascular disease who have had a stroke or episodes of transient ischemic attacks;
• in patients with ischemic heart disease who have angina or have had myocardial infarction;
• for the treatment of perioperative pain in coronary artery bypass grafting (CABG) (or when using cardiopulmonary bypass);
• in patients with severe hepatic or renal impairment;
• during breastfeeding;
• in the third trimester of pregnancy;
• in patients under 18 years of age.

Interaction with other medicinal products and other forms of interaction.

Interaction studies have not been conducted, except for interactions with warfarin.

Aceclofenac is metabolized via cytochrome P450 2C9, and in vitro data indicate that aceclofenac may be an inhibitor of this enzyme. Therefore, a risk of pharmacokinetic interaction is possible when administered concomitantly with phenytoin, cimetidine, tolbutamide, phenylbutazone, amiodarone, miconazole, and sulfaphenazole. As with other NSAIDs, there is an increased risk of pharmacokinetic interaction with other drugs eliminated via active renal secretion, such as methotrexate and lithium-containing preparations. Aceclofenac is almost completely bound to plasma albumin, and thus displacement-type interactions with other protein-bound drugs are possible.

Due to the lack of pharmacokinetic interaction studies with aceclofenac, the information below is based on data from other NSAIDs.

Combinations to be avoided

Methotrexate. NSAIDs inhibit tubular secretion of methotrexate; in addition, a minor metabolic interaction may occur, leading to reduced methotrexate clearance. Therefore, the concomitant use of NSAIDs should be avoided when high-dose methotrexate is administered.

Cardiac glycosides, digoxin. NSAIDs may exacerbate heart failure, reduce GFR (glomerular filtration rate), and inhibit renal clearance of glycosides, leading to increased plasma levels of glycosides. Concomitant use should be avoided unless frequent monitoring of digoxin concentrations is performed.

Lithium-containing preparations and digoxin. Some NSAIDs inhibit renal clearance of lithium and digoxin, leading to increased serum concentrations of both substances. Concomitant use should be avoided unless frequent monitoring of lithium and digoxin concentrations is performed.

Anticoagulants. NSAIDs inhibit platelet aggregation and damage the gastrointestinal mucosa, which may potentiate the effect of anticoagulants and increase the risk of gastrointestinal bleeding in patients taking anticoagulants. Concomitant use of aceclofenac with oral anticoagulants of the coumarin group, ticlopidine, and thrombolytics should be avoided unless careful patient monitoring is performed.

Quinolone antibiotics. Animal studies show that NSAIDs increase the risk of seizures associated with quinolone antibiotics. Patients receiving NSAIDs and quinolone antibiotics have an increased risk of developing seizures.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs). When used concomitantly with NSAIDs, the risk of gastrointestinal bleeding is increased (see section "Special precautions for use").

Combinations requiring dose adjustment and cautious use

Methotrexate. Possible interaction between NSAIDs and methotrexate should be considered, even at low methotrexate doses, especially in patients with impaired renal function. Renal function parameters should be monitored during concomitant use. Caution is required if NSAIDs and methotrexate have been administered within 24 hours of each other, as methotrexate concentration may increase, thereby increasing the toxicity of this drug.

Cyclosporine, tacrolimus. When NSAIDs are used concomitantly with cyclosporine or tacrolimus, the risk of increased nephrotoxicity due to reduced renal prostacyclin production should be considered. Therefore, renal function parameters should be closely monitored during concomitant use.

Other analgesics, NSAIDs, including selective cyclooxygenase-2 inhibitors. Concomitant use of two or more NSAIDs (including acetylsalicylic acid) should be avoided, as this increases the frequency of adverse effects (see section "Special precautions for use").

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

Corticosteroids. The risk of gastrointestinal ulceration or bleeding increases (see section "Special precautions for use").

Diuretics. Aceclofenac, like other NSAIDs, may suppress diuretic activity, reduce the diuretic effect of furosemide and bumetanide, and diminish the antihypertensive effect of thiazides. Concomitant use with potassium-sparing diuretics may lead to increased potassium levels; therefore, serum potassium levels should be monitored regularly.

Aceclofenac did not affect blood pressure control when used concomitantly with bendroflumethiazide, although interactions with other diuretics cannot be excluded.

Antihypertensive agents. NSAIDs may also reduce the effectiveness of antihypertensive drugs. Concomitant use of ACE inhibitors or angiotensin II receptor antagonists with NSAIDs may lead to impaired renal function. The risk of acute renal failure, which is usually reversible, increases in certain patients with impaired renal function, such as elderly or dehydrated patients. Therefore, caution should be exercised when combining with NSAIDs, especially in elderly patients. Patients should consume adequate fluid and be under appropriate surveillance (monitoring of renal function at the start of concomitant therapy and periodically during treatment).

Hypoglycemic agents. Clinical studies show that diclofenac can be used together with oral hypoglycemic agents without affecting their clinical efficacy. However, there are isolated reports of hypoglycemic and hyperglycemic effects. Thus, when taking aceclofenac, dosage adjustment of agents that may cause hypoglycemia should be considered.

Zidovudine. Concomitant use of NSAIDs and zidovudine increases the risk of hematological toxicity. Data exist on increased risk of hemarthrosis and hematomas in HIV (+) patients with hemophilia receiving zidovudine and ibuprofen.

Special precautions for use.

Concomitant use of aceclofenac and NSAIDs, including selective COX-2 inhibitors, should be avoided.

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

Gastrointestinal (GI) effects

Gastrointestinal bleeding, ulceration, or perforation, sometimes fatal, have been reported with all NSAIDs at any time during therapy, both in the presence and absence of warning symptoms, and regardless of a history of serious gastrointestinal pathology.

The risk of bleeding, ulceration, and gastrointestinal perforation increases with higher NSAID doses, in patients with a history of peptic ulcer, particularly if complicated by hemorrhage or perforation (see section "Contraindications"), and in elderly patients. These patients should receive the lowest effective dose. Concomitant therapy with gastroprotective agents (e.g., misoprostol or proton pump inhibitors) is required for these patients, as well as for patients taking low-dose acetylsalicylic acid (aspirin) or other drugs that negatively affect gastrointestinal status (see section "Interaction with other medicinal products and other forms of interaction").

Patients with gastrointestinal disorders, including elderly patients, should be informed about any unusual gastrointestinal symptoms (particularly gastrointestinal bleeding), especially at the beginning of treatment. Particular caution is required in patients who are concomitantly taking medications that increase the risk of bleeding or ulceration, such as systemic corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents (such as acetylsalicylic acid) (see section "Interaction with other medicinal products and other forms of interaction").

If gastrointestinal bleeding or ulceration occurs in patients taking aceclofenac, treatment should be discontinued.

Cardiovascular and cerebrovascular effects

Patients with hypertension and/or mild to moderate congestive heart failure require appropriate monitoring and special caution, as fluid retention and edema have been reported with NSAID use. Clinical trials and epidemiological data indicate that some NSAIDs (particularly at high doses and with long-term use) may slightly increase the risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

Particular caution is advised when administering aceclofenac to patients with heart failure (NYHA functional class I) and those with cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, and smoking). Since the adverse cardiovascular effects increase with higher doses and longer duration of treatment, the lowest effective daily dose should be used for the shortest possible duration. The need for continued symptomatic treatment and the efficacy of therapy should be regularly reassessed.

Aceclofenac should be used with caution and under close medical supervision in patients with the following conditions (due to the risk of exacerbation) (see section "Adverse reactions"):

− symptoms indicating gastrointestinal tract disorders, including upper and lower gastrointestinal regions;

− history of gastrointestinal ulcer, bleeding, or perforation;

− ulcerative colitis;

− Crohn's disease;

− bleeding tendency, SLE (systemic lupus erythematosus), porphyria, and disorders of hematopoiesis and hemostasis.

Effects on liver and kidneys

NSAID use may cause dose-dependent reduction in prostaglandin synthesis and lead to acute renal failure. The importance of prostaglandins in maintaining renal blood flow should be considered when administering the drug to patients with impaired cardiac, renal, or hepatic function, patients receiving diuretics, patients after surgery, and elderly patients.

Caution is advised when using the drug in patients with mild to moderate hepatic or renal impairment, as well as in patients with other conditions associated with fluid retention. In these patients, NSAID use may lead to worsening renal function and fluid retention. Caution is also required when administering aceclofenac to patients taking diuretics or those at increased risk of hypovolemia. The lowest effective dose should be used, and renal function should be monitored regularly. Renal adverse effects are usually reversible upon discontinuation of aceclofenac.

Aceclofenac use should be discontinued if liver function test abnormalities persist or worsen, if clinical signs of liver disease develop, or if other manifestations occur (e.g., eosinophilia, rash). Hepatitis may develop without prodromal symptoms. NSAID use in patients with hepatic porphyria may trigger an attack.

Systemic lupus erythematosus and mixed connective tissue disease

Patients with systemic lupus erythematosus and mixed connective tissue diseases have an increased risk of developing aseptic meningitis (see section "Adverse reactions").

Hypersensitivity and skin reactions

Like other NSAIDs, aceclofenac may cause allergic reactions, including anaphylactic/anaphylactoid reactions, even upon first administration. Severe skin reactions (some of which may be fatal), including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely following NSAID use (see section "Adverse reactions"). The highest risk of these reactions occurs early in treatment, particularly within the first month of therapy. If skin rashes, mucosal lesions in the oral cavity, or other signs of hypersensitivity occur, aceclofenac should be discontinued.

In rare cases, complications such as serious skin and soft tissue infections may occur during varicella (chickenpox). At present, the role of NSAIDs in worsening these infections cannot be excluded. Therefore, aceclofenac should be avoided during varicella.

Hematological disorders

Aceclofenac may cause reversible inhibition of platelet aggregation (see section "Interaction with other medicinal products and other forms of interaction").

Respiratory system disorders

Caution is advised when administering the drug to patients with bronchial asthma, including a history of asthma, as NSAID use may provoke sudden bronchospasm in such patients.

Elderly patients

Caution is required when administering the drug to elderly patients (aged 65 years and older), as they are more likely to experience adverse effects (particularly bleeding and gastrointestinal perforation) with NSAID use. Complications may be fatal. In addition, elderly patients more frequently suffer from renal, hepatic, or cardiovascular disorders.

Long-term use

All patients receiving long-term treatment with nonsteroidal anti-inflammatory drugs should be under close medical supervision (including complete blood count, liver and kidney function tests).

Excipients

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

There are no data on the use of aceclofenac during pregnancy.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development.

Epidemiological data suggest an increased risk of miscarriage and congenital heart defects and gastroschisis following the use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of congenital heart defects increases from less than 1% to approximately 1.5%. The risk increases with higher doses and longer duration of treatment.

In animal studies, prostaglandin synthesis inhibitors lead to pre- and post-implantation embryo/fetal loss and increased embryonic and fetal mortality. An increased incidence of various malformations, including cardiovascular defects, has also been observed in animals treated with prostaglandin synthesis inhibitors during organogenesis.

From the 20th week of pregnancy, aceclofenac use may cause oligohydramnios due to fetal renal dysfunction. This effect may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, there have been reports of arterial duct constriction after treatment in the second trimester, which in most cases resolved after stopping the drug. Therefore, Diklotol® should not be prescribed during the first and second trimesters of pregnancy, except in cases of extreme necessity. If aceclofenac is used by a woman attempting to become pregnant or during the first or second trimester of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible.

Prenatal monitoring for oligohydramnios and arterial duct constriction may be advisable after aceclofenac exposure for several days starting from the 20th week of pregnancy. Diklotol® treatment should be discontinued if oligohydramnios or arterial duct constriction is detected.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors:

• may affect the fetus, causing cardiopulmonary toxicity (premature constriction/closure of the arterial duct and pulmonary hypertension);
• may affect the fetus, causing renal dysfunction that may progress to renal failure with oliguria (see above).

In women at the end of pregnancy and in newborns, the drug may affect bleeding time due to its antiplatelet effect, which may occur even after very low doses;

the drug may inhibit uterine contractions, leading to delayed or prolonged labor.

Thus, the use of aceclofenac is contraindicated during the third trimester of pregnancy (see sections "Contraindications" and "Special precautions for use").

Period of breastfeeding

There is no information on the passage of aceclofenac into human breast milk. However, no significant penetration of radiolabeled (C14) aceclofenac into rat milk has been observed.

Like other NSAIDs, aceclofenac passes into breast milk in small amounts; therefore, the drug is contraindicated in women during breastfeeding to avoid undesirable effects on the infant.

Fertility

Aceclofenac, like other cyclooxygenase/prostaglandin synthesis inhibitors, may impair fertility and is not recommended for women attempting to conceive. Women experiencing difficulties with conception or undergoing fertility investigations should discontinue aceclofenac use.

Ability to affect reaction speed when driving or operating machinery.

Patients experiencing symptoms such as weakness, dizziness, somnolence, vertigo, or other central nervous system effects while taking NSAIDs should refrain from driving or operating other potentially dangerous machinery.

Method of administration and dosing.

Diclotol®, coated tablets, are intended for oral administration and should be taken with at least ½ glass of liquid. It is recommended to take Diclotol® with food. Adverse effects can be minimized by keeping the duration of treatment as short as possible, necessary to control symptoms (see section "Special instructions").

Adults. The maximum recommended dose is 200 mg daily, administered as two doses of 100 mg each (1 tablet in the morning and 1 tablet in the evening).

Elderly patients. These patients should be carefully monitored, as they more frequently exhibit impaired renal, hepatic, or cardiovascular function and are more likely to be receiving concomitant therapy for other conditions, which increases the risk of serious adverse reactions. If NSAID therapy is necessary, it should be administered at the lowest effective dose and for the shortest possible duration. Dose reduction is generally not required. Close monitoring is essential to detect gastrointestinal bleeding during NSAID therapy promptly, and recommendations described in the section "Special instructions" should be followed.

Hepatic impairment. In patients with mild or moderate hepatic impairment, the dose of aceclofenac should be reduced. The recommended initial dose is 100 mg daily (see section "Special instructions").

Renal impairment. There is insufficient data regarding the need for dose adjustment of aceclofenac in patients with mild renal impairment; however, caution should be exercised when administering the drug to these patients (see section "Special instructions").

Children.

There are no clinical data on the use of aceclofenac; therefore, this medication is contraindicated in this age group.

Overdose.

There are no reported cases of aceclofenac overdose in humans.

Possible symptoms

Headache, nausea, vomiting, stomach pain, dizziness, vertigo, gastrointestinal irritation, gastrointestinal bleeding, diarrhea, disorientation, excitement, coma, tinnitus, arterial hypotension, respiratory depression, loss of consciousness, seizures. In severe poisoning, acute renal failure and hepatic dysfunction may occur.

Management

Management of acute NSAID poisoning includes administration of antacids (if necessary) and other supportive and symptomatic treatments for complications such as arterial hypotension, renal failure, seizures, gastrointestinal mucosal irritation, and respiratory depression.

Management of acute aceclofenac poisoning after oral intake includes prevention of drug absorption by gastric lavage and administration of activated charcoal (repeated doses) as soon as possible after overdose. Forced diuresis, dialysis, or hemoperfusion may be insufficiently effective in removing NSAIDs due to their high degree of plasma protein binding and extensive metabolism.

However, adequate diuresis should be maintained.

Renal and hepatic functions should be closely monitored.

The patient should be observed for at least four hours after ingestion of a potentially toxic amount of the drug.

In cases of frequent or prolonged seizures, intravenous diazepam should be administered. Other interventions may be indicated depending on the patient's clinical condition.

Adverse Reactions

Gastrointestinal tract: the most common adverse reactions were gastrointestinal. Gastrointestinal ulcers, perforation, or gastrointestinal bleeding, sometimes fatal, may occur during NSAID therapy, particularly in elderly patients (see section "Special precautions"). Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, epigastric pain, melena, hematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease have been reported with NSAID use (see section "Special precautions"). Gastritis has been observed less frequently.

Hypersensitivity and skin reactions: non-specific allergic reactions may occur during NSAID therapy, including anaphylactic reactions, respiratory tract reactivity such as asthma, worsening of asthma, bronchospasm, or dyspnea, and various skin reactions, including rashes of different types, pruritus, urticaria, purpura, angioedema, and less frequently exfoliative and bullous dermatitis (including Stevens-Johnson syndrome and toxic epidermal necrolysis).

Neurological disorders and sensory organ disorders: optic neuritis, cases of aseptic meningitis (particularly in patients with autoimmune disorders such as systemic lupus erythematosus or mixed connective tissue disease) presenting with symptoms such as neck stiffness (rigidity), fever, disorientation, confusion, hallucinations, malaise.

Hematological disorders: agranulocytosis, aplastic anemia.

Edema, arterial hypertension, and heart failure have been reported in association with NSAID use.

Clinical studies and epidemiological data indicate that some NSAIDs (particularly at high doses and with prolonged use) are associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke) (see section "Special precautions").

The table below summarizes adverse events reported in clinical studies and with the use of the medicinal product Diklotol®, grouped by organ systems and frequency of occurrence.

Other adverse effects observed with the use of NSAIDs

Very rare (<1/10000):

Renal and urinary tract disorders: interstitial nephritis.

Skin and subcutaneous tissue disorders: bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare), photosensitization.

In exceptional cases, severe skin infections and soft tissue infections have been observed during NSAID use in patients with varicella (see also sections "Special precautions" and "Interaction with other medicinal products and other types of interactions").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicinal product registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, and their legal representatives are encouraged to report all 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 at a temperature not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

10 tablets in a blister, 3 or 10 blisters in a cardboard pack.

14 tablets in a blister, 2 blisters in a cardboard pack.

Prescription status.

Prescription-only medicine.

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and location of operations.

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

INSTRUCTION

for medical use of the medicinal product

DICLOTOLÒ

(DICLOTOLÒ)

Composition:

Active ingredient: aceclofenac;

1 tablet contains 100 mg of aceclofenac;

Excipients: microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, stearic acid, Opadry-YS-1-7027 White (hydroxypropylmethylcellulose), titanium dioxide (E 171), triacetin.

Dosage form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex, film-coated tablets.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Acetic acid derivatives and related substances.

ATC code M01AB16.

Pharmacological properties.

Pharmacodynamics.

Aceclofenac is a non-steroidal agent with anti-inflammatory and analgesic effects. The mechanism of action of this drug is believed to be based on inhibition of prostaglandin synthesis.

Pharmacokinetics.

Absorption

After oral administration, aceclofenac is rapidly absorbed, with its bioavailability being almost 100%. Peak plasma concentration is reached approximately within 1.25–3 hours after administration. Food intake slows absorption but does not affect its extent.

Distribution

Aceclofenac is highly bound to plasma proteins (> 99.7%). It penetrates into synovial fluid, where its concentration reaches approximately 60% of the plasma concentration. The volume of distribution is approximately 30 L.

Elimination

The mean elimination half-life is 4–4.3 hours. Clearance is 5 liters per hour. Approximately two-thirds of the administered dose is excreted in the urine, predominantly as conjugated hydroxylated metabolites. Only 1% of a single oral dose is excreted unchanged.

Aceclofenac is likely metabolized via CYP2C9 to its main metabolite, 4-OH-aceclofenac, which has negligible clinical activity. Diclofenac and 4-OH-diclofenac have been identified among the numerous metabolites.

Special patient groups

No changes in the pharmacokinetics of aceclofenac have been observed in elderly patients.

In patients with impaired liver function, slower elimination of aceclofenac was observed after a single dose. However, in studies with repeated administration of 100 mg daily, no differences in pharmacokinetic parameters were observed between patients with mild to moderate hepatic cirrhosis and healthy volunteers.

In patients with mild or moderate renal impairment, no clinically significant differences in pharmacokinetics were observed after a single dose.

Clinical characteristics.

Indications.

Symptomatic therapy of pain and inflammation in osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, as well as other musculoskeletal disorders associated with pain (e.g., periarthritis of the shoulder and scapula or extra-articular rheumatism).

As an analgesic in conditions associated with pain (including low back pain, dental pain, and primary (functional) dysmenorrhea).

Contraindications.

Aceclofenac is contraindicated:

• in patients with hypersensitivity to aceclofenac or to any excipient of the medicinal product (see section "Composition");
• in patients in whom acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (NSAIDs) induce asthma attacks, acute rhinitis, angioedema, or urticaria, as well as patients with hypersensitivity to these drugs;
• in patients with a history of gastrointestinal bleeding or ulcer perforation associated with previous NSAID therapy;
• in patients with active peptic ulcer or gastrointestinal bleeding, including history of such (two or more separate confirmed episodes of ulcer development or bleeding);
• in patients with active bleeding or bleeding disorders (hemophilia or coagulation disorders);
• in patients with congestive heart failure (NYHA functional class II-IV), ischemic heart disease, peripheral arterial disease, or cerebrovascular disorders;
• in patients with cerebrovascular disease who have experienced stroke or transient ischemic attacks;
• in patients with ischemic heart disease who have angina pectoris or have had myocardial infarction;
• for treatment of perioperative pain in coronary artery bypass grafting (or when using cardiopulmonary bypass equipment);
• in patients with severe hepatic or renal insufficiency;
• during breastfeeding;
• in the last trimester of pregnancy;
• in patients under 18 years of age.

Interaction with other medicinal products and other forms of interaction.

Interaction studies have not been conducted, except for interaction with warfarin.

Aceclofenac is metabolized via cytochrome P450 2C9, and in vitro data indicate that aceclofenac may be an inhibitor of this enzyme. Therefore, a risk of pharmacokinetic interaction is possible when co-administered with phenytoin, cimetidine, tolbutamide, phenylbutazone, amiodarone, miconazole, and sulfaphenazole. As with other NSAIDs, there is an increased risk of pharmacokinetic interaction with other drugs eliminated via active renal secretion, such as methotrexate and lithium salts. Aceclofenac is almost completely bound to plasma albumin, and thus displacement-type interactions with other protein-bound drugs are possible.

Due to lack of pharmacokinetic interaction studies with aceclofenac, the information below is based on data from other NSAIDs.

Should avoid concomitant use

Methotrexate. NSAIDs inhibit tubular secretion of methotrexate; in addition, a minor metabolic interaction may occur, leading to reduced methotrexate clearance. Therefore, NSAIDs should be avoided when high-dose methotrexate is administered.

Cardiac glycosides, digoxin. NSAIDs may exacerbate heart failure, reduce GFR (glomerular filtration rate), and inhibit renal clearance of glycosides, leading to increased plasma levels of glycosides. Concomitant use should be avoided unless frequent monitoring of digoxin concentrations is performed.

Lithium preparations and digoxin. Some NSAIDs inhibit renal clearance of lithium and digoxin, leading to increased serum concentrations of both substances. Concomitant use should be avoided unless frequent monitoring of lithium and digoxin concentrations is performed.

Anticoagulants. NSAIDs inhibit platelet aggregation and damage the gastrointestinal mucosa, which may potentiate the effect of anticoagulants and increase the risk of gastrointestinal bleeding in patients taking anticoagulants. Concomitant use of aceclofenac with oral anticoagulants of the coumarin group, ticlopidine, and thrombolytics should be avoided unless careful patient monitoring is conducted.

Quinolone antibiotics. Animal studies show that NSAIDs increase the risk of seizures associated with quinolone antibiotics. Patients taking NSAIDs and quinolone antibiotics have an increased risk of developing seizures.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs). When used concomitantly with NSAIDs, the risk of gastrointestinal bleeding is increased (see section "Special precautions for use").

Combinations requiring dose adjustment and caution in use

Methotrexate. Potential interaction between NSAIDs and methotrexate should be considered, even at low methotrexate doses, especially in patients with impaired renal function. Renal function parameters should be monitored during concomitant use. Caution is required if NSAIDs and methotrexate have been taken within 24 hours, as methotrexate concentration may increase, thereby increasing the toxicity of this drug.

Cyclosporine, tacrolimus. When NSAIDs are taken concomitantly with cyclosporine or tacrolimus, the risk of increased nephrotoxicity due to reduced renal prostacyclin production should be considered. Therefore, renal function parameters should be closely monitored during concomitant use.

Other analgesics, NSAIDs, including selective cyclooxygenase-2 inhibitors. Concomitant use of two or more NSAIDs (including acetylsalicylic acid) should be avoided, as this increases the frequency of adverse events (see section "Special precautions for use").

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

Corticosteroids. The risk of developing ulcers or gastrointestinal bleeding increases (see section "Special precautions for use").

Diuretics. Aceclofenac, like other NSAIDs, may suppress diuretic activity, reduce the diuretic effect of furosemide and bumetanide, and reduce the antihypertensive effect of thiazides. Concomitant use with potassium-sparing diuretics may lead to increased potassium levels; therefore, serum potassium levels should be monitored regularly.

Aceclofenac did not affect blood pressure control when used concomitantly with bendroflumethiazide, although interactions with other diuretics cannot be excluded.

Antihypertensive agents. NSAIDs may also reduce the effectiveness of antihypertensive drugs. Concomitant use of ACE inhibitors or angiotensin II receptor antagonists with NSAIDs may lead to impaired renal function. The risk of acute renal failure, which is usually reversible, increases in certain patients with impaired renal function, such as elderly or dehydrated patients. Therefore, caution should be exercised when using NSAIDs concomitantly, especially in elderly patients. Patients should consume adequate fluids and be under appropriate surveillance (monitoring of renal function at the beginning of concomitant therapy and periodically during treatment).

Hypoglycemic agents. Clinical studies show that diclofenac can be used together with oral hypoglycemic agents without affecting their clinical efficacy. However, there are isolated reports of hypoglycemic and hyperglycemic effects of the drug. Thus, when taking aceclofenac, dose adjustments of drugs that may cause hypoglycemia should be considered.

Zidovudine. Concomitant use of NSAIDs and zidovudine increases the risk of hematological toxicity. There are data indicating an increased risk of hemarthrosis and hematomas in HIV (+) patients with hemophilia who are receiving zidovudine and ibuprofen.

Special precautions for use.

Concomitant use of aceclofenac and NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

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

Gastrointestinal (GI) effects

GI bleeding, ulceration, or perforation have been reported with all NSAIDs at any time during therapy, both in the presence and absence of symptoms, regardless of prior serious gastrointestinal pathology.

The risk of bleeding, ulceration, and GI perforation increases with higher NSAID doses, particularly in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. These patients should receive the lowest effective dose. Concomitant therapy with gastroprotective agents (e.g., misoprostol or proton pump inhibitors) is required. Such protective therapy is also recommended for patients taking low-dose acetylsalicylic acid (aspirin) or other drugs that adversely affect the gastrointestinal tract (see section "Interaction with other medicinal products and other forms of interaction").

Patients with gastrointestinal disorders, including the elderly, should be informed about any unusual gastrointestinal symptoms (particularly GI bleeding), especially during initial treatment. Particular caution is required in patients who are concurrently taking medications that increase the risk of bleeding or ulceration, such as systemic corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents (e.g., acetylsalicylic acid) (see section "Interaction with other medicinal products and other forms of interaction").

If GI bleeding or ulceration occurs in patients taking aceclofenac, treatment should be discontinued.

Cardiovascular and cerebrovascular effects

Patients with hypertension and/or mild to moderate heart failure require appropriate monitoring and caution, as fluid retention and edema have been reported with NSAID use. Clinical trials and epidemiological data indicate that some NSAIDs (particularly when used at high doses and for prolonged periods) may slightly increase the risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

Particular caution should be exercised when administering aceclofenac to patients with heart failure (NYHA functional class I) and those with cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes, smoking). As the adverse cardiovascular effects increase with higher doses and longer treatment duration, the lowest effective daily dose should be used for the shortest possible duration. The need for continued symptomatic treatment and the efficacy of therapy should be regularly reassessed.

Aceclofenac should be used with caution and under close medical supervision in patients with the following conditions (due to the risk of exacerbation) (see section "Adverse reactions"):

− symptoms suggestive of gastrointestinal disorders, including upper and lower GI tract involvement;

− history of peptic ulcer, GI bleeding, or perforation;

− ulcerative colitis;

− Crohn's disease;

− bleeding tendencies, SLE (systemic lupus erythematosus), porphyria, and disorders of hematopoiesis and hemostasis.

Effects on liver and kidneys

NSAID use may cause dose-dependent reduction in prostaglandin synthesis and lead to acute renal failure. The importance of prostaglandins in maintaining renal blood flow should be considered when administering the drug to patients with impaired cardiac, renal, or hepatic function, those receiving diuretics, postoperative patients, and the elderly.

Caution is advised when using the drug in patients with mild to moderate hepatic or renal impairment and in those with conditions associated with fluid retention. In these patients, NSAID use may impair renal function and cause fluid retention. Caution is also required when administering aceclofenac to patients taking diuretics or those at increased risk of hypovolemia. The lowest effective dose should be used, and renal function should be monitored regularly. Renal adverse effects are usually reversible upon discontinuation of aceclofenac.

Aceclofenac therapy should be discontinued if liver function test abnormalities persist or worsen, if clinical signs of liver disease develop, or if other manifestations occur (e.g., eosinophilia, rash). Hepatitis may develop without prodromal symptoms. NSAID use in patients with hepatic porphyria may trigger an acute attack.

Systemic lupus erythematosus and mixed connective tissue disease

Patients with systemic lupus erythematosus and mixed connective tissue diseases have an increased risk of developing aseptic meningitis (see section "Adverse reactions").

Hypersensitivity and skin reactions

Like other NSAIDs, aceclofenac may cause allergic reactions, including anaphylactic/anaphylactoid reactions, even upon first use. Severe skin reactions (some of which may be fatal), including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely following NSAID use (see section "Adverse reactions"). The highest risk for these reactions occurs during the initial phase of treatment, particularly within the first month of use. If skin rashes, mucosal lesions in the oral cavity, or other signs of hypersensitivity occur, aceclofenac should be discontinued.

In special cases, complications such as serious skin and soft tissue infections may occur during varicella (chickenpox). The role of NSAIDs in worsening these infections cannot currently be excluded. Therefore, aceclofenac should be avoided during varicella.

Hematological disorders

Aceclofenac may cause reversible inhibition of platelet aggregation (see section "Interaction with other medicinal products and other forms of interaction").

Respiratory system disorders

Caution should be exercised when administering the drug to patients with bronchial asthma, including a history of asthma, as NSAID use may provoke sudden bronchospasm in such patients.

Elderly patients

Caution should be exercised when using the drug in elderly patients (aged 65 years and older), as they are more likely to experience adverse effects (particularly bleeding and GI perforation) with NSAID use. Complications may be fatal. Additionally, elderly patients more frequently have renal, hepatic, or cardiovascular disorders.

Long-term use

All patients receiving long-term treatment with nonsteroidal anti-inflammatory drugs should be under close medical supervision (including complete blood count, and liver and kidney function tests).

Excipients

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

There are no data on the use of aceclofenac during pregnancy.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development.

Epidemiological data suggest an increased risk of miscarriage, congenital heart defects, and gastroschisis following the use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of congenital heart defects increases from less than 1% to approximately 1.5%. The risk increases with higher doses and longer duration of treatment.

In animal studies, prostaglandin synthesis inhibitors have been associated with pre- and post-implantation embryonic and fetal loss and increased incidence of various malformations, including cardiovascular defects, when administered during organogenesis.

From the 20th week of pregnancy, aceclofenac use may cause oligohydramnios due to fetal renal dysfunction. This effect may occur soon after initiation of treatment and is usually reversible upon discontinuation. Additionally, there have been reports of arterial duct constriction following second-trimester treatment, which in most cases resolved after stopping the drug. Therefore, Diklotol® should not be prescribed during the first and second trimesters of pregnancy, except in cases of extreme necessity. If aceclofenac is used in women attempting to conceive or during the first or second trimester, the dose should be as low as possible and the duration of treatment as short as possible.

Prenatal monitoring for oligohydramnios and arterial duct constriction may be advisable following aceclofenac exposure starting from the 20th week of pregnancy. Diklotol® should be discontinued if oligohydramnios or arterial duct constriction is detected.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors:

• may affect the fetus, causing cardiopulmonary toxicity (premature constriction/closure of the arterial duct and pulmonary hypertension);
• may affect the fetus by causing renal dysfunction, potentially progressing to renal failure with oliguria (see above).

In women near term and in newborns, the drug may affect bleeding time due to its antiplatelet effect, which may occur even after very low doses;

the drug may inhibit uterine contractions, leading to delayed or prolonged labor.

Therefore, the use of aceclofenac is contraindicated during the third trimester of pregnancy (see sections "Contraindications" and "Special precautions for use").

Lactation period

There is no information on the passage of aceclofenac into human breast milk. However, minimal transfer of radiolabeled (C14) aceclofenac into rat milk has been observed.

Like other NSAIDs, aceclofenac passes into breast milk in small amounts; therefore, the drug is contraindicated in breastfeeding women to avoid potential adverse effects on the infant.

Fertility

Aceclofenac, like other cyclooxygenase/prostaglandin synthesis inhibitors, may impair fertility and is not recommended for women attempting to conceive. Women experiencing infertility or undergoing fertility investigations should discontinue aceclofenac.

Ability to influence reaction speed when driving or operating machinery.

Patients who experience symptoms such as weakness, dizziness, somnolence, vertigo, or other central nervous system effects during NSAID therapy should refrain from driving or operating machinery.

Method of administration and dosing.

Diclotol®, coated tablets, are intended for oral administration and should be taken with at least ½ glass of liquid. Diclotol® is preferably taken with food. Adverse effects can be minimized by keeping the duration of treatment as short as possible, necessary to control symptoms (see section "Special precautions for use").

Adults. The maximum recommended dose is 200 mg daily, administered in two doses of 100 mg (1 tablet in the morning and 1 tablet in the evening).

Elderly patients. These patients should be carefully monitored, as they more frequently have impaired renal or hepatic function, cardiovascular disorders, and are more likely to receive concomitant therapy for other conditions, which increases the risk of serious adverse reactions. If NSAID therapy is necessary, it should be administered at the lowest effective dose and for the shortest possible duration. Dose reduction is generally not required. Patients should be closely monitored for gastrointestinal bleeding during NSAID therapy, and recommendations described in the section "Special precautions for use" should be followed.

Hepatic impairment. For patients with mild to moderate hepatic impairment, the dose of aceclofenac should be reduced. The recommended initial dose is 100 mg daily (see section "Special precautions for use").

Renal impairment. There is no information indicating that dose adjustment of aceclofenac is required in patients with mild renal impairment; however, caution should be exercised when administering the drug to these patients (see section "Special precautions for use").

Children.

There are no clinical data on the use of aceclofenac; therefore, this medication is contraindicated in this age group.

Overdose.

There are no data on aceclofenac overdose in humans.

Possible symptoms

Headache, nausea, vomiting, epigastric pain, dizziness, somnolence, gastrointestinal irritation, gastrointestinal bleeding, diarrhea, disorientation, excitement, coma, tinnitus, arterial hypotension, respiratory depression, loss of consciousness, seizures. In severe poisoning, acute renal failure and hepatic dysfunction may occur.

Management

Management of acute NSAID poisoning includes administration of antacids (if necessary) and other supportive and symptomatic treatments for complications such as arterial hypotension, renal failure, seizures, gastrointestinal mucosal irritation, and respiratory depression.

Management of acute poisoning following oral intake of aceclofenac includes prevention of drug absorption by gastric lavage and administration of activated charcoal (repeated doses) as soon as possible after overdose. Forced diuresis, dialysis, or hemoperfusion may be insufficiently effective in eliminating NSAIDs due to their high degree of plasma protein binding and extensive metabolism.

However, adequate urine output should be maintained.

Renal and hepatic functions should be closely monitored.

The patient should be observed for at least four hours after ingestion of a potentially toxic amount of the drug.

In cases of frequent or prolonged seizures, intravenous diazepam should be administered. Other interventions may be indicated depending on the patient's clinical condition.

Adverse Reactions

Gastrointestinal tract: The most frequently reported adverse reactions were gastrointestinal. Gastrointestinal ulcers, perforation, or gastrointestinal bleeding, sometimes fatal, may occur during NSAID therapy, particularly in elderly patients (see section "Special Warnings and Precautions for Use"). Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, and exacerbations of colitis and Crohn’s disease have been reported with NSAID use (see section "Special Warnings and Precautions for Use"). Gastritis has been observed less frequently.

Hypersensitivity and skin reactions: Non-specific allergic reactions may occur during NSAID therapy, including anaphylactic reactions, respiratory tract reactivity such as asthma, worsening of asthma, bronchospasm, or dyspnea, and various skin reactions, including rashes of different types, pruritus, urticaria, purpura, and angioedema. Rarely, exfoliative and bullous dermatitis (including epidermal necrolysis and erythema multiforme) have been reported.

Neurological disorders and sensory organ disorders: Optic neuritis, cases of aseptic meningitis (particularly in patients with autoimmune disorders such as systemic lupus erythematosus or mixed connective tissue disease) have been reported. Symptoms may include neck stiffness (rigidity), fever, disorientation, confusion, hallucinations, and malaise.

Hematological disorders: Agranulocytosis, aplastic anemia.

Edema, arterial hypertension, and heart failure have been reported in association with NSAID use.

Clinical studies and epidemiological data suggest that some NSAIDs (particularly when used at high doses and for prolonged periods) may slightly increase the risk of arterial thrombotic events (e.g., myocardial infarction or stroke) (see section "Special Warnings and Precautions for Use").

The table below lists adverse events reported during clinical studies and with the use of the medicinal product Diklotol®, grouped by organ system and frequency of occurrence.

Other adverse reactions observed with the use of NSAIDs

Very rare (<1/10,000):

Renal and urinary disorders: interstitial nephritis.

Skin and subcutaneous tissue disorders: bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare), photosensitization.

In isolated cases, serious skin infections and soft tissue infections have been observed during NSAID use in patients with varicella (see also sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all 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 at a temperature not exceeding 25 °C in the original packaging.

Keep out of the reach of children.

Packaging.

10 tablets in a blister, 3 or 10 blisters in a cardboard box.

14 tablets in a blister, 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and location of operations.

Plot No. M-3, Indore Special Economic Zone, Phase-II, Pithampur, Distt. Dhar, Madhya Pradesh, Pin 454774, India.