Aertal

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AERTAL® (AIRTAL®)

Composition:

Active substance: aceclofenac;

One film-coated tablet contains 100 mg of aceclofenac;

Excipients:

Tablet core: glycerol distearate, sodium croscarmellose, povidone, microcrystalline cellulose;

Coating: Sepifilm 752 White (hypromellose, microcrystalline cellulose, titanium dioxide (E 171), macrogol stearate).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex, film-coated tablets, approximately 8 mm in diameter. One side of the tablet bears an engraved "A".

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 considered 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%). Aceclofenac penetrates into synovial fluid, where its concentration reaches approximately 60% of that in plasma. The volume of distribution is approximately 30 L.

Elimination

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

Aceclofenac is likely metabolized via CYP2C9 to the main metabolite 4-OH-aceclofenac, which has negligible clinical activity. Diclofenac and 4-OH-diclofenac have been detected among several 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 with 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.

• Osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and other musculoskeletal disorders associated with pain (e.g., periarthritis of the shoulder and arm, and other extra-articular manifestations of rheumatism).
• Conditions associated with pain (including low back pain, dental pain, and primary 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) have previously triggered asthma attacks, acute rhinitis, angioedema, or urticaria, as well as in patients with known 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 (two or more distinct documented episodes of ulcer 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 transient ischemic attacks;
• in patients with ischemic heart disease who have angina pectoris or a history of myocardial infarction;
• for the treatment of perioperative pain in coronary artery bypass graft (CABG) surgery (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 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 exists 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 the lack of pharmacokinetic interaction studies with aceclofenac, the information below is based on data from other NSAIDs.

Should be avoided

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 and digoxin preparations. Some NSAIDs inhibit renal clearance of lithium and digoxin, resulting in 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 receiving anticoagulant therapy. 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 receiving NSAIDs and quinolone antibiotics have an increased risk of developing seizures.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs). Concomitant use with NSAIDs increases the risk of gastrointestinal bleeding (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, particularly 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, as methotrexate concentrations 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 (COX-2) inhibitors. Concomitant use of two or more NSAIDs (including acetylsalicylic acid) should be avoided, as this increases the frequency of adverse effects.

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 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 efficacy 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, usually reversible, renal failure increases in certain patients with pre-existing renal impairment, such as elderly or dehydrated patients. Therefore, caution is required when combining these agents, especially in elderly patients. Patients should maintain adequate fluid intake and be under appropriate surveillance (monitoring of renal function at the start of concomitant therapy and periodically during treatment).

Hypoglycemic agents. Clinical studies indicate that diclofenac can be used together with oral hypoglycemic agents without affecting their clinical efficacy. However, isolated reports of hypoglycemic and hyperglycemic effects have been reported. Thus, when taking aceclofenac, dosage adjustments of agents that may cause hypoglycemia may be necessary.

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 who are receiving zidovudine and ibuprofen.

Special precautions for use

Concomitant use of Aertal® 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 below related to the gastrointestinal tract and cardiovascular system).

Gastrointestinal (GI) tract effects

GI 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, regardless of prior history of serious gastrointestinal pathology.

The risk of GI bleeding, ulceration, and perforation increases with higher NSAID doses, 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 negatively affect the gastrointestinal tract (see section "Interaction with other medicinal products and other forms of interaction").

Patients with gastrointestinal disorders, particularly elderly patients, should be instructed to report any unusual gastrointestinal symptoms (especially GI bleeding), including at the beginning of 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 (such as acetylsalicylic acid) (see section "Interaction with other medicinal products and other forms of interaction").

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

Cardiovascular and cerebrovascular effects

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

Particular caution is required when administering aceclofenac to patients with heart failure (NYHA functional class I) or cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking). Since 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 therapeutic efficacy should be reviewed regularly.

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, or disorders of hematopoiesis and hemostasis.

Effects on liver and kidneys

NSAID use may cause dose-dependent reduction in prostaglandin synthesis and 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 deterioration of renal function and fluid retention. Caution is also required when administering Aertal® 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.

Treatment with aceclofenac should be discontinued if liver function test abnormalities persist or worsen, or if clinical symptoms of liver disease or other manifestations (e.g., eosinophilia, rash) occur. 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 or mixed connective tissue disorders have an increased risk of developing aseptic meningitis (see section "Adverse reactions").

Hypersensitivity and skin reactions

Like other NSAIDs, Aertal® 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 such 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, Aertal® 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 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, GI perforation) with NSAID use. Complications may be fatal. Additionally, 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 renal function tests).

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 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 caused pre- and post-implantation embryo/fetal loss and increased embryonic and fetal mortality. In addition, an increased incidence of various malformations, including cardiac defects, has been observed in animals treated with prostaglandin synthesis inhibitors during organogenesis.

From the 20th week of gestation, 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. There have also been reports of arterial duct constriction after second-trimester treatment, which in most cases resolved after stopping the drug. Therefore, Aertal® should not be used 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.

Fetal monitoring for oligohydramnios and arterial duct constriction may be advisable after aceclofenac exposure, starting from the 20th week of pregnancy. Aertal® 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 by 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 oligohydramnios (see above).

In late pregnancy and in the newborn, the drug may prolong bleeding time due to its antiplatelet effect, which may occur even after very low doses; it may also inhibit uterine contractions, leading to delayed or prolonged labor.

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

Breastfeeding period

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

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

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

Ability to affect reaction speed when driving or operating machinery

Patients who experience weakness, dizziness, vertigo, or other central nervous system symptoms while taking NSAIDs should refrain from driving or operating machinery.

Method of Administration and Dosage

Aertal®, film-coated tablets, are intended for oral administration and should be taken with at least ½ glass of liquid. It is advisable to take Aertal® with food.

Adverse effects can be minimized by keeping the duration of treatment as short as possible, while still achieving adequate symptom control (see section "Special Warnings and Precautions for Use").

Adults

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

Elderly Patients

Careful monitoring of these patients is required, as they more frequently have impaired renal or hepatic function, cardiovascular disorders, and are often receiving concomitant therapy for other conditions, which increases the risk of serious adverse reactions. If NSAIDs are necessary, they 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 early during NSAID therapy, and recommendations described in the section "Special Warnings and Precautions for Use" should be followed.

Hepatic Impairment

In 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 Warnings and Precautions for Use").

Renal Impairment

There is insufficient data to recommend dose adjustment of aceclofenac in patients with mild renal impairment; however, caution should be exercised when administering the drug to such patients (see section "Special Warnings and Precautions for Use").

Children

There are no clinical data on the use of Aertal® in children; therefore, this medication is not recommended for use in this age group.

Overdose

There are no reported cases of aceclofenac overdose in humans.

Possible symptoms

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

Treatment

Management of acute poisoning with non-steroidal anti-inflammatory drugs 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.

In cases of acute aceclofenac overdose, treatment should include measures to prevent drug absorption, such as gastric lavage and administration of activated charcoal (repeated doses) as soon as possible after ingestion. Forced diuresis, dialysis, or hemoperfusion may be insufficiently effective for elimination of NSAIDs due to their high degree of plasma protein binding and extensive metabolism.

Adverse Reactions

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

Hypersensitivity and skin reactions: non-specific allergic reactions may occur during NSAID use, including anaphylactic reactions, respiratory tract reactivity (including asthma, worsening of asthma, bronchospasm, or dyspnoea), and various skin reactions such as 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) presenting with symptoms such as neck stiffness (rigidity), fever, disorientation, confusion, hallucinations, and malaise.

Haematological disorders: agranulocytosis, aplastic anaemia.

Oedema, arterial hypertension, and heart failure have been reported in association 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) (see section "Special precautions").

The table below summarises adverse events reported in clinical trials and during the use of the drug Aertal®, grouped by organ systems and frequency of occurrence.

Other adverse effects observed with the use of NSAIDs

Very rare (<1/10000):

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 administration of NSAIDs in patients with varicella (chickenpox) (see also sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C. Keep the medication out of reach of children.

Packaging.

10 film-coated tablets in a blister; 2 or 6 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Gedeon Richter Plc., Hungary.

Manufacturer's address and place of business.

H-1103 Budapest, Demréni út 19-21, Hungary.