Aertal

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

Composition:

active substance: aceclofenac;

1 sachet of oral suspension powder contains 100 mg of aceclofenac;

excipients: sorbitol (E 420), sodium saccharin, aspartame (E 951), colloidal anhydrous silicon dioxide, hypromellose, titanium dioxide (E 171), milk flavor, caramel flavor, creamy flavor.

Pharmaceutical form: Powder for oral suspension.

Basic physicochemical properties: white or almost white powder.

Pharmacotherapeutic group: Non-steroidal anti-inflammatory and antirheumatic agents. Acetic acid derivatives and related substances. ATC code M01A B16.

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%. Maximum plasma concentration is reached approximately 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%). Aceclofenac 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 litres per hour. Approximately two-thirds of the administered dose is excreted in the urine, primarily 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 multiple-dose studies administering 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 to moderate renal impairment, no clinically significant differences in pharmacokinetics were observed after a single dose.

Clinical characteristics.

Indications.

• Osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and other disorders of the musculoskeletal system associated with pain (e.g., periarthritis of the shoulder and other extra-articular manifestations of rheumatism).
• Conditions associated with pain (including back pain, dental pain, and primary dysmenorrhea).

Contraindications.

Aceclofenac is contraindicated:

• in patients with hypersensitivity to aceclofenac or to any excipient of the drug (see section "Composition");
• in patients in whom acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs) induce asthma attacks, bronchospasm, acute rhinitis, angioedema, or urticaria, as well as in 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 in the history (two or more separate documented 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 had a stroke or episodes of transient ischemic attacks;
• in patients with ischemic heart disease who have angina or have had a myocardial infarction;
• for the treatment of perioperative pain in coronary artery bypass grafting (or when using a cardiopulmonary bypass machine);
• in patients with severe hepatic or renal insufficiency;
• 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 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 by active renal secretion, such as methotrexate and lithium preparations. Aceclofenac is almost completely bound to plasma albumin, so 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 avoid concomitant use:

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

Cardiac glycosides, digoxin. NSAIDs may exacerbate heart failure, reduce glomerular filtration rate (GFR), and inhibit renal clearance of glycosides, leading to increased plasma levels of glycosides. Concomitant use should be avoided unless frequent monitoring of digoxin concentration 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 (GI) mucosa, which may potentiate the effect of anticoagulants and increase the risk of GI bleeding in patients taking anticoagulants. Concomitant use of aceclofenac with oral anticoagulants of the coumarin group, ticlopidine, thrombolytics, and heparin 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 GI 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 doses of methotrexate, 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 effects.

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

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

Diuretics. Aceclofenac, like other NSAIDs, may suppress the activity of diuretics, 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.

Antihypertensive agents. NSAIDs may also reduce the effect 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 fluid and be under appropriate supervision (monitoring of renal function at the start of concomitant therapy and periodically during treatment).

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

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 adjustment of agents that may cause hypoglycemia should be considered.

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

Special precautions for use.

Concomitant use of Aertal® 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 gastrointestinal and cardiovascular systems described below).

Gastrointestinal (GI) effects

GI bleeding, ulceration, or perforation, which may be fatal, have been reported with all NSAIDs at any time during therapy, both with and without warning symptoms, and regardless of whether the patient has a 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, particularly if complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. These patients should receive the lowest effective dose. Combination 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 or other drugs that negatively affect the GI tract (see section "Interaction with other medicinal products and other forms of interaction").

Patients with gastrointestinal disorders, including elderly patients, should report any unusual GI symptoms (especially gastrointestinal 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 mild or moderate hypertension and/or mild or moderate congestive heart failure require appropriate monitoring and special caution, as fluid retention and edema have been reported with NSAID use.

There is insufficient data to exclude this risk with aceclofenac.

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).

Patients with congestive heart failure (NYHA functional class I) and those with cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, and smoking) should use aceclofenac with particular caution. 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 the effectiveness of therapy should be reviewed periodically.

Aceclofenac should be used with caution and under close medical supervision in patients with a history of cerebrovascular hemorrhage.

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 "Undesirable effects"):

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

− history of GI ulcer, bleeding, or perforation;

− ulcerative colitis;

− Crohn’s disease;

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

Effects on liver and kidneys

NSAIDs 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 should be exercised when using the drug in patients with mild or 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 renal dysfunction and fluid retention. Caution is also advised when using Aertal® in patients taking diuretics or in individuals at increased risk of hypovolemia. The lowest effective dose should be used, and renal function should be monitored regularly. Renal 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 provoke an attack.

Hypersensitivity and skin reactions

Like other NSAIDs, Aertal® 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 with NSAID use (see section "Undesirable effects"). The highest risk of these reactions occurs early in treatment, and most cases develop within the first month of therapy. If skin rash, 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. The role of NSAIDs in worsening these infections cannot currently be excluded. Therefore, Aertal® should be avoided in patients with varicella.

Systemic lupus erythematosus (SLE) and mixed connective tissue disease

Patients with SLE and mixed connective tissue diseases have an increased risk of developing aseptic meningitis (see section "Undesirable effects").

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 (especially GI bleeding and perforation) with NSAID use. Complications may be fatal. Elderly patients also more frequently suffer from renal, hepatic, or cardiovascular diseases.

Long-term use

All patients receiving long-term NSAID therapy should be under close medical supervision (including complete blood count, liver and kidney function tests).

Excipients

One sachet of Aertal® oral powder for suspension contains 2.64 g of sorbitol, which may cause gastrointestinal discomfort and diarrhea. This product is contraindicated in patients with hereditary fructose intolerance.

Aertal® oral powder for suspension contains aspartame, a source of phenylalanine. Patients with phenylketonuria should be aware that one sachet contains 5.61 mg of phenylalanine.

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 loss and embryonic and fetal mortality. Increased incidence of various malformations, including cardiac 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 may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, there are reports of arterial duct constriction after second-trimester treatment, most of which resolved after stopping therapy. Therefore, Aertal® should not be prescribed during the first and second trimesters 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.

Fetal monitoring for oligohydramnios and arterial duct constriction should be considered after several days of 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 ductus arteriosus and pulmonary hypertension);
• may affect the fetus by causing renal dysfunction, which may progress to renal failure with oligohydramnios (see above).

In women (at the end of pregnancy) and newborns, the drug may affect:

• bleeding time due to antiplatelet effect, which may occur even after very low doses;
• the drug may 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, no significant transfer of radiolabeled (C14) aceclofenac into rat milk has been observed.

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

Fertility

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

Ability to affect reaction speed when driving or operating machinery.

Patients who experience symptoms such as weakness, dizziness, vertigo, or other central nervous system effects while taking NSAIDs should not drive or operate other potentially dangerous machinery.

Method of Administration and Dosage

Method of Administration

Aertal®, powder for oral suspension, is intended for oral use. The contents of one sachet should be dissolved in 40–60 mL of water and taken immediately.

Concomitant food intake slows the rate of absorption of the active substance, but does not reduce the extent of absorption from the gastrointestinal tract.

Dosage

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Special Warnings and Precautions for Use").

Adults. The recommended dose is one sachet twice daily (one sachet in the morning and one in the evening).

Elderly patients. Dose reduction is usually not required; however, precautionary measures indicated in the section "Special Warnings and Precautions for Use" should be considered.

Close monitoring of these patients is essential, as they are more likely to develop impaired renal or hepatic function and cardiovascular disorders. They also frequently receive concomitant therapy for other conditions, which increases the risk of serious adverse reactions. When NSAIDs are necessary, they should be administered at the lowest effective dose and for the shortest possible duration. Dose reduction is generally not required. Careful monitoring is essential to detect gastrointestinal bleeding associated with NSAID therapy at an early stage, 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 information to determine whether dose adjustment of aceclofenac is required 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.

The safety and efficacy of Aertal® in children and adolescents have not been established; therefore, this medication is not recommended for use 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, confusion, restlessness, 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 NSAID poisoning includes administration of antacids (if necessary) and other supportive symptomatic treatment of complications such as arterial hypotension, renal failure, seizures, gastrointestinal mucosal irritation, and respiratory depression.

In cases of acute aceclofenac overdose, treatment involves prevention of drug absorption by 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 protein binding and extensive metabolism.

Adverse Reactions

Gastrointestinal tract: The most common adverse reactions were gastrointestinal (GI) in nature. 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, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation 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.

Fluid retention, hypertension and oedema have been reported in association with NSAID therapy.

Aceclofenac is structurally and metabolically related to diclofenac, which, according to extensive clinical and epidemiological data, is associated with a small increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke), particularly with high-dose or long-term use. Epidemiological data also suggest an increased risk of acute coronary syndrome and myocardial infarction associated with aceclofenac use (see sections "Contraindications" and "Special warnings and precautions for use").

Hypersensitivity and skin reactions: Non-specific allergic reactions may occur during NSAID therapy, 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, angioedema, and less frequently, exfoliative and bullous dermatitis (including epidermal necrolysis and erythema multiforme).

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, with symptoms including neck stiffness, fever, confusion, altered consciousness, hallucinations, and malaise.

Haematological disorders: Agranulocytosis, aplastic anaemia.

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

The table below lists adverse reactions reported in clinical trials and during post-marketing use of the medicinal product Aertal®, grouped by organ system and frequency: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000).

Other adverse effects observed during the use of NSAIDs

Rare:

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 special cases, severe skin infections and soft tissue infections have been observed during the use of NSAIDs in patients with varicella (chickenpox) (see also sections "Special instructions" and "Interaction with other medicinal products and other types of interactions").

Reporting suspected adverse reactions

Reporting of suspected adverse reactions during the post-marketing period is very important. It allows ongoing monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions.

Shelf life: 4 years.

Storage conditions: No special storage conditions required.

Keep out of reach and sight of children.

Packaging. 20 sachets with powder in a cardboard pack.

Supply category: Prescription only.

Manufacturer/Marketing Authorization Holder: Gedeon Richter Plc., Hungary.

Address: 19-21 Demrédi Street, Budapest, H-1103, Hungary.