Acemetacin

Caution in administration of acemetacin with alcohol or central nervous system drugs.

Co-administration of acemetacin and corticosteroids is associated with increased risk of gastrointestinal ulceration or bleeding.

Acemetacin should be used with caution in patients with bleeding. Inhibition of platelet aggregation may occur.

The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. Renal function should be monitored in these patients.

The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. Renal function should be monitored in these patients.

NSAIDs may enhance the effects of anti-coagulants, such as warfarin.

Use caution when acemetacin administered concurrently, particularly in large doses, with coumarin-derivative anticoagulants (warfarin), sulphonylureas, hydantoins or sulfonamides.

Co-administration of acemetacin and anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs) is associated with increased risk of gastro-intestinal bleeding.

Hyperkalaemia has been reported with use of indomethacin and this should be considered when administration with potassium-sparing diuretics is proposed.

Acemetacin decreases elimination of penicillin.

Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

Acetylsalicylic acid reduces the concentration of acemetacin.

Co-administration of acemetacin and ciclosporin is associated with increased risk of nephrotoxicity.

NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Furosemide accelerates the elimination of acemetacin.

Acemetacin decreases the elimination of lithium.

Acemetacin decreases the elimination of methotrexate.

Probenecid decreases the elimination of acemetacin.

Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.

In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis after the administration of acemetacin.

Aggravation of psychiatric disorders, epilepsy or parkinsonism may occur after the administration of acemetacin.

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5 %. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. During the first and second trimester of pregnancy, acemetacin should not be given unless clearly necessary. If acemetacin is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure with oligo-hydroamniosis;

the mother and the neonate, at the end of pregnancy, to:

• possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.
• inhibition of uterine contractions resulting in delayed or prolonged labour.

Consequently, acemetacin is contraindicated during the third trimester of pregnancy.

In limited studies so far available, NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breastfeeding.

Fertility

The use of acemetacin may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of Emflex should be considered.

Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected, patients should not drive or operate machinery. These effects will be enhanced in combination with alcohol.

Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories:

Very common (≥1/10)
Common (≥1/100 to <1/10)
Uncommon (≥1/1,000 to <1/100)
Rare (≥1/10,000 to <1/1,000)
Very rare (<1/10,000)
Not known (cannot be estimated from the available data)

In case of the adverse drug reactions described below it must be considered that these are mainly dose-related and may vary inter-individually.

The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or gastrointestinal bleeding, sometimes fatal, particularly in the elderly, may occur.

Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely. In particular the risk for the occurrence of gastrointestinal bleeding depends on the dose range and the duration of treatment.

Hypersensitivity

Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or © assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angiodema and, more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Cardiovascular and cerebrovascular

Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment.

Clinical trials and epidemiological data suggest that use of some NSAIDs (especially when used at high doses and in long-term treatment) may be associated with a small increase in the risk for arterial thrombotic events (for example myocardial infarction or stroke).

Infections and infestations

In very rare cases, exacerbation of inflammation caused by infection (e.g. development of necrotising fasciitis) has been described in a temporal relationship with the systemic use of non-steroidal anti-inflammatory agents. This may be associated with the mechanism of action of NSAIDs.

Therefore, the patient should contact a doctor if any symptoms of the infection recur or become worse under treatment with acemetacin. The doctor shall check whether an anti-infectious /antibiotic therapy should be indicated.

Blood and the lymphatic system disorders

Very rare: anaemia caused by occult blood loss from the gastrointestinal tract, haemolytic anaemia, pancytopenia (anaemia including aplastic anaemia, leucopenia, agranulocytosis, thrombocytopenia). The initial symptoms may include: fever, sore throat, superficial lesions in the mouth, flu-like symptoms, severe tiredness, epistaxis and subcutaneous haemorrhage.

In these cases, use of the medicinal product must be discontinued immediately and a doctor must be consulted. Any self-medication with analgesic agents and/or antipyretics shall not happen.

In case of long-term treatment, the blood count should be checked at regular intervals.

An influence on thrombocytes aggregation as well as increased haemorrhagic diathesis is possible.

Immune system disorders

Common: hypersensitivity reactions, such as skin rashes and pruritus.

Uncommon: urticaria

Very rare: severe general hypersensitivity reactions. These may manifest in the form of: oedema of the face and the eyelids, swollen tongue, internal laryngeal oedema with stenosis of the airways (angioneurotic oedema), respiratory distress that may lead to an asthma attack, aggravated asthma, tachycardia, blood pressure decrease leading to life-threatening shock.

Should the patient experience any of these phenomena (which may occur as early as upon the first use of this medicinal product), medical assistance will be required.

Very rare: allergy-related vasculitis and pneumonitis.

Endocrine disorders

Very rare: hyperglycaemia and glucosuria.

Metabolism and nutrition disorders:

Rare: hyperkalaemia

Psychiatric disorders

Common: agitation.

Rare: irritability, confusion.

Very rare: mental disorders, disorientation, anxiety, nightmares, tremor, psychosis, hallucination, depression and transitory loss of consciousness that may lead to coma.

Treatment with acemetacin may intensify the symptoms of preexisting psychiatric diseases.

Nervous system disorders

Common: central nervous disorders such as headache, sleepiness/fatigue, dizziness, malaise and drowsiness.

Very rare: sensibility disorders, muscular asthenia, hyperhidrosis, dysgeusia, impaired memory, sleep disorders, seizures, reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus, mixed connective tissue disease) with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation.

Administration of acemetacin may intensify the symptoms of epilepsy and Parkinson’s disease.

Frequency not known: optic neuritis, paraesthesia

Eye disorders

Uncommon: In the course of long-term treatment with indometacin, the main metabolite of acemetacin, pigment degeneration of the retina and corneal opacity have been reported.

Blurred or double vision may be a typical symptom.

Ear and labyrinth disorders

Very rare: Tinnitus and transitory hearing impairment.

Cardiac disorders

Very rare: palpitations, angina pectoris, cardiac failure

Vascular disorders

Very rare: hypertension

Frequency not known: circulatory collapse

Gastrointestinal disorders

Very common: gastrointestinal disorders such as nausea, vomiting, abdominal pain, diarrhoea and minor haemorrhage from the gastrointestinal tract which, in exceptional cases, can cause anaemia.

Common: dyspepsia, flatulence, abdominal cramps, loss of appetite and gastrointestinal ulcers (sometimes accompanied by bleeding and perforation)

Uncommon: blood can appear in vomit, faeces or diarrhoea.

Very rare: stomatitis, inflammation of the tongue, lesions on the oesophagus, complaints in the lower abdomen (e.g. non-specific, bleeding inflammation of the colon) exacerbation of Crohn’s disease or ulcerative colitis and constipation have been reported. Formation of intestinal diaphragm-like strictures; pancreatitis.

The patient shall be instructed to discontinue the medicinal product and to consult a doctor immediately in case of any severe abdominal pain and/or the occurrence of meleana or haematemesis.

Hepatobiliary disorders

Common: hepatic enzyme increased

Uncommon: hepatic damage (toxic hepatitis with or without icterus, cholestasis

Very rare: taking a fulminant course in cases and at times without prodromal symptoms).

The patient’s liver values should therefore be monitored at regular intervals.

Skin and subcutaneous tissue disorders

Uncommon: alopecia

Very rare: eczema, enanthema, erythema, photosensitivity reaction, minor and extensive cutaneous bleeding, exfoliative dermatitis and rash with bullous eruption, which may also take a grave course such as Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell’s syndrome).

Renal and urinary disorders

Uncommon: development of oedema (e.g. peripheral oedema), in particular in patients with hypertension and/or impaired renal function.

Very rare: micturition disorders, increase in blood urea, acute renal insufficiency, proteinuria, haematuria or renal damage (interstitial nephritis, nephrotic syndrome, papillary necrosis).

Therefore, the patient’s renal function should be checked at regular intervals.

Reproductive system and breast disorders

Very rare: vaginal haemorrhage.