Emflex Capsules

Rheumatoid arthritis, osteoarthritis, low back pain, and post-operative pain and inflammation.

Method of administration:

For oral administration.

To be taken preferably with or after food.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).

Posology:

The recommended starting dose is 120mg/day in divided doses, increasing to 180mg/day in divided doses, depending on patient response.

Special populations:

Elderly:

The elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy.

Paediatric population:

The safety in children and adolescents is not established

• Hypersensitivity to the active substance, indomethacin or to any of the excipients listed in section 6.1

• Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

• NSAIDS are contra-indicated in patients who have previously shown hypersensitivity reactions (e.g., asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin or other non-steroidal anti-inflammatory drugs.

• Severe heart failure, hepatic failure and renal failure (see section 4.4).

• During the last trimester of pregnancy (see section 4.6)

• History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

• Nasal polyps associated with angioneurotic oedema.

• Blood formation disorder of unclear aetiology

• Children and adolescents

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2, and GI and cardiovascular risks below).

The use of Emflex with concomitant NSAIDS including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).

Elderly:

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2).

Respiratory disorders:

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. Patients who suffer from asthma, hay fever, swollen nasal mucosae or chronic respiratory disease are at particular risk of hypersensitivity reactions

Cardiovascular, renal and hepatic impairment:

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 (see also section 4.3). An increase in the parameters of liver and kidney function tests has been in observed in some patients being treated with Emflex. Under long-term treatment, monitoring of liver and kidney function is strongly recommended.

Cardiovascular and cerebrovascular effects:

Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for acemetacin.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with acemetacin after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g., hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Gastrointestinal bleeding, ulceration and perforation:

GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events. Inhibition of platelet aggregation may occur.

Emflex should only be used after careful assessment of the risk/benefit ratio in patients with a history of gastric or duodenal ulcers if not contraindicated according to section 4.3.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3) and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and section 4.5).

Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin (see section 4.5).

When GI bleeding or ulceration occurs in patients receiving acemetacin, the treatment should be withdrawn.

In patients with an increased haemorrhagic tendency, platelet aggregation may be affected and the tendency to bleed may be increased.

Under long term treatment haemogram and blood coagulation monitoring is strongly recommended.

NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see section 4.8).

SLE and mixed connective tissue disease:

In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (see section 4.8).

Dermatological:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Emflex should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

Impaired female fertility:

The use of Emflex 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.

Eye disorders:

Eye changes may occur in chronic rheumatoid disease and patients should receive periodic ophthalmological examinations and therapy discontinued if changes occur.

Neurological:

Aggravation of psychiatric disorders, epilepsy or parkinsonism may occur.

Other:

Signs and symptoms of infection may be masked.

Emflex should only be used with careful medical observation in Varicella zoster virus infections (chickenpox, herpes zoster) due to a possibly increased risk of severe cutaneous complications

Special care is required when Emflex is given immediately before or after surgeries.

As this product contains lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Other analgesics including cyclooxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs (including aspirin, other salicylates, diflusinal) as this may increase the risk of adverse effects (see section 4.4).

Anti-hypertensives: reduced anti-hypertensive effect.

Diuretics: Reduced diuretic effect should be considered when treating patients with compromised cardiac function or hypertension. Diuretics can increase the risk of nephrotoxicity of NSAIDs. Furosemide accelerates the excretion of acemetacin.

Diuretics and antihypertensives: NSAIDS may weaken the effect of diuretic agents and hypertensive agents. In patients with impaired renal function (such as dehydrated patients or elderly patients), concomitant use of an ACE inhibitor and/or angiotensin-II receptor antagonist and a medicinal product inhibiting cyclooxygenase may lead to further exacerbation of renal function (including the possibility of acute renal failure) which is normally reversible. Therefore, such a combination should be used with caution only, in particular in the elderly. These patients should be encouraged to drink adequate liquids, and regular control of renal laboratory values should be considered after such combination therapy has been initiated.

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

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

Phenytoin: decreased elimination of phenytoin.

Lithium: decreased elimination of lithium.

Methotrexate: decreased elimination of methotrexate.

Ciclosporin: Increased risk of nephrotoxicity.

Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see section 4.4).

Anti-coagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see section 4.4). ). In case of concomitant treatment, it is therefore recommended to monitor the patient's blood clotting status.

Quinolone antibiotics: 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.

Penicillin antibiotics:

May delay the elimination of penicillin

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastro-intestinal bleeding (see section 4.4). NSAIDS may reduce the effect of SSRIs.

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

Zidovudine: 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.

Probenecid, Sulphinpyrazone : Decreased elimination of acemetacin.

Anti-psychotics: increased drowsiness with haloperidol.

Alcohol: Under treatment with NSAIDs, concomitant consumption of alcohol may intensify substance-related adverse effects, in particular the occult blood loss from the gastrointestinal tract.

Antacids:

Antacids can reduce the resorption rate of acemetacin

Pregnancy

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.

Breast-feeding

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

See section 4.4 Special warnings and precautions for use, regarding female fertility.

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 (See section 4.4).

Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease (See section 4.4) 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 (c) 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) (See section 4.4).

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 Emflex. 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 Emflex 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 (see section 4.4)

Administration of Emflex 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 (see section 4.4).

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professional are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

a) Symptoms

Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, occasionally convulsions. In cases of significant poisoning acute renal failure and liver damage are possible.

b) Therapeutic measures

Patients should be treated symptomatically as required.

Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose.

Good urine output should be ensured.

Renal and liver function should be closely monitored.

Patients should be observed for at least four hours after ingestion of potentially toxic amounts.

Frequent or prolonged convulsions should be treated with intravenous diazepam.

Other measures may be indicated by the patient's clinical condition.

Acemetacin is a glycolic acid ester of indomethacin and the pharmacological activity resulting from acemetacin administration in man is derived from the presence of both acemetacin and indomethacin. The precise pharmacological mode of action of acemetacin is not known. However, unlike other NSAIDs, acemetacin is only a relatively weak inhibitor of prostaglandin synthetase.

Prostaglandins are known to have an antisecretory and cytoprotective effect on the gastric mucosa. Acemetacin shows activity in many of the established in vitro tests of anti-inflammatory activity, including inhibition of the release of a number of mediators of inflammation.

Acemetacin is well absorbed after oral administration. Its major metabolite is indomethacin which, after repeated administration, is present at levels in excess of those of acemetacin. Acemetacin is bound to plasma protein to a slightly lesser extent than indomethacin and has a relatively short plasma elimination half-life. It is eliminated by both hepatic and renal mechanisms. The pharmacokinetics appear to be linear at recommended therapeutic doses, unaffected by moderate renal or hepatic impairment, and unchanged in the elderly.

Emflex Capsules show similar toxicity to other non-steroidal anti-inflammatory drugs.

Gelatine capsule (colourings: Ferric oxide red E172, Ferric oxide yellow E172 and titanium dioxide E171), lactose, magnesium stearate, silicon dioxide, talc and sodium dodecylsulphate.

None known.

5 years

Store below 25° C.

White polypropylene bottles with polypropylene screw caps.

Pack sizes: 90, 56, 60 and 30 capsules.

PVC/PVDC foil blister packs in cartons:

Pack sizes: 90, 60, 56, 30, 10, and 6 capsules

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.