BERLIND 75 RETARD - summary of medicine characteristics

Berlind 75 Retard

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 75 mg of indometacin

Excipients with known effect: Each capsule contains 36.20mg of lactose and 110.2mg of sucrose

For the full list of excipients, see section 6.1

Modified release capsule

Dark blue cap and transparent body. The body is marked with ’IND 75’ on one side and plain on the other.

4.1 Therapeutic indications

Non-steroidal analgesic and anti-inflammatory agent indicated for the active stages of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, degenerative joint disease of the hip, acute musculoskeletal disorders and low back pain. Also indicated inperiarticular disorders such as bursitis, tendinitis, synovitis, tenosynovitis and capsulitis.

Also indicated in inflammation, pain and oedema following orthopaedic procedures; and the treatment of pain and associated symptoms of primary dysmenorrhoea.

Berlind 75 Retard is not indicated for acute gouty arthritis, as clinical evidence is not currently available for this dosage form in this condition.

4.2 Posology and method of administration

Posology

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

The dosage of indometacin should be carefully adjusted to suit the needs of the individual patient.

In order to reduce the possibility of gastro-intestinal disturbances, Berlind 75 Retard should always be taken with food or an antacid.

In chronic conditions, starting therapy with a low dosage, increasing this gradually as necessary, and continuing a trial of therapy for an adequate period (in some cases, up to one month) will give best results with minimum of unwanted reactions. The recommended oral dosage range is 50mg to 200mg daily in divided doses.

Adults:One capsule once or twice daily, depending on patient needs and response.

Dysmenorrhoea: up to 75mg a day, starting with onset of cramps or bleeding, and continuing for as long as symptoms usually last.

Older people:

Indometacin should be used with particular care in older patients who are more prone to adverse reactions. If indometacin is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for gastrointestinal bleeding during treatment with indometacin..

Paediatric population:

Safety for use in children has not been established. It is therefore not recommended for use in children.

Method of administration

For oral administration.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

History of peptic ulcer or active recurrent peptic.

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

Recurrent history of gastrointestinal bleeding or perforation (two or more distinct episodes of proven ulceration or bleeding).

In patients with nasal polyps associated with angioneurotic oedema.

In patients who have experienced acute asthmatic attacks, rhinitis or urticaria as a result of therapy withibuprofen, aspirin or other non-steroidal anti-inflammatory drugs.

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

Safety for use in children has not been established.

Pregnancy and lactation

Indometacin should not be used during the third trimester of pregnancy or lactation (see section 4.6).

4.4 Special warnings and precautions for use

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).

Headache, sometimes accompanied by dizziness and light-headedness, may occur, usually early in treatment. Starting therapy with a low dosage and increasing it gradually will usually minimise the incidence of headache. These symptoms frequently disappear on continuing therapy or reducing the dosage, but if headache persists despite dosage reduction, indometacin should be withdrawn. Patients should be warned that they may experience dizziness and, if they do, should not drive a car or undertake potentially dangerous activities needing alertness.

Respiratory effects

Indometacin should be used cautiously in patients with a history of bronchial asthma and in patients with psychiatric disorders, epilepsy, or Parkinsonism, as indometacin may tend to aggravate these disorders.

Gastrointestinal effects

NSAIDs should only be given with care to patients with a history of gastro-intestinal disease.

Gastro-intestinal disturbances may be minimised by giving indometacin orally with food, milk or an antacid. They usually disappear on reducing the dosage; if not, the risks of continuing therapy should be weighed against the possible benefits. If gastro-intestinal bleeding or ulceration does occur, indometacin should immediately be discontinued.

Single or multiple ulceration including perforation and haemorrhage of the oesophagus, stomach, duodenum or small or large intestine have been reported to occur with Indometacin. Fatalities have been reported in some instances. Rarely, intestinal ulceration has been associated with stenosis and obstruction.

Gastro-intestinal bleeding without obvious ulcer formation and perforation of pre-existing sigmoid lesions (diverticulum, carcinoma, etc.) have occurred. Increased abdominal pain in ulcerative colitis patients or the development of ulcerative colitis and regional ileitis have been reported to occur rarely.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease), 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.

Cardiovascular effects

Fluid retention and peripheral oedema have been observed in some patients taking Indometacin. Indometacin should therefore be used with caution in patients with cardiac dysfunction, hypertension or other conditions predisposing to fluid retention.

Indometacin may mask the signs and symptoms of infection. Indometacin should be used with caution in patients with existing but controlled infection. Caution is advised with concomitant use of live vaccines.

Eye disorder

In patients with rheumatoid arthritis, eye changes may occur which may be related to the underlying disease or to the therapy. Therefore, in chronic rheumatoid disease, ophthalmological examinations at periodic intervals are recommended. Discontinue therapy if eye changed are observed.

Other Miscellaneous effects

Patients should be periodically observed to allow early detection of any unwanted effects on peripheral blood (anaemia), liver function or gastro-intestinal tract especially during prolonged therapy and drug hypersensitivity.

Indometacin can inhibit platelet aggregation. The effect usually disappears within 24 hours of discontinuing indometacin. Bleeding time is prolonged (but within normal range) in normal adults. Because this effect may be exaggerated in patients with underlying haemostatic defects, indometacin should be used cautiously in patients with coagulation defects.

Renal effects

As with other non-steroidal anti-inflammatory drugs, there have been reports of acute interstitial nephritis with haematuria, proteinuria, and occasionally nephrotic syndrome in patients receiving long-term administration of indometacin.

In patients with reduced renal blood flow where renal prostaglandins play a major role in maintaining renal perfusion, administration of a non-steroidal anti-inflammatory agent may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with renal or hepatic dysfunction, diabetes mellitus, advanced age, extracellular volume depletion, congestive heart failure, sepsis, or concomitant use of any nephrotoxic drug. A non-steroidal anti-inflammatory drug should be given with caution and renal function should be monitored in any patient who may have reduced renal reserve. Discontinuation of non-steroidal antiinflammatory therapy is usually followed by recovery to the pre-treatment state.

Increase in plasma potassium concentration, including hyperkalaemia has been reported, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninaemic-hypoaldosteronism state (see section 4.5).

Since indometacin is eliminated primarily by the kidneys, patients with significantly impaired renal function should be closely monitored; a lower daily dosage should be used to avoid excessive drug accumulation.

SLE and mixed connective tissue disorders

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 effects

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. Indometacin should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Concomitant medication

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 antiplatelet agents such as aspirin (see section 4.5).

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Care should be taken in patient treated with any of the following drugs as interactions have been reported in some patients:

Asprin:

The use of indometacin with aspirin or other salicylates is not recommended. Controlled clinical studies have shown no enhanced therapeutic effect, and one study showed a significant increase in the incidence of gastro-intestinal side effects. A study in normal volunteers showed that chronic administration of 3.6 g aspirin with indometacin lowered the indometacin blood levels by approximately 20%.

Diflunisal:

Co-administration of diflunisal with indometacin increases the plasma level of indometacin by about a third with a concomitant decrease in renal clearance. Fatal gastro-intestinal haemorrhage has occurred. The combination should not be used.

Other NSAIDSincluding cyclooxygenase-2 selective inhibitors:

The concomitant use of Indometacin with other NSAIDs, including cyclooxygenase-2 selective inhibitors is not recommended due to theincreased possibility of gastro-intestinal toxicity, with little or no increase in efficacy (See section 4.4).

Anti-coagulants:

Although clinical studies suggest that indometacin does not influence thehypoprothrom­binaemia induced by anticoagulants, patients also receiving anticoagulants should be closely observed for alterations of the prothrombin time. The risk of ulceration and bleeding is increased with indometacin (see section 4.4).

Probenecid:

Co-administration of probenecid may increase plasma levels of indometacin. When increases in the dose of indometacin are made under these circumstances, they should be made cautiously and in small increments.

Methotrexate:

Caution should be exercised with simultaneous use of Indometacin with methotrexate. Indometacin has been reported to decrease tubular secretion of methotrexate and to potentiate toxicity.

Ciclosporin:

Administration of NSAIDs concomitantly with ciclosporin has been associated with an increase in ciclosporin-induced- toxicity, possibly due to decreased synthesis of renal prostaciclin. NSAIDs should be used with caution in patients taking ciclosporin,and renal function should be monitored carefully.

Lithium:

Indometacin 50 mg three times a day produced a clinically relevant elevation of plasma lithium and reduction in renal lithium clearance in psychiatric patients and normal subjects with steady-state plasma lithium concentrations. This effect has been attributed to inhibition of prostaglandin synthesis. As a consequence, when indometacin and lithium are given concomitantly, the patient should be observed carefully for signs of lithium toxicity. In addition, the frequency of monitoring serum lithium concentrations should be increased at the outset of such combination drug treatment.

Diuretics:

In some patients the administration of indometacin can reduce the diuretic and antihypertensive effect of loop , thiazides and potassium sparing diuretics (furosemide).

Therefore, when indometacin and diuretics are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

Indometacin reduces basal plasma rennin activity (PRA), as well as those elevations of PRA induced by furosemide administration, or salt or volume depletion. These facts should be considered when evaluating plasma rennin activity in hypertensive patients.

It has been reported that the addition of triamterene to a maintenance schedule of indometacin resulted in reversible acute renal failure in two of four healthy volunteers. Indometacin and triamterene should not be administered together.

Indometacin and potassium-sparing diuretics each may be associated with increased plasma potassium levels. The potential effects of Indometacin and potassium-sparing diuretics on potassium kinetics and renal function should be considered when these agents are administered concurrently.

Most of the above effects concerning diuretics have been attributed, at least in part, to mechanisms involving inhibition of prostaglandin synthesis by indometacin.

Cardiac glycosides/Digoxin:

NSAIDs may exacerbate cardiac failure, reduce glomerular filtration rate (GFR) and increase plasma glycoside levels. Indometacin given concomitantly with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Therefore, when indometacin and digoxin are used concomitantly, serum digoxin levels should be closely monitored.

Anti-hypertensive medications:

Co-administration of Indometacin and some antihypertensive agents may attenuate acutely the hypotensive effect of the latter, due partly to indometacin's in­hibition of prostaglandin synthesis. Therefore, caution should be exercised when considering the addition of Indometacin to the regimen of a patient taking any of the following antihypertensive agents: alpha-adrenergic blocking agents, ACE inhibitors, beta-adrenergic blocking agents, angiotensin-2-receptor antagonists, diuretics, hydralazine or nifedipine or losartan. An increased risk of hyperkalaemia has also been reported when NSAIDs are taken with ACE inhibitors.

Phenylpropano­lamine:

Hypertensive crises have been reported due to oral phenylpropanolamine alone and, rarely, to phenylpropanolamine given with indometacin. This additive effect is probably due partly to indometacin's in­hibition of prostaglandin synthesis. Caution should be exercised when indometacin and phenylpropanolamine are administered concomitantly.

Corticosteroids:

The risk of gastro-intestinal bleeding and ulceration associated with NSAIDs is increased when used with corticosteroids.

Mifepristone:

NSAIDs and aspirin should be avoided until atleast 8–12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Quinolones Antibiotics:

There have been reports that 4-quinolones may induce convulsions in patients with or without a history of convulsions; taking NSAIDs at the same time may also induce them. Also skin reactions and neurotoxicity have been reported with ciprofloxacin.

Tacrolimus:

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

Antiplatelet drugs and selective serotonin reuptake inhibitors (SSRIs):

Increased risk of gastrointestinal bleeding (see section 4.4).

Increased risk of bleeding with clopidogrel. Indometacin can inhibit platelet aggregation an effect which disappears within 24 hours of discontinuation; the bleeding time may be prolonged and this effect may be exaggerated in patients with an underlying haemostatic defect.

Antidiabetics:

The effect of sulphonylureas may be increased by NSAIDs. Isolated case of metabolic acidosis with metformin.

Antiepileptics:

The effect of phenytoin possibly increased by NSAIDs.

Antipsychotics:

Increased drowsiness with indometacin and haloperidol.

Antivirals:

Pharmacokinetic changes have been recorded with zalcitabine/in­dometacin.. Risk of indometacin toxicity with ritonavir, avoid concomitant use.

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

Benzodiazepines:

Increased risk of dizziness with diazepam and indometacin.

Muscle Relaxants:

Increased risk of baclofen toxicity due to reduced rate of excretion.

Muromonab-CD3 :

Significant rise in incidence of psychosis and encephalopathy in patients receiving both these drugs.

Pentoxifylline:

Possible increased risk of bleeding when taken with NSAIDs.

Desmopressin:

Effect potentiated by indometacin.

Tiludronic acid:

The bioavailability of tiludronic acid is increased by indometacin.

Triamterene:

Indometacin and triamterene should not be administered together since reversible renal failure may be induced.

Vasodilators:

Possible increased risk of bleeding with NSAIDs.

4.6 Fertility, pregnancy and lactation

Pregnancy:

Indometacin should be used during the first two trimesters of pregnancy only if the potential benefit justifies the potential risk to the foetus.

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. Indometacin should be used during the first two trimesters of pregancny only if the potential benefits justifies the potential risk to the foetus. If indometacin 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.

The known effects of indometacin and other drugs of this class on the human foetus during the third trimester of pregnancy include:

– Constriction of the ductus arteriosus prenatally

– Tricuspid incompetence

– Pulmonary hypertension

– Non-closure of the ductus arterisosus postnatally which may be resistant to medical management

– Myocardial degenerative changes

– Platelet dysfunction with resultant bleeding

– Intracranial bleeding

– Renal injury/dysgenesis which may result in prolonged or permanent renal failure

with oligohydroamniosis

– Gastro- intestinal bleeding or perforation and increased risk of necrotising enterocolitis.

At the end of pregnancy, indometacin treatment may expose the mother 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.

Use of Indometacin during the third trimester of pregnancy is not recommended.

Breast-feeding:

Administration of Indometacin is not recommended in breast-feeding mothers. Indomethacin is excreted in breast milk

Fertility:

The use of indometacin 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 indometacin should be considered.

4.7 Effects on ability to drive and use machines

Patients should be warned that they may experience headaches, dizziness, drowsiness, fatigue and visual disturbances and if they do, should not drive or undertake activities requiring alertness.

4.8 Undesirable effects

Nervous system disorders: headaches, dizziness, light-headedness, depression, vertigo and fatigue (including malaise and listlessness). Reactions reported infrequently include mental confusion, anxiety, syncope, drowsiness, convulsions, coma, peripheral neuropathy, muscle weakness, involuntary muscle movements, insomnia and psychiatric disturbances such as hallucinations and depersonalisation. Rarely, paraesthesia, dysarthria, aggravation of epilepsy and Parkinsonism. Other CNS effects include 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), depression, vertigo, dysarthria, syncope, coma, cerebral oedema, nervousness, anxiety. These effects are often transient and disappear frequently with continued treatment or with reduced dosage. However, occasionally, sever reactions require stopping therapy.

Gastrointestinal disorders: The more frequent reactions are nausea, anorexia, vomiting, epigastric discomfort, abdominal pain, constipation, and diarrhoea. Others which may develop are ulceration – single or multiple of oesophagus, stomach, duodenum or small or large intestine, including perforation and haemorrhage with a few fatalities, particularly in the elderly, having been reported; gastro-intestinal tract bleeding without obvious ulcer formation; and increased abdominal pain when used in patients with pre-existing ulcerative colitis. Reactions occurring infrequently are stomatitis; gastritis; dyspepsia; flatulence; melaena; haematemesis; epistaxis; bleeding from the sigmoid colon – occult or from a diverticulum – and perforation of pre-existing sigmoid lesions (diverticula, carcinoma). Rarely, intestinal strictures (diaphragms) and intestinal ulceration followed by stenosis and obstruction has been reported. With suppositories, tenesmus and irritation of the rectal mucosa have occasionally been reported. Other gastro-intestinal side effects which may or may not be caused by indomethacin include: ulcerative colitis and regional ileitis. Pancreatitis has been reported very rarely.

Hepatobiliary disorders: cholestasis. Rarely, abnormal liver function, hepatitis and jaundice (some fatalities have been reported).

Cardiovascular and cerebrovascular: Oedema, increased blood pressure, tachycardia, chest pain, arrhythmia, palpitations hypotension, congestive heart failure and cardiac failure have been reported in association with NSAID treatment.

Clinical trial and epidemiological data suggest the 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 infarcation or stroke) (see section 4.4).

Dermatological/Hy­persensitivity: : pruritus, urticaria, angioneurotic oedema, angiitis, erythema nodosum, skin rash and photosensitivity, exfoliative dermatitis, Stevens Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, hair loss, bullous reactions including sweating and exacerbation of psoriasis rapid fall in blood pressure resembling a shock-like state, acute anaphylaxis, acute respiratory distress including sudden dyspnoea, asthma and pulmonary oedema (all infrequent). Bronchospasm may be precipitated in patients suffering from, or with a history of, bronchial asthma or allergic disease.

Blood and lymphatic disorders: infrequently, blood dyscrasias may occur, including including leucopenia, neutropenia, petechiae or ecchymosis, purpura, aplastic and haemolytic anaemia, agranulocytosis, bone-marrow depression, disseminated intravascular coagulation, and particularly thrombocytopenia. Because some patients may develop anaemia secondary to obvious or occult gastro-intestinal bleeding, appropriate blood determinations are recommended.

Eye disorders: infrequently, blurred vision, diplopia, optic neuritis, and orbital and peri-orbital pain. Corneal deposits and retinal disturbances, including those of the macula, have been reported in patients with rheumatoid arthritis on prolonged therapy, but similar changes may also be expected in patients with rheumatoid arthritis who have not received indometacin, ophthalmic examinations are desirable in patients given prolonged treatment.

Ear and labyrinth disorders: tinnitus, hearing disturbances (rarely deafness) have been reported.

Genito-urinary disorders: proteinuria, nephrotic syndrome, interstitial nephritis, and renal insufficiency including renal failure (all rare), blood urea elevation, and haematuria (all infrequent).

Musculo-skeletal and connective tissue disorders: muscle weakness and acceleration of cartilage degeneration.

Miscellaneous: vaginal bleeding, hyperglycaemia, glycosuria, hyperkalaemia, flushing and sweating, epistaxis, breast changes including enlargement and tenderness, gynaecomastia, and ulcerative stomatitis (all rare).

Laboratory tests: Borderline elevation of one or more liver tests may occur, and significant elevation of ALT (SGPT) or AST (SGOT) have been seen in less than 1% of patients receiving therapy with NSAIDs in controlled clinical trials. If abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations such as rash or eosinophilia occur, indometacin treatment should be stopped.

False-negative results in the dexamethasone suppression test (DST) in patients being treated with indometacin have been reported. Thus, results of this test should be used with caution in these patients.

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 professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms

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

Management

Patients should be treated symptomatically and supportively as required. The stomach should be emptied as quickly as possible if the ingestion is recent and correction of severe electrolyte abnormalities may need to be considered.

If vomiting has not occurred spontaneously, the patient should be induced to vomit with syrup of ipecac. Alternatively, in adults, if the patient is unable to vomit gastric lavage should be performed. Once the stomach has been emptied, 25 or 50 g of activated charcoal may be given. Depending on the condition of the patient, close medical observation and nursing care may be required. The patient should be followed for several days because gastro-interstinal ulceration and haemorrhage have been reported as adverse reactions of indometacin. Use of antacids may be helpful.

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.

It can be noted that indometacin has biphasic plasma elimination with the terminal phase showing a half-life ranging between 2.6 and 11.2 hours.

5 PHARMACOLOGICAL PROPERTIES

ATC CODE: M01A B01

Indometacin is a non-steroidal analgesic, antipyretic and anti-inflammatory agent. It is an inhibitor of prostaglandin synthetase.

The analgesic properties have been attributed to both central and peripheral effect, which are distinct from its anti-inflammatory activity.

5.2 Pharmacokinetic properties

Absorption: The formulation has a gradual in vitro release profile over 8 hours. Absorption is slowed but remains virtually complete when taken with food.

Distribution: More than 90% is bound to plasma proteins. It is distributed into synovial fluid, CNS and placenta. Low concentrations have been found in breast milk.

Metabolism: It is metabolised in the liver primarily by O-demethylation and N-deacetylation, it also undergoes glucuronidation and enterohepatic circulation. Half-life is between 3 – 11 hours.

Elimination: Mainly excreted in the urine (approximately 60%, the pH of the urine can affect this amount) and lesser amounts in the faeces. Indometacin is also excreted in milk in small amounts.

The following pharmacokinetic particulars were obtained with -Indometacin MR 75 mg Capsules; (n=8) t/^     : 3.999 hours

t/0     :   3.853 hours

Tmax     :   6.182 hours

Cmax     :   2.192 Mg/ml

AUC0.24 : 31.190 Mg/ml/hours

5.3 Preclinical safety data

No relevant information

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sucrose, corn starch, lactose, povidone, talc, magnesium stearate, polymers of methacrylic acid, acrylic acid esters and methacrylic acid esters. Capsule shell: titanium dioxide (E171), erythrosine (E127), indigotine (E132), yellow iron oxide (E172) and gelatin.

6.2 Incompatibilities

See section.4.5

6.3 Shelf life 3 years

6.4 Special precautions for storage

Store in a dry place below 25°C. Store in the original package in order to protect from light.

6.5 Nature and contents of container

Capsule container, i.e. polypropylene securitainer with polyethylene closure.

Number of capsule per container: 28 or 100.

Not all pack sizes may be marketed

6.6 Special precautions for disposal and other handling

No special requirements for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Tillomed Laboratories Ltd

220 Butterfield, Great Marlings

Luton

LU2 8DL

UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 11311/0452