PARDELPRIN MR CAPSULES 75mg

INDOMETACIN MODIFIED RELEASE CAPSULES

Each capsule contains 75mg of Indometacin.

Dark blue (head) and clear (body) hard gelatin Size 2 capsules printed “C” and “IR” in grey.

Indometacin has non-steroidal analgesic and anti-inflammatory properties.

It is indicated for the following conditions:

• active stages of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, degenerative joint disease of the hip, acute musculoskeletal disorders and low back pain.

• periarticular disorders such as bursitis, tendinitis, synovitis, tenosynovitis and capsulitis.

• inflammation, pain and oedema following orthopaedic procedures

• treatment of pain and associated symptoms of primary dysmenorrhoea.

Pardelprin is for oral administration and should always be given with food or milk to reduce the chance of gastro-intestinal disturbance. To minimise the evolution of unwanted reactions it is helpful in chronic conditions to start the therapy with a low dosage, increasing as required.

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

Dysmenorrhoea: One capsule a day, starting with onset of cramps or bleeding, and continuing for as long as symptoms usually last.

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

Children: Safety for use in children has not been established.

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

Method of Administration

Oral use.

• Known hypersensitivity to NSAIDs, other ingredients in the product or other non-steroidal anti-inflammatory drugs.

• NSAIDs are contraindicated in patients with angioneurotic oedema or who have, with aspirin or other non-steroidal anti-inflammatory drugs experienced acute asthmatic attacks, urticaria or rhinitis in response to aspirin or other NSAIDs.

• Use with concomitant NSAIDs including cyclooxygenase 2 specific inhibitors (see section 4.5).

• Active peptic ulcer, a history of gastro-intestinal lesions.

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

• Severe heart failure.

• Not to be used in patients with nasal polyps.

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

• Safety in children has not been established.

• 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).

•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 infartion or stroke). There are insufficient data to exclude such a risk for indometacin.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with indometacin 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).

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

• Gastro-intestinal disorders which occur can be reduced by giving indometacin with food, milk or antacids.

• Patients should be carefully observed to detect any unusual manifestations of drug sensitivity.

• Indometacin should be used cautiously in patients with impaired renal function, bleeding disorders, psychiatric disorders, epilepsy or parkinsonism, as it may tend to aggravate these.

• Indometacin may mask the signs and symptoms of infectious disease and this should be borne in mind in order to avoid delay in starting treatment for infections. Indometacin should be used with caution in patients with an existing, albeit controlled infection. Caution is advised with concomitant use of live vaccines.

• In patients with renal, cardiac, hepatic impairment, hypertension, heart failure or conditions predisposing to fluid retention caution is required since the use of NSAIDs may result in deterioration of renal function (see section 4.8). The dose should be kept as low as possible and renal function should be monitored. NSAIDs may also cause fluid retention which may further aggravate these conditions.

• In patients with reduced renal blood flow where renal prostaglandins play a major role in maintaining renal perfusion, administration of a NSAID 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. Indometacin should be given with caution and renal function should be monitored in any patient who may have reduced renal reserve. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

• Particular care should be taken with older patients who are more susceptible to side-effects from indometacin (see section 4.2).

• 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.

• Caution is advised in patients with pre-existing sigmoid lesions (such as diverticulum or carcinoma) or ulcerative colitis or Crohns disease(or the development of these conditions) as indometacin can aggravate these conditions.

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

• 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 previous history of serious GI events. When GI bleeding or ulceration occurs in patients receiving indometacin, the treatment should be withdrawn.

• 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).

• 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.

• Indometacin should be used with caution in patients with coagulation defects as indometacin can inhibit platelet aggregation. This effect may be exaggerated in patients with underlying haemostatic defects. Inhibition of platelet aggregation usually disappears within 24 hours of discontinuing indometacin.

• Caution is required in post-operative patients as bleeding time is prolonged (but within normal range) in normal adults.

• During prolonged therapy, periodic ophthalmic examinations are recommended, as corneal deposits and retinal disturbances have been reported. 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 are periodic intervals are recommended. Therapy should be discontinued if eye changes are observed.

• Patients should be periodically observed to allow early detection of any unwanted effects on peripheral blood (anaemia), liver function (also see section 4.8 Undesirable effects), or gastrointestinal tract especially during prolonged therapy.

• Caution should be advised in patients receiving concomitant medications which could increase the risk of gastrotoxicity or bleeding, such as corticoseroids, anticoagulants such as warfarin or anti-platelet agents such as aspirin (see section 4.5).

• Avoid concomitant use of two or more NSAIDs.

• Analgesics – avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects.

• Antibacterials - NSAIDs possibly increase the risk of convulsions with 4-quinolones. Also skin reactions and neurotoxicity have been reported with ciprofloxacin.

• Anticoagulants- NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see section 4.4).

• Antidepressants (SSRI) – increased risk of bleeding.

• Antidiabetics – the effect of sulphonylureas may be increased by NSAIDs. Isolated case of metabolic acidosis with metformin.

• Antiepileptics – effect of phenytoin possibly increased by NSAIDs.

• Antihypertensives - indometacin may acutely reduce the antihypertensive effect of beta-blockers due partly to indometacin's inhibition of prostaglandin synthesis. Patients receiving dual therapy should have the antihypertensive effect of their therapy reassessed. 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, hydralazine or nifedipine. Hyperkalaemia has also been reported with ACE inhibitors.

• Antiplatelet drugs – 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.

• Antipsychotics – increased drowsiness with indometacin and haloperidol.

• Antivirals – pharmacokinetic changes have been recorded with zalcitabine/indometacin. Also increased risk of haematological toxicity with zidovudine. Risk of indometacin toxicity with ritonavir, avoid concomitant use.

• Benzodiazepines – increased risk of dizziness with diazepam and indometacin.

• Cardiac Glycosides - NSAIDs may exacerbate heart failure, reduce GFR, and increase plasma-cardiac glycoside concentration.

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

• Corticosteroids– increased risk of gastrointestinal bleeding and ulceration (see section 4.4). If the patient is receiving corticosteroids concomitantly, a reduction in dosage of these may be possible but should only be effected slowly under supervision.

• Cytotoxics–caution should be employed in use with cyclophosphamide as acute water intoxication has been reported. Indometacin may decrease the tubular secretion of methotrexate thus potentiating toxicity; simultaneous use should be undertaken with caution.

• Desmopressin– effect potentiated by indometacin.

• Diflunisal- avoid concomitant use. Increased plasma levels of indometacin by about a third with a concomitant decrease in renal clearance occurs. Fatal gastro-intestinal haemorrhage has occurred.

• Diuretics– NSAIDS may reduce the effectiveness of all types of diuretics. Indometacin may reduce the diuretic and antihypertensive effect of thiazides and furosemide in some patients. Indometacin may cause blocking of the furosemide -induced increase in plasma renin activity. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

• Lithium - indometacin is an inhibitor of prostaglandin synthesis and therefore the following drug interactions may occur; indometacin may raise plasma lithium levels and reduce lithium clearance in subjects with steady state plasma lithium concentrations. At the onset of such combined therapy, plasma lithium concentration should be monitored more frequently.

• Mifepristone - manufacturer recommends avoid NSAIDs until 8-12 days after mifepristone administration.

• 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.

• 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.

• Salicylates-use of indometacin with aspirin or other salicylates is not recommended because there is no enhancement of therapeutic effect while the incidence of gastro-intestinal side-effects is increased. Moreover, co-administration of aspirin may decrease the blood concentration of indometacin.

• Tacrolimus – increased risk of nephrotoxicity

• Tiludronic acid – bisphosphonates bioavailability 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.

• Laboratory tests: borderline elevations of one or more liver tests may occur, and significant elevations 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 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.

Pregnancy: Congenital abnormalities have been reported in association with NSAID administration in man; however, these are low in frequency and do not appear to follow any discernible pattern. In view of the known effects of NSAIDs on the foetal cardiovascular system (risk of closure of the ductus arteriosus), use in the last trimester of pregnancy is contraindicated. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child (see section 4.3). NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit to the patients outweighs the potential risk to the foetus.

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

See section 4.4 for information on female fertility.

Patients should be warned not to drive as they may experience dizziness, drowsiness, fatigue or visual disturbances. They should make sure they are not affected before driving or operating machinery.

•Blood and lymphatic system disorders: blood dyscrasias (thrombocytopenia, neutropenia, leukopenia, agranulocytosis, petechiae, ecchymosis, purpura, aplastic or haemolytic anaemia), bone marrow depression, petechiae, elevation of blood urea, epistaxis, ecchymosis, purpura, and disseminated intravascular coagulation) may occur infrequently. Some patients manifest anaemia secondary to obvious or occult gastro-intestinal bleeding.

•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).

•Metabolism and nutrition disorders: hyperglycaemia, hyperkalaemia and glycosuria have been reported rarely.

•Nervous system disorders: headache, dizziness and lightheadedness are common side effects. Starting therapy with a low dose and increasing gradually minimises the incidence of headache. These symptoms frequently disappear on continued therapy or reducing the dosage, but if headache persists despite dosage reduction, indometacin should be withdrawn. Other CNS effects include reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus or mixed connective tissue disease) with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (see section 4.4), depression, vertigo, fatigue, malaise, dysarthria, syncope, coma, cerebral oedema, nervousness, confusion, anxiety and other psychiatric disturbances, depersonalisation, hallucinations, drowsiness, convulsions and aggravation of epilepsy, peripheral neuropathy, paraesthesia, involuntary movements, insomnia and parkinsonism. These effects are often transient and abate or disappear on reduced or stopping treatment. However, the severity of these may, on occasion, require cessation of therapy.

•Eye disorders: blurred vision, optic neuritis, diplopia and orbital and peri-orbital pain are seen infrequently. Corneal deposits and retinal or macular disturbances disturbances have been reported in some patients with rheumatoid arthritis on prolonged therapy with indometacin, and ophthalmic examinations are desirable in patients given prolonged treatment.

•Ear disorders: tinnitus or hearing disturbances (rarely deafness) have been reported.

•Cardiac disorders: there have been reports of oedema, hypertension, hypotension, tachycardia, chest pain, arrhythmia, palpitations and cardiac failure.

•Vascular disorders: flushing has been reported.

•Respiratory, thoracic and mediastinal disorders: pulmonary eosinophilia. There may be bronchospasm in patients with a history of bronchial asthma or other allergic disease.

•Gastrointestinal disorders: nausea, anorexia, vomiting, gastritis, epigastric discomfort or abdominal pain, constipation or diarrhoea all have been reported; more rarely, stomatitis, flatulence, ulceration at any point in the gastro-intestinal tract (even with resultant stenosis and obstruction), bleeding (even without obvious ulceration or from a diverticulum) and perforation of pre-existing sigmoid lesions (such as diverticulum or carcinoma) have occurred; and increased abdominal pain or exacerbation of the condition in patients with ulcerative colitis or Crohns disease (or the development of this condition) and regional ileitis have been rarely reported. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4). If gastro-intestinal bleeding does occur treatment with indometacin should be discontinued. Gastro-intestinal disorders which occur can be reduced by giving indometacin with food, milk or antacids.

•Hepato-biliary disorders: cholestasis, elevation of LFTs (see section 4.5). Rarely hepatitis and jaundice (associated with some fatalities).

•Skin and subcutaneous tissue disorders: itching, urticaria, angioneurotic oedema, angiitis, photosensitivity, erythema nodosum, rash and exfoliative dermatitis all have been reported infrequently - as have Stevens Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, hair loss, sweating and exacerbation of psoriasis.

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

•Renal and urinary disorders: haematuria, nephrotic syndrome, proteinuria, interstitial nephritis, renal insufficiency or failure have all been reported. In patients with renal, cardiac or hepatic impairment, caution is required since the use of non-steroidal anti-inflammatory drugs may result in deterioration of renal function. The dose should be kept as low as possible and renal function should be monitored.

•Reproductive system and breast disorders: vaginal bleeding, interstitial nephritis, breast changes (enlargement, tenderness, gynaecomastia).

• Clinical trial and epidemiological data suggest that the use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).

Symptoms: 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.

Treatment: 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. 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.

ATC CODE: M01A B01

Indometacin is a non-steroidal anti-inflammatory agent with analgesic and antipytretic properties.

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

Absorption: The formulation has a gradual in vitro release profile over 8 hours.

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 mik.

Metabolism: It is metabolised in the liver primarily by demethylation and 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. Lesser amounts in the faeces. Indometacin is also excreted in milk in small amounts.

The following pharmacokinetic particulars were obtained with indometacin MR 75mg Capsules; (n=8)

None stated.

Also contains: 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.

Printing ink: shellac glaze, titanium dioxide (E171) and iron oxide black (E172).

See under interactions with other medicaments and other forms of interaction section.

Shelf-life

In the medicinal product as packaged for sale: 36 months.

Shelf-life after dilution/reconstitution

Not applicable.

Shelf-life after first opening

Not applicable.

Store in a dry place below 25°C.

Protect from light.

Capsule container: ie polypropylene securitainer with polyethylene closure.

Number of capsules per container: 28 or 100.

Not applicable.

Name or style and permanent address of registered place of business of the holder of the Marketing Authorisation:

Actavis UK Limited

(Trading style: Actavis)

Whiddon Valley

BARNSTAPLE

N Devon EX32 8NS

PL 0142/0436

12.8.97

Renewed – 18.03.09

11.05.09