Consumer medicine information

Indocid Capsule And Suppository

Indometacin

BRAND INFORMATION

Brand name

Indocid Suppositories

Active ingredient

Indometacin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Indocid Capsule And Suppository.

What is in this leaflet

This leaflet answers some common questions about INDOCID. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking INDOCID against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What INDOCID is used for

INDOCID contains indometacin as the active ingredient. It belongs to a group of medicines called Non-Steroidal Anti-Inflammatory Drugs (or NSAID).

INDOCID is used to relieve pain and reduce inflammation (swelling, redness and soreness) that may occur in the following conditions:

  • different types of arthritis including rheumatoid arthritis, osteoarthritis, gouty arthritis and ankylosing spondylitis
  • muscle and bone injuries such as sprains, strains, low back pain (lumbago) and tendonitis, such as tennis elbow
  • swelling and pain after setting broken or dislocated bones
  • menstrual cramps (period pain).

Ask your doctor if you have any questions about why INDOCID has been prescribed for you.

Your doctor may have prescribed it for another reason.

This medicine is only available with a doctor’s prescription.

There is no evidence that it is addictive.

Before you use it

When you must not use it

Do not use INDOCID if you have ever had an allergic reaction to:

  • indometacin
  • any of the ingredients listed at the end of this leaflet
  • aspirin or any other NSAID medicines.

Many medicines used to treat headache, period pain and other aches and pains contain aspirin or NSAID medicines.

Symptoms of an allergic reaction to these medicines may include asthma, shortness of breath, wheezing or difficulty in breathing; swelling of the face, lips, tongue or any other parts of the body; fainting; rash, itching or hives on the skin.
If you are allergic to aspirin or NSAID medicines and use INDOCID, the above symptoms may be severe.

Ask your doctor or pharmacist if you are not sure if you are taking any of these medicines.

Do not use INDOCID if you are pregnant, or intend to become pregnant

The safety of this medicine during pregnancy has not been established.

Do not use it if you are breast-feeding or intend to breast-feed.

It is not recommended for use while breastfeeding as it is found in breast milk.

Do not use INDOCID if:

  • you have an active peptic ulcer (i.e. stomach or duodenal ulcer) or have had peptic ulcers more than once before
  • you have severe heart failure
  • you have severe liver failure
  • you have recently had heart bypass surgery
  • you have had an inflamed rectum (back passage) or recent bleeding from the rectum. This only applies to INDOCID suppositories.

Do not use INDOCID if:

  • the packaging is torn or shows signs of tampering
  • the expiry date (EXP) printed on the pack has passed.
    If you use this medicine after the expiry date has passed, it may not work as well.

Do not use this medicine to treat any other complaints unless your doctor has instructed you to do so.

Do not give INDOCID to children under 2 years of age.

The safety of this medicine in children under 2 years of age has not been established.

Before you start to use it

Tell your doctor if you are allergic to any other medicines including aspirin, other NSAID medicines or any other substances such as foods, dyes or preservatives.

Tell your doctor if you have or have had any of the following medical conditions:

  • heartburn, indigestion, stomach ulcer or other stomach problems
  • bowel or intestinal problems such as ulcerative colitis
  • kidney or liver disease
  • high blood pressure or heart disease
  • history of chest pain (angina), heart problems or stroke
  • a tendency to bleed or other blood problems
  • diabetes mellitus or sugar diabetes
  • psychiatric problems
  • seizures or fits (epilepsy)
  • Parkinson's disease.

Tell your doctor if you currently have an infection.

INDOCID may hide some of the signs of an infection and may make you think, mistakenly, that you are better or that it is less serious than it might be.

Signs of an infection include fever, pain, swelling or redness.

If you have not told your doctor about any of the above, tell them before you use any INDOCID.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and INDOCID may interfere with each other. These include:

  • aspirin, salicylates or other NSAID medicines (e.g. ibuprofen or diflunisal)
  • anticoagulants such as warfarin, a medicine used to prevent blood clots
  • digoxin, a medicine used to treat heart failure
  • lithium, a medicine used to treat severe mood swings
  • probenecid, a medicine used to treat gout
  • diuretics, also called fluid or water tablets
  • some medicines used to treat high blood pressure in combination with a thiazide diuretic
  • decongestants
  • cyclosporin, a medicine used to suppress the immune system
  • methotrexate, a medicine used to treat arthritis and some cancers.

These medicines may be affected by INDOCID or may affect how well it works. You may need to take different amounts of your medicine or you may need to take different medicines.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while using INDOCID.

Use in the elderly

Elderly patients may be more sensitive to the effects or side effects of this medicine.

How to use it

INDOCID CAPSULES

How many capsules to take

Your doctor will tell you how many capsules you need to take each day. The dose will depend on the condition being treated and your response to the treatment. Your initial dose will be maintained or adjusted until a satisfactory response is noted.

Tell your doctor of any changes in your condition, as you may require a change in the dose of INDOCID.

How to take the capsules

Take the capsules straight after food or milk with a full glass of water.

It may also be taken with an antacid, if advised by your doctor or pharmacist.

This may help reduce the possibility of stomach and bowel problems.

INDOCID SUPPOSITORIES

How much to use

Your doctor will tell you how many suppositories you need to use each day.

How to use the suppositories

If possible, go to the toilet and empty your bowels before using the suppository.

They work best if your bowels are empty.

Follow these steps to use a suppository:

  1. Wash your hands thoroughly with soap and water.
  2. Feel the suppository while it is still in the foil.
  3. If it feels soft, keep in the foil, chill it in the fridge or by holding it under cold water for a few minutes. Do not remove the foil wrapper while you are chilling it.
  4. Put on a disposable glove, if desired (available from a pharmacy).
  5. Remove the entire foil wrapper from the suppository.
  6. Moisten the suppository by dipping it briefly in cool water.
  7. Lie on your side and raise your knee to your chest.
  8. Push the suppository gently into your rectum (back passage).
  9. Remain lying down for a few minutes so that the suppository dissolves.
  10. Throw away used materials and wash your hands thoroughly.

Try not to go to the toilet and open your bowels for at least an hour after using the suppository.

The suppository takes about one hour to be completely absorbed and do its work.

If you are not sure how to use a suppository, ask your doctor or pharmacist.

How long to use it

Continue using this medicine for as long as your doctor tells you.

Depending on your condition, you may need this medicine for a few days, a few weeks or for longer periods.

As with other NSAID medicines, if you are using INDOCID for arthritis, it will not cure your condition but it should help to control pain, swelling and stiffness. If you have arthritis, INDOCID should be taken every day for as long as your doctor prescribes.

For sprains and strains, INDOCID is usually only needed for a few days.

For menstrual cramps INDOCID should be taken at the start of bleeding or cramps and continued for as long as the cramps last.

If you forget to use it

If it is almost time for your next dose, skip the dose you missed and take or use your next dose when you are meant to. Otherwise, take the capsule or use the suppository as soon as you remember, and then go back to using it as you would normally.

If you are not sure whether to skip the dose, talk to your doctor or pharmacist.

Do not use a double dose to make up for the dose that you missed.

If you have trouble remembering to use your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have taken too much INDOCID or have swallowed a suppository. Do this even if there are no signs of discomfort or poisoning.

If you take too much INDOCID, you may suffer nausea, vomiting, intense headache, dizziness, confusion, fatigue, numbness or fits.

While you are using it

Things you must do

Tell your doctor immediately if you become pregnant while using INDOCID.

Tell any other doctors, dentists and pharmacists who are treating you that you are using INDOCID, especially if you are being started on any new medicines.

Tell your doctor if you get an infection while using INDOCID.

INDOCID may hide some of the signs of an infection and may make you think, mistakenly, that you are better or that it is less serious than it might be.

Signs of an infection include fever, pain, swelling or redness.

Things you must not do

Do not give INDOCID to anyone else, even if they have the same condition as you.

Things to be careful of

Be careful driving or operating machinery until you know how INDOCID affects you.

As with other NSAID medicines, this medicine may cause dizziness or light-headedness in some people. If this occurs, do not drive. If you drink alcohol, dizziness or lightheadedness may be worse.

Things to be aware of

INDOCID can increase blood pressure in some people, so your doctor will want to check your blood pressure from time to time.

As blurred vision is a possible side effect of long term therapy with INDOCID, patients should visit their optometrist for regular eye checks.

Side Effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using INDOCID.

INDOCID helps most people with pain and inflammation, but it may have unwanted side effects in a few people. If you are over 65 years of age you may have an increased chance of getting side effects. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following common side effects and they worry you:

  • stomach upset or pain including nausea (feeling sick), vomiting, heartburn, indigestion. Some of the stomach upsets, such as nausea and heartburn, may be reduced by taking the capsules with food or an antacid, if advised by your doctor or pharmacist.
  • loss of appetite
  • constipation, diarrhoea
  • hearing disturbances
  • headache, dizziness, light-headedness may occur in the first few days of treatment If this worries you or continues, contact your doctor.
  • tiredness
  • change in mood for example, depression
  • irritation or discomfort in the back passage (this happens only with the suppositories).

Tell your doctor immediately if you notice any of the following:

  • severe pain or tenderness in the stomach
  • eye problems such as blurred vision or difficulty seeing
  • fast or irregular heartbeats, also called palpitations
  • signs of frequent or worrying infections such as fever, severe chills, sore throat or mouth ulcers
  • bleeding or bruising more easily than normal
  • signs of anaemia, such as tiredness, being short of breath, looking pale
  • yellowing of the skin and eyes, also called jaundice
  • unusual weight gain, swelling of ankles or legs
  • dark coloured or cloudy urine or pain in the kidney region
  • difficulty in passing water (urinating) or a sudden decrease in the amount of urine passed.

These are all serious side effects. You may need urgent medical attention. Serious side effects are rare.

If any of the following happen, stop using INDOCID and tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • vomiting blood or material that looks like coffee grounds. This may occur at any time during use and without warning
  • bleeding from the back passage, black sticky bowel motions (stools) or bloody diarrhoea. This may occur at any time during use and without warning
  • swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing
  • asthma, wheezing, shortness of breath
  • sudden or severe itching, skin rash, hives
  • severe dizziness, lightheadedness or fainting
  • seizures or fits
  • pain or tightness in the chest.

These are serious side effects that need urgent medical attention or hospitalisation. These side effects are rare.

Tell your doctor if you notice anything else that is making you feel unwell.

Some people may get other side effects while using INDOCID.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

After using INDOCID

Storage

Keep your capsules and suppositories in their original pack until it is time to take them.

Do not take the suppositories out of the foil until it is time to use them.

If you take the capsules and suppositories out of the box or blister they may not keep as well.

Keep this medicine in a cool dry place where the temperature stays below 25°C.

Do not store it or any other medicine in the bathroom or near a sink. Do not leave it in the car or on window sills.

Heat and dampness can destroy some medicines.

Keep it where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop using INDOCID or it has passed its expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

INDOCID capsules:

Yellow capsule marked with ‘25’ in black on either the body or cap.

A pack contains 50 capsules.

INDOCID suppositories:

White opaque torpedo-shaped suppository with a yellow tinge. Each is wrapped in foil.

A pack contains 20 suppositories.

Ingredients

INDOCID capsules:

Each INDOCID capsule contains 25 mg of indometacin as the active ingredient.

It also contains the inactive ingredients:

  • lactose
  • lecithin
  • silica-colloidal anhydrous
  • magnesium stearate
  • gelatin
  • titanium dioxide
  • iron oxide yellow CI77492
  • opacode monogramming ink S-1-17823 black.

INDOCID capsules do not contain sucrose, gluten, tartrazine or any other azo dyes.

INDOCID suppositories:

Each INDOCID suppository contains 100 mg of indometacin as the active ingredient.

It also contains the inactive ingredients:

  • butylated hydroxyanisole
  • butylated hydroxytoluene
  • edetic acid
  • glycerol
  • macrogol 3350
  • macrogol 8000.

INDOCID suppositories do not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

BRAND INFORMATION

Brand name

Indocid Suppositories

Active ingredient

Indometacin

Schedule

S4

 

Name of the medicine

Indometacin.

Excipients.

Capsules.

Lactose, lecithin, anhydrous colloidal silica, magnesium stearate, gelatin, titanium dioxide, iron oxide yellow CI77492 and Opacode monogramming ink S-1-17823 Black.

Suppositories.

Butylated hydroxyanisole, butylated hydroxytoluene, edetic acid, glycerol, macrogol 3350 and macrogol 8000.

Description

Chemical name: 1-(4-chlorobenzoyl) -5-methoxy-2-methyl -1H-indole -3-acetic acid. Molecular formula: C19H16NO4Cl. MW: 357.78. Indometacin occurs as a yellowish white powder with a melting point of about 156°C to 160°C. It is insoluble in water and in hydrocarbons, but is soluble in alcohols, acetone, ethylene dichloride and acetonitrile. Stable crystalline solvates are formed with alcohols. Indometacin is soluble but unstable in alkaline solution. Both the solid and the solution must be protected from sunlight. In the dry state, the sodium salt is reasonably stable.
Each Indocid capsule contains 25 mg of indometacin. Each Indocid suppository contains 100 mg of indometacin.

Pharmacology

Indocid (indometacin) is a highly effective nonsteroidal anti-inflammatory drug (NSAID) with marked analgesic and antipyretic properties.
Indometacin is a potent inhibitor of prostaglandin synthesis in vitro. Concentrations are reached during therapy which have been demonstrated to have an effect in vivo as well.
Indometacin has been shown to be an effective anti-inflammatory agent, appropriate for long-term use in rheumatoid arthritis, ankylosing spondylitis and osteoarthritis.
Indometacin affords relief of symptoms; it does not alter the progressive course of the underlying disease.
Indocid has been found effective in relieving the pain, reducing the fever, swelling, redness and tenderness of acute gouty arthritis.
The prostaglandin inhibitory effect of Indocid has been shown to be useful in the relief of pain and associated symptoms of primary dysmenorrhoea.
Prostaglandins sensitise afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Moreover, prostaglandins are known to be among the mediators of inflammation. Since indometacin is an inhibitor of prostaglandin synthesis, the mode of action may be due to a decrease of prostaglandins in peripheral tissues.
Indometacin has been reported to diminish basal and CO2 stimulated cerebral blood flow in healthy volunteers following acute oral and intravenous administration. In one study, after one week of treatment with orally administered indometacin, this effect on basal cerebral blood flow had disappeared. The clinical significance of this effect has not been established.

Pharmacokinetics.

Absorption of capsules.

Following single oral doses of Indocid capsules 25 mg or 50 mg, indometacin is readily absorbed, attaining peak plasma concentrations of approximately 1 and 2 microgram/mL, respectively, at about two hours. Orally administered Indocid capsules are virtually 100% bioavailable, with 90% of the dose absorbed within four hours.
Indometacin is eliminated via renal excretion, metabolism and biliary excretion. Indometacin undergoes appreciable enterohepatic circulation. The mean half-life of indometacin is estimated to be about 4.5 hours. With a typical therapeutic regimen of 25 or 50 mg t.i.d., the steady state plasma concentrations of indometacin average 1.4 times those following the first dose.

Absorption of capsules.

The rate of absorption is more rapid from the rectal suppository than from Indocid capsules. Ordinarily, therefore, the total amount absorbed from the suppository would be expected to be at least equivalent to the capsule. In controlled clinical trials, however, the amount of indometacin absorbed was found to be somewhat less (80 to 90%) than that absorbed from Indocid capsules. This is probably because some subjects did not retain the material from the suppository for the one hour necessary to assure complete absorption. Since the suppository dissolves rather quickly rather than melting slowly, it is seldom recovered in recognisable form if the patient retains the suppository for more than a few minutes.

Excretion.

Indometacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl and desmethyl-desbenzoyl metabolites, all in the unconjugated form. About 60% of an oral dosage is recovered in urine as drug and metabolites (26% as indometacin and its glucuronide) and 33% is recovered in faeces (1.5% as indometacin).
About 90% of indometacin is bound to protein in plasma over the expected range of therapeutic plasma concentrations.

Clinical Trials

In a gastroscopic study in 45 healthy subjects, the number of gastric mucosal abnormalities was significantly higher in the group receiving Indocid capsules than in the group taking Indocid suppositories or placebo.
In a double blind comparative clinical study involving 175 patients with rheumatoid arthritis, however, the incidence of upper gastrointestinal adverse effects with Indocid suppositories or capsules was comparable. The incidence of lower gastrointestinal adverse effects was greater in the suppository group.

Anti-inflammatory action.

The anti-inflammatory activity of indometacin was first demonstrated in animals, by measuring the ability of the compound to inhibit either granuloma formation or oedema induced by subplantar injection of carrageenin in rats. The latter appears to correlate well with antirheumatic activity in man. Assays of relative potency indicated that indometacin was more potent than acetylsalicylic acid (aspirin), phenylbutazone or hydrocortisone; the potency ratios differed with the test employed.
The inhibition of carrageenin induced oedema by indometacin is specific; the compound failed to inhibit oedema induced by a variety of agents other than carrageenin, nor did it reduce oedema if the drug was administered after the oedema had been established.
As with other anti-inflammatory agents, the mechanism of action of indometacin is unknown. Indometacin is fully active in the absence of the adrenals and its activity is readily demonstrable by direct application of the compound to the site of action. Unlike anti-inflammatory steroids, indometacin in intact animals did not affect the size of the adrenals or the thymus, nor did it retard gain in bodyweight; these are sensitive indicators of adrenal activation. The anti-inflammatory activity of combinations of indometacin and a steroid was that of either drug alone in comparable doses.
Experiments have shown indometacin to have a favourable effect upon adjuvant induced polyarthritis in rats; it was more active than phenylbutazone or acetylsalicylic acid in suppressing the delayed manifestations of disseminated arthritis. This response is said to correlate well with clinical antiarthritic activity.

Antipyretic activity.

The antipyretic activity of indometacin has been demonstrated in rabbits and rats injected with bacterial pyrogen and in the classical yeast induced fever assay in rats. A direct comparison of peak antipyretic activity in the yeast fever test showed indometacin to be about nine times as potent as aminopyrine, 24 times as potent as phenylbutazone, and 43 times as potent as acetylsalicylic acid.
The antipyretic activity of indometacin has been confirmed clinically by observation in patients with a variety of febrile conditions.

Analgesic activity.

Indometacin is active in animal tests designed to assay analgesic activity of non-narcotic analgesics. Moderate doses raise the response threshold when pressure is applied to the yeast inflamed foot of the rat, but do not affect responses to thermal stimuli, or to pressure on a noninflamed foot.
Qualitatively, indometacin behaves like an analgesic of the anti-inflammatory antipyretic type typified by the salicylates, and not of the narcotic type typified by morphine.
When single oral doses of indometacin were assayed in the inflamed foot assay, the compound was found to be about 28 times as potent as acetylsalicylic acid (aspirin) and about 14 times as potent as phenylbutazone.

Indications

Indocid is indicated in active stages of rheumatoid arthritis, osteoarthritis, degenerative joint disease of the hip, ankylosing spondylitis and gout.
It is also indicated for:
Acute musculoskeletal disorders such as bursitis, tendonitis, synovitis, tenosynovitis, capsulitis of the shoulder, sprains and strains.
Low back pain (commonly referred to as lumbago).
Inflammation, pain and oedema following orthopaedic surgical procedures and nonsurgical procedures associated with reduction and immobilisation of fractures or dislocations.
Pain and associated symptoms of primary dysmenorrhoea.

Contraindications

Indocid should not be used in:
Patients who are hypersensitive to any component of this product.
Patients in whom acute asthmatic attacks, urticaria or rhinitis are precipitated by acetylsalicylic acid or other non-steroidal anti-inflammatory agents.
Patients with severe heart failure.
Patients with severe hepatic impairment.
As with other anti-inflammatory agents, indometacin may mask the signs and symptoms of peptic ulcer. Because indometacin itself may cause peptic ulceration or irritation of the gastrointestinal tract, it should not be given to patients with active peptic ulcer or with a recurrent history of gastrointestinal ulceration.
Indocid is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery.
Indocid suppositories are contraindicated in patients with a history of proctitis or recent rectal bleeding.

Precautions

Use in pregnancy.

(Category C)
Indocid should not be given to pregnant women since safety for this use has not been established.
Data from epidemiological studies suggest an increased risk of miscarriage after the use of a prostaglandin synthesis inhibitor in early pregnancy.
Category C: Nonsteroidal anti-inflammatory drugs have an inhibitory effect on prostaglandin synthesis and, when given during the third trimester of pregnancy, may cause closure of the fetal ductus arteriosus, tricuspid incompetence and pulmonary hypertension; nonclosure of ductus arteriosus postnatally which may be resistant to medical management; myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or failure, renal injury/ dysgenesis which may result in prolonged or permanent renal failure, oligohydramnios, gastrointestinal bleeding or perforation, increased risk of necrotising enterocolitis, and delayed labour and birth.
Administration of Indocid is not recommended during pregnancy.

Use in lactation.

Administration of Indocid is not recommended during lactation. Indocid is excreted in breast milk.
Carefully consider the potential benefits and risks of Indocid and other treatment options before deciding to use Indocid. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.
As advancing years appear to increase the possibility of side effects, Indocid should be used with greater care in the elderly.
Safe conditions for use in children under two years of age have not been established. Children should be monitored closely and periodic evaluations of liver function should be performed at appropriate intervals. Cases of hepatotoxicity including fatalities have been reported.

Cardiovascular effects.

Cardiovascular thrombotic events.

Observational studies have shown that nonselective NSAIDs may be associated with an increased risk of serious cardiovascular thrombotic events, including myocardial infarction, stroke and heart failure, which may increase with dose and duration of use and patients with cardiovascular disease, history of atherosclerotic cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. There are a lack of data from randomised, placebo controlled studies. However, to minimise the potential risk for an adverse cardiovascular event, especially in patients with CV risk factors, the lowest effective dose should be used for the shortest possible duration.
Physicians and patients should remain alert for such CV events even in the absence of previous CV symptoms. Patients should be informed about signs and/or symptoms of serious CV toxicity and the steps to take if they occur.
There is no evidence to suggest that concurrent use of aspirin mitigates the increased risk of serious CV events associated with NSAID use. However, the concurrent use of NSAIDs and aspirin does increase the risk of serious GI events.

Hypertension.

NSAIDs can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking antihypertensives along with NSAIDs may have impaired antihypertensive response and hence NSAIDs should be administered with caution in patients with hypertension. Furthermore, when given to patients with hypertension, blood pressure should be monitored closely during the initiation of NSAID treatment and at regular intervals thereafter.

Congestive heart failure, fluid retention and oedema.

Congestive heart failure, fluid retention and peripheral oedema have been observed in some patients taking Indocid. Therefore, as with other nonsteroidal anti-inflammatory drugs, Indocid should be used with caution in patients with cardiac dysfunction, hypertension or other conditions predisposing to fluid retention.

Serious gastrointestinal effects.

All NSAIDs can cause gastrointestinal discomfort and serious, potentially fatal gastrointestinal effects such as ulcers, bleeding and perforation, which may increase with dose or duration of use, but can occur at any time without warning. Upper GI ulcers, gross bleeding or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-time therapy is not without risk.
Caution is advised in patients with risk factors for gastrointestinal events who may be at greater risk of developing serious gastrointestinal events, e.g. the elderly, those with a history of serious gastrointestinal events, smoking and alcoholism. When gastrointestinal bleeding or ulcerations occur in patients receiving NSAIDs, the drug should be withdrawn immediately. Doctors should warn patients about the signs and symptoms of serious gastrointestinal toxicity.
The concurrent use of aspirin and NSAIDs also increases the risk of serious gastrointestinal adverse events.
Because of the occurrence and at times severity of gastrointestinal reactions, the risks of continuing therapy with Indocid in the face of such symptoms must be weighed against the possible benefits to the individual patient.
Gastrointestinal 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 and regional ileitis have been reported to occur rarely.
Pancreatitis has been reported with an unknown frequency.

Severe skin reactions.

NSAIDs, including Indocid, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be fatal and may occur without warning. These serious adverse events are idiosyncratic and are independent of dose or duration of use. Patients should be informed about the signs and symptoms of serious skin reactions and to consult their doctor at the first appearance of skin rash or any other sign of hypersensitivity.

Platelet aggregation.

Indocid, like other nonsteroidal anti-inflammatory agents, can inhibit platelet aggregation. This effect is of shorter duration than that seen with acetylsalicylic acid and usually disappears within 24 hours after discontinuation of Indocid. Indocid has been shown to prolong bleeding time (but within the normal range) in normal subjects. Because this effect may be exaggerated in patients with underlying haemostatic defects, Indocid should be used with caution in persons with coagulation defects.

Anticoagulants.

Concurrent use of NSAIDs and warfarin has been associated with severe, sometimes fatal haemorrhage, especially in the elderly. The exact mechanism is unknown, but may involve enhanced bleeding from NSAID induced gastrointestinal ulceration, or an additive effect of anticoagulation by warfarin and inhibition of platelet function by NSAIDs. Indocid should be used in combination with warfarin only if absolutely necessary, and patients taking this combination should be closely monitored. In postmarketing experience, bleeding has been reported in patients on concomitant treatment with anticoagulants and Indocid. Caution should be exercised when Indocid and anticoagulants are administered concomitantly. Adjustment of the dosage for oral anticoagulants may be required.

Suppository.

Tenesmus and irritation of the rectal mucosa have been reported occasionally with the use of Indocid suppositories.

Ocular effects.

Corneal deposits and retinal disturbances, including those of the macula, have been observed in some patients who had received prolonged therapy with Indocid. The prescribing physician should be alert to the possible association between the changes noted and Indocid; however, similar eye changes have been observed in patients with rheumatoid arthritis who have not received indometacin. It is advisable to discontinue therapy if such changes are observed. Blurred vision may be a significant symptom and warrants a thorough ophthalmological examination. Since these changes may be asymptomatic, ophthalmological examination at periodic intervals is desirable in patients where therapy is prolonged.

Central nervous system effects.

Headache, sometimes accompanied by dizziness or lightheadedness, may occur, usually early in treatment with indometacin. Although the severity of these effects rarely requires discontinuing therapy, if headache persists despite dosage reduction, indometacin therapy should be discontinued. Patients should be warned that they may experience dizziness and in this event should not operate motor vehicles and should avoid potentially dangerous activities which require alertness.
Indometacin should be used with caution in patients with psychiatric disturbances, epilepsy or parkinsonism, since it may, in some instances, tend to aggravate these conditions.

Infections.

In common with other anti-inflammatory analgesic antipyretic drugs, indometacin possesses the potential for masking the signs and symptoms which ordinarily accompany infectious disease. The physician should be alert to this possibility to avoid undue delay in initiating appropriate treatment of the infection. Indometacin should be used with caution in patients with existing, but controlled, infection.

Renal function.

As with other nonsteroidal 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.
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. In patients with reduced renal blood flow, where renal prostaglandins play a major role in maintaining renal perfusion, administration of a nonsteroidal 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. Caution should be used when initiating the treatment with Indocid in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with Indocid. Caution is also recommended in patients with pre-existing kidney disease. A nonsteroidal 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 NSAID therapy is usually followed by recovery to the pretreatment state.
Increases in serum potassium concentration, including hyperkalaemia, have 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 Interactions with Other Medicines).
Since Indocid 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. Therefore, treatment with Indocid is not recommended in these patients with advanced renal disease. If Indocid therapy must be initiated, close monitoring of the patient's renal function is advisable.

Laboratory tests.

As with other nonsteroidal anti-inflammatory drugs, borderline elevations of one or more liver function tests may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may resolve with continued therapy.
Significant (3 times the upper limit of normal) elevations of SGPT (ALT) or SGOT (AST) occurred in controlled clinical trials in less than 1% of patients receiving therapy with non-steroidal anti-inflammatory drugs. Physicians and patients should remain alert for hepatotoxicity. Patients should be informed about the signs and/or symptoms of hepatotoxicity. A patient with symptoms and/or signs suggesting liver dysfunction (e.g. nausea, fatigue, lethargy, pruritis, jaundice, abdominal tenderness in the right upper quadrant and "flu-like" symptoms), or in whom an abnormal liver function test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Indocid.
If abnormal liver function tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop or if systemic manifestations occur (e.g. eosinophilia, rash, etc.), therapy should be discontinued.
False negative results in the dexamethasone suppression test (DST) in patients being treated with Indocid have been reported. Thus results of the DST should be interpreted with caution in these patients.

Interactions

Acetylsalicylic acid (aspirin).

The use of Indocid in conjunction with acetylsalicylic acid or other salicylates is not recommended. Controlled clinical studies have shown that the combined use of Indocid and acetylsalicylic acid does not produce any greater therapeutic effect than the use of Indocid alone. Furthermore, in one of these clinical studies, the incidence of gastrointestinal side effects was significantly increased with combined therapy. In a study in normal volunteers, it was found that chronic concurrent administration of 3.6 g of acetylsalicylic acid per day decreases indometacin blood levels approximately 20%.

Diflunisal.

The combined use of Indocid and diflunisal has been associated with fatal gastrointestinal haemorrhage. The coadministration of diflunisal and Indocid results in an increase of about 30 to 35% in indometacin plasma levels and a concomitant decrease in renal clearance of indometacin and its conjugate. Therefore, Indocid and diflunisal should not be used concomitantly.

Other NSAIDs.

The concomitant use of Indocid and other NSAIDs is not recommended due to the increased possibility of gastrointestinal toxicity, with little or no increase in efficacy.

Probenecid.

When Indocid is given to patients receiving probenecid, the plasma levels of indometacin are likely to be increased. Therefore, a lower total daily dosage of Indocid may produce a satisfactory therapeutic effect. When increases in the dose of Indocid are made under these circumstances they should be made cautiously and in small increments.

Methotrexate.

Caution should be used if Indocid is administered simultaneously with methotrexate. Indocid has been reported to decrease the tubular secretion of methotrexate and to potentiate toxicity.

Cyclosporine.

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

Lithium.

Indometacin 50 mg t.i.d. 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 carefully observed for signs of lithium toxicity. (Read circulars for lithium preparations for lithium preparations before use of such concomitant therapy.) In addition, the frequency of monitoring serum lithium concentrations should be increased at the outset of such combination drug treatment.

Digoxin.

Indocid given concomitantly with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Therefore, when Indocid and digoxin are used concomitantly, serum digoxin levels should be closely monitored.

Diuretics.

In some patients, the administration of Indocid can reduce the diuretic, natriuretic and antihypertensive effects of loop, potassium sparing, and thiazide diuretics. Therefore, when Indocid and diuretics are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.
Indocid reduces basal plasma renin activity (PRA) as well as those elevations of PRA induced by frusemide administration, or salt or volume depletion. These facts should be considered when evaluating plasma renin activity in hypertensive patients.
It has been reported that the addition of triamterene to a maintenance schedule of Indocid resulted in reversible acute renal failure in two of four healthy volunteers. Indocid and triamterene should not be administered together.
Indocid and potassium sparing diuretics each may be associated with increased serum potassium levels. The potential effects of Indocid 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 Indocid.

Antihypertensive medications.

Coadministration of Indocid and some antihypertensive agents has resulted in an attenuation of the latter's hypotensive effect acutely, due at least in part to indometacin's inhibition of prostaglandin synthesis. The prescriber should, therefore, exercise caution when considering the addition of Indocid to the regimen of a patient taking one of the following antihypertensive agents: an alpha-adrenergic blocking agent (such as prazosin), an angiotensin converting enzyme inhibitor (such as captopril or lisinopril), a beta-adrenergic blocking agent , a diuretic (see Diuretics), hydralazine or losartan (an angiotensin II receptor antagonist). In some patients with compromised renal function (e.g. elderly patients or patients who are volume depleted, including those on diuretic therapy), the coadministration of an NSAID and an ACE inhibitor or angiotensin II antagonist may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible.
These interactions should be considered in patients taking an NSAID concomitantly with diuretics and ACE inhibitors. Therefore, the combination should be administered with caution, especially in the elderly.

Beta-adrenergic receptor blocking agents.

A decrease in the antihypertensive effect of beta-adrenergic receptor blocking agents by nonsteroidal anti-inflammatory drugs including indometacin has been reported. Therefore, when using a beta-blocking agent to treat hypertension, patients should be observed carefully in order to confirm that the desired therapeutic effect has been obtained.

Combination use of angiotensin converting enzyme inhibitors or angiotensin receptor antagonists, anti-inflammatory drugs and thiazide diuretics.

The use of an angiotensin converting enzyme (ACE) inhibiting drug (ACE inhibitor or angiotensin receptor antagonist), an anti-inflammatory drug (NSAID or cyclooxygenase-2 (COX-2) inhibitor) and a thiazide diuretic at the same time increases the risk of renal impairment. This includes use in fixed combination products containing more than one class of drug. Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the institution of the combination. The combination of drugs from these three classes should be used with caution particularly in elderly patients or those with pre-existing renal impairment.

Phenylpropanolamine.

Hypertensive crises have been reported due to oral phenylpropanolamine alone and rarely (< 1/1000) to phenylpropanolamine given with Indocid. This additive effect is probably due at least in part to indometacin's inhibition of prostaglandin synthesis. Caution should be exercised when Indocid and phenylpropanolamine are administered concomitantly.

Adverse Effects

Central nervous system.

Central nervous sytem adverse effects are headache, dizziness, lightheadedness, 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, psychic disturbances such as depersonalisation, psychotic episodes and rarely paraesthesias, dysarthria, aggravation of epilepsy and parkinsonism. These are often transient and disappear frequently with continued treatment or with a reduction of dosage. However, the severity of these may, on occasion, require stopping therapy.

Gastrointestinal.

Gastrointestinal reactions which occur most frequently are nausea, anorexia, vomiting, epigastric distress, 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 having been reported; gastrointestinal tract bleeding without obvious ulcer formation; and increased abdominal pain when used in patients with pre-existing ulcerative colitis. Rarely, intestinal strictures (diaphragms) and intestinal ulceration followed by stenosis and obstruction has been reported. Reactions which occur infrequently are stomatitis, gastritis, flatulence, bleeding from the sigmoid colon (occult) or from a diverticulum, and perforation of pre-existing sigmoid lesions (diverticula, carcinoma). Other gastrointestinal side effects which may or may not be caused by indometacin include ulcerative colitis and regional ileitis.
Studies in man with radioactive chromate tagged red blood cells indicate that the highest recommended oral dosage of indometacin (50 mg, 4 times a day) produces less faecal blood loss than average doses of acetylsalicylic acid (600 mg 4 times a day).

Hepatic.

Hepatic reactions reported on rare occasions are jaundice and hepatitis; and some fatal cases have been reported.

Cardiovascular/ renal.

Cardiovascular/ renal reactions which may occur infrequently include oedema, elevation of blood pressure, tachycardia, chest pain, arrhythmia, palpitations, hypotension, congestive heart failure, BUN elevation and haematuria.

Hypersensitivity.

Hypersensitivity reactions reported infrequently are pruritus, urticaria, angiitis, erythema nodosum, skin rashes, exfoliative dermatitis, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, loss of hair, acute respiratory distress, a rapid fall in blood pressure resembling a shock-like state, acute anaphylaxis, angioneurotic oedema, sudden dyspnoea, asthma and pulmonary oedema.

Haematological.

Haematological reactions which may develop infrequently in conjunction with indometacin therapy are leucopenia, petechiae or ecchymosis, purpura, aplastic and haemolytic anaemia and thrombocytopenia and disseminated intravascular coagulation. Rarely, agranulocytosis and bone marrow depression have been reported, but a definite relationship to indometacin has not been established.
Some patients may manifest anaemia secondary to obvious or occult gastrointestinal bleeding. Therefore, appropriate blood determinations are recommended.

Eye.

Blurred vision, diplopia and orbital and periorbital pain may occur infrequently. Corneal deposits and retinal disturbances, including those of the macula, have been reported in some patients with rheumatoid arthritis on prolonged therapy with Indocid. Similar eye changes have been observed in some patients with this disease who have not received Indocid.

Ear.

Tinnitus, hearing disturbances and deafness (rarely) have been reported to occur.

Genitourinary.

Reported rarely: proteinuria, nephrotic syndrome, interstitial nephritis and renal insufficiency, including renal failure.

Miscellaneous.

Miscellaneous adverse reactions reported rarely include vaginal bleeding, hyperglycaemia and glycosuria, hyperkalaemia, flushing and sweating, epistaxis, ulcerative stomatitis, and breast changes including enlargement and tenderness, or gynaecomastia.

The following local adverse reactions have been associated with use of Indocid suppositories.

Tenesmus; proctitis; rectal bleeding, burning, pain, discomfort and itching.

Adverse effects, causal relationship unknown.

The following additional adverse effects have been reported, however a causal relationship to therapy with Indocid has not been established.

Cardiovascular.

Thrombophlebitis.

Haematologic.

Although there have been several reports of leukaemia, the supporting information is weak.

Genitourinary.

Urinary frequency.

Miscellaneous.

Rare occurrences of fulminant necrotizing fasciitis, particularly in association with group A β-haemolytic Streptococcus, have been described in persons treated with nonsteroidal anti-inflammatory agents, sometimes with fatal outcome (see also Precautions).

Dosage and Administration

Indocid is available for oral administration as a 25 mg capsule and as a rectal suppository containing 100 mg of indometacin.
The recommended dosage of Indocid is 50 mg to 200 mg daily in divided doses and should be individually adjusted to the patient's response and tolerance. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.
Patients on long-term treatment should be reviewed regularly with regards to efficacy, risk factors and ongoing need for treatment.
Unlike some other potent antirheumatic agents, an initial high "loading" dose of Indocid is not necessary. In chronic rheumatic disorders, initiating therapy with low doses, increasing gradually when necessary, and continuing for an adequate period (up to one month is recommended) will produce maximum benefit and minimise adverse reactions.
In patients with persistent night pain and/or morning stiffness, a dose of up to 100 mg at bedtime may be helpful in affording relief. It is rarely necessary to exceed a dosage of 200 mg/day.
In the treatment of acute gouty arthritis, the recommended daily dosage is 150 mg to 200 mg until all symptoms and signs subside.
In primary dysmenorrhoea, the recommended dosage is 25 mg three times a day starting with onset of cramps or bleeding and continuing for as long as the symptoms usually last.
To minimise the possibility of gastrointestinal disturbances, it is recommended that oral Indocid be taken with food, milk or an antacid.

Overdosage

The following symptoms may be observed following overdosage: nausea, vomiting, intense headache, dizziness, mental confusion, disorientation or lethargy. There have been reports of paraesthesias, numbness and convulsions.
No specific information is available on the treatment of overdosage with Indocid. Treatment is symptomatic and supportive. Therapy with Indocid should be discontinued and the patient observed closely. If possible, activated charcoal should be given within one hour of ingestion, with then correction of dehydration and electrolyte imbalance by established procedures. The patient should be followed for several days because gastrointestinal ulceration and haemorrhage have been reported as adverse reactions of indometacin. Use of antacids may be helpful.
Contact the Poisons Information Centre on 131 126 for advice on overdose management.

Presentation

Indocid 25 mg, white powder in an opaque ivory capsule. Marked with "25" on the capsule in black. Supplied in PVC/PVDC/Al blister packs of 50.
Indocid suppositories, 100 mg, white opaque with yellowish cast. Supplied in 20's, foil pack.

Storage

Store below 25°C.

Poison Schedule

S4.