Consumer medicine information

Arthrexin

Indometacin

BRAND INFORMATION

Brand name

Arthrexin

Active ingredient

Indometacin

Schedule

What is in this leaflet

This leaflet answers some common questions about ARTHREXIN. 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 ARTHREXIN 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 ARTHREXIN is used for

ARTHREXIN contains the active ingredient, indometacin. It belongs to a group of medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs).

ARTHREXIN 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, ankylosing spondylitis and degenerative joint disease of the hip
gout
muscle and bone injuries such as sprains, strains, low back pain (lumbago) and tendonitis, such as tennis elbow
pain and swelling after setting broken or dislocated bones
menstrual cramps (period pain)

Although ARTHREXIN can relieve the symptoms of pain and inflammation, it will not cure your condition.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is not addictive.

It is available only with a doctor's prescription.

There is not enough information to recommend the use of this medicine for children under the age of 2 years

Before you take ARTHREXIN

When you must not take it

Do not take ARTHREXIN if you have an allergy to:

any medicine containing indometacin
aspirin or any other NSAID medicines
any of the ingredients listed at the end of this leaflet

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

If you are not sure if you are taking any of these medicines, ask your doctor or pharmacist.

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin

If you are allergic to aspirin or NSAID medicines and use ARTHREXIN, the above symptoms may be severe.

Do not take this medicine if you are pregnant or intend to become pregnant. ARTHREXIN may affect your developing baby if you take it during pregnancy. If it is necessary for you to take ARTHREXIN, your doctor will discuss the risks and benefits of taking it during pregnancy.

Women considering pregnancy should not use ARTHREXIN unless advised to by their doctor. ARTHREXIN may have a reversible inhibitory effect on fertility.

Do not breastfeed if you are taking this medicine. The active ingredient in ARTHREXIN passes into breast milk and there is a possibility that your baby may be affected.

Do not take ARTHREXIN if:

you have an active peptic ulcer (i.e. a stomach or duodenal ulcer) or have had peptic ulcers more than once before
you have severe heart failure
you have recently had heart bypass surgery
you have severe liver failure
you experience asthma attacks, hives or rash or itching of the nose, throat or eyes with aspirin or other NSAIDs
you are vomiting blood or material that looks like coffee grounds
you are bleeding from the back passage, have black sticky bowel motions or bloody diarrhoea

Do not take this medicine after the expiry date printed on the pack has passed or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, including aspirin and other NSAID medicines, foods, dyes or preservatives.

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

stomach ulcers or other stomach problems
heartburn or indigestion
bowel or intestinal problems such as ulcerative colitis
kidney or liver disease
diabetes
high blood pressure or heart disease
history of chest pain (angina), heart problems or stroke
history of swelling in the feet or ankles
a tendency to bleed or other blood problems
psychiatric problems
seizures or fits (epilepsy)
Parkinson's disease
asthma
eye disease

Tell your doctor if you currently have an infection. ARTHREXIN may hide some of the signs of an infection. This 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 start taking ARTHREXIN.

Taking other medicines

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

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

aspirin, salicylates or other NSAID medicines (e.g. ibuprofen)
anticoagulants such as warfarin, a medicine used to prevent blood clots
cardiac glycosides such as digoxin, a medicine used to treat heart failure or irregular heart beats
lithium, a medicine used to treat mood swings and some types of depression
probenecid, a medicine used to treat gout
diuretics, also known as fluid or water tablets
some medicines used to treat high blood pressure or heart conditions, including ACE inhibitors or betablockers or medicines used in combination with a thiazide diuretic
decongestants
ciclosporin, a medicine used to prevent organ transplant rejection or suppress the immune system
methotrexate, a medicine used to treat arthritis and certain types of cancers
corticosteroids
mifepristone
quinolone antibiotics
vancomycin

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

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking ARTHREXIN.

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

How to take ARTHREXIN

Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box/bottle, ask your doctor or pharmacist for help.

How much 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.

The dose varies from patient to patient. The usual dose is between 50 mg and 200 mg per day, given in divided doses.

Elderly patients may need smaller doses.

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

The dose for menstrual cramps (period pain) is usually one 25 mg capsule every eight hours, starting with the onset of bleeding or cramps.

How to take it

Swallow the capsules whole with a full glass of water.

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

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

When to take it

Take ARTHREXIN with or immediately after food.

How long to take it

Continue taking your medicine for as long as your doctor tells you to.

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 ARTHREXIN for arthritis, it will not cure your condition but it should help to control pain, swelling and stiffness. If you have arthritis, ARTHREXIN should be taken every day for as long as your doctor prescribes.

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

For gout, ARTHREXIN can be stopped when all symptoms subside.

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

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

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

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much ARTHREXIN. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of an overdose may include nausea, vomiting, headache, dizziness, confusion, fatigue, numbness or fits.

While you are taking ARTHREXIN

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking ARTHREXIN.

Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. ARTHREXIN may cause prolonged bleeding and may need to be stopped before surgery.

If you become pregnant while taking this medicine, tell your doctor immediately.

Tell your doctor if you get an infection while taking ARTHREXIN. ARTHREXIN 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 are about to have any blood tests, tell your doctor that you are taking this medicine.

Keep all of your doctor's appointments so that your progress can be checked. ARTHREXIN 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 ARTHREXIN, patients should visit their optometrist for regular eye checks.

Things you must not do

Do not take ARTHREXIN to treat any other complaints unless your doctor tells you to.

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

Do not stop taking your medicine or lower the dosage without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how ARTHREXIN affects you. As with other NSAID medicines, this medicine may cause dizziness or light-headedness in some people. If this occurs, do not drive, operate machinery or do anything else that could be dangerous.

If you drink alcohol, the dizziness or light-headedness may be worse.

Side effects

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

This medicine helps most people with pain or inflammation, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

If you are over 65 years of age, have liver or kidney problems or are diabetic, you may have an increased chance of getting side effects.

Do not be alarmed by the following list of side effects. You may not experience any of them.

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

Tell your doctor or pharmacist if you notice any of the following and they worry you:

stomach upset or pain including nausea (feeling sick), vomiting, cramps, loss of appetite
heartburn or indigestion (possible symptoms of an ulcer in the tube that carries food from the throat to the stomach)

Some of the stomach upset, such as nausea and heartburn, may be reduced by taking the capsules with food or an antacid, if advised by your doctor or pharmacist.

constipation, diarrhoea
hearing disturbances such as buzzing or ringing in the ears
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 such as depression, anxiety or irritability

These are the more common side effects of ARTHREXIN.

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 or 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
drowsiness, disorientation, forgetfulness
shakiness, sleeplessness, nightmares
tingling or numbness of the hands or feet

If any of the following happen, 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
sudden or severe itching, skin rash or hives, blistering or peeling of the skin
asthma, wheezing, shortness of breath
severe dizziness, light-headedness or fainting
seizures or fits
pain or tightness in the chest

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are rare.

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

Other side effects not listed above may also occur in some people.

After taking ARTHREXIN

Storage

Keep your capsules in the pack until it is time to take them. If you take the capsules out of the pack they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 30°C.

Do not store ARTHREXIN or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. 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 taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine left over.

Product description

What it looks like

ARTHREXIN capsules are white opaque hard gelatin capsules, marked "IN-25" on both body and cap.

Each carton contains 50 capsules.

Ingredients

ARTHREXIN contains 25 mg of indometacin as the active ingredient.

The capsules also contain:

lactose monohydrate
sodium starch glycollate
sodium lauryl sulfate
magnesium stearate
Empty hard gelatin capsules bovine size 3 white-opaque/white-opaque G3ICSRA0399 1 U (proprietary ingredient: 140186)
Opacode Black A-10259 (proprietary ingredient: 1659)

The capsules are gluten free.

Manufacturer

Alphapharm Pty Ltd trading as Viatris
(ABN 93 002 359 739)
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

ARTHREXIN 25 mg capsules: AUST R 353404

This leaflet was prepared in October 2023.

arthrexin_cmi\Oct23/00

Published by MIMS November 2023

BRAND INFORMATION

Brand name

Arthrexin

Active ingredient

Indometacin

Schedule

1 Name of Medicine

Indometacin.

2 Qualitative and Quantitative Composition

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

Excipients with known effect.

Contains sugars as lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Arthrexin capsules are size 3 white opaque hard gelatin capsules, marked "IN-25" on both body and cap.

4 Clinical Particulars

4.1 Therapeutic Indications

Arthrexin is indicated in active stages of: rheumatoid arthritis; osteoarthritis; degenerative joint disease of the hip; ankylosing spondylitis; 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.

4.2 Dose and Method of Administration

The recommended dosage of Arthrexin is 50 to 200 mg daily in divided doses and should be individually adjusted to 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 Arthrexin 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). This 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 signs and symptoms 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, Arthrexin should be taken with food, milk or an antacid.

4.3 Contraindications

Indometacin 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 (aspirin) or other non-steroidal anti-inflammatory agents (NSAIDs);
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.
Indometacin is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.
For use in pregnancy and lactation, see Section 4.6 Fertility, Pregnancy and Lactation.

4.4 Special Warnings and Precautions for Use

Carefully consider the potential benefits and risks of indometacin and other treatment options before deciding to use indometacin. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.

Cardiovascular effects.

Cardiovascular thrombotic events.

Observational studies have indicated that non-selective nonsteroidal anti-inflammatory drugs (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 cardiovascular risk factors may also be at greater risk. There are a lack of data from randomised, placebo controlled studies. However, to minimise the potential risk of an adverse cardiovascular event (CV), especially in those with cardiovascular 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 that the concurrent use of acetylsalicylic acid mitigates the increased risk of serious cardiovascular events associated with NSAID use. However, the concurrent use of NSAIDs and acetylsalicylic acid does increase the risk of serious GI events.

Hypertension.

NSAIDs may lead to the onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of cardiovascular events. Patients taking anti-hypertensives with NSAIDs may have an impaired anti-hypertensive 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 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 indometacin. Therefore, as with other NSAIDs, Arthrexin 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 to 6 months and in about 2 to 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-term therapy is not without risk.
Single or multiple ulcerations, 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.
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 occurs 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 increase the risk of serious gastrointestinal adverse events.
Because of the occurrence and at times severity of gastrointestinal reactions, the risks of continuing therapy with Arthrexin 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 indometacin, can cause serious cutaneous adverse events such as exfoliative dermatitis, toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome (see Drug reaction with eosinophilia and systemic symptoms (DRESS)) 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 advised of the signs and symptoms of serious skin reactions and to consult their physician at the first appearance of a skin rash or any other sign of hypersensitivity.

Drug reaction with eosinophilia with systemic symptoms (DRESS).

DRESS has been reported in patients taking NSAIDs. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, haematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue the NSAID and evaluate the patient immediately.

Platelet aggregation.

Indometacin, like other NSAIDs, 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 Arthrexin. Indometacin 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, Arthrexin 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. Indometacin 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 indometacin. Caution should be exercised when indometacin and anticoagulants are administered concomitantly. Adjustment of dosage for oral anticoagulants may be required.

Ocular effects.

Corneal deposits and retinal disturbances, including those of the macula, have been observed in some patients who had received prolonged therapy with indometacin. The prescribing physician should be alert to the possible association between the changes noted and Arthrexin; 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 in whom therapy is prolonged.
Adverse ophthalmological effects have been observed with non-steroidal anti-inflammatory agents; accordingly, patients who develop visual disturbances during treatment with Arthrexin should have an ophthalmological examination.

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.
Arthrexin 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 diseases. 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.

Use in renal impairment.

As with other NSAIDs, 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 an 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. Caution should be used when initiating the treatment with indometacin in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with indometacin. Caution is also recommended in patients with pre-existing kidney disease. An NSAID should be given with caution and renal function should be monitored in any patient who may have reduced renal reserve. Discontinuation of non-steroidal anti-inflammatory therapy is usually followed by recovery to the pre-treatment 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 Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
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. Therefore, treatment with indometacin is not recommended in these patients with advanced renal disease. If indometacin therapy must be initiated, close monitoring of the patient's renal function is advisable.

Use in the elderly.

As advancing years appear to increase the possibility of side effects, Arthrexin should be used with greater care in the elderly.

Paediatric use.

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.

Effects on laboratory tests.

As with other NSAIDs, borderline elevations of one or more liver 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 NSAIDs. 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, pruritus, jaundice, abdominal tenderness, in the right upper quadrant and "flu-like" symptoms), or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Arthrexin.
If abnormal liver 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 indometacin have been reported. Thus, results of the DST should be interpreted with caution in these patients.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Acetylsalicylic acid.

The use of Arthrexin in conjunction with acetylsalicylic acid or other salicylates is not recommended. Controlled clinical studies have shown that the combined use of indometacin and acetylsalicylic acid does not produce any greater therapeutic effect than the use of indometacin 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 indometacin and diflunisal has been associated with fatal gastrointestinal haemorrhage. The coadministration of diflunisal and indometacin 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, Arthrexin and diflunisal should not be used concomitantly.

Other NSAIDs.

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

Anticoagulants.

Although clinical studies suggest that indometacin does not influence the hypoprothrombinaemia induced by anticoagulants, patients also receiving anticoagulants should be closely observed for alterations of the prothrombin time.

Probenecid.

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

Methotrexate.

Caution should be used if Arthrexin is administered simultaneously with methotrexate. Indometacin has been reported to decrease the 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 prostacyclin. In patients taking ciclosporin, NSAIDs should be used with caution and the patients' renal function monitored carefully.

Lithium.

Indometacin 50 mg three times daily 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. (Refer to literature 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.

Cardiac glycosides/ digoxin.

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

Diuretics.

In some patients, the administration of Arthrexin can reduce the diuretic, natriuretic and antihypertensive effects of loop, potassium sparing and thiazide diuretics. Therefore, when Arthrexin 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 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 indometacin resulted in reversible acute renal failure in two of four healthy volunteers. Arthrexin and triamterene should not be administered together.
Arthrexin and potassium sparing diuretics each may be associated with increased serum potassium levels. The potential effects of Arthrexin 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.

Antihypertensive medications.

Coadministration of indometacin 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. Therefore, caution should be exercised by the prescriber when considering the addition of Arthrexin to the patient's medication regimen when the patient is taking any 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 Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, 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.

β-Adrenergic receptor blocking agents.

A decrease in the antihypertensive effect of β-adrenergic receptor blocking agents by nonsteroidal anti-inflammatory drugs including indometacin has been reported. Therefore, when using a β-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 ACE inhibitors or angiotensin receptor antagonists, anti-inflammatory drugs and thiazide diuretics.

The use of an 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 indometacin. This additive effect is probably due partly to indometacin's ability to inhibit prostaglandin synthesis. Caution should be exercised when Arthrexin and phenylpropanolamine are administered together.

Corticosteroids.

The risk of gastrointestinal bleeding and ulceration associated with NSAIDs is increased when used with corticosteroids.

Mifepristone.

NSAIDs and aspirin should be avoided until at least 8 to 12 days after administration of mifepristone.

Quinolone 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.

Vancomycin.

Studies in premature neonates being treated for patent ductus arteriosus have shown that concomitant administration of indometacin and vancomycin may have additive nephrotoxic effects. As such, caution is advised during concurrent or subsequent use of indometacin and vancomycin, as indometacin may increase the risk of vancomycin related toxicities. Where possible, monitor vancomycin levels and adjust the vancomycin dose and/or dosing interval accordingly.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Indometacin should be used with caution in women of child-bearing age who are thinking to get pregnant. Consider withdrawal of NSAIDs, including indomethacin, in women who have difficulties conceiving or who are being medically evaluated for infertility.
Prostaglandins have been reported to play an important role in human ovulation and implantation. Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development.
Clinical studies have shown that NSAIDs including indomethacin have an inhibitory (delay) reversible effect on healthy women ovulation.
(Category C)
Non-steroidal anti-inflammatory drugs have an inhibitory effect on prostaglandin synthesis and, when given during the third trimester of pregnancy, may cause closure of the foetal ductus arteriosus, tricuspid incompetence and pulmonary hypertension, non-closure 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 (see Oligohydramnios and neonatal renal impairment), gastrointestinal bleeding or perforation, increased risk of necrotising enterocolitis and delayed labour and birth.
Indometacin 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.

Oligohydramnios and neonatal renal impairment.

Use of NSAIDs from about 20 weeks gestation may cause foetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment.
These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation.
Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some post-marketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.
If, after careful consideration of alternative treatment options for pain management, NSAID treatment is necessary from about 20 weeks, limit use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if treatment extends beyond 48 hours. Discontinue treatment with NSAIDs if oligohydramnios occurs.
Administration of indometacin is not recommended during pregnancy or lactation. Indometacin is excreted in breast milk.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Central nervous system.

Central nervous system 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, paraesthesia, dysarthria, aggravation of epilepsy and parkinsonism. These are often transient and disappear frequently with continued treatment or with a reduction in 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 humans with radioactive chromate tagged red blood cells indicate that the highest recommended oral dosage of indometacin (50 mg, four times a day) produces less faecal blood loss than average doses of acetylsalicylic acid (600 mg, four times a day).

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. Hypersensitivity reactions with unknown frequency are Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome.

Haematological.

Haematological reactions which may develop infrequently with indometacin therapy are leucopenia, petechiae or ecchymosis, purpura, aplastic and haemolytic anaemia, 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 indometacin. Similar eye changes have been observed in some patients with this disease who have not received indometacin.

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.

Pregnancy, puerperium and perinatal conditions.

Oligohydramnios, neonatal renal impairment.

Adverse effects - causal relationship unknown.

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

Cardiovascular.

Thrombophlebitis.

Haematological.

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

Genitourinary.

Urinary frequency.

Miscellaneous.

Rare occurrences of fulminant necrotising 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 Section 4.4 Special Warnings and Precautions for Use).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

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 indometacin. Treatment is symptomatic and supportive. Therapy with indometacin should be discontinued and the patient observed closely. If possible, activated charcoal should be given within 1 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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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.
Indometacin has been found effective in relieving pain, reducing fever, swelling, redness and tenderness of acute gouty arthritis.
The prostaglandin inhibitory effect of indometacin 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.

Clinical trials.

Anti-inflammatory action.

The anti-inflammatory activity of indometacin was first demonstrated in animals, 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, 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 9 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 and about 14 times as potent as phenylbutazone.

5.2 Pharmacokinetic Properties

Absorption.

Following single oral doses of indometacin 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 indometacin capsules are virtually 100% bioavailable, with 90% of the dose absorbed within four hours.

Distribution.

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.

Excretion.

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 mg or 50 mg three times a day, the steady-state plasma concentrations of indometacin average 1.4 times those following the first dose.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Arthrexin capsules contain the following inactive excipients: lactose monohydrate, sodium starch glycollate, sodium lauryl sulfate, magnesium stearate, empty hard gelatin capsules bovine size 3 white-opaque/white-opaque G3ICSRA0399 (ARTG PI 140186) and Opacode Black A-10259 (ARTG PI 1659).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Container type: bottle (HDPE with PP cap) and blister pack (PVC/PVDC).

Pack sizes.

Bottle: 6, 30, 50, 90, 250 and 1000 capsules.
Blister pack: 30, 50 and 90 capsules.
Some strengths, pack sizes and/or pack types may not be marketed.

Australian Register of Therapeutic Goods (ARTG).

AUST R 353403 - Arthrexin indometacin 25 mg capsule bottle.
AUST R 353404 - Arthrexin indometacin 25 mg capsule blister pack.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

Indometacin is a white to yellow, crystalline powder; odourless or almost odourless.
Structural formula:

Chemical name: 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid.
Molecular formula: C₁₉H₁₆ClNO₄.
Molecular weight: 357.8.

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Arthrexin 25 mg