Agilex

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

It is indicated for the following conditions:

- active stages of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, degenerative joint disease of the hip, acute musculoskeletal disorders, gout and lumbago.

- inflammation, pain and oedema following orthopaedic procedures.

- treatment of pain and associated symptoms of primary dysmenorrhoea.

Since Agilex is not a simple analgesic, its use should be limited to the above conditions.

Agilex Oral Suspension is indicated for:

• Moderate to severe rheumatoid arthritis including acute flares of chronic disease
• Moderate to severe ankylosing spondylitis
• Moderate to severe osteoarthritis
• Acute painful shoulder (bursitis and/or tendinitis)
• Acute gouty arthritis

Non-steroidal anti-inflammatory agent indicated for the active stages of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute musculoskeletal disorders, degenerative joint disease of the hip, low-back pain, and acute gouty arthritis.

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

Posology

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

To reduce the possibility of gastro-intestinal disturbances, Agilex capsules should always be taken with food, milk or an antacid and in chronic conditions start the therapy with a low dosage, increasing as required.

Adults: The recommended oral dosage range is 50-200mg daily.

Acute rheumatoid arthritis: Initially 25mg two or three times a day.

Chronic rheumatic disorders: 25mg two or three times daily. (If response is inadequate, gradually increase by 25mg. Adequate response is usually achieved with not more than 150mg daily, rarely more than 200mg daily).

Sudden flare up of chronic condition: Increase if necessary, by 25mg daily until a satisfactory response is obtained, or a dosage of 150-200mg daily is reached. (If this causes any adverse effects, it should be reduced to a tolerable level for two or three days, then carefully increased, as tolerated).

Acute musculoskeletal disorders: Initially 50mg two or three times daily, according to severity for 10-14 days. Normally 150mg daily, rarely 200mg daily.

Lumbago: 50mg two or three times daily, according to severity. Duration of treatment is not normally more than five days, but may be continued for up to 10 days.

Gout: Acute attack: 50mg three or four times daily until symptoms subside.

Following orthopaedic procedures: Normally 100-150mg daily in divided doses until symptoms subside.

Additional considerations: In conditions where patients require a dosage of 150-200mg a day, it is often possible to reduce this gradually to a maintenance level of 75-100mg a day. In patients with persistent night pain and/or morning stiffness, a dose of up to 100mg at bed time may be helpful in affording relief. It is rarely necessary to exceed a dosage of 200mg a day.

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

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

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.

Method of Administration

For oral administration.

To be taken preferably with or after food.

General Dosing Instructions

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

After observing the response to initial therapy with indomethacin, the dose and frequency should be adjusted to suit an individual patient's needs.

Adverse reactions generally appear to correlate with the dose of indomethacin. Therefore, every effort should be made to determine the lowest effective dosage for the individual patient.

Dosage recommendations for active stages of the following:

Moderate To Severe Rheumatoid Arthritis Including Acute Flares Of Chronic Disease; Moderate To Severe Ankylosing Spondylitis ; And Moderate To Severe Osteoarthritis

Agilex 25 mg (5 mL) twice a day or three times a day. If this is well tolerated, increase the daily dosage by 25 mg (5 mL) or by 50 mg (10 mL), if required by continuing symptoms, at weekly intervals until a satisfactory response is obtained or until a total daily dose of 150- 200 mg (30 - 40 mL) is reached. Doses above this amount generally do not increase the effectiveness of the drug.

In patients who have persistent night pain and/or morning stiffness, the giving of a large portion, up to a maximum of 100 mg (20 mL), of the total daily dose at bedtime may be helpful in affording relief. The total daily dose should not exceed 200 mg (40 mL). In acute flares of chronic rheumatoid arthritis, it may be necessary to increase the dosage by 25 mg (5 mL) or, if required, by 50 mg (10 mL) daily. If minor adverse effects develop as the dosage is increased, reduce the dosage rapidly to a tolerated dose and observe the patient closely.

If severe adverse reactions occur, stop the drug. After the acute phase of the disease is under control, an attempt to reduce the daily dose should be made repeatedly until the patient is receiving the smallest effective dose or the drug is discontinued.

Careful instructions to, and observations of, the individual patient are essential to the prevention of serious, irreversible, including fatal, adverse reactions.

As advancing years appear to increase the possibility of adverse reactions, Agilex should be used with greater care in the elderly.

Acute Painful Shoulder (Bursitis And/Or Tendinitis )

Agilex 75-150 mg (15-30 mL) daily in 3 or 4 divided doses.

The drug should be discontinued after the signs and symptoms of inflammation have been controlled for several days. The usual course of therapy is 7-14 days.

Acute Gouty Arthritis

Agilex 50 mg (10 mL) three times a day until pain is tolerable. The dose should then be rapidly reduced to complete cessation of the drug. Definite relief of pain has been reported within 2 to 4 hours.

Tenderness and heat usually subside in 24 to 36 hours, and swelling gradually disappears in 3 to 5 days.

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

In order to reduce the possibility of gastro-intestinal disturbances, 'Agilex' Capsules should always be taken with food or an antacid.

In chronic conditions, starting therapy with a low dosage, increasing this gradually as necessary, and continuing a trial of therapy for an adequate period (in some cases, up to one month) will give the best results with a minimum of unwanted reactions. The recommended oral dosage range is 50 mg to 200 mg daily in divided doses. Paediatric dosage not established.

Dosage in dysmenorrhoea: Up to 75 mg a day, starting with onset of cramps or bleeding, and continuing for as long as the symptoms usually last.

Dosage in acute gouty arthritis: 150 mg to 200 mg daily in divided doses until all symptoms and signs subside.

Use in the elderly: 'Agilex' should be used with particular care in older patients who are more prone to adverse reactions.

- NSAIDs are contraindicated in patients who have previously shown hypersensitivity reactions (eg asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin, or other non-steroidal anti-inflammatory drugs.

- Hypersensitivity to Agilex or to any of the excipients.

- Severe heart failure, hepatic failure and renal failure.

- Not to be used in patients who have nasal polyps

- During the last trimester of pregnancy.

- Safety in children has not been established.

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

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

Agilex is contraindicated in the following patients:

• Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to indomethacin or any components of the drug product
• History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients
• In the setting of coronary artery bypass graft (CABG) surgery

A history of peptic ulcer or active peptic ulcer; a recurrent history of gastro-intestinal lesions; in patients who have nasal polyps associated with angioneurotic oedema, who show sensitivity to indomethacin or any of the ingredients in this product, or who have experienced acute asthmatic attacks, urticaria or rhinitis as a result of therapy with aspirin or other non-steroidal anti-inflammatory drugs.

Safety for use in children has not been established.

<'Pregnancy and lactation').

- The use of Agilex capsules with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors, should be avoided

- Cardiovascular and cerebrovascular effects

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

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

Discontinuation of NSAID therapy is usually followed by recovery to the pre-treatment state.

- Elderly:

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

- Respiratory disorders:

Caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.

- Caution is advised in patients with pre-existing sigmoid lesions (such as diverticulum or carcinoma) (or the development of these conditions) as

Agilex can aggravate these conditions.

- Gastrointestinal bleeding, ulceration and perforation:

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

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

The risk of GI bleeding, ulceration or perforation is higher with increasing

NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation , and in the elderly.).

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

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

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

- SLE and mixed connective tissue disease:

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

- Impaired female fertility:

The use of Agilex may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of Agilex should be considered.

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

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

- During prolonged therapy, periodic ophthalmic examinations are recommended, as corneal deposits and retinal disturbances have been reported. In patients with rheumatoid arthritis, eye changes may occur which may be related to the underlying disease or to the therapy.

Therefore, in chronic rheumatoid disease, ophthalmological examinations are periodic intervals are recommended. Therapy should be discontinued if eye changes are observed.

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

- Medication Overuse Headache (MOH):

After long term treatment with analgesics, headache may develop or aggravate. Headache caused by overuse of analgesics (MOH - medication-overuse headache) should be suspected in patients who have frequent or daily headaches despite (or because of) regular use of analgesics. Patients with medication overuse headache should not be treated by increasing the dose. In such cases the use of analgesics should be discontinued in consultation with a doctor.

- Avoid concomitant use of two or more NSAIDs.

- Dermatological:

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

- Increases in plasma 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.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.

To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as indomethacin, increases the risk of serious gastrointestinal (GI) events.

Status Post Coronary Artery Bypass Graft (CABG) Surgery

Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG.

Post-MI Patients

Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and allcause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.

Avoid the use of Agilex in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If Agilex is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

Gastrointestinal Bleeding, Ulceration, And Perforation

NSAIDs, including indomethacin, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.

Risk Factors For GI Bleeding, Ulceration, And Perforation

Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.

Strategies To Minimize The GI Risks In NSAID-treated patients:

• Use the lowest effective dosage for the shortest possible duration.
• Avoid administration of more than one NSAID at a time.
• Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.
• Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
• If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue Agilex until a serious GI adverse event is ruled out.
• In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding.

Hepatotoxicity

Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported.

Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including indomethacin.

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue Agilex immediately, and perform a clinical evaluation of the patient.

Hypertension

NSAIDs, including Agilex, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs.

Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.

Heart Failure And Edema

The Coxib and traditional NSAID Trialists' Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.

Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of indomethacin may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]).

Avoid the use of Agilex in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If Agilex is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

Renal Toxicity And Hyperkalemia

Renal Toxicity

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.

Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dosedependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

No information is available from controlled clinical studies regarding the use of Agilex in patients with advanced renal disease. The renal effects of Agilex may hasten the progression of renal dysfunction in patients with preexisting renal disease.

Correct volume status in dehydrated or hypovolemic patients prior to initiating Agilex. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of Agilex. Avoid the use of Agilex in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If Agilex is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.

It has been reported that the addition of the potassium-sparing diuretic, triamterene, to a maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Â Indomethacin and triamterene should not be administered together.

Hyperkalemia

Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.

Both Indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently.

Anaphylactic Reactions

Indomethacin has been associated with anaphylactic reactions in patients with and without known hypersensitivity to indomethacin and in patients with aspirin-sensitive asthma.

Seek emergency help if an anaphylactic reaction occurs.

Exacerbation Of Asthma Related To Aspirin Sensitivity

A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, Agilex is contraindicated in patients with this form of aspirin sensitivity. When Agilex is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

Serious Skin Reactions

NSAIDs, including indomethacin, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of Agilex at the first appearance of skin rash or any other sign of hypersensitivity. Agilex is contraindicated in patients with previous serious skin reactions to NSAIDs.

Premature Closure Of Fetal Ductus Arteriosus

Indomethacin may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Agilex, in pregnant women starting at 30 weeks of gestation (third trimester).

Hematologic Toxicity

Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with Agilex has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including Agilex, may increase the risk of bleeding events. Co-morbid conditions, such as coagulation disorders, or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding.

Masking Of Inflammation And Fever

The pharmacological activity of Agilex in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

Laboratory Monitoring

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically.

Central Nervous System Effects

Agilex may aggravate depression or other psychiatric disturbances, epilepsy, and parkinsonism, and should be used with considerable caution in patients with these conditions. Discontinue Agilex if severe CNS adverse reactions develop.

Agilex may cause drowsiness; therefore, caution patients about engaging in activities requiring mental alertness and motor coordination, such as driving a car. Indomethacin may also cause headache. Headache which persists despite dosage reduction requires cessation of therapy with Agilex.

Ocular Effects

Corneal deposits and retinal disturbances, including those of the macula, have been observed in some patients who had received prolonged therapy with Agilex. Be alert to the possible association between the changes noted and Agilex. 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, ophthalmologic examination at periodic intervals is desirable in patients receiving prolonged therapy. Agilex is not indicated for long-term treatment.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with Agilex and periodically during the course of ongoing therapy.

Cardiovascular Thrombotic Events

Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately.

Gastrointestinal Bleeding, Ulceration, And Perforation

Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding.

Hepatotoxicity

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop Agilex and seek immediate medical therapy.

Heart Failure And Edema

Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur.

Anaphylactic Reactions

Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur.

Serious Skin Reactions

Advise patients to stop Agilex immediately if they develop any type of rash and to contact their healthcare provider as soon as possible.

Female Fertility

Advise females of reproductive potential who desire pregnancy that NSAIDs, including Agilex, may be associated with a reversible delay in ovulation.

Fetal Toxicity

Inform pregnant women to avoid use of Agilex and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus.

Avoid Concomitant Use Of NSAIDs

Inform patients that the concomitant use of Agilex with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.

Use Of NSAIDs And Low-Dose Aspirin

Inform patients not to use low-dose aspirin concomitantly with Agilex until they talk to their healthcare provider.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

In an 81-week chronic oral toxicity study in the rat at doses up to 1 mg/kg/day (0.05 times the MRHD on a mg/m² basis), indomethacin had no tumorigenic effect. Indomethacin produced no neoplastic or hyperplastic changes related to treatment in carcinogenic studies in the rat (dosing period 73 to 110 weeks) and the mouse (dosing period 62 to 88 weeks) at doses up to 1.5 mg/kg/day (0.04 times [mice] and 0.07 times [rats] the MRHD on a mg/m² basis, respectively).

Mutagenesis

Indomethacin did not have any mutagenic effect in in vitro bacterial tests and a series of in vivo tests including the host-mediated assay, sex-linked recessive lethals in Drosophila, and the micronucleus test in mice.

Impairment Of Fertility

Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect on fertility in mice in a two generation reproduction study (0.01 times the MRHD on a mg/m² basis) or a two litter reproduction study in rats (0.02 times the MRHD on a mg/m² basis).

Use In Specific Populations

Pregnancy

Risk Summary

Use of NSAIDs, including Agilex, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Agilex, in pregnant women starting at 30 weeks of gestation (third trimester).

There are no adequate and well-controlled studies of Agilex in pregnant women.

Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. In animal reproduction studies retarded fetal ossification was observed with administration of indomethacin to mice and rats during organogenesis at doses 0.1 and 0.2 times, respectively, the maximum recommended human dose (MRHD, 200 mg (40 mL)). In published studies in pregnant mice, indomethacin produced maternal toxicity and death, increased fetal resorptions, and fetal malformations at 0.1 times the MRHD. When rat and mice dams were dosed during the last three days of gestation, indomethacin produced neuronal necrosis in the offspring at 0.1 and 0.05 times the MRHD, respectively. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as indomethacin, resulted in increased pre- and post-implantation loss.

Clinical Considerations

Labor or Delivery

There are no studies on the effects of Agilex during labor or delivery. In animal studies, NSAIDs, including indomethacin, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.

Data

Animal data

Reproductive studies were conducted in mice and rats at dosages of 0.5, 1.0, 2.0, and 4.0 mg/kg/day. Except for retarded fetal ossification at 4 mg/kg/day (0.1 times [mice] and 0.2 times [rats] the MRHD on a mg/m² basis, respectively) considered secondary to the decreased average fetal weights, no increase in fetal malformations was observed as compared with control groups. Other studies in mice reported in the literature using higher doses (5 to 15 mg/kg/day, 0.1 to 0.4 times MRHD on a mg/m² basis) have described maternal toxicity and death, increased fetal resorptions, and fetal malformations.

In rats and mice, maternal indomethacin administration of 4.0 mg/kg/day (0.2 times and 0.1 times the MRHD on a mg/m² basis) during the last 3 days of gestation was associated with an increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses however no increase in neuronal necrosis was observed at 2.0 mg/kg/day as compared to the control groups (0.1 times and 0.05 times the MRHD on a mg/m² basis). Administration of 0.5 or 4.0 mg/kg/day to offspring during the first 3 days of life did not cause an increase in neuronal necrosis at either dose level.

Lactation

Risk Summary

Based on available published clinical data, indomethacin may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Agilex and any potential adverse effects on the breastfed infant from the Agilex or from the underlying maternal condition.

Data

In one study, levels of indomethacin in breast milk were below the sensitivity of the assay (<20 mcg/L) in 11 of 15 women using doses ranging from 75 mg orally to 300 mg rectally daily (0.94 to 4.29 mg/kg daily) in the postpartum period. Based on these levels, the average concentration present in breast milk was estimated to be 0.27% of the maternal weight-adjusted dose. In another study indomethacin levels were measured in breast milk of eight postpartum women using doses of 75 mg daily and the results were used to calculate an estimated infant daily dose. The estimated infant dose of indomethacin from breast milk was less than 30 mcg/day or 4.5 mcg/kg/day assuming breast milk intake of 150 mL/kg/day. This is 0.5% of the maternal weight-adjusted dosage or about 3% of the neonatal dose for treatment of patent ductusarteriosus.

Females And Males Of Reproductive Potential

Infertility

Females

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including Agilex, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including Agilex, in women who have difficulties conceiving or who are undergoing investigation of infertility.

Pediatric Use

Safety and effectiveness in pediatric patients 14 years of age and younger has not been established.

Agilex should not be prescribed for pediatric patients 14 years of age and younger unless toxicity or lack of efficacy associated with other drugs warrants the risk.

In experience with more than 900 pediatric patients reported in the literature or to the manufacturer who were treated with Agilex Capsules, side effects in pediatric patients were comparable to those reported in adults. Experience in pediatric patients has been confined to the use of Agilex Capsules.

If a decision is made to use indomethacin for pediatric patients two years of age or older, such patients should be monitored closely and periodic assessment of liver function is recommended. There have been cases of hepatotoxicity reported in pediatric patients with juvenile rheumatoid arthritis, including fatalities. If indomethacin treatment is instituted, a suggested starting dose is 1-2 mg/kg/day given in divided doses. Maximum daily dosage should not exceed 3 mg/kg/day or 150-200 mg/day, whichever is less. Limited data are available to support the use of a maximum daily dosage of 4 mg/kg/day or 150- 200 mg/day, whichever is less. As symptoms subside, the total daily dosage should be reduced to the lowest level required to control symptoms, or the drug should be discontinued.

Geriatric Use

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects.

Indomethacin may cause confusion or rarely, psychosis ; physicians should remain alert to the possibility of such adverse effects in the elderly.

Indomethacin and its metabolites are known to be substantially excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, use caution in this patient population, and it may be useful to monitor renal function.

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

'Agilex' should be used cautiously in patients with a history of bronchial asthma and in patients with psychiatric disorders, epilepsy, or parkinsonism, as indomethacin may tend to aggravate these disorders.

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

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

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

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

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

'Agilex' may mask the signs and symptoms of infection. 'Agilex' should be used with caution in patients with existing but controlled infection.

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

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

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

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

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

Increases in plasma 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 4.5 'Interaction with other medicaments and other forms of interaction').

Since 'Agilex' 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.

Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.

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

- Blood and lymphatic disorders: blood dyscrasias (such as thrombocytopenia,

neutropenia, leucopenia, agranulocytosis, aplastic anaemia and haemolytic anaemia), bone marrow depression, petechiae, ecchymoses, purpura, and disseminated intravascular coagulation may occur infrequently. As some patients manifest anaemia secondary to obvious or occult gastro-intestinal bleeding, appropriate blood determinations are recommended. Epistaxis has been reported rarely.

- Hypersensitivity:Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis, (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, rhinitis or (c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angiodema and, more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

- Metabolic and nutrition disorders: Hyperglycaemia, glycosuria, hyperkalaemia has been reported rarely.

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

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

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

- Cardiac disorders: There have been reports of hypotension, tachycardia, chest pain, arrhythmia, palpitations.

- Cardiovascular and cerebrovascular:

Oedema hypertension and cardiac failure have been reported in association with NSAID treatment.

- Vascular disorders: flushing has been reported rarely.

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

- Gastrointestinal disorders: The most commonly-observed adverse events are gastrointestinal in nature. Anorexia, epigastric discomfort,ulceration at any point in the gastro-intestinal tract (even with resultant stenosis and obstruction), bleeding (even without obvious ulceration or from a diverticulum) and perforation of preexisting sigmoid lesions (such as diverticulum or carcinoma), increased abdominal pain or exacerbation of the condition in patients with ulcerative colitis or Crohns disease (or the development of this condition), intestinal strictures and regional ileitis have been rarely reported. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur. If gastro-intestinal bleeding does occur treatment with Agilex should be discontinued. Gastro-intestinal disorders which occur can be reduced by giving Agilex with food, milk or antacids. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.

- Hepato-biliary disorders: cholestasis, borderline elevations of one or more liver tests may occur, and significant elevations of ALT (SGPT) or AST (SGOT) have been seen in less than 1% of patients receiving therapy with NSAIDs in controlled clinical trials. If abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations such as rash or eosinophilia occur, Agilex should be stopped. Abnormal liver function, hepatitis and jaundice.

- Skin and subcutaneous tissue disorders: pruritus, urticaria, angioneurotic oedema, angiitis, erythema nodosum, rash, photosensitivity, exfoliative dermatitis, bullous reactions including Stevens Johnson syndrome and Toxic Epidermal Necrolysis (very rare). Photosensitivity, erythema multiforme, hair loss, sweating and exacerbation of psoriasis.

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

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

- Reproductive system and breast disorders: vaginal bleeding, breast changes (enlargement, tenderness, gynaecomastia)

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

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Cardiovascular Thrombotic Events
• GI Bleeding, Ulceration and Perforation
• Hepatotoxicity
• Hypertension
• Heart Failure and Edema
• Renal Toxicity and Hyperkalemia
• Anaphylactic Reactions
• Serious Skin Reactions
• Hematologic Toxicity

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In a gastroscopic study in 45 healthy subjects, the number of gastric mucosal abnormalities was significantly higher in the group receiving Agilex Capsules than in the group taking Agilex 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 Agilex Suppositories or Capsules was comparable. The incidence of lower gastrointestinal adverse effects was greater in the suppository group.

The adverse reactions for Agilex Capsules listed in the following table have been arranged into two groups: (1) incidence greater than 1%; and (2) incidence less than 1%. The incidence for group (1) was obtained from 33 double-blind controlled clinical trials reported in the literature (1,092 patients). The incidence for group (2) was based on reports in clinical trials, in the literature, and on voluntary reports since marketing. The probability of a causal relationship exists between Agilex and these adverse reactions, some of which have been reported only rarely.

The adverse reactions reported with Agilex Capsules may also occur with use of the suspension.

Table 1 : Summary of Adverse Reactions for Agilex Capsules

Causal relationship unknown: Other reactions have been reported but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, the possibility cannot be excluded. Therefore, these observations are being listed to serve as alerting information to physicians:

Cardiovascular: Thrombophlebitis

Hematologic: Although there have been several reports of leukemia, the supporting information is weak

Genitourinary: Urinary frequency

A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group Aβ hemolytic streptococcus, has been described in persons treated with nonsteroidal anti-inflammatory agents, including indomethacin, sometimes with fatal outcome

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

Gastro-intestinal - the more frequent reactions 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; gastro-intestinal tract bleeding without obvious ulcer formation; and increased abdominal pain when used in patients with pre-existing ulcerative colitis. Reactions occurring infrequently are stomatitis; gastritis; flatulence; bleeding from the sigmoid colon - occult or from a diverticulum - and perforation of pre-existing sigmoid lesions (diverticula, carcinoma). Rarely, intestinal strictures (diaphragms) and intestinal ulceration followed by stenosis and obstruction has been reported. With suppositories, tenesmus and irritation of the rectal mucosa have occasionally been reported. Pancreatitis has been reported with an unknown frequency. Other gastro-intestinal side effects which may or may not be caused by indomethacin include: ulcerative colitis and regional ileitis.

Hepatic - rarely, hepatitis and jaundice. (Some fatalities reported.)

Cardiovascular/Renal - oedema, increased blood pressure, tachycardia, chest pain, arrhythmia, palpitation, hypotension, congestive heart failure, blood urea elevation, and haematuria (all infrequent).

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

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

Ocular - infrequently, blurred vision, diplopia, and orbital and peri-orbital pain. Corneal deposits and retinal disturbances, including those of the macula, have been reported in patients with rheumatoid arthritis on prolonged therapy, but similar changes may also be expected in patients with rheumatoid arthritis who have not received indomethacin.

Aural - tinnitus, hearing disturbances (rarely deafness).

Genito-urinary - proteinuria, nephrotic syndrome, interstitial nephritis, and renal insufficiency including renal failure (all rare).

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

Laboratory tests

Borderline elevations of one or more liver tests may occur, and significant elevations of ALT (SGPT) or AST (SGOT) have been seen in less than 1% of patients receiving therapy with non-steroidal anti-inflammatory drugs in controlled clinical trials. If abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations such as rash or eosinophilia occur, 'Agilex' should be stopped.

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme.

Website: www.mhra.gov.uk/yellowcard

a) Symptoms:

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

b) Therapeutic measure

Patients should be treated symptomatically as required. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose. Good urine output should be ensured. Renal and liver function should be closely monitored. Patients should be observed for at least four hours after ingestion of potentially toxic amounts. Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patient's clinical condition.

Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare.

Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

For additional information about overdosage treatment contact a poison control center (1-800-222- 1222).

The following symptoms may be observed following overdosage: nausea, vomiting, intense headache, dizziness, mental confusion, disorientation, or lethargy. There have been reports of paraesthesia, numbness, and convulsions.

Treatment is symptomatic and supportive. The stomach should be emptied as quickly as possible if the ingestion is recent and correction of severe electrolyte abnormalities may need to be considered.

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

The plasma elimination of indomethacin is biphasic with the half-life of the terminal plasma half-life phase between 2.6 and 11.2 hours.

ATC CODE: M01A B01

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

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

Indomethacin has anti-inflammatory, antipyretic, and analgesic effects, it is an inhibitor of prostaglandin synthetase.

Absorption: Agilex is readily absorbed from the gastrointestinal tract; peak plasma concentrations are reached in about 0.5-2 hours after a dose.

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

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

Elimination: Mainly excreted in the urine, approximately 60%, the pH of the urine can affect this amount. Lesser amounts in the faeces. Agilex is also excreted in milk in small amounts.

Absorption

Following single oral doses of Agilex Capsules 25 mg or 50 mg, indomethacin is readily absorbed, attaining peak plasma concentrations of about 1 and 2 mcg/mL, respectively, at about 2 hours. Orally administered Agilex Capsules are virtually 100% bioavailable, with 90% of the dose absorbed within 4 hours. A single 50 mg dose of Agilex Oral Suspension was found to be bioequivalent to a 50 mg Agilex Capsule when each was administered with food. With a typical therapeutic regimen of 25 or 50 mg three times a day, the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose.

Distribution

Indomethacin is highly bound to protein in plasma (about 99%) over the expected range of therapeutic plasma concentrations. Indomethacin has been found to cross the blood-brain barrier and the placenta, and appears in breast milk.

Elimination

Metabolism

Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, anddesmethyldesbenzoyl metabolites, all in the unconjugated form. Appreciable formation of glucuronide conjugates of each metabolite and of indomethacin are formed.

Excretion

Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. About 60% of an oral dose is recovered in urine as drug and metabolites (26% as indomethacin and its glucuronide), and 33% is recovered in feces (1.5% as indomethacin). The mean half-life of indomethacin is estimated to be about 4.5 hours.

Indomethacin is rapidly and almost completely absorbed on oral administration, and peak plasma levels are reached in ½ to 2 hours. Absorption is slowed but remains virtually complete when taken with food. About 90% is bound to plasma proteins. It appears to undergo enterohepatic cycling. It is metabolised partly by O-demethylation, partly by N-deacylation, and unchanged drug and metabolites are partly conjugated with glucoronic acid, in man, it is excreted unchanged and as it metabolites in both urine and faeces.

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

No relevant information.

Not applicable.

'Agilex' Capsules should always be taken with food or an antacid.