MOTRIN Tablet Ref.[10883] Active ingredients: Ibuprofen

• Patients with heart disease and high blood pressure should not take this drug unless directed by a physician.
• Caution in patients with heart failure, hypertension or other conditions predisposing to fluid retention.
• Caution in patients prone to gastrointestinal tract irritation, particularly those with a history of peptic ulcer, diverticulosis or other inflammatory disease of the gastrointestinal tract such as ulcerative colitis and Crohn’s disease.
• The elderly and patients with impaired renal function, heart failure, liver dysfunction, and those taking diuretics are at increased risk of renal toxicity.
• If persistent urinary symptoms (bladder pain, dysuria, urinary frequency), hematuria and cystitis occur, the drug should be stopped immediately.
• Ibuprofen use by women who are trying to conceive, during the first and second trimester of pregnancy, or if nursing.

General

Several medical conditions that can predispose patients to the adverse effects of non-steroidal anti-inflammatory drugs in general may be applicable to ibuprofen.

Patients with any serious medical condition should consult a physician before using ibuprofen as an analgesic or antipyretic (1).

In common with other anti-inflammatory drugs, ibuprofen may mask the usual signs of infection.

If symptoms persist or get worse, or if new symptoms occur, patients should stop use and consult a physician.

Cardiovascular

Some patients with pre-existing hypertension may develop worsening of blood pressure control when placed on an NSAID and regular monitoring of blood pressure should be performed under such circumstances. NSAIDs may exacerbate congestive heart failure.

Patients who are taking low-dose ASA as cardio protective therapy should consult with a health professional prior to taking ibuprofen (see also Drug Interactions – Acetylsalicylic Acid).

NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke. This risk may increase with dose and duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.

Gastrointestinal

Serious GI toxicity, such as ulceration, perforation, obstruction and gastrointestinal bleeding, sometimes severe and occasionally fatal, can occur at any time, with or without symptoms in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs) including ibuprofen. The risk may increase with dose and duration of use.

GI symptoms, such as dyspepsia, are common, usually developing early in therapy. Health providers should remain alert for ulceration and bleeding in patients treated with non-steroidal anti-inflammatory drugs, even in the absence of previous GI tract symptoms.

In patients observed in clinical trials of such agents, symptomatic upper GI ulcers, gross bleeding, or perforation occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of patients treated for one year. The risk continues beyond one year. The incidence of these complications is related to dose, past history of known ulcer disease, and advanced age (see Special Populations). Studies have shown that the use of oral corticosteroids increases the risk of upper gastrointestinal complications associated with NSAIDs (2,3,4,5,6)

Ibuprofen should be given under close medical supervision to patients with a history of ulcer of the upper gastrointestinal tract or inflammatory disease of the gastrointestinal tract such as ulcerative colitis and Crohn’s disease. In these cases the health provider must weigh the benefits of treatment against the possible hazards.

Health providers should inform patients about the signs and symptoms of serious GI toxicity and instruct them to contact a health provider immediately if they experience persistent dyspepsia or other symptoms or signs suggestive of gastrointestinal ulceration or bleeding.

Because serious GI tract ulceration and bleeding can occur without warning symptoms, health providers should follow chronically treated patients and watch for the signs and symptoms of ulceration and bleeding and should inform the patients of the importance of this follow-up.

If ulceration is suspected or confirmed, or if GI bleeding occurs ibuprofen should be discontinued immediately, appropriate treatment instituted and the patient monitored closely.

No studies, to date, have identified any group of patients not at risk of developing ulceration and bleeding. The major risk factors are a prior history of serious GI events and increasing age. Possible risk factors include Helicobacter pylori infection, excess alcohol intake, smoking, and concomitant oral steroids, anti-coagulants, anti-platelet agents (including ASA), other NSAIDs, or selective serotonin reuptake inhibitors (SSRIs).

The administration of ibuprofen with food or milk is recommended since occasional and mild heartburn, upset stomach or stomach pain may occur with its use. Patients should be advised to seek the consultation of a physician if gastrointestinal side effects occur consistently, persist, or appear to worsen (1).

Genitourinary

Some NSAIDs are associated with persistent urinary symptoms (bladder pain, dysuria, urinary frequency), hematuria or cystitis. The onset of these symptoms may occur at any time after the initiation of therapy with an NSAID. Should urinary symptoms occur, in the absence of an alternate explanation, treatment with ibuprofen should be stopped to ascertain if symptoms disappear. This should be done before urological investigations or treatments are considered.

Hematologic

Ibuprofen, like other non-steroidal anti-inflammatory agents, can inhibit platelet aggregation but the effect is quantitatively less than that seen with acetylsalicylic acid. Ibuprofen has been shown to prolong bleeding time (but within the normal range) in normal subjects. Because this prolonged bleeding effect may be exaggerated in patients with underlying haemostatic defects, ibuprofen should be avoided by persons with intrinsic coagulation defects and by those on anticoagulant therapy. Concurrent therapy of ibuprofen with warfarin requires close monitoring of INR (see Drug Interactions).

Also, patients with underlying medical or pharmacologically-induced haemostatic defects could experience further prolongation of bleeding time through the inhibition of platelet aggregation induced to varying degrees by this class of drugs (1).

Blood dyscrasias (such as neutropenia, leukopenia, thrombocytopenia, aplastic anemia and agranulocytosis) associated with the use of non-steroidal anti-inflammatory drugs are rare, but could occur with severe consequences.

Hepatic

As with other nonsteroidal anti-inflammatory drugs, borderline elevations of one or more liver enzyme tests (AST, ALT, ALP) may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy.

A patient with symptoms and/or signs suggesting liver dysfunction, 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 this drug. Severe hepatic reactions including jaundice and cases of fatal hepatitis have been reported with nonsteroidal anti-inflammatory drugs. Very rarely, ibuprofen has been reported to cause vanishing bile duct syndrome (70-73). Patients should seek medical advice if they develop sudden onset abdominal pain or chronic abdominal pain associated with loss of appetite and/or jaundice and/or new onset itching.

Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop (e.g. jaundice), or if systemic manifestations occur (e.g. eosinophilia, associated with rash, etc.), this drug should be discontinued.

If there is a need to prescribe this drug in the presence of impaired liver function, it must be done under strict observation.

Immune

Patients sensitive to any one of the nonsteroidal anti-inflammatory drugs may be sensitive to any of the other NSAIDs also.

As with NSAIDs in general, some patients may experience urticaria and angioedema upon exposure to ibuprofen. Ibuprofen should not be given to patients with the complete or partial syndrome of ASA-intolerance (See Contraindications).

Neurologic

Some patients may experience drowsiness, dizziness, vertigo, tinnitus or hearing loss with the use of ibuprofen. If patients experience these side effects, they should exercise caution in carrying out activities that require alertness.

In occasional rare cases, with some NSAIDs, the symptoms of aseptic meningitis (stiff neck, severe headaches, nausea and vomiting, fever or clouding of consciousness) have been observed. Patients with autoimmune disorders (systemic lupus erythematosus, mixed connective tissues diseases, etc.) seem to be pre-disposed. Therefore, in such patients, the health provider must be vigilant to the development of this complication.

Ophthalmologic

Blurred and/or diminished vision, scotoma, and/or changes in colour vision have been reported. If a patient develops such complaints while taking ibuprofen, the drug should be discontinued. Patients with any visual disturbances should have an ophthalmologic examination.

Peri-Operative Considerations

In general, NSAIDs should be discontinued prior to surgeries to decrease the risk of post-operative bleeding.

Renal

Long-term administration of nonsteroidal anti-inflammatory drugs to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of acute interstitial nephritis with hematuria, proteinuria, and occasionally nephrotic syndrome.

A second form of renal toxicity has been seen in patients with pre-renal conditions leading to reduction in renal blood flow or blood volume, where the renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of a non-steroidal anti-inflammatory drug may cause a dose dependent reduction in prostaglandin formation and may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function (Glomerular Filtration Rate (GFR) <60 ml/min or 1 ml/sec), patients on salt restricted diets, those with congestive heart failure, cirrhosis, liver dysfunction, those taking diuretics, angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, cyclosporin, ASA and the elderly. Serious or life-threatening renal failure has been reported in patients with normal or impaired renal function after short-term therapy with NSAIDs. Even patients at risk who demonstrate the ability to tolerate an NSAID under stable conditions may decompensate during periods of added stress, for example during states of fluid restriction as can occur during gastroenteritis. Discontinuation of nonsteroidal anti-inflammatory therapy is usually followed by recovery to the pretreatment state.

NSAIDs can increase the risk of hyperkalemia. In patients on dialysis, NSAIDs should be used with caution.

Fluid retention and edema have been observed in patients treated with ibuprofen. Therefore, as with many other NSAIDs, the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be borne in mind. Ibuprofen should be used with caution in patients with heart failure, hypertension or other conditions predisposing to fluid retention. Ask patients who are on chronic therapy and at risk for fluid retention to weigh themselves at regular intervals to assist in monitoring for fluid accumulation.

With nonsteroidal anti-inflammatory treatment there is a potential risk of hyperkalemia, particularly in patients with conditions such as diabetes mellitus or renal failure; elderly patients; or in patients receiving concomitant therapy with angiotensin-II receptor antagonists, adrenergic blockers, angiotensin-converting enzyme inhibitors or some diuretics. Patients at risk should be monitored periodically during long-term therapy.

Respiratory

ASA-induced asthma is an uncommon but very important indication of ASA and NSAID sensitivity. It occurs more frequently in patients with asthma who have nasal polyps.

Skin

Ibuprofen may cause a severe allergic reaction, especially in patients allergic to acetylsalicylic acid. Symptoms may include hives, facial swelling, asthma (wheezing), shock, skin reddening, rash or blisters with or without pyrexia or erythema. If any of these symptoms occur, patients should stop use and seek medical help right away.

In rare cases, serious skin reactions such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), exfoliative dermatitis and erythema multiforme (EM), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP) have been associated with the use of some NSAIDs and have been reported very rarely in patients receiving ibuprofen. Because the rate of these reactions is low, they have usually been noted during post-marketing surveillance in patients taking other medications also associated with the potential development of these serious skin reactions. Thus, causality is not clear. These reactions are potentially life threatening but may be reversible if the causative agent is discontinued and appropriate treatment instituted. Patients should be advised that if they experience a skin rash they should discontinue their NSAID and contact their physician for assessment and advice, including which additional therapies to discontinue.

Special Populations

Pregnant Women

No evidence specifically identifies exposure to analgesic doses of ibuprofen as a cause of harm to either mother or fetus during pregnancy (1, 7). Non-steroidal anti-inflammatory drugs in general, however, are known to affect the action of prostaglandin synthetase which could alter a variety of the physiological functions of prostaglandins or platelets during delivery such as facilitating uterine contraction in the mother, premature closure of the fetal ductus arteriosus which may result in persistent pulmonary hypertension in the newborn infant, and platelet-related haemostasis. Patients should therefore be advised not to use ibuprofen during pregnancy without the advice of a physician, particularly during the last trimester (1). Caution should be exercised in prescribing MOTRIN to women who are trying to conceive, during the first and second trimesters of pregnancy, or if nursing.

Nursing Women

Pharmacokinetic studies indicated that following oral administration of ibuprofen 400 mg the level of drug that appeared in breast milk was below detection levels of 1 μg/mL. The amount of ibuprofen to which an infant would be exposed through this source was considered negligible (8). However, since the absolute safety of ibuprofen ingested under these circumstances has not been determined, nursing mothers should be advised to consult a physician before using ibuprofen (1).

Geriatrics (>65 years of age)

Patients older than 65 years and frail or debilitated patients are most susceptible to a variety of adverse reactions from nonsteroidal anti-inflammatory drugs (NSAIDs); the incidence of these adverse reactions increases with dose and duration of treatment. In addition, these patients are less tolerant to ulceration and bleeding. Most reports of fatal GI events are in this population, especially those with cardiovascular disease. Older patients are also at risk of lower esophageal ulceration and bleeding. Elderly patients appear to be more susceptible to the central nervous system reactions; cognitive dysfunction (forgetfulness, inability to concentrate, a feeling of separation from the surroundings) in such patients has been reported.

For such patients, consideration should be given to a starting dose lower than the one usually recommended, with individual adjustment when necessary and under close supervision.

Pediatrics

Caregivers should ask a physician before use if they believe that the child maybe dehydrated. Not drinking fluids, excessive fluid loss due to vomiting, diarrhea and high fevers may contribute to the risk of dehydration.

Clinical Trial & Post-Market Adverse Drug Reactions

The most common adverse reactions encountered with nonsteroidal anti-inflammatory drugs are gastrointestinal, of which gastric or duodenal ulcer, with or without bleeding, is the most severe. Fatalities have occurred, particularly in the elderly.

Experience reported with prescription use of ibuprofen has included the following adverse reactions. Note: Reactions listed below under Causal Relationship Unknown are those where a causal relationship could not be established; however, in these rarely reported events, the possibility of a relationship to ibuprofen also cannot be excluded.

Serious Drug Interactions

• Use with acetylsalicylic acid (ASA) or other NSAIDs, including ibuprofen, may result in possible additive adverse side effects.
• Use with acetaminophen, may increase the risk of adverse renal effect.
• Use with anticoagulants may increase the risk of GI adverse events (e.g., bleeding).
• Use with hypoglycemic agents (oral agents and insulin) may increase the risk of hypoglycaemia.
• Use with antihypertensives may interfere with circulatory control.
• Use with diuretics may reduce the diuretic effect.
• Use with methotrexate may increase the risk of methotrexate toxicity.
• Use with lithium may increase the risk of lithium toxicity.

Acetylsalicylic Acid (ASA) or other NSAIDs

The use of ibuprofen in addition to any other NSAID is not recommended because of the absence of any evidence demonstrating synergistic benefits and the potential for additive side effects.

Animal studies show that ASA given with NSAID agents, including ibuprofen, yield a net decrease in anti-inflammatory activity with lowered blood levels of the non-ASA drug. Single dose bioavailability studies in normal volunteers have failed to show an effect of ASA on ibuprofen blood levels. Correlative clinical studies have not been done.

Also, some NSAIDs may interfere with the anti-platelet effects of low dose ASA (81-325 mg per day), possibly by competing with ASA for access to the active site of cyclooxygenase-I.

The concomitant administration of ibuprofen but not acetaminophen has been shown to antagonize the irreversible platelet inhibition induced by ASA (9). Regular use of ibuprofen in patients with increased cardiovascular risk may limit the cardio protective effects of ASA (9,10). To minimize this interaction, regular users of ibuprofen and low-dose, immediate-release ASA should take the ibuprofen at least one hour after or 11 hours before the daily low-dose ASA. The use of delayed-release (e.g. enteric coated) ASA is not recommended when using ibuprofen regularly. Healthcare professionals should advise consumers and patients regarding the appropriate concomitant use of ibuprofen and ASA.

Anti-Platelet Agents (including ASA)

See Warnings and Precautions – Hematologic section.

Anticoagulants

See Warnings and Precautions -Hematologic section.

Coumarin Type Anticoagulants

Several short-term controlled studies failed to show that ibuprofen significantly affected prothrombin time or a variety of other clotting factors when administered to individuals on coumarin-type anticoagulants. However, bleeding has been reported when ibuprofen and other NSAID agents have been administered to patients on coumarin-type anticoagulants. The use of ibuprofen in patients who are taking anticoagulants should therefore be avoided because of the possibility of enhanced GI bleeding or an additive effect due to ibuprofen’s reversible anti- platelet actions.

Oral hypoglycemics

Ibuprofen may increase the hypoglycemic effects of oral sulfonylurea hypoglycemic agents.

Anti-hypertensives

NSAIDs may diminish the antihypertensive effect of Angiotensin Converting Enzyme (ACE) inhibitors.

Combinations of ACE inhibitors, diuretics and NSAIDs might have an increased risk for acute renal failure and hyperkalemia. In longer term therapy blood pressure and kidney function should be monitored more closely, as occasionally there can be a substantial increase in blood pressure.

Diuretics

Ibuprofen, because of its fluid retention properties, can decrease the diuretic and anti-hypertensive effects of diuretics, and increased diuretic dosage may be needed. Patients with impaired renal function taking potassium-sparing diuretics who develop ibuprofen-induced renal insufficiency might be in serious danger of fatal hyperkalemia.

Glucocorticoids

Some studies have shown that the concomitant use of NSAIDs and oral glucocorticoids increases the risk of GI side effects such as ulceration and bleeding. This is especially the case in older (>65 years of age) individuals.

Lithium

Monitoring of plasma lithium concentrations is advised when stopping or starting an NSAID, as increased lithium concentrations can occur.

Other Drug Interactions

Although ibuprofen binds to a significant extent to plasma proteins, interactions with other protein-bound drugs occur uncommonly. Nevertheless, caution should be observed when other drugs also having a high affinity for protein binding sites are used concurrently. Some observations have suggested a potential for ibuprofen to interact with digoxin, methotrexate, and phenytoin. However, the mechanisms and clinical significance of these observations are presently not known.

Patients taking other prescribed medications should consult a physician before using ibuprofen to assure its compatibility with the other medications (1).