Brustan N Ibuprofen Tablets

PRESCRIBING INFORMATION

BRUSTAN-N
(Ibuprofen Tablets BP 400 mg)

For the Use of a Registered Medical Practitioner Only.

 

Cardiovascular Risk1,2

• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see
WARNINGS AND PRECAUTIONS).

• BRUSTAN-N tablets are contraindicated for treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS).

Gastrointestinal Risk1

• NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinaI events (see WARNINGS AND PRECAUTION).

 

COMPOSITION

Each film-coated tablet contains:

lbuprofen BP 400mg

Inactive ingredients: Maize starch, calcium hydrogen phosphate (dihydrate), microcrystalline cellulose, tartazine lake Cl. No.19140, sunset yellow lake CI.15985, purified water, gelatin, purified talc, colloidal anhydrous silica, hypromellose, macrogol, titanium dioxide, sodium lauryl sulphate, opacode black, isopropyl alcohol.

 

DESCRIPTION2,3

BRUSTAN-N tablets contain ibuprofen, which (2RS)-2-[4- (2-Methylypropyl)phenyl]propionic acid. Ibuprofen is a non-steroidal anti-inflammatory agent with a molecular formula of C13H18O2. Its molecular weight is 206.3.

 

INDICATIONS4,5

BRUSTAN-N tablets are used for the relief of rheumatic or muscular pain, pain of non-serious arthritic conditions, backache, neuralgia, migraine, headache, dental pain, dysmenorrhoea, feverishness and for the relief of the symptoms of cold and influenza.

 

DOSE AND METHOD OF ADMINISTRATION3,5

For oral administration and short term use only.

Adults, the elderly and young persons over 12 years of age

The minimum effective dose should be used for the shortest time necessary to relieve symptoms. If the product is required for more than 10 days or if the symptoms worsen, the patient should consult a doctor.

1 tablet to be taken up to three times a day, as required. The tablets should be taken with water.

Leave at least 4 hours between doses and do not take more than 3 tablets of BRUSTAN-N (1200 mg) in any 24 hour period.

Not to be given to children under 12 years of age.

 

USE IN SPECIAL POPULATIONS

Pregnancy

While no teratogenic effects have been demonstrated in animal experiments, use of ibuprofen should, if possible, be avoided during the first 6 months of pregnancy.

During the 3rd trimester, ibuprofen is contraindicated, as there is a risk of premature closure of the foetal ductus arteriosus with possible persistent pulmonary hypertension. The onset of labour may be delayed and duration of labour increased, with increased bleeding tendency in both mother and child (see CONTRAINDICATIONS).

Lactation

In limited studies ibuprofen appears in the breast milk in very low concentrations and is unlikely to affect the breast-fed infant adversely.

Geriatrics

The elderly are at increased risk of the serious consequences of adverse reactions especially gastrointestinal bleeding and perforation which may be fatal.

 

CONTRAINDICATIONS2,4,5

• Hypersensitivity to ibuprofen or any of the constituents in the product.

• Ibuprofen is contra-indicated in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angiodema or urticaria) in response to aspirin or other non-steroidal anti-inflammatory drugs.

• Active or previous peptic ulcer (two or more episodes of proven ulceration or bleeding) (see WARNINGS AND PRECAUTIONS).

• History of upper gastrointestinal bleeding or perforation, related to previous NSAID therapy (see WARNINGS AND PRECAUTIONS).

• Patients with severe hepatic failure, renal failure or heart failure (see WARNINGS AND PRECAUTIONS).

• Use in last trimester of pregnancy (see USE IN SPECIAL POPULATIONS).

• For the treatment pre-operative pain in the setting of coronary artery bypass graft CABG) surgery (see WARNINGS AND PRECAUTIONS).

 

WARNINGS AND PRECAUTIONS2,4,5

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 event, myocardial infarction and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.
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 [see CONTRAINDICATIONS].

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 does increase the risk of serious gastrointestinal (Gl) events.

Gastrointestinal Effects: Risk of Ulceration, Bleeding, and Perforation

NSAIDs, including ibuprofen, can cause serious GI adverse events including inflammation, bleeding, ulceration, and perforation of the 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 occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.

Patients with a prior history of peptic ulcer disease and/or GI bleeding who use NSAIDs have a greater than 10 fold increased risk for developing a GI bleed compared to treated patients with neither of these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most reports of spontaneous fatal GI events are in elderly or debilitated patients, and therefore special care should be taken in treating this population.

To minimize the potential risk for an adverse GI event in patients treated with an NSAID, use the lowest effective dose for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered.

Hepatic Effects

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAID s, including ibuprofen. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions have been reported, including jaundice, fulminant hepatitis, liver necrosis and hepatic failure, some with fatal outcomes.

A patient with symptoms and/or signs suggesting liver dysfunction, or with abnormal liver test values, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with ibuprofen. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), ibuprofen should be discontinued.

Hypertension

NSAIDs, including Ibuprofen, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Use NSAIDs, including ibuprofen, with caution in patients with hypertension. Monitor blood pressure closely during the initiation of NSAID treatment and throughout the course of therapy.

Patients taking ACE inhibitors, thiazides, or loop diuretics may have impaired response to these therapies when taking NSAIDs.

Congestive Heart Failure and Oedema

Fluid retention and oedema have been observed in some patients taking NSAIDs. Use ibuprofen with caution in patients with fluid retention or heart failure.

Renal Effects

Use caution when initiating treatment with ibuprofen in patients with considerable dehydration. 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 dose dependent 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, heart failure, liver dysfunction, those taking diuretics or ACE inhibitors, 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 ibuprofen in patients with advanced renal disease. Ibuprofen is contraindicated in patients with severe renal failure (see CONTRAINDICATIONS).

Anaphylactoid Reactions

As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to ibuprofen. lbuprofen is contraindicated in patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS).

Serious Skin Reactions

NSAIDs, including ibuprofen, 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 manifestations, and to discontinue ibuprofen at the first appearance of skin rash or any other sign of hypersensitivity.

Pregnancy

Starting at 30 weeks gestation, ibuprofen, and other NSAIDs, is contraindicated in pregnant women as premature closure of the ductus arteriosus in the fetus may occur (see USE IN SPECIFIC POPULATIONS and CONTRAINDICATIONS).

Masking Inflammation and Fever

The pharmacological activity of ibuprofen in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.

Hematological Effects

Anaemia may occur in patients receiving NSAIDs, including ibuprofen. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect on erythropoiesis. In patients on long-term treatment with NSAIDs, including ibuprofen, check haemoglobin or haematocrit if they exhibit any signs or symptoms of anemia or blood loss.

NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effects on platelet function are less severe quantitatively, of shorter duration, and reversible. Carefully monitor patients who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants.

Preexisting Asthma

Patients with asthma may have aspirin-sensitive asthma.

The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross-reactivity between aspirin and NSAIDs has been reported in such aspirin-sensitive patients, including bronchospasm, ibuprofen is contraindicated in patients with this form of aspirin sensitivity and should be used with caution in all patients with preexisting asthma.

Ophthalmological Effects

Blurred or diminished vision, scotomata, and changes in colour vision have been reported with oral ibuprofen. Discontinue ibuprofen if a patient develops such complaints, and refer the patient for an ophthalmologic examination that includes central visual fields and colour vision testing.

Aseptic Meningitis

Aseptic meningitis with fever and coma has been observed in patients on oral ibuprofen therapy. Although it is probably more likely to occur in patients with systemic lupus erythematosus and related connective tissue diseases, it has been reported in patients who do not have underlying chronic disease. If signs or symptoms of meningitis develop in a patient on ibuprofen, give consideration to whether or not the signs or symptoms are related to ibuprofen therapy.

Monitoring

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding.

Patients on long-term treatment with NSAIDs should have CBC and chemistry profiles checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g. eosinophilia, rash), or abnormal liver tests persist or worsen, discontinue ibuprofen.

Effects on Ability to Drive and Use Machines

None expected at recommended doses and duration of therapy.

 

DRUG INTERACTIONS4,5

Ibuprofen should not be used in combination with

Aspirin: unless low-dose aspirin (not above 75mg daily) has been advised by a doctor, as this may increase the risk of adverse reactions (see WARNINGS AND PRECAUTIONS).

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. However; the limitations of these data and the uncertainties regarding extrapolation of ex-vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use.

Other NSAIDs including cyclooxygenase-2 selective inhibitors: as these may increase the risk of adverse effects (see WARNINGS AND PRECAUTIONS).

Ibuprofen should be used with caution in combination with

Corticosteroids: may increase the risk of adverse reactions, especially of the gastrointestinal tract (see WARNINGS AND PRECAUTIONS).

Antihypertensives and diuretics: NSAIDs may diminish the effects of these drugs. Diuretics can increase the risk of nephrotoxicity of NSAlDs.

Anticoagulants: NSAIDS may enhance the effects of anticoagulants, such as warfarin.

Anti-platelet agents and selective serotonin-reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding.

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Lithium: There is evidence for potential increase in plasma levels of lithium.

Methotrexate: There is the potential for increased plasma Ievels of methotrexate.

Ciclosporin: lncreased risk of nephrotoxicity.

Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Tacrolimus: Possible increase risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine: There is evidence of an increased risk of haemarthrosis and haematoma in HIV positive haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Quinolone antibiotics: Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDS and quinolones may have an increased risk of developing convulsions.

 

UNDESIRABLE EFFECTS4

Hypersensitivity reactions have been reported and these may consist of

a) Non specific allergic reactions and anaphylaxis,

b) Respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea or

c) Various skin reactions, e.g. pruritus, urticaria, angioedema, and more rarely, exfoliative and bullous dermatoses (including epidermal necrolysis, and erythema multiforme).

The list of the following adverse effects relates to those experienced with ibuprofen at OTC doses, from short-term use. In chronic conditions, under long term treatment, additional adverse effects may occur.

Infections and infestations Very rare Aseptic meningitis
Blood and lymphatic disorders Very rare Haemetopoietic disorders (anaemia, haemolitic anaemia, aplastic anaemia), leucopenia, thrombocytopenia, pancytopenia, agranulocytosis)
First signs are: fever, sore throat superficial mouth ulcers, flu-like symptoms, severe exhaustion, nose and skin bleeding.
Uncommon Hypersensitivity reactions with urticaria and pruritus.
Immune system disorders u Very rare In patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissue disease) during treatment with ibuprofen, single cases of symptoms of aseptic meningitis such as stiff neck, headache, nausea, vomiting, fever or disorientation have been observed.

Severe hypersensitivity reactions. Symptoms could be: facial, tongue and larynx swelling, dysponea, tachycardia, hypotension, (anaphylaxis, angioedema or severe shock).

Exacerbation of asthma and bronchospasm.

Psychiatric disorders Very rare Nervousness
Nervous System Uncommon Headache
Eye disorders Very rare Visual disturbance
Ear and labyrinth disorders Very rare Tinnitus and vertigo
Cardiac disorders Very rare Cardiac failure, angina pectoris
Vascular disorders Very rare Hypertension
Respiratory, thoracic and mediastinal disorders Very rare Asthma, bronchospasm, dyspnoea and wheezing
Gastrointestinal disorders Uncommon Abdominal pain, abdominal distenion, dyspepsia and nausea.

Clinical trial and epidemiological data suggest that use of ibuprofen (particularly at high doses 2400 mg daily) and in long-term treatment may be associated with a small increases risk of arterial thrombotic events (for example myocardial infarction or stroke).

 

OVERDOSE4’5

In children ingestion of more than 400 mg/kg may cause symptoms. In adults the dose response effect is less clear cut. The half-life in overdose is 1.5-3 hours.

Symptoms

Most patients who have ingested clinically important amounts of NSAIDs will develop no more than nausea, vomiting, epigastric pain, or more rarely diarrhoea. Tinnitus, headache and gastrointestinal bleeding are also possible. In more serious poisoning, toxicity is seen in the central nervous system, manifesting as vertigo, headache, respiratory depression, dyspnoea, drowsiness, occasionally excitation and disorientation or coma. Occasionally patents develop convulsions. In serious poisoning, hypotension, hyperkalaemia, and metabolic acidosis may occur and the prothrombin time /INR may be prolonged, probably due to interference with the actions of circulating clotting factors. Acute renal failure and liver damage may occur. Exacerbation of asthma is possible in asthmatics.

Management

Should be symptomatic and supportive and include maintenance of a clear airway and monitoring of cardiac and vital signs until stable. Consider oral administration of activated charcoal if the patient presents within 1 hour of ingestion of a potentially toxic amount. If frequent or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma.

 

PHARMACODYNAMIC AND PHARMACOKINETIC PROPERTIES4,5

Pharmacodynamic effect

Ibuprofen is a phenylpropionic acid derivative NSAID that has demonstrated its efficacy by inhibition of prostaglandin synthesis. In humans, ibuprofen reduces inflammatory pain, swelling and fever. Furthermore, ibuprofen reversibly inhibits platelet aggregation.
Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. In one study, when a single dose of ibuprofen 400 mg was taken within 8 hour before or within 30 minutes after immediate release aspirin dosing (81 mg), a decreased effect of aspirin on the formation of thromboxane or platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation of ex-vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use.

Pharmacokinetics

lbuprofen is rapidly absorbed following administration and is rapidly distributed throughout the whole body. The excretion is rapid and complete via the kidneys.

Maximum plasma concentrations are reached 45 minutes after ingestion if taken on an empty stomach. When taken with food, peak levels are observed after 1 to 2 hours. These times may vary with different dosage forms. The half life of ibuprofen is about 2 hours.

In limited studies, ibuprofen appears in the breast milk in very low concentrations.

 

PRECLINICAL SAFETY6,7

Carcinogenesis, mutagenesis, impairment of fertility

Th sub-chronic and chronic toxicity of ibunrofen in animal experiments consisted mainly of lesions and ulcerations in the gastro-intestinal tract.

In-vitro and in-vivo investigations have produced no clinically relevant evidence of ibuprofen having mutagenic effects. In studies in rats and mice, no evidence of carcinogenic effects of ibuprofen was found.

Ibuprofen led to an inhibition of ovulation in rabbits and impaired implantation in various animal species (rabbit, rat and mouse). Experimental studies in rats and rabbits have shown that ibuprofen crosses the placenta. Following administration of maternotoxic doses, an increased rate of malformations (ventricular septal defects) occurred in the progeny of rats.

In animal studies it has been observed that the use of NSAIDs, known to inhibit prostaglandin synthesis, may increase the incidence of dystocia and delayed parturition.
Ibuprofen has no embryotoxic or teratogenic activity when administered in ulceragenic doses.

 

STORAGE

Store below 25°C, protected from moisture.

KEEP ALL MEDICINES OUT OF THE REACH OF CHILDREN.

 

SUPPLY

Box of 10’s, 24×10’s.

 

REFERENCES

1. Proposed NSAID Package Insert Labeling Template 1, Revised in XXX/05, accessed online from http://www.fda.gov/download/Drugs/DrugSafety/PostmarketDrugSafetylnformationforPatientsandProviders/ucm106230.pdf on 3rd January 2012.

2. US Prescribing Information of CALDOLOR Injection, Cumberland Pharmaceuticals Inc., USA, June 2009.

3. Canada Product Monograph of ADVIL ADULTS, Pfizer Canada Inc., April 2011.

4. UK Summary of Product Characteristics of ANADIN IBUPROFEN 200mg Tablets, Pfizer Consumer Healthcare Ltd, March 2011.

5. UK Summary of Product Characteristics of ANADIN ULTRA DOUBLE STRENGTH 400mg Capsules, Pfizer Consumer Healthcare Ltd, October 2011.

6. UK Summary of Product Characteristics of ANADIN LIQUIFAST 200mg Effervescent Tablets, Pfizer Consumer Healthcare, April 2010.

7.Adams SS et al (1969). Absorption, distribution and toxicity of ibuprofen. Toxicology and applied Pharmacology. 15:310-330.

 

Information compiled in January 2012.

 

CALDOLOR, ANADIN and ADVIL are the trademarks of Cumberland Pharmaceuticals Inc, Pfizer Consumer HeaIthcare and Pfizer Canada Inc. respectively and are not the trademarks of Sun Pharmaceutical Ind. Ltd.

The makers of these brands are not affiliated with and do not endorse Sun Pharmaceutical Ind. Ltd. or its products.

 

Manufactured in India by

Sun Pharmaceutical Ind. Ltd.

Industrial Area – 3

Dewas – 455 001

Leave a Reply