Ibuprofen

MARKSANS PHARMA LIMITED

FULL PRESCRIBING INFORMATION: CONTENTS*

• BOXED WARNING
• IBUPROFEN DESCRIPTION
• CLINICAL PHARMACOLOGY
• IBUPROFEN INDICATIONS AND USAGE
• IBUPROFEN CONTRAINDICATIONS
• WARNINGS
  • Cardiovascular Effects
  • Gastrointestinal Effects-Risk of Ulceration, Bleeding, and Perforation
  • Renal Effects
  • Advanced Renal Disease
  • Anaphylactoid Reactions
  • Skin Reactions
  • Pregnancy
• PRECAUTIONS
  • General Precautions
  • Information for Patients
  • Laboratory Tests
  • Drug Interactions
  • Pregnancy
  • Labor And Delivery
  • Nursing Mothers
  • Pediatric Use
  • Geriatric Use
  • Hepatic effects
  • Hematological effects
  • Preexisting asthma
  • Ophthalmological effects
  • Aseptic meningitis
• IBUPROFEN ADVERSE REACTIONS
• OVERDOSAGE
• IBUPROFEN DOSAGE AND ADMINISTRATION
• HOW SUPPLIED
• SPL Medguide
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

FULL PRESCRIBING INFORMATION

IBUPROFEN DESCRIPTION

CLINICAL PHARMACOLOGY

Ibuprofen tablets contain ibuprofen which possesses analgesic and antipyretic activities. Its mode of action, like that of other NSAIDs, is not completely understood, but may be related to prostaglandin synthetase inhibition.

IBUPROFEN INDICATIONS AND USAGE

IBUPROFEN CONTRAINDICATIONS

WARNINGS

Cardiovascular Effects

Gastrointestinal Effects-Risk of Ulceration, Bleeding, and Perforation

Renal Effects

Advanced Renal Disease

Anaphylactoid Reactions

Skin Reactions

Pregnancy

PRECAUTIONS

General Precautions

Information for Patients

• Ibuprofen tablets like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain , shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects ).
• Ibuprofen tablets, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia , melena , and hematemesis . Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects- Risk of Ulceration, Bleeding and Perforation ).
• Ibuprofen tablets, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs hypersensitivity such as itching, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
• Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
• Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
• Patients should be informed of the signs of an anaphylactoid reaction (e.g. difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS ).
• In late pregnancy, as with other NSAIDs, ibuprofen tablets should be avoided because it may cause premature closure of the ductus arteriosus.

Laboratory Tests

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 their CBC and chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash etc.), or abnormal liver tests persist or worsen, ibuprofen tablets should be discontinued.

Drug Interactions

ACE-inhibitors

Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.

 Aspirin

When ibuprofen tablets are administered with aspirin, its protein binding is reduced, although the clearance of free ibuprofen tablets is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of ibuprofen and aspirin is not generally recommended because of the potential for increased adverse effects.

Diuretics

Clinical studies, as well as post marketing observations, have shown that ibuprofen tablets can reduce the natriuretic effect-of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS , Renal Effects ), as well as to assure diuretic efficacy.

Lithium

Ibuprofen produced an elevation of plasma lithium levels and a reduction in renal lithium clearance in a study of eleven normal volunteers. The mean minimum lithium concentration increased 15%and the renal clearance of lithium was decreased by 19%during this period of concomitant drug administration. This effect has been attributed to inhibition of renal prostaglandin synthesis by ibuprofen. Thus, when ibuprofen and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. (Read circulars for lithium preparation before use of such concurrent therapy.)

Methotrexate

NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.

Warfarin-type anticoagulants

Several short-term controlled studies failed to show that ibuprofen tablets significantly affected prothrombin times or a variety of other clotting factors when administered to individuals on coumarin-type anticoagulants. However, because bleeding has been reported when ibuprofen tablets and other NSAIDs have been administered to patients on coumarin-type anticoagulants, the physician should be cautious when administering ibuprofen tablets to patients on anticoagulants. The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that the users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.

H-2 Antagonists

In studies with human volunteers, co-administration of cimetidine or ranitidine with ibuprofen had no substantive effect on ibuprofen serum concentrations.

Pregnancy

Teratogenic Effects

Nonteratogenic Effects

Labor And Delivery

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human-milk and because of the potential for serious adverse reactions in nursing infants from ibuprofen tablets, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of ibuprofen tablets in pediatric patients have not been established.

Geriatric Use

As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).

Hepatic effects

Hematological effects

Preexisting asthma

Ophthalmological effects

Aseptic meningitis

IBUPROFEN ADVERSE REACTIONS

The most frequent type of adverse reaction occurring with ibuprofen tablets is gastrointestinal . In controlled clinical trials the percentage of patients reporting one or more gastrointestinal complaints ranged from 4%to 16%.

In controlled studies when ibuprofen tablets were compared to aspirin and indomethacin in equally effective doses, the overall incidence of gastrointestinal complaints was about half that seen in either the aspirin- or indomethacin-treated patients.

Adverse reactions observed during controlled clinical trials at an incidence greater than 1%are listed in the table. Those reactions listed in Column one encompass observations in approximately 3,000 patients. More than 500 of these patients were treated for periods of at least 54 weeks.

Still other reactions occurring less frequently than 1 in 100 were reported in controlled clinical trials and from marketing experience. These reactions have been divided into two categories: Column two of the table lists reactions with therapy with ibuprofen tablets where the probability of a causal relationship exists: for the reactions in Column three, a causal relationship with ibuprofen tablets has not been established.

Reported side effects were higher at doses of 3200 mg/day than at doses of 2400 mg or less per day in clinical trials of patients with rheumatoid arthritis . The increases in incidence were slight and still within the ranges reported in the table.

*Reactions are classified under "Probable Causal Relationship (PCR)" if there has been one positive rechallenge or if three or more cases occur which might be causally related. Reactions are classified under "Causal Relationship Unknown" if seven or more events have been reported but the criteria for PCR have not been met.
†Reactions occurring in 3%to 9%of patients treated with ibuprofen tablets. (Those reactions occurring in less than 3%of the patients are unmarked).

OVERDOSAGE

Approximately 1½ hours after the reported ingestion of from 7 to 10 ibuprofen tablets (400 mg), a 19-month old child weighing 12 kg was seen in the hospital emergency room, apneic and cyanotic , responding only to painful stimuli. This type of stimulus, however, was sufficient to induce respiration . Oxygen and parenteral fluids were given; a greenish-yellow fluid was aspirated from the stomach with no evidence to indicate the presence of ibuprofen . Two hours after ingestion the child's condition seemed stable; she still responded only to painful stimuli and continued to have periods of apnea lasting from 5 to 10 seconds. She was admitted to intensive care and sodium bicarbonate was administered as well as infusions of dextrose and normal saline. By four hours post-ingestion she could be aroused easily, sit by herself and respond to spoken commands. Blood level of ibuprofen was 102.9 µg/mL approximately 8½ hours after accidental ingestion. At 12 hours she appeared to be completely recovered.

In two other reported cases where children (each weighing approximately 10 kg) accidentally, acutely ingested approximately 120 mg/kg, there were no signs of acute intoxication or late sequelae . Blood level in one child 90 minutes after ingestion was 700 µg/mL — about 10 times the peak levels seen in absorption-excretion studies.

A 19-year old male who had taken 8,000 mg of ibuprofen over a period of a few hours complained of dizziness , and nystagmus was noted. After hospitalization, parenteral hydration and three days bed rest, he recovered with no reported sequelae.

In cases of acute overdosage, the stomach should be emptied by vomiting or lavage, though little drug will likely be recovered if more than an hour has elapsed since ingestion. Because the drug is acidic and is excreted in the urine, it is theoretically beneficial to administer alkali and induce diuresis . In addition to supportive measures, the use of oral activated charcoal may help to reduce the absorption and reabsorption of ibuprofen tablets.

IBUPROFEN DOSAGE AND ADMINISTRATION

HOW SUPPLIED

Ibuprofen tablets are available in the following strengths:

400 mg (white to off white, round, biconvex, film coated tablets debossed with ‘121’ on one side and plain on other side)

Bottles of 30             (NDC 25000-121-03)

Bottles of 500            (NDC 25000-121-12)

600 mg (white to off white, capsule shaped, biconvex, film coated tablets debossed with ‘122’ on one side and plain on other side)

Bottles of 30             (NDC 25000-122-03)

Bottles of 500            (NDC 25000-122-12)

800 mg (white to off white, capsule shaped, biconvex, film coated tablets debossed with ‘123’ on one side and plain on other side)

Bottles of 30             (NDC 25000-123-03)

Bottles of 500            (NDC 25000-123-12)

Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].

Rxonly

Manufactured for:

Marksans Pharma Inc.

Lake Grove, NY 11755, USA

Manufactured by:

Marksans Pharma Ltd.

Verna, Goa-403 722, India

Iss. 07/08

SPL Medguide

Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

(See the end of this Medication Guide for a list of prescription NSAID medicines)

What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines may increase the chance of a heart attack or stroke that can lead to death.This chance increases:

• with longer use of NSAID medicines
• in people who have heart disease

NSAID medicines should never be used right before or after a heart surgery called a "coronary artery bypass graft (CABG)."

NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding:

• can happen without warning symptoms
• may cause death

The chance of a person getting an ulcer or bleeding increases with:

• taking medicines called "corticosteroids" and "anticoagulants"
• longer use
• smoking
• drinking alcohol
• older age
• having poor health

NSAID medicines should only be used:

• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed

What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:

• different types of arthritis
• menstrual cramps and other types of short-term pain

Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?

Do not take an NSAID medicine:

• if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine
• for pain right before or after heart bypass surgery

Tell your healthcare provider:

• about all of your medical conditions
• about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist.
• if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy.
• if you are breastfeeding. Talk to your doctor.

What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

Get emergency help right away if you have any of the following symptoms:

• shortness of breath or trouble breathing
• chest pain
• weakness in one part or side of your body
• slurred speech
• swelling of the face or throat

Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms:

• nausea
• more tired or weaker than usual
• itching
• your skin or eyes look yellow
• stomach pain
• flu-like symptoms
• vomit blood
• there is blood in your bowel movement or it is black and sticky like tar
• unusual weight gain
• skin rash or blisters with fever
• swelling of the arms and legs, hands and feet

These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines.

Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

• Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.
• Some of these NSAID medicines are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.

NSAID medicines that need a prescription

*Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is usually used for less than 10 days to treat pain. The OTC NSAID label warns that long term continuous use may increase the risk of heart attack or stroke.

 This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured for:

Marksans Pharma Inc.

Lake Grove, NY 11755, USA

Manufactured by:

Marksans Pharma Ltd.

Verna, Goa-403 722, India

Iss. 07/08

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL