IBUPROFEN tablet, film coated

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Active ingredient:
IBUPROFEN (UNII: WK2XYI10QM) (IBUPROFEN - UNII:WK2XYI10QM)
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PRESCRIPTION DRUG
Therapeutic indications:
Carefully consider the potential benefits and risks of ibuprofen tablets and other treatment options before deciding to use ibuprofen. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ). Ibuprofen tablets are indicated for relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis. Ibuprofen tablets are indicated for relief of mild to moderate pain. Ibuprofen tablets are also indicated for the treatment of primary dysmenorrhea. Controlled clinical trials to establish the safety and effectiveness of ibuprofen tablets in children have not been conducted. Ibuprofen tablets are contraindicated in patients with known hypersensitivity to ibuprofen. Ibuprofen tablets should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS, Anaphylactoid Reac
Product summary:
Ibuprofen tablets are available in the following strengths, colors and sizes: 400 mg (white, round shaped, film-coated tablets engraved "IBU" over "400" on one side). Bottles of 15 NDC 71205-464-15 Bottles of 20 NDC 71205-464-20 Bottles of 30 NDC 71205-464-30 Bottles of 60 NDC 71205-464-60 Bottles of 90 NDC 71205-464-90 Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Rx only Distributed by: Strides Pharma lnc. East Brunswick, NJ 08816 Revised: 11/2020 Repackaged by: Proficient Rx LP Thousand Oaks, CA 91320
Authorization status:
Abbreviated New Drug Application
Authorization number:
71205-464-15, 71205-464-20, 71205-464-30, 71205-464-60, 71205-464-90

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SPL MEDGUIDE

Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

What is the most important information I should know about medicines called Nonsteroidal Anti-

Inflammatory Drugs (NSAIDs)?

NSAIDs can cause serious side effects, including:

Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment

and may increase:

o with increasing doses of NSAIDs

o with longer use of NSAIDs

Do not take NSAIDs right before or after a heart surgery called a "coronary artery bypass graft (CABG)."

Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may

have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.

Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth

to the stomach), stomach and intestines:

o anytime during use

o without warning symptoms

o that may cause death

The risk of getting an ulcer or bleeding increases with :

o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs

o taking medicines called "corticosteroids", "anticoagulants", "SSRls", or "SNRls"

o increasing doses of NSAIDs

o longer use of NSAIDs

o smoking

o drinking alcohol

o older age

o poor health

o advanced liver disease

o bleeding problems

NSAIDs should only be used:

o exactly as prescribed

o at the lowest dose possible for your treatment

o for the shortest time needed

What are NSAIDs?

NSAIDs 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 NSAIDs?

Do not take NSAIDs:

if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs

right before or after heart bypass surgery.

Before taking NSAlDS , tell your healthcare provider about all of your medical conditions , including if

you:

have liver or kidney problems

have high blood pressure

have asthma

are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may

harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and

30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb

around your baby. You should not take NSAIDs after about 30 weeks of pregnancy.

are breastfeeding or plan to breast feed.

Tell your healthcare provider about all of the medicines you take, including prescription or over-the-

counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with

each other and cause serious side effects. Do not start taking any new medicine without talking to your

healthcare provider first.

What are the possible side effects of NSAIDs?

NSAIDs can cause serious side effects, including:

See "What is the most important information I should know about medicines called Nonsteroidal Anti-

inflammatory Drugs (NSAIDs)?

new or worse high blood pressure

heart failure

liver problems including liver failure

kidney problems including kidney failure

low red blood cells (anemia)

life-threatening skin reactions

life threatening allergic reactions

Other side effects of NSAIDs include:

stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness.

Get emergency help right away if you get 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 taking your NSAID and call your healthcare provider right away if you get any of the following

symptoms:

nausea

more tired or weaker than usual

diarrhea

itching

your skin or eyes look yellow

indigestion or 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

If you take too much of your NSAID, call your healthcare provider or get medical help right away.

These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider

or pharmacist about NSAIDs.

You may report side effects to Strides Pharma Inc. at 1-877-244-9825 or go to www.strides.com or FDA

at 1-800-FOA-1088 or www.fda.gov/medwatch.

Other information about NSAIDs

Aspirin is an NSAID 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 NSAIDs 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.

General information about the safe and effective use of NSAIDs

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not

use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if

they have the same symptoms that you have. It may harm them.

If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your

pharmacist or healthcare provider for information about NSAIDs that is written for health professionals.

Distributed by:

Strides Pharma Inc.

East Brunswick, NJ 08816

Revised: 11/2020

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

Repackaged by:

Proficient Rx LP

Thousand Oaks, CA 91320

Revised: 12/2020

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Version: 1

Effective Time: 20201201

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IBUPROFEN- ibuprofen tablet, film coated

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Ibuprofen tablets

BOXED WARNING

Cardiovascular Thrombolic Events

Gastrointestinal Risk

DESCRIPTION

Ibuprofen tablets contain the active ingredient ibuprofen, which is (±) - 2 - (p - isobutylphenyl)

propionic acid. Ibuprofen is a white powder with a melting point of 74° to 77° C and is very slightly

soluble in water (<1 mg/mL) and readily soluble in organic solvents such as ethanol and acetone.

The structural formula is represented below:

Ibuprofen tablets, a nonsteroidal anti-inflammatory drug (NSAID), is available in 400 mg, 600 mg, and

800 mg tablets for oral administration. Inactive ingredients: colloidal silicon dioxide, microcrystalline

cellulose, pregelatinized starch, sodium starch glycolate, talc, magnesium stearate, Opadry II contains

hypromellose, polyethylene glycol, sodium citrate, lactose monohydrate and titanium dioxide.

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.

In clinical studies in patients with rheumatoid arthritis and osteoarthritis, ibuprofen tablets have been

shown to be comparable to aspirin in controlling pain and inflammation and to be associated with a

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious

cardiovascular thrombotic events, including myocardial infarction, and stroke, which can be

fatal. This risk may occur early in treatment and may increase with duration of use (see

WARNINGS and PRECAUTIONS ).

Ibuprofen tablets is contraindicated in the setting of coronary artery bypass graft (CABG)

surgery (see CONTRAINDICATIONS and WARNINGS) .

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 gastrointestinal events (see WARNINGS ).

statistically significant reduction in the milder gastrointestinal side effects (see ADVERSE

REACTIONS). Ibuprofen tablets may be well tolerated in some patients who have had gastrointestinal

side effects with aspirin, but these patients when treated with ibuprofen tablets should be carefully

followed for signs and symptoms of gastrointestinal ulceration and bleeding. Although it is not

definitely known whether ibuprofen tablets causes less peptic ulceration than aspirin, in one study

involving 885 patients with rheumatoid arthritis treated for up to one year, there were no reports of

gastric ulceration with ibuprofen tablets whereas frank ulceration was reported in 13 patients in the

aspirin group (statistically significant p<.001).

Gastroscopic studies at varying doses show an increased tendency toward gastric irritation at higher

doses. However, at comparable doses, gastric irritation is approximately half that seen with aspirin.

Studies using

Cr-tagged red cells indicate that fecal blood loss associated with ibuprofen tablets in

doses up to 2400 mg daily did not exceed the normal range, and was significantly less than that seen in

aspirin-treated patients.

In clinical studies in patients with rheumatoid arthritis, ibuprofen tablets have been shown to be

comparable to indomethacin in controlling the signs and symptoms of disease activity and to be

associated with a statistically significant reduction of the milder gastrointestinal (see ADVERSE

REACTIONS) and CNS side effects.

Ibuprofen tablets may be used in combination with gold salts and/or corticosteroids.

Controlled studies have demonstrated that ibuprofen tablets are a more effective analgesic than

propoxyphene for the relief of episiotomy pain, pain following dental extraction procedures, and for

the relief of the symptoms of primary dysmenorrhea.

In patients with primary dysmenorrhea, ibuprofen tablets have been shown to reduce elevated levels of

prostaglandin activity in the menstrual fluid and to reduce resting and active intrauterine pressure, as

well as the frequency of uterine contractions. The probable mechanism of action is to inhibit

prostaglandin synthesis rather than simply to provide analgesia.

Pharmacodynamics

In a healthy volunteer study, ibuprofen 400 mg given once daily, administered 2 hours prior to

immediate-release aspirin (81 mg) for 6 days, showed an interaction with the antiplatelet activity of

aspirin as measured by % serum thromboxane B2 (TxB2) inhibition at 24 hours following the day-6

aspirin dose [53%]. An interaction was still observed, but minimized, when ibuprofen 400 mg given

once-daily was administered as early as 8 hours prior to the immediate-release aspirin dose [90.7%].

However, there was no interaction with the antiplatelet activity of aspirin when ibuprofen 400 mg, given

once daily, was administered 2 hours after (but not concomitantly, 15 min, or 30 min after) the

immediate-release aspirin dose [99.2%].

In another study, where immediate-release aspirin 81 mg was administered once daily with ibuprofen

400 mg given three times daily (1, 7, and 13 hours post-aspirin dose) for 10 consecutive days, the mean

% serum thromboxane B2 (TxB2) inhibition suggested no interaction with the antiplatelet activity of

aspirin [98.3%]. However, there were individual subjects with serum TxB2 inhibition below 95%, with

the lowest being 90.2%.

When a similarly designed study was conducted with enteric-coated aspirin, where healthy subjects

were administered enteric-coated aspirin 81 mg once daily for 6 days and ibuprofen 400 mg three times

daily (2, 7 and 12 h post-aspirin dose) for 6 days, there was an interaction with the antiplatelet activity at

24 hours following the day-6 aspirin dose [67%]. [See Precautions/Drug Interactions].

Pharmacokinetics

The ibuprofen in ibuprofen tablets is rapidly absorbed. Peak serum ibuprofen levels are generally

attained one to two hours after administration. With single doses up to 800 mg, a linear relationship

exists between amount of drug administered and the integrated area under the serum drug concentration

vs time curve. Above 800 mg, however, the area under the curve increases less than proportional to

increases in dose. There is no evidence of drug accumulation or enzyme induction.

The administration of ibuprofen tablets either under fasting conditions or immediately before meals

yields quite similar serum ibuprofen concentration-time profiles. When ibuprofen tablets are

administered immediately after a meal, there is a reduction in the rate of absorption but no appreciable

decrease in the extent of absorption. The bioavailability of the drug is minimally altered by the presence

of food.

A bioavailability study has shown that there was no interference with the absorption of ibuprofen when

ibuprofen tablets were given in conjunction with an antacid containing both aluminum hydroxide and

magnesium hydroxide.

Ibuprofen is rapidly metabolized and eliminated in the urine. The excretion of ibuprofen is virtually

complete 24 hours after the last dose. The serum half-life is 1.8 to 2.0 hours.

Studies have shown that following ingestion of the drug, 45% to 79% of the dose was recovered in the

urine within 24 hours as metabolite A (25%), (+)-2-[p-(2hydroxymethyl-propyl) phenyl] propionic acid

and metabolite B (37%), (+)-2-[p- (2carboxypropyl)phenyl] propionic acid; the percentages of free and

conjugated ibuprofen were approximately 1% and 14%, respectively.

INDICATIONS AND USAGE

Carefully consider the potential benefits and risks of ibuprofen tablets and other treatment options

before deciding to use ibuprofen. Use the lowest effective dose for the shortest duration consistent

with individual patient treatment goals (see WARNINGS).

Ibuprofen tablets are indicated for relief of the signs and symptoms of rheumatoid arthritis and

osteoarthritis.

Ibuprofen tablets are indicated for relief of mild to moderate pain.

Ibuprofen tablets are also indicated for the treatment of primary dysmenorrhea.

Controlled clinical trials to establish the safety and effectiveness of ibuprofen tablets in children have

not been conducted.

CONTRAINDICATIONS

Ibuprofen tablets are contraindicated in patients with known hypersensitivity to ibuprofen.

Ibuprofen tablets should not be given to patients who have experienced asthma, urticaria, or allergic-

type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to

NSAIDs have been reported in such patients (see WARNINGS, Anaphylactoid Reactions,

and PRECAUTIONS, Preexisting Asthma).

Ibuprofen tablets are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see

WARNINGS).

WARNINGS

CARDIOVASCULAR EFFECTS

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 ibuprofen, increases the risk of serious gastrointestinal (GI) events (see WARNINGS).

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 to 14 days following CABG surgery found an increased incidence of myocardial infarction and

stroke. NSAIDs are contraindicated in the setting of CABG (see CONTRAINDICATIONS).

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 all-

cause 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 ibuprofen tablets in patients with a recent MI unless the benefits are expected to

outweigh the risk of recurrent CV thrombotic events. If ibuprofen tablets is used in patients with a

recent MI, monitor patients for signs of cardiac ischemia.

Hypertension

NSAIDs including ibuprofen tablets, can lead to onset of new hypertension or worsening of pre-

existing hypertension, either of which may contribute to the increased incidence of CV events. Patients

taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs.

NSAIDs, including ibuprofen tablets, should be used with caution in patients with hypertension. Blood

pressure (BP) should be monitored closely 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 ibuprofen 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) (see DRUG

INTERACTIONS).

Avoid the use of ibuprofen tablets in patients with severe heart failure unless the benefits are expected

to outweigh the risk of worsening heart failure. If ibuprofen tablets is used in patients with severe heart

failure, monitor patients for signs of worsening heart failure.

Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation

NSAIDs, including ibuprofen tablets, can cause serious gastrointestinal (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 to 6 months, and in about 2% to

4% of patients treated for one year. These trends continue with longer duration of use, increasing the

likelihood of developing a serious GI event at some time during the course of therapy. However, even

short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those with

a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history or peptic ulcer

disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for

developing a GI bleed compared to patients treated 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 spontaneous reports of 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, the lowest

effective dose should be used 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.

Renal Effects

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 a 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 and ACE inhibitors, and the

elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Advanced Renal Disease

No information is available from controlled clinical studies regarding the use of ibuprofen tablets in

patients with advanced renal disease. Therefore, treatment with ibuprofen tablets is not recommended in

these patients with advanced renal disease. If ibuprofen tablet therapy must be initiated, close monitoring

of the patients renal function is advisable.

Anaphylactoid Reactions

As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to

ibuprofen tablets. Ibuprofen tablets should not be given to 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 and PRECAUTIONS, Preexisting Asthma). Emergency help should be

sought in cases where an anaphylactoid reaction occurs.

Skin Reactions

NSAIDs, including ibuprofen tablets, can cause serious skin adverse events such as exfoliative

dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal.

These serious events may occur without warning. Patients should be informed about the signs and

symptoms of serious skin manifestations and use of the drug should be discontinued at the first

appearance of skin rash or any other sign of hypersensitivity.

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking

NSAIDs such as ibuprofen tablets. Some of these events have been fatal or life-threatening. DRESS

typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling.

Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis,

or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is

often present. Because this disorder is variable in its presentation, other organ systems not noted here

may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or

lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present,

discontinue ibuprofen tablets and evaluate the patient immediately.

Fetal Toxicity

Premature Closure of Fetal Ductus Arteriosus:

Avoid use of NSAIDs, including ibuprofen tablets, in pregnant women at about 30 weeks gestation and

later. NSAIDs including ibuprofen tablets, increase the risk of premature closure of the fetal ductus

arteriosus at approximately this gestational age.

Oligohydramnios/Neonatal Renal Impairment:

Use of NSAIDs, including ibuprofen tablets, at about 20 weeks gestation or later in pregnancy may

cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment.

These adverse outcomes are seen, on average, after days to weeks of treatment, although

oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation.

Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of

prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In

some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange

transfusion or dialysis were required.

If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit ibuprofen tablets

use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of

amniotic fluid if ibuprofen tablets treatment extends beyond 48 hours. Discontinue ibuprofen tablets if

oligohydramnios occurs and follow up according to clinical practice [see PRECAUTIONS; Pregnancy].

PRECAUTIONS

General

Ibuprofen tablets cannot be expected to substitute for corticosteroids or to treat corticosteroid

insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on

prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to

discontinue corticosteroids.

The pharmacological activity of ibuprofen tablets in reducing fever and inflammation may diminish the

utility of these diagnostic signs in detecting complications of presumed noninfectious, painful

conditions.

Hepatic effects

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs,

including ibuprofen tablets. 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, including jaundice, fulminant

hepatitis, liver necrosis, and hepatic failure, some of them with fatal outcomes have been reported.

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 tablets. If clinical signs and symptoms consistent with liver disease develop, or

if systemic manifestations occur (e.g., eosinophilia, rash, etc.), ibuprofen tablets should be

discontinued.

Hematological effects

Anemia is sometimes seen in patients receiving NSAIDs, including ibuprofen tablets. This may be due

to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon

erythropoiesis. Patients on long-term treatment with NSAIDs, including ibuprofen tablets, should have

their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.

In two postmarketing clinical studies the incidence of a decreased hemoglobin level was greater than

previously reported. Decrease in hemoglobin of 1 gram or more was observed in 17.1% of 193 patients

on 1600 mg ibuprofen daily (osteoarthritis), and in 22.8% of 189 patients taking 2400 mg of ibuprofen

daily (rheumatoid arthritis). Positive stool occult blood tests and elevated serum creatinine levels were

also observed in these studies.

NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients.

Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible.

Patients receiving ibuprofen tablets who may be adversely affected by alterations in platelet function,

such as those with coagulation disorders or patients receiving anticoagulants should be carefully

monitored.

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, including bronchospasm, between aspirin and NSAIDs has been reported in such aspirin-

sensitive patients, ibuprofen tablets should not be administered to patients with this form of aspirin

sensitivity and should be used with caution in patients with preexisting asthma.

Ophthalmological effects

Blurred and/or diminished vision, scotomata, and/or changes in color vision have been reported. If a

patient develops such complaints while receiving ibuprofen tablets, the drug should be discontinued,

and the patient should have an ophthalmologic examination which includes central visual fields and

color vision testing.

Aseptic Meningitis

Aseptic meningitis with fever and coma has been observed on rare occasions in patients on 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 an underlying

chronic disease. If signs or symptoms of meningitis develop in a patient on ibuprofen tablets, the

possibility of its being related to ibuprofen tablets should be considered.

INFORMATION FOR PATIENTS

Patients should be informed of the following information before initiating therapy with an NSAID

and periodically during the course of ongoing therapy. Patients should also be encouraged to

read the NSAID Medication Guide that accompanies each prescription dispensed.

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 (see WARNINGS)

Serious Skin Reactions, including DRESS

Advise patients to stop taking ibuprofen tablets immediately if they develop any type of rash or fever

and to contact their healthcare provider as soon as possible [see Warnings].

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 (see

WARNINGS).

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

Pharmacodynamic studies have demonstrated interference with the antiplatelet activity of aspirin when

ibuprofen 400 mg, given three times daily, is administered with enteric-coated low-dose aspirin. The

interaction exists even following a once-daily regimen of ibuprofen 400 mg, particularly when

ibuprofen is dosed prior to aspirin. The interaction is alleviated if immediate-release low-dose aspirin

is dosed at least 2 hours prior to a once-daily regimen of ibuprofen; however, this finding cannot be

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 of hypersensitivity such as itching, and should ask for

medical advice when observing any indicative sign or symptoms.

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.

extended to enteric-coated low-dose aspirin [see Clinical Pharmacology/Pharmacodynamics].

Because there may be an increased risk of cardiovascular events due to the interference of ibuprofen

with the antiplatelet effect of aspirin, for patients taking low-dose aspirin for cardioprotection who

require analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of

aspirin, or non-NSAID analgesics, where appropriate.

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

Risk Summary

Use of NSAIDs, including ibuprofen tablets, can cause premature closure of the fetal ductus arteriosus

and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment.

Because of these risks, limit dose and duration of ibuprofen tablets use between about 20 and 30 weeks

of gestation, and avoid ibuprofen tablets use at about 30 weeks of gestation and later in pregnancy [see

WARNINGS; Fetal Toxicity].

Premature Closure of Fetal Ductus Arteriosus

Use of NSAIDs, including ibuprofen tablets, at about 30 weeks gestation or later in pregnancy increases

the risk of premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment

Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of

fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment.

Data from observational studies regarding other 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. 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 ibuprofen,

resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an

important role in fetal kidney development. In published animal studies, prostaglandin synthesis

inhibitors have been reported to impair kidney development when administered at clinically relevant

doses.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Premature Closure of Fetal Ductus Arteriosus:

Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs,

including ibuprofen tablets, can cause premature closure of the fetal ductus arteriosus (see WARNINGS;

Fetal Toxicity).

Oligohydramnios/Neonatal Renal Impairment

If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest

effective dose and shortest duration possible. If ibuprofen tablets treatment extends beyond 48 hours,

consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue

ibuprofen tablets and follow up according to clinical practice (see WARNINGS; Fetal Toxicity).

Data

Human Data

Premature Closure of Fetal Ductus Arteriosus:

Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in

pregnancy may cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment:

Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation

or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some

cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of

treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID

initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with

cessation of the drug. There have been a limited number of case reports of maternal NSAID use and

neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of

neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or

dialysis.

Methodological limitations of these postmarketing studies and reports include lack of a control group;

limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other

medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and

neonatal outcomes with maternal NSAID use.

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