NAPROXEN tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
NAPROXEN (UNII: 57Y76R9ATQ) (NAPROXEN - UNII:57Y76R9ATQ)
Available from:
Bryant Ranch Prepack
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Carefully consider the potential benefits and risks of naproxen tablets and other treatment options before deciding to use naproxen tablets. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation) . Naproxen as naproxen tablets are indicated: - For the relief of the signs and symptoms of rheumatoid arthritis - For the relief of the signs and symptoms of osteoarthritis - For the relief of the signs and symptoms of ankylosing spondylitis - For the relief of the signs and symptoms of juvenile arthritis - For relief of the signs and symptoms of tendonitis - For relief of the signs and symptoms of bursitis - For relief of the signs and symptoms of acute gout - For the management of pain - For the management of primary dysmenorrhea Naproxen tablets are contraindicated in the following patients: - Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to naproxen, napr
Product summary:
Product: 63629-8107 NDC: 63629-8107-1 20 TABLET in a BOTTLE NDC: 63629-8107-2 30 TABLET in a BOTTLE NDC: 63629-8107-3 60 TABLET in a BOTTLE
Authorization status:
Abbreviated New Drug Application
Authorization number:
63629-8107-1, 63629-8107-2, 63629-8107-3

Bryant Ranch Prepack

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Medication Guide for Nonsteroidal Anti-

Inflammatory Drugs (NSAIDs)

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:

with increasing doses of NSAIDs

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:

anytime during use

without warning symptoms

that may cause death

The risk of getting an ulcer or bleeding increases with:

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

taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs”

increasing doses of NSAIDs

longer use of NSAIDs

smoking

drinking alcohol

older age

poor health

advanced liver disease

bleeding problems

NSAIDs should only be used:

exactly as prescribed

at the lowest dose possible for your treatment

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 NSAIDs, tell your health care 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. Talk to your health care provider if you are considering

taking NSAIDs during pregnancy. You should not take NSAIDs after 29 weeks of pregnancy.

are breastfeeding or plan to breast feed.

Tell your health care 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 new medicine without talking to your health care 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 health care 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, legs, hands, and feet

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

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

pharmacist about NSAIDs.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-

1088.

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 health

care 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 health care provider. You can ask your

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

Manufactured by:

Amneal Pharmaceuticals Pvt. Ltd.

Ahmedabad, INDIA 382220

Distributed by:

Amneal Pharmaceuticals

Bridgewater, NJ 08807

Rev. 06-2016-01

For more information, go to www.amneal.com or call 1-877-835-5472.

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

Revised: 8/2019

Document Id: f4e73df1-1258-496c-bc33-19b9b6108d2d

34391-3

Set id: 45ad1acd-9722-42cb-bf0b-b0210a887d24

Version: 1

Effective Time: 20190807

Bryant Ranch Prepack

NAPROXEN- naproxen tablet

Bryant Ranch Prepack

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Naproxen Tablets, USP

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL

EVENTS

Cardiovascular Thrombotic Events

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).

Naproxen Tablets are contraindicated in the setting of coronary artery bypass graft

(CABG) surgery (see CONTRAINDICATIONS, WARNINGS).

Gastrointestinal Bleeding, Ulceration, and Perforation

NSAIDs cause an increased risk of serious gastrointestinal (GI) 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

and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater

risk for serious GI events (see WARNINGS).

DESCRIPTION

Naproxen, USP is a propionic acid derivative related to the arylacetic acid group of nonsteroidal anti-

inflammatory drugs.

The chemical name for naproxen, USP is (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid. Naproxen,

USP has the following structure:

Naproxen, USP has a molecular weight of 230.26 and a molecular formula of C

H O .

Naproxen, USP is an odorless, white to off-white crystalline substance. It is lipid-soluble, practically

insoluble in water at low pH and freely soluble in water at high pH. The octanol/water partition

coefficient of naproxen, USP at pH 7.4 is 1.6 to 1.8.

Naproxen, USP is available as white tablets containing 250 mg of naproxen, USP, white tablets

containing 375 mg of naproxen, USP and white tablets containing 500 mg of naproxen, USP for oral

administration. The inactive ingredients are croscarmellose sodium, povidone and magnesium stearate.

CLINICAL PHARMACOLOGY

Mechanism of Action

Naproxen has analgesic, anti-inflammatory, and antipyretic properties. The sodium salt of naproxen has

been developed as a more rapidly absorbed formulation of naproxen for use as an analgesic.

The mechanism of action of the naproxen, like that of other NSAIDs, is not completely understood but

involves inhibition of cyclooxygenase (COX-1 and COX-2).

Naproxen is a potent inhibitor of prostaglandin synthesis in vitro. Naproxen concentrations reached

during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the

action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation.

Because naproxen is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease

of prostaglandins in peripheral tissues.

Pharmacokinetics

Naproxen is rapidly and completely absorbed from the gastrointestinal tract with an in vivo

bioavailability of 95%. The different dosage forms of naproxen are bioequivalent in terms of extent of

absorption (AUC) and peak concentration (C

); however, the products do differ in their pattern of

absorption. These differences between naproxen products are related to both the chemical form of

naproxen used and its formulation. Even with the observed differences in pattern of absorption, the

elimination half-life of naproxen is unchanged across products ranging from 12 to 17 hours. Steady-

state levels of naproxen are reached in 4 to 5 days, and the degree of naproxen accumulation is

consistent with this half-life. This suggests that the differences in pattern of release play only a

negligible role in the attainment of steady-state plasma levels.

Abs orption

NAPROXEN

After administration of naproxen tablets, peak plasma levels are attained in 2 to 4 hours.

Dis tribution

Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99%

albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in

plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher

doses (average trough C 36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of

naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a

concentration equivalent to approximately 1% of maximum naproxen concentration in plasma (see

PRECAUTIONS; Nursing Mothers).

Elimination

Metabolism

Naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen, and both parent and

metabolites do not induce metabolizing enzymes. Both naproxen and 6-0-desmethyl naproxen are further

metabolized to their respective acylglucuronide conjugated metabolites.

Excretion

The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is

excreted in the urine, primarily as naproxen (<1%), 6-0-desmethyl naproxen (<1%) or their conjugates

(66% to 92%). The plasma half-life of the naproxen anion in humans ranges from 12 to 17 hours. The

corresponding half-lives of both naproxen’s metabolites and conjugates are shorter than 12 hours, and

their rates of excretion have been found to coincide closely with the rate of naproxen disappearance

from the plasma. Small amounts, 3% or less of the administered dose, are excreted in the feces. In

patients with renal failure metabolites may accumulate (see WARNINGS; Renal Toxicity and

Hyperkalemia).

Special Populations

Geriatric Patients

Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma

fraction of naproxen is increased in the elderly, although the unbound fraction is <1% of the total

naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported

to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in

younger subjects. The clinical significance of this finding is unclear, although it is possible that the

increase in free naproxen concentration could be associated with an increase in the rate of adverse

events per a given dosage in some elderly patients.

Race

Pharmacokinetic differences due to race have not been studied.

Hepatic Impairment

Naproxen pharmacokinetics has not been determined in subjects with hepatic insufficiency.

Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma

proteins (albumin) reduce the total plasma concentration of naproxen, but the plasma concentration of

unbound naproxen is increased. Caution is advised when high doses are required and some adjustment of

dosage may be required in these patients. It is prudent to use the lowest effective dose.

Renal Impairment

Naproxen pharmacokinetics has not been determined in subjects with renal insufficiency. Given that

naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for

naproxen metabolites to accumulate in the presence of renal insufficiency. Elimination of naproxen is

decreased in patients with severe renal impairment. Naproxen-containing products are not recommended

for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30

mL/min) (see WARNINGS; Renal Toxicity and Hyperkalemia).

Drug Interaction Studies

Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced,

although the clearance of free NSAID was not altered. The clinical significance of this interaction is

not known. See Table 1 for clinically significant drug interactions of NSAIDs with aspirin (see

PRECAUTIONS; Drug Interactions).

CLINICAL STUDIES

General Information

Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis, juvenile arthritis,

ankylosing spondylitis, tendonitis and bursitis, and acute gout. Improvement in patients treated for

rheumatoid arthritis was demonstrated by a reduction in joint swelling, a reduction in duration of

morning stiffness, a reduction in disease activity as assessed by both the investigator and patient, and by

increased mobility as demonstrated by a reduction in walking time. Generally, response to naproxen has

not been found to be dependent on age, sex, severity or duration of rheumatoid arthritis.

In patients with osteoarthritis, the therapeutic action of naproxen has been shown by a reduction in joint

pain or tenderness, an increase in range of motion in knee joints, increased mobility as demonstrated by a

reduction in walking time, and improvement in capacity to perform activities of daily living impaired by

the disease.

In a clinical trial comparing standard formulations of naproxen 375 mg twice a day (750 mg a day) vs 750

mg twice a day (1500 mg/day), 9 patients in the 750 mg group terminated prematurely because of

adverse events. Nineteen patients in the 1500 mg group terminated prematurely because of adverse

events. Most of these adverse events were gastrointestinal events.

In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and juvenile arthritis, naproxen has

been shown to be comparable to aspirin and indomethacin in controlling the aforementioned measures of

disease activity, but the frequency and severity of the milder gastrointestinal adverse effects (nausea,

dyspepsia, heartburn) and nervous system adverse effects (tinnitus, dizziness, lightheadedness) were

less in naproxen-treated patients than in those treated with aspirin or indomethacin.

In patients with ankylosing spondylitis, naproxen has been shown to decrease night pain, morning

stiffness and pain at rest. In double-blind studies the drug was shown to be as effective as aspirin, but

with fewer side effects.

In patients with acute gout, a favorable response to naproxen was shown by significant clearing of

inflammatory changes (e.g., decrease in swelling, heat) within 24 to 48 hours, as well as by relief of

pain and tenderness.

Naproxen has been studied in patients with mild to moderate pain secondary to postoperative,

orthopedic, postpartum episiotomy and uterine contraction pain and dysmenorrhea. Onset of pain relief

can begin within 1 hour in patients taking naproxen and within 30 minutes in patients taking naproxen

sodium. Analgesic effect was shown by such measures as reduction of pain intensity scores, increase in

pain relief scores, decrease in numbers of patients requiring additional analgesic medication, and delay

in time to remedication. The analgesic effect has been found to last for up to 12 hours.

Naproxen may be used safely in combination with gold salts and/or corticosteroids; however, in

controlled clinical trials, when added to the regimen of patients receiving corticosteroids, it did not

appear to cause greater improvement over that seen with corticosteroids alone. Whether naproxen has a

“steroid-sparing” effect has not been adequately studied. When added to the regimen of patients

receiving gold salts, naproxen did result in greater improvement. Its use in combination with salicylates

is not recommended because there is evidence that aspirin increases the rate of excretion of naproxen

and data are inadequate to demonstrate that naproxen and aspirin produce greater improvement over that

achieved with aspirin alone. In addition, as with other NSAIDs, the combination may result in higher

frequency of adverse events than demonstrated for either product alone.

Cr blood loss and gastroscopy studies with normal volunteers, daily administration of 1000 mg of

naproxen as 1000 mg of naproxen tablets has been demonstrated to cause statistically significantly less

gastric bleeding and erosion than 3250 mg of aspirin.

Geriatric Patients

The hepatic and renal tolerability of long-term naproxen administration was studied in two double-blind

clinical trials involving 586 patients. Of the patients studied, 98 patients were age 65 and older and 10

of the 98 patients were age 75 and older. Naproxen was administered at doses of 375 mg twice daily or

750 mg twice daily for up to 6 months. Transient abnormalities of laboratory tests assessing hepatic and

renal function were noted in some patients, although there were no differences noted in the occurrence

of abnormal values among different age groups.

INDICATIONS AND USAGE

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

deciding to use naproxen tablets. Use the lowest effective dosage for the shortest duration consistent

with individual patient treatment goals (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and

Perforation).

Naproxen as naproxen tablets are indicated:

For the relief of the signs and symptoms of rheumatoid arthritis

For the relief of the signs and symptoms of osteoarthritis

For the relief of the signs and symptoms of ankylosing spondylitis

For the relief of the signs and symptoms of juvenile arthritis

For relief of the signs and symptoms of tendonitis

For relief of the signs and symptoms of bursitis

For relief of the signs and symptoms of acute gout

For the management of pain

For the management of primary dysmenorrhea

CONTRAINDICATIONS

Naproxen tablets are contraindicated in the following patients:

Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to naproxen,

naproxen sodium, or any components of the drug product (see

WARNINGS; Anaphylactic Reactions, Serious Skin Reactions).

History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs.

Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients (see

WARNINGS; Anaphylactic Reactions, Exacerbation of Asthma Related to Aspirin Sensitivity).

In the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS; Cardiovascular

Thrombotic Events).

WARNINGS

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 naproxen, increases the risk of serious gastrointestinal (GI) events (see WARNINGS; Gastrointestinal

Bleeding, Ulceration, and Perforation).

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

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

recent MI, monitor patients for signs of cardiac ischemia.

Gastrointestinal Bleeding, Ulceration, and Perforation

NSAIDs, including naproxen cause serious gastrointestinal (GI) adverse events including inflammation,

bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine,

which can be fatal. These serious adverse events can occur at any time, with or without warning

symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI

adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation

caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2%

to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.

Risk Factors for GI Bleeding, Ulceration, and Perforation

Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater

than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors.

Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer

duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or

selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general

health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients.

Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI

bleeding.

Strategies to Minimize the GI Risks in NSAID-treated patients:

Use the lowest effective dosage for the shortest possible duration.

Avoid administration of more than one NSAID at a time.

Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of

bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies

other than NSAIDs.

Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.

If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue

naproxen tablets until a serious GI adverse event is ruled out.

In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more

closely for evidence of GI bleeding (see PRECAUTIONS; Drug Interactions).

Hepatotoxicity

Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in

approximately 1% of patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic

injury, including fulminant hepatitis, liver necrosis and hepatic failure have been reported.

Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients taking

NSAIDs including naproxen.

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy,

diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs

and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g.,

eosinophilia, rash, etc.), discontinue naproxen tablets immediately, and perform a clinical evaluation of

the patient.

Hypertens ion

NSAIDs, including naproxen tablets, can lead to new onset of hypertension or worsening of preexisting

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

angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired

response to these therapies when taking NSAIDs (see PRECAUTIONS; Drug Interactions).

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

therapy.

Heart Failure and Edema

The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials

demonstrated an approximately two-fold increase in hospitalization 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 naproxen 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

PRECAUTIONS; Drug Interactions).

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

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

failure, monitor patients for signs of worsening heart failure.

Renal Toxicity and Hyperkalemia

Renal Toxicity

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

Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in

the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a 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, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and

ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by

recovery to the pretreatment state

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

patients with advanced renal disease. The renal effects of naproxen tablets may hasten the progression

of renal dysfunction in patients with preexisting renal disease.

Correct volume status in dehydrated or hypovolemic patients prior to initiating naproxen tablets.

Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or

hypovolemia during use of naproxen tablets (see PRECAUTIONS; Drug Interactions). Avoid the use of

naproxen tablets in patients with advanced renal disease unless the benefits are expected to outweigh the

risk of worsening renal function. If naproxen tablets are used in patients with advanced renal disease,

monitor patients for signs of worsening renal function.

Hyperkalemia

Increases in serum potassium concentration, including hyperkalemia, have been reported with use of

NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these

effects have been attributed to a hyporeninemic hypoaldosteronism state.

Anaphylactic Reactions

Naproxen has been associated with anaphylactic reactions in patients with and without known

hypersensitivity to naproxen and in patients with aspirin-sensitive asthma (see CONTRAINDICATIONS,

WARNINGS; Exacerbation of Asthma Related to Aspirin Sensitivity).

Exacerbation of Asthma Related to Aspirin Sensitivity

A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic

rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to

aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been

reported in such aspirin-sensitive patients, naproxen tablets are contraindicated in patients with this form

of aspirin sensitivity (see CONTRAINDICATIONS). When naproxen tablets are used in patients with

preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and

symptoms of asthma.

Serious Skin Reactions

NSAIDs, including naproxen, can cause serious skin adverse reactions such as exfoliative dermatitis,

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

serious events may occur without warning. Inform patients about the signs and symptoms of serious skin

reactions and to discontinue the use of naproxen tablets at the first appearance of skin rash or any other

sign of hypersensitivity. Naproxen tablets are contraindicated in patients with previous serious skin

reactions to NSAIDs (see CONTRAINDICATIONS).

Premature Closure of Fetal Ductus Arteriosus

Naproxen may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including

naproxen tablets, in pregnant women starting at 30 weeks of gestation (third trimester) (see

PRECAUTIONS; Pregnancy).

Hematologic Toxicity

Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid

retention, or an incompletely described effect on erythropoiesis. If a patient treated with naproxen

tablets has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including naproxen tablets, may increase the risk of bleeding events. Co-morbid conditions

such as coagulation disorders, or concomitant use of warfarin and other anticoagulants, antiplatelet

agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake

inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding (see

PRECAUTIONS; Drug Interactions).

PRECAUTIONS

General

Naproxen-containing products such as naproxen tablets, and other naproxen products should not be used

concomitantly since they all circulate in the plasma as the naproxen anion.

Naproxen 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 and the patient should be observed closely for any evidence of adverse

effects, including adrenal insufficiency and exacerbation of symptoms of arthritis.

Patients with initial hemoglobin values of 10g or less who are to receive long-term therapy should have

hemoglobin values determined periodically.

Because of adverse eye findings in animal studies with drugs of this class, it is recommended that

ophthalmic studies be carried out if any change or disturbance in vision occurs.

Information for Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each

prescription dispensed. Inform patients, families, or their caregivers of the following information

before initiating therapy with naproxen tablets and periodically during the course of ongoing therapy.

Cardiovascular Thrombotic Events

Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain,

shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health

care provider immediately (see WARNINGS; Cardiovascular Thrombotic Events).

Gastrointestinal Bleeding, Ulceration, and Perforation

Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia,

melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose

aspirin for cardiac prophylaxis, inform patients of the increased risk for the signs and symptoms of GI

bleeding (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation).

Hepatotoxicity

Inform patients 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, instruct

patients to stop naproxen tablets and seek immediate medical therapy (see WARNINGS; Hepatotoxicity).

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; Heart Failure and Edema).

Anaphylactic Reactions

Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face

or throat). Instruct patients to seek immediate emergency help if these occur (see

CONTRAINDICATIONS, WARNINGS; Anaphylactic Reactions).

Serious Skin Reactions

Advise patients to stop naproxen tablets immediately if they develop any type of rash and to contact their

healthcare provider as soon as possible (see WARNINGS; Serious Skin Reactions).

Female Fertility

Advise females of reproductive potential who desire pregnancy that NSAIDs, including VOLTAREN,

may be associated with a reversible delay in ovulation (see PRECAUTIONS; Carcinogenesis,

Mutagenesis, Impairment of Fertility).

Fetal Toxicity

Inform pregnant women to avoid use of naproxen tablets and other NSAIDs starting at 30 weeks

gestation because of the risk of the premature closing of the fetal ductus arteriosus (see WARNINGS;

Premature Closure of Fetal Ductus Arteriosus).

Avoid Concomitant Use of NSAIDs

Inform patients that the concomitant use of naproxen tablets with other NSAIDs or salicylates (e.g.,

diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little

or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation,

PRECAUTIONS; Drug Interactions). Alert patients that NSAIDs may be present in “over-the-counter”

medications for treatment of colds, fever, or insomnia.

Use of NSAIDS and Low-Dose Aspirin

Inform patients not to use low-dose aspirin concomitantly with naproxen tablets until they talk to their

healthcare provider (see PRECAUTIONS; Drug Interactions).

Activities Requiring Alertness

Caution should be exercised by patients whose activities require alertness if they experience

drowsiness, dizziness, vertigo or depression during therapy with naproxen.

Masking of Inflammation and Fever

The pharmacological activity of naproxen tablets in reducing inflammation, and possibly fever, may

diminish the utility of diagnostic signs in detecting infections.

Laboratory Monitoring

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or

signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile

periodically (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation, and Hepatotoxicity).

Drug Interactions

See Table 1 for clinically significant drug interactions with naproxen.

Table 1: Clinically Significant Drug Interactions with Naproxen

Drugs That Interfere with Hemostasis

Clinical

Impact:

Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding.

The concomitant use of naproxen and anticoagulants has an increased risk of serious

bleeding compared to the use of either drug alone.

Serotonin release by platelets plays an important role in hemostasis. Case-control and

cohort epidemiological studies showed that concomitant use of drugs that interfere

with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an

NSAID alone.

Intervention:

Monitor patients with concomitant use of naproxen tablets with anticoagulants (e.g.,

warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs),

and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see

WARNINGS; Hematologic Toxicity).

As pirin

Clinical

Impact:

Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic

doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs

alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with

a significantly increased incidence of GI adverse reactions as compared to use of the

NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).

Intervention:

Concomitant use of naproxen tablets and analgesic doses of aspirin is not generally

recommended because of the increased risk of bleeding (see WARNINGS; Hematologic

Toxicity). Naproxen tablets are not a substitute for low dose aspirin for cardiovascular

protection.

ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers

Clinical

NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme

(ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including

propranolol).

Clinical

Impact:

In patients who are elderly, volume-depleted (including those on diuretic therapy), or

have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs

may result in deterioration of renal function, including possible acute renal failure.

These effects are usually reversible.

Intervention:

During concomitant use of naproxen tablets and ACE-inhibitors, ARBs, or beta-

blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.

During concomitant use of naproxen tablets and ACE-inhibitors or ARBs in patients

who are elderly, volume-depleted, or have impaired renal function, monitor for signs of

worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When

these drugs are administered concomitantly, patients should be adequately hydrated.

Assess renal function at the beginning of the concomitant treatment and periodically

thereafter.

Diuretics

Clinical

Impact:

Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the

natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some

patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin

synthesis.

Intervention

During concomitant use of naproxen tablets with diuretics, observe patients for signs of

worsening renal function, in addition to assuring diuretic efficacy including

antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).

Digoxin

Clinical

Impact:

The concomitant use of naproxen with digoxin has been reported to increase the serum

concentration and prolong the half-life of digoxin.

Intervention:During concomitant use of naproxen tablets and digoxin, monitor serum digoxin levels.

Lithium

Clinical

Impact:

NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium

clearance. The mean minimum lithium concentration increased 15%, and the renal clearance

decreased by approximately 20%. This effect has been attributed to NSAID inhibition of

renal prostaglandin synthesis.

Intervention:

During concomitant use of naproxen tablets and lithium, monitor patients for signs of

lithium toxicity.

Methotrexate

Clinical

Impact:

Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate

toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).

Intervention:

During concomitant use of naproxen tablets and methotrexate, monitor patients for

methotrexate toxicity.

Cyclos porine

Clinical

Impact:

Concomitant use of naproxen tablets and cyclosporine may increase cyclosporine’s

nephrotoxicity.

Intervention:

During concomitant use of naproxen tablets and cyclosporine, monitor patients for signs of

worsening renal function.

NSAIDs and Salicylates

Clinical

Impact:

Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate)

increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS;

Gastrointestinal Bleeding, Ulceration and Perforation).

Intervention:The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.

Pemetrexed

Clinical

Impact:

Concomitant use of naproxen tablets and pemetrexed may increase the risk of pemetrexed-

associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing

information).

Intervention:

During concomitant use of naproxen tablets and pemetrexed, in patients with renal

impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for

myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g.,

diclofenac, indomethacin) should be avoided for a period of two days before, the day of,

and two days following administration of pemetrexed. In the absence of data regarding

potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g.,

meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least

five days before, the day of, and two days following pemetrexed administration.

Antacids and Sucralfate

Clinical

Impact:

Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and

sucralfate can delay the absorption of naproxen.

Intervention:

Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide,

and sucralfate with naproxen tablets are not recommended. Due to the gastric pH elevating

effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration

of naproxen tablets are not recommended.

Choles tyramine

Clinical

Impact:

Concomitant administration of cholestyramine can delay the absorption of naproxen.

Intervention:Concomitant administration of cholestyramine with naproxen tablets are not recommended.

Probenecid

Clinical

Impact:

Probenecid given concurrently increases naproxen anion plasma levels and extends its

plasma half-life significantly.

Intervention:

Patients simultaneously receiving naproxen tablets and probenecid should be observed for

adjustment of dose if required.

Other albumin-bound drugs

Clinical

Impact:

Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for

interaction with other albumin-bound drugs such as coumarin-type anticoagulants,

sulphonylureas, hydantoins, other NSAIDs, and aspirin.

Intervention:

Patients simultaneously receiving naproxen tablets and a hydantoin, sulphonamide or

sulphonylurea should be observed for adjustment of dose if required.

Drug/Laboratory Test Interactions

Bleeding times

Clinical

Impact:

Naproxen may decrease platelet aggregation and prolong bleeding time.

Intervention:This effect should be kept in mind when bleeding times are determined.

Porter-Silber test

Clinical

Impact:

The administration of naproxen may result in increased urinary values for 17 ketogenic

steroids because of an interaction between the drug and/or its metabolites with m-di-

nitrobenzene used in this assay.

Intervention:

Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be

artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued

72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.

Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)

Clinical

Impact:

Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).

Intervention:This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

A 2-year study was performed in rats to evaluate the carcinogenic potential of naproxen at rat doses of

8, 16, and 24 mg/kg/day (0.05, 0.1, and 0.16 times the maximum recommended human daily dose

[MRHD] of 1500 mg/day based on a body surface area comparison). No evidence of tumorigenicity

was found.

Mutagenesis

Studies to evaluate the mutagenic potential of naproxen tablets have not been completed.

Impairment of fertility

Male rats were treated with 2, 5, 10, and 20 mg/kg naproxen by oral gavage for 60 days prior to mating

and female rats were treated with the same doses for 14 days prior to mating and for the first 7 days of

pregnancy. There were no adverse effects on fertility noted (up to 0.13 times the MRDH based on body

surface area).

Pregnancy

Risk Summary

Use of NSAIDs, including naproxen tablets, during the third trimester of pregnancy increases the risk of

premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including naproxen tablets, in

pregnant women starting at 30 weeks of gestation (third trimester) (see WARNINGS; Premature Closure

of Fetal Ductus Arteriosus).

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

Data from observational studies regarding potential embryofetal risks of NSAID use in women in the

first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically

recognized pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major

malformations, and 15% to 20% for pregnancy loss. In animal reproduction studies in rats, rabbit, and

mice no evidence of teratogenicity or fetal harm when naproxen was administered during the period of

organogenesis at doses 0.13, 0.26, and 0.6 times the maximum recommended human daily dose of 1500

mg/day, respectively. Based on animal data, prostaglandins have been shown to have an important role in

endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies,

administration of prostaglandin synthesis inhibitors such as naproxen, resulted in increased pre- and

post-implantation loss.

Data

Human Data

There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay

preterm labor there is an increased risk of neonatal complications such as necrotizing enterocolitis,

patent ductus arteriosus and intracranial hemorrhage. Naproxen treatment given in late pregnancy to

delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction and

abnormal prostaglandin E levels in preterm infants. Because of the known effects of nonsteroidal anti-

inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during

pregnancy (particularly starting at 30-weeks of gestation, or third trimester) should be avoided.

Animal Data

Reproduction studies have been performed in rats at 20 mg/kg/day (0.13 times the maximum

recommended human daily dose of 1500 mg/day based on body surface area comparison), rabbits at 20

mg/kg/day (0.26 times the maximum recommended human daily dose, based on body surface area

comparison), and mice at 170 mg/kg/day (0.6 times the maximum recommended human daily dose based

on body surface area comparison) with no evidence of impaired fertility or harm to the fetus due to the

drug. 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 naproxen, resulted in increased pre- and post-implantation

loss.

Labor and Delivery

There are no studies on the effects of naproxen tablets during labor or delivery. In animal studies,

NSAIDS, including naproxen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the

incidence of stillbirth.

Nursing Mothers

The naproxen anion has been found in the milk of lactating women at a concentration equivalent to

approximately 1% of maximum naproxen concentration in plasma. The developmental and health benefits

of breastfeeding should be considered along with the mother’s clinical need for naproxen tablets and

any potential adverse effects on the breastfed infant from the naproxen tablets or from the underlying

maternal condition.

Females and Males of Reproductive Potential

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including naproxen

tablets, may delay or prevent rupture of ovarian follicles, which has been associated with reversible

infertility in some women. Published animal studies have shown that administration of prostaglandin

synthesis inhibitors has the potential to disrupt prostaglandin- mediated follicular rupture required for

ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in

ovulation.

Consider withdrawal of NSAIDs, including naproxen tablets, in women who have difficulties

conceiving or who are undergoing investigation of infertility.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 2 years have not been established.

Pediatric dosing recommendations for juvenile arthritis are based on well-controlled studies (see

DOSAGE AND ADMINISTRATION). There are no adequate effectiveness or dose-response data for

other pediatric conditions, but the experience in juvenile arthritis and other use experience have

established that single doses of 2.5 to 5 mg/kg (as naproxen suspension, see DOSAGE AND

ADMINISTRATION), with total daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric

patients over 2 years of age. Safety and effectiveness in pediatric patients below the age of 2 years have

not been established.

Geriatric Use

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious

cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly

patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor

patients for adverse effects (see WARNINGS; Cardiovascular Thrombotic Events, Gastrointestinal

Bleeding, Ulceration, and Perforation, Hepatotoxicity, Renal Toxicity and Hyperkalemia, PRECAUTIONS;

Laboratory Monitoring).

Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma

fraction of naproxen is increased in the elderly. Caution is advised when high doses are required and

some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly,

it is prudent to use the lowest effective dose.

Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of

nonsteroidal anti-inflammatory drugs. Elderly or debilitated patients seem to tolerate peptic ulceration

or bleeding less well when these events do occur. Most spontaneous reports of fatal GI events are in

the geriatric population (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation).

Naproxen is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug

may be greater in patients with impaired renal function. Because elderly patients are more likely to have

decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal

function. Geriatric patients may be at a greater risk for the development of a form of renal toxicity

precipitated by reduced prostaglandin formation during administration of nonsteroidal anti-inflammatory

drugs (see WARNINGS; Renal Toxicity and Hyperkalemia).

ADVERSE REACTIONS

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

Cardiovascular Thrombotic Events (see WARNINGS)

GI Bleeding, Ulceration and Perforation (see WARNINGS)

Hepatotoxicity (see WARNINGS)

Hypertension (see WARNINGS)

Heart Failure and Edema (see WARNINGS)

Renal Toxicity and Hyperkalemia (see WARNINGS)

Anaphylactic Reactions (see WARNINGS)

Serious Skin Reactions (see WARNINGS)

Hematologic Toxicity (see WARNINGS)

Adverse reactions reported in controlled clinical trials in 960 patients treated for rheumatoid arthritis

or osteoarthritis are listed below. In general, reactions in patients treated chronically were reported 2 to

10 times more frequently than they were in short-term studies in the 962 patients treated for mild to

moderate pain or for dysmenorrhea. The most frequent complaints reported related to the

gastrointestinal tract.

A clinical study found gastrointestinal reactions to be more frequent and more severe in rheumatoid

arthritis patients taking daily doses of 1500 mg naproxen compared to those taking 750 mg naproxen (see

CLINICAL PHARMACOLOGY).

In controlled clinical trials with about 80 pediatric patients and in well-monitored, open-label studies

with about 400 pediatric patients with juvenile arthritis treated with naproxen, the incidence of rash and

prolonged bleeding times were increased, the incidence of gastrointestinal and central nervous system

reactions were about the same, and the incidence of other reactions were lower in pediatric patients than

in adults.

In patients taking naproxen in clinical trials, the most frequently reported adverse experiences in

approximately 1% to 10% of patients are:

Gastrointestinal (GI) Experiences, including: heartburn , abdominal pain , nausea , constipation ,

diarrhea, dyspepsia, stomatitis

Central Nervous System: headache , dizziness , drowsiness , lightheadedness, vertigo

Dermatologic: pruritus (itching) , skin eruptions*, ecchymoses , sweating, purpura

Special Senses: tinnitus , visual disturbances, hearing disturbances

Cardiovascular: edema , palpitations

General: dyspnea , thirst

Incidence of reported reaction between 3% and 9%. Those reactions occurring in less than 3% of the

patients are unmarked.

In patients taking NSAIDs, the following adverse experiences have also been reported in approximately

1% to 10% of patients.

Gastrointestinal (GI) Experiences, including: flatulence, gross bleeding/perforation, GI ulcers

(gastric/duodenal), vomiting

General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding time, rashes

The following are additional adverse experiences reported in <1% of patients taking naproxen during

clinical trials and through postmarketing reports. Those adverse reactions observed through

postmarketing reports are italicized.

Body as a Whole:anaphylactoid reactions, angioneurotic edema, menstrual disorders, pyrexia (chills and

fever)

Cardiovascular:congestive heart failure, vasculitis, hypertension, pulmonary edema

Gastrointestinal:inflammation, bleeding (sometimes fatal, particularly in the elderly), ulceration,

perforation and obstruction of the upper or lower gastrointestinal tract. Esophagitis, stomatitis, hematemesis,

pancreatitis, vomiting, colitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn’s

disease).

Hepatobiliary: jaundice, abnormal liver function tests, hepatitis (some cases have been fatal)

Hemic and Lymphatic:eosinophilia, leucopenia, melena, thrombocytopenia, agranulocytosis,

granulocytopenia, hemolytic anemia, aplastic anemia

Metabolic and Nutritional:hyperglycemia, hypoglycemia

Nervous System: inability to concentrate, depression, dream abnormalities, insomnia, malaise, myalgia,

muscle weakness, aseptic meningitis, cognitive dysfunction, convulsions

Respiratory:eosinophilic pneumonitis, asthma

Dermatologic:alopecia, urticaria, skin rashes, toxic epidermal necrolysis, erythema multiforme, erythema

nodosum, fixed drug eruption, lichen planus, pustular reaction, systemic lupus erythematoses, bullous

reactions, including Stevens-Johnson syndrome, photosensitive dermatitis, photosensitivity reactions,

including rare cases resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa. If skin

fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be

discontinued and the patient monitored.

Special Senses:hearing impairment, corneal opacity, papillitis, retrobulbar optic neuritis, papilledema

Urogenital:glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal

disease, renal failure, renal papillary necrosis, raised serum creatinine

Reproduction (female):infertility

In patients taking NSAIDs, the following adverse experiences have also been reported in <1% of

patients.

Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death

Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, myocardial infarction

Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, glossitis, eructation

Hepatobiliary: hepatitis, liver failure

Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia

Metabolic and Nutritional: weight changes

Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, tremors,

convulsions, coma, hallucinations

Respiratory: asthma, respiratory depression, pneumonia

Dermatologic: exfoliative dermatitis

Special Senses: blurred vision, conjunctivitis

Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria

OVERDOSAGE

Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness,

nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care.

Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and

coma have occurred, but were rare. Because naproxen sodium may be rapidly absorbed, high and early

blood levels should be anticipated. A few patients have experienced convulsions, but it is not clear

whether or not these were drug-related. It is not known what dose of the drug would be life threatening

(see WARNINGS; Cardiovascular Thrombotic Events, Gastrointestinal Bleeding, Ulceration, and

Perforation, Hypertension, Renal Toxicity and Hyperkalemia).

Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no

specific antidotes. Hemodialysis does not decrease the plasma concentration of naproxen because of

the high degree of its protein binding. Consider emesis and/or activated charcoal (60 to 100 g in adults,

1 to 2 g/kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen

within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended

dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due

to high protein binding.

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

1222).

DOSAGE AND ADMINISTRATION

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

deciding to use naproxen tablets. Use the lowest effective dose for the shortest duration consistent with

individual patient treatment goals (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and

Perforation).

After observing the response to initial therapy with naproxen tabltes, the dose and frequency should be

adjusted to suit an individual patient’s needs.

Different dose strengths and formulations (i.e., tablets, suspension) of the drug are not

necessarily bioequivalent. This difference should be taken into consideration when changing

formulation.

Although naproxen tablets, naproxen suspension, naproxen delayed-release tablets, and naproxen sodium

tablets all circulate in the plasma as naproxen, they have pharmacokinetic differences that may affect

onset of action. Onset of pain relief can begin within 1 hour in patients taking naproxen.

The recommended strategy for initiating therapy is to choose a formulation and a starting dose likely to

be effective for the patient and then adjust the dosage based on observation of benefit and/or adverse

events. A lower dose should be considered in patients with renal or hepatic impairment or in elderly

patients (see WARNINGS; Hepatotoxicity, and Renal Toxicity and Hyperkalemia, and PRECAUTIONS;

Geriatric Use).

Geriatric Patients

Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma

fraction of naproxen is increased in the elderly. Caution is advised when high doses are required and

some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly,

it is prudent to use the lowest effective dose.

Patients With Moderate to Severe Renal Impairment

Naproxen-containing products are not recommended for use in patients with moderate to severe and

severe renal impairment (creatinine clearance <30 mL/min) (see WARNINGS; Renal Effects).

Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis

Naproxen Tablets

250 mg

or 375 mg

or 500 mg

twice daily

twice daily

twice daily

During long-term administration, the dose of naproxen may be adjusted up or down depending on the

clinical response of the patient. A lower daily dose may suffice for long-term administration. The

morning and evening doses do not have to be equal in size and the administration of the drug more

frequently than twice daily is not necessary.

In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg/day for

limited periods of up to 6 months when a higher level of antiinflammatory/analgesic activity is required.

When treating such patients with naproxen 1500 mg/day, the physician should observe sufficient

increased clinical benefits to offset the potential increased risk. The morning and evening doses do not

have to be equal in size and administration of the drug more frequently than twice daily does not

generally make a difference in response (see CLINICAL PHARMACOLOGY).

Acute Gout

The recommended starting dose is 750 mg of naproxen tablets followed by 250 mg every 8 hours until

the attack has subsided.

HOW SUPPLIED

Product: 63629-8107

NDC: 63629-8107-1 20 TABLET in a BOTTLE

NDC: 63629-8107-2 30 TABLET in a BOTTLE

NDC: 63629-8107-3 60 TABLET in a BOTTLE

Medication Guide for Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

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:

with increasing doses of NSAIDs

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:

anytime during use

without warning symptoms

that may cause death

The risk of getting an ulcer or bleeding increases with:

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

taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs”

increasing doses of NSAIDs

longer use of NSAIDs

smoking

drinking alcohol

older age

poor health

advanced liver disease

bleeding problems

NSAIDs should only be used:

exactly as prescribed

at the lowest dose possible for your treatment

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 NSAIDs, tell your health care 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. Talk to your health care provider if you are considering

taking NSAIDs during pregnancy. You should not take NSAIDs after 29 weeks of pregnancy.

are breastfeeding or plan to breast feed.

Tell your health care 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 new medicine without

talking to your health care 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 health care 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, legs, hands, and feet

If you take too much of your NSAID, call your health care provider or get medical help right

away.

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

provider or pharmacist about NSAIDs.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-

FDA-1088.

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

health care 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 health care provider. You can ask

your pharmacist or health care provider for information about NSAIDs that is written for health

professionals.

Manufactured by:

Amneal Pharmaceuticals Pvt. Ltd.

Ahmedabad, INDIA 382220

Distributed by:

Amneal Pharmaceuticals

Bridgewater, NJ 08807

Rev. 06-2016-01

For more information, go to www.amneal.com or call 1-877-835-5472.

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

NAPROXEN 500MG TABLET

NAPROXEN

naproxen tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 36 29 -8 10 7(NDC:6 516 2-19 0 )

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

NAPRO XEN (UNII: 57Y76 R9 ATQ) (NAPROXEN - UNII:57Y76 R9 ATQ)

NAPROXEN

50 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

PO VIDO NE, UNSPECIFIED (UNII: FZ9 8 9 GH9 4E)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

Product Characteristics

Color

WHITE

S core

no sco re

S hap e

CAPSULE

S iz e

16 mm

Flavor

Imprint Code

IP19 0 ;50 0

Bryant Ranch Prepack

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 36 29 -8 10 7-1

20 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/25/20 19

2

NDC:6 36 29 -8 10 7-2

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/25/20 19

3

NDC:6 36 29 -8 10 7-3

6 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/25/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 759 27

0 2/18 /20 10

Labeler -

Bryant Ranch Prepack (171714327)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Bryant Ranch Prepack

171714327

REPACK(6 36 29 -8 10 7) , RELABEL(6 36 29 -8 10 7)

Revised: 8/2019

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