Expediente 2484-D-09 H. Cámara de Diputados de la Nación PROYECTO DE LEY Texto facilitado por los firmantes del proyecto. Debe tenerse en cuenta que solamente podrá ser tenido por auténtico el texto publicado en el respectivo Trámite Parlamentario, editado por la Imprenta del Congreso de la Nación. El Senado y Cámara de Diputados,. Publicidad Electoral y de Actos
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Pe7734038-1 naproxen sodium 275-550mg.pmdPE7734038-1 Naproxen Sodium Tablets 275-550mg Cut Size : 270 x 420 mm 6 pt helv condensed Pharma code: 640 Date: 11.03.2008 (Front)
Naproxen Sodium Tablets USP
• For the relief of the signs and symptoms of rheumatoid arthritis Medication Guide
• For the relief of the signs and symptoms of osteoarthritis • For the relief of the signs and symptoms of ankylosing spondylitis Non-Steroidal Anti-Inflammatory
• For the relief of the signs and symptoms of juvenile arthritis Cardiovascular Risk
• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and Naproxen suspension is recommended for juvenile rheumatoid arthritis in order to obtain the maximum dosage flexibility stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or (See the end of this Medication Guide for a list of risk factors for cardiovascular disease may be at greater risk (see WARNINGS).
Naproxen as naproxen sodium tablets are also indicated: • Naproxen as naproxen sodium tablets is contraindicated for the treatment of peri-operative pain in the setting • For relief of the signs and symptoms of tendonitis of coronary artery bypass graft (CABG) surgery (see WARNINGS).
• For relief of the signs and symptoms of bursitis What is the most important information I should
• For relief of the signs and symptoms of acute gout know about medicines called Non-Steroidal Anti-
• NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and Inflammatory Drugs (NSAIDs)?
perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and • For the management of primary dysmenorrhea NSAID medicines may increase the
without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see
chance of a heart attack or stroke that
can lead to death. This chance increases:
Naproxen sodium is contraindicated in patients with known hypersensitivity to naproxen.
Naproxen is a propionic acid derivative related to the arylacetic acid group of nonsteroidal anti-inflammatory drugs.
Naproxen sodium should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions aftertaking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such The chemical name for naproxen sodium is (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid sodium salt. Naproxen patients (see WARNINGS: Anaphylactoid Reactions and PRECAUTIONS: Preexisting Asthma).
NSAID medicines should never be used
Naproxen sodium is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft right before or after a heart surgery
(CABG) surgery (see WARNINGS).
called a “coronary artery bypass graft
NSAID medicines can cause ulcers and
Cardiovascular Thrombotic Events
bleeding in the stomach and intestines
Naproxen sodium has a molecular weight of 252.23 and a molecular formula of C H NaO .
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased at any time during treatment. Ulcers and
Naproxen sodium is a white to creamy white, crystalline solid, freely soluble in water at neutral pH.
risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDS,both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV bleeding:
Naproxen sodium tablets are available as blue tablets containing 275 mg of naproxen sodium and as blue tablets disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the containing 550 mg of naproxen sodium for oral administration. The inactive ingredients are croscarmellose sodium, lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the colloidal silicon dioxide, povidone, magnesium stearate, microcrystalline cellulose and talc. The coating suspension development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs for the naproxen sodium 275 mg tablet may contain Opadry blue 03F50544. The coating suspension for the naproxen and/or symptoms of serious CV events and the steps to take if they occur.
The chance of a person getting an ulcer
sodium 550 mg tablet may contain Opadry blue 03F50544.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events or bleeding increases with:
associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see Pharmacodynamics
Gastrointestinal Effects – Risk of Ulceration, Bleeding and Perforation).
“corticosteroids” and “anticoagulants” Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. The sodium Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following salt of naproxen has been developed as a more rapidly absorbed formulation of naproxen for use as an analgesic.
CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).
The mechanism of action of the naproxen anion, like that of other NSAIDs, is not completely understood but may be Hypertension
related to prostaglandin synthetase inhibition.
NSAIDs, including naproxen sodium, can lead to onset of new hypertension or worsening of pre-existing hypertension, Pharmacokinetics
either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have Naproxen is rapidly and completely absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%.
impaired response to these therapies when taking NSAIDs. NSAIDs, including naproxen sodium, should be used with The different dosage forms of naproxen are bioequivalent in terms of extent of absorption (AUC) and peak concentration caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID NSAID medicines should only be used:
); however, the products do differ in their pattern of absorption. These differences between naproxen products treatment and throughout the course of therapy.
are related to both the chemical form of naproxen used and its formulation. Even with the observed differences in Congestive Heart Failure and Edema
pattern of absorption, the elimination half-life of naproxen is unchanged across products ranging from 12 to Fluid retention, edema, and peripheral edema have been observed in some patients taking NSAIDs. Naproxen sodium 17 hours. Steady-state levels of naproxen are reached in 4 to 5 days, and the degree of naproxen accumulation is should be used with caution in patients with fluid retention, hypertension, or heart failure. Since each naproxen sodium consistent with this half-life. This suggests that the differences in pattern of release play only a negligible role in the tablet contains 25 mg or 50 mg of sodium (about 1 mEq per each 250 mg of naproxen), this should be considered in attainment of steady-state plasma levels.
patients whose overall intake of sodium salt must be severely restricted.
What are Non-Steroidal Anti-Inflammatory Drugs
Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation
NSAIDs, including naproxen sodium, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, After administration of naproxen sodium, peak plasma levels are attained in 1 to 2 hours. The difference in rates NSAID medicines are used to treat pain and redness, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal.
between the two products is due to the increased aqueous solubility of the sodium salt of naproxen used in naproxen swelling, and heat (inflammation) from medical These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs.
Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin- in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood • menstrual cramps and other types of short- bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough C 36.5, without risk. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed.
49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The naproxen anion has Only 1 in 5 patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic.
Who should not take a Non-Steroidal Anti-
been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen Inflammatory Drug (NSAID)?
concentration in plasma (see PRECAUTIONS: Nursing Mothers).
NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding.
Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than Do not take an NSAID medicine:
10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that • if you had an asthma attack, hives, or other allergic Naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen, and both parent and metabolites do not increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or reaction with aspirin or any other NSAID medicine induce metabolizing enzymes. Both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most • for pain right before or after heart bypass surgery acylglucuronide conjugated metabolites.
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 Tell your healthcare provider:
The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and • about all your medical conditions.
urine, primarily as naproxen (<1%), 6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). The plasma symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if • about all of the medicines you take. NSAIDs and half-life of the naproxen anion in humans ranges from 12 to 17 hours. The corresponding half-lives of both naproxen’s a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event some other medicines can interact with each other metabolites and conjugates are shorter than 12 hours, and their rates of excretion have been found to coincide is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
and cause serious side effects. Keep a list of your
closely with the rate of naproxen disappearance from the plasma. In patients with renal failure metabolites may Renal Effects
medicines to show to your healthcare provider
accumulate (see WARNINGS: Renal Effects).
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also and pharmacist.
been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In • if you are pregnant. NSAID medicines should not
these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen levels following a 5 mg/kg single dose of prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients be used by pregnant women late in their
naproxen suspension (see DOSAGE AND ADMINISTRATION) were found to be similar to those found in normal
at greatest risk of this reaction are those with impaired renal function, hypovolemia, heart failure, liver dysfunction, salt pregnancy.
adults following a 500 mg dose. The terminal half-life appears to be similar in pediatric and adult patients.
depletion, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of nonsteroidal anti-inflammatory • if you are breastfeeding. Talk to your doctor.
Pharmacokinetic studies of naproxen were not performed in pediatric patients younger than 5 years of age.
drug therapy is usually followed by recovery to the pretreatment state (see WARNINGS: Advanced Renal Disease).
Pharmacokinetic parameters appear to be similar following administration of naproxen suspension or tablets in What are the possible side effects of Non-
Advanced Renal Disease
Steroidal Anti-Inflammatory Drugs (NSAIDs)?
No information is available from controlled clinical studies regarding the use of naproxen sodium in patients with advanced renal disease. Therefore, treatment with naproxen sodium is not recommended in these patients with advanced renal Serious side effects
Other side effects
Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of disease. If naproxen sodium therapy must be initiated, close monitoring of the patient’s renal function is advisable.
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 As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to naproxen sodium.
total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. The clinical significance of this Naproxen sodium should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after increase in the rate of adverse events per a given dosage in some elderly patients.
taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS: Preexisting Asthma). Emergency help
should be sought in cases where an anaphylactoid reaction occurs.
Pharmacokinetic differences due to race have not been studied.
NSAIDs, including naproxen sodium, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Naproxen pharmacokinetics has not been determined in subjects with hepatic insufficiency.
Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur withoutwarning. 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.
Naproxen pharmacokinetics has not been determined in subjects with renal insufficiency. Given that naproxen, itsmetabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to Pregnancy
accumulate in the presence of renal insufficiency. Elimination of naproxen is decreased in patients with severe renal In late pregnancy, as with other NSAIDs, naproxen sodium should be avoided because it may cause premature closure of 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).
Naproxen-containing products such as naproxen sodium tablets and other naproxen products should not be used
Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis, juvenile arthritis, ankylosing spondylitis, concomitantly since they all circulate in the plasma as the naproxen anion.
tendonitis and bursitis, and acute gout. Improvement in patients treated for rheumatoid arthritis was demonstrated Naproxen sodium cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt by a reduction in joint swelling, a reduction in duration of morning stiffness, a reduction in disease activity as discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should assessed by both the investigator and patient, and by increased mobility as demonstrated by a reduction in walking have their therapy tapered slowly if a decision is made to discontinue corticosteroids and the patient should be observed time. Generally, response to naproxen has not been found to be dependent on age, sex, severity or duration of closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis.
Patients with initial hemoglobin values of 10 g or less who are to receive long-term therapy should have hemoglobin values In patients with osteoarthritis, the therapeutic action of naproxen has been shown by a reduction in joint pain or Get emergency help right away if you have any of
tenderness, an increase in range of motion in knee joints, increased mobility as demonstrated by a reduction in The pharmacological activity of naproxen sodium in reducing fever and inflammation may diminish the utility of these the following symptoms:
walking time, and improvement in capacity to perform activities of daily living impaired by the disease.
diagnostic signs in detecting complications of presumed noninfectious, noninflammatory painful conditions.
• shortness of breath or trouble breathing In a clinical trial comparing standard formulations of naproxen 375 mg bid (750 mg a day) vs 750 mg bid Because of adverse eye findings in animal studies with drugs of this class, it is recommended that ophthalmic studies be (1500 mg/day), 9 patients in the 750 mg group terminated prematurely because of adverse events. Nineteen patients carried out if any change or disturbance in vision occurs.
in the 1500 mg group terminated prematurely because of adverse events. Most of these adverse events were • weakness in one part or side of your body Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including naproxen In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and juvenile arthritis, naproxen has been sodium. Hepatic abnormalities may be the result of hypersensitivity rather than direct toxicity. These laboratory abnormalities shown to be comparable to aspirin and indomethacin in controlling the aforementioned measures of disease activity, may progress, may remain essentially unchanged, or may be transient with continued therapy. The SGPT (ALT) test is but the frequency and severity of the milder gastrointestinal adverse effects (nausea, dyspepsia, heartburn) and probably the most sensitive indicator of liver dysfunction. Notable elevations of ALT or AST (approximately three or more Stop your NSAID medicine and call your
nervous system adverse effects (tinnitus, dizziness, lightheadedness) were less in naproxen-treated patients than in times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In healthcare provider right away if you have any of
those treated with aspirin or indomethacin.
addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic the following symptoms:
In patients with ankylosing spondylitis, naproxen has been shown to decrease night pain, morning stiffness and pain failure, some of them with fatal outcomes have been reported.
at rest. In double-blind studies the drug was shown to be as effective as aspirin, but with fewer side effects.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, In patients with acute gout, a favorable response to naproxen was shown by significant clearing of inflammatory should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with naproxen 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 If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (eg, eosinophilia, episiotomy and uterine contraction pain and dysmenorrhea. Onset of pain relief can begin within 30 minutes in rash, etc.), naproxen sodium should be discontinued.
patients taking naproxen sodium. Analgesic effect was shown by such measures as reduction of pain intensity Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma proteins (albumin) reduce scores, increase in pain relief scores, decrease in numbers of patients requiring additional analgesic medication, and the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. Caution is delay in time to remedication. The analgesic effect has been found to last for up to 12 hours.
advised when high doses are required and some adjustment of dosage may be required in these patients. It is prudent to Naproxen may be used safely in combination with gold salts and/or corticosteroids; however, in controlled clinical • there is blood in your bowel movement or it is trials, when added to the regimen of patients receiving corticosteroids, it did not appear to cause greater improvement Hematological Effects
over that seen with corticosteroids alone. Whether naproxen has a “steroid-sparing” effect has not been adequately Anemia is sometimes seen in patients receiving NSAIDs, including naproxen sodium. This may be due to fluid retention, studied. When added to the regimen of patients receiving gold salts, naproxen did result in greater improvement. Its occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment use in combination with salicylates is not recommended because there is evidence that aspirin increases the rate of with NSAIDs, including naproxen sodium, should have their hemoglobin or hematocrit checked if they exhibit any signs or excretion of naproxen and data are inadequate to demonstrate that naproxen and aspirin produce greater improvement • swelling of the arms and legs, hands and feet over that achieved with aspirin alone. In addition, as with other NSAIDs, the combination may result in higher NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their frequency of adverse events than demonstrated for either product alone.
effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving naproxen sodium These are not all the side effects with NSAID In 51Cr blood loss and gastroscopy studies with normal volunteers, daily administration of 1100 mg of naproxen who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients medicines. Talk to your healthcare provider or sodium has been demonstrated to cause statistically significantly less gastric bleeding and erosion than 3250 mg of receiving anticoagulants, should be carefully monitored.
pharmacist for more information about NSAID Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has The hepatic and renal tolerability of long-term naproxen administration was studied in two double-blind clinical trials Other information about Non-Steroidal Anti-
been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between involving 586 patients. Of the patients studied, 98 patients were age 65 and older and 10 of the 98 patients were age Inflammatory Drugs (NSAIDs)
aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, naproxen 75 and older. Naproxen was administered at doses of 375 mg twice daily or 750 mg twice daily for up to 6 months.
sodium should not be administered to patients with this form of aspirin sensitivity and should be used with caution in • Aspirin is an NSAID medicine but it does not Transient abnormalities of laboratory tests assessing hepatic and renal function were noted in some patients, although increase the chance of a heart attack. Aspirin can there were no differences noted in the occurrence of abnormal values among different age groups.
Information for Patients
cause bleeding in the brain, stomach, and INDICATIONS AND USAGE
Patients should be informed of the following information before initiating therapy with an NSAID and periodically
intestines. Aspirin can also cause ulcers in the Carefully consider the potential benefits and risks of naproxen sodium tablets and other treatment options before during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that
deciding to use naproxen sodium tablets. Use the lowest effective dose for the shortest duration consistent with accompanies each prescription dispensed.
individual patient treatment goals (see WARNINGS).
1. Naproxen sodium, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be PE7734038-1 Naproxen Sodium Tablets 275-550mg Cut Size : 270 x 420 mm 6 pt helv condensed Pharma code: 640 Date: 11.03.2008 (Back)
• Some of these NSAID medicines are sold in lower alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this doses without a prescription (over-the-counter).
Central Nervous System: headache*, dizziness*, drowsiness*, lightheadedness, vertigo
follow-up (see WARNINGS: Cardiovascular Effects).
Talk to your healthcare provider before using over- Dermatologic: pruritus (itching)*, skin eruptions*, ecchymoses*, sweating, purpura
2. Naproxen sodium, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and Special Senses: tinnitus*, visual disturbances, hearing disturbances
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, Cardiovascular: edema*, palpitations
and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, General: dyspnea*, thirst
NSAID medicines that need a prescription
melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see *Incidence of reported reaction between 3% and 9%. Those reactions occurring in less than 3% of the patients are Generic Name
WARNINGS: Gastrointestinal Effects- Risk of Ulceration, Bleeding, and Perforation).
3. Naproxen sodium like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, In patients taking NSAIDs, the following adverse experiences have also been reported in approximately 1% to 10% of which may result in hospitalizations 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 Gastrointestinal (GI) Experiences, including: flatulence, gross bleeding/perforation, GI ulcers (gastric/duodenal), vomiting
such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding time, rashes
be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as The following are additional adverse experiences reported in <1% of patients taking naproxen during clinical trials andthrough postmarketing reports. Those adverse reactions observed through postmarketing reports are italicized.
4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual disorders, pyrexia (chills and fever)
5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (eg, nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, patients should be instructed Cardiovascular: congestive heart failure, vasculitis, hypertension, pulmonary edema
to stop therapy and seek immediate medical therapy.
Gastrointestinal: gastrointestinal bleeding and/or perforation, hematemesis, pancreatitis, vomiting, colitis, nonpeptic
6. Patients should be informed of the signs of an anaphylactoid reaction (eg, difficulty breathing, swelling of the face or gastrointestinal ulceration, ulcerative stomatitis, esophagitis, peptic ulceration throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).
Hepatobiliary: jaundice, abnormal liver function tests, hepatitis (some cases have been fatal)
7. In late pregnancy, as with other NSAIDs, naproxen sodium should be avoided because it may cause premature closure Hemic and Lymphatic: eosinophilia, leucopenia, melena, thrombocytopenia, agranulocytosis, granulocytopenia, hemolytic
8. Caution should be exercised by patients whose activities require alertness if they experience drowsiness, dizziness, Metabolic and Nutritional: hyperglycemia, hypoglycemia
vertigo or depression during therapy with naproxen.
Nervous System: inability to concentrate, depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness,
aseptic meningitis, cognitive dysfunction, convulsions Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for Respiratory: eosinophilic pneumonitis, asthma
signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis, erythema multiforme, erythema nodosum, fixed
profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic drug eruption, lichen planus, pustular reaction, systemic lupus erythematoses, Stevens-Johnson syndrome, photosensitive manifestations occur (eg, eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, naproxen sodium should be 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 Drug Interactions
should be discontinued and the patient monitored.
Special Senses: hearing impairment, corneal opacity, papillitis, retrobulbar optic neuritis, papilledema
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal
consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.
failure, renal papillary necrosis, raised serum creatinine Antacids and Sucralfate
Reproduction (female): infertility
Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the 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
When naproxen sodium tablets are administered with aspirin, its protein binding is reduced, although the clearance of free Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, glossitis, eructation
naproxen is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant Hepatobiliary: hepatitis, liver failure
administration of naproxen sodium and aspirin is not generally recommended because of the potential of increased adverse Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia
Metabolic and Nutritional: weight changes
As with other NSAIDs, concomitant administration of cholestyramine can delay the absorption of naproxen.
Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, tremors, convulsions, coma,
Respiratory: asthma, respiratory depression, pneumonia
Clinical studies, as well as postmarketing observations, have shown that naproxen sodium tablets can reduce the natriuretic This Medication Guide has been approved by the effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin Dermatologic: exfoliative dermatitis
synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see Special Senses: blurred vision, conjunctivitis
WARNINGS: Renal Effects), as well as to assure diuretic efficacy.
Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria
NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum Significant naproxen overdosage may be characterized by lethargy, dizziness, drowsiness, epigastric pain, abdominal lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have Glenmark Generics Ltd.
discomfort, heartburn, indigestion, nausea, transient alterations in liver function, hypoprothrombinemia, renal dysfunction, been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered metabolic acidosis, apnea, disorientation or vomiting. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, concurrently, subjects should be observed carefully for signs of lithium toxicity.
respiratory depression, and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic Methotrexate
ingestion of NSAIDs, and may occur following an overdose. Because naproxen sodium may be rapidly absorbed, high and NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. Naproxen sodium early blood levels should be anticipated. A few patients have experienced convulsions, but it is not clear whether or not and other nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular secretion of methotrexate in an these were drug-related. It is not known what dose of the drug would be life threatening. The oral LD of the drug is animal model. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when 543 mg/kg in rats, 1234 mg/kg in mice, 4110 mg/kg in hamsters, and greater than 1000 mg/kg in dogs.
NSAIDs are administered concomitantly with methotrexate.
Patients should be managed by symptomatic and supportive care following a NSAID overdose. There are no specific Warfarin
antidotes. Hemodialysis does not decrease the plasma concentration of naproxen because of the high degree of its protein Glenmark Generics Inc., USA
The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of binding. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be serious GI bleeding higher than users of either drug alone. No significant interactions have been observed in clinical indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose. Forced diuresis, studies with naproxen and coumarin-type anticoagulants. However, caution is advised since interactions have been seen alkalinization of urine or hemoperfusion may not be useful due to high protein binding.
with other nonsteroidal agents of this class. The free fraction of warfarin may increase substantially in some subjects and naproxen interferes with platelet function.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of naproxen sodium tablets and other treatment options before deciding
Other Information Concerning Drug Interactions
to use naproxen sodium tablets. Use the lowest effective dose for the shortest duration consistent with individual patient Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound treatment goals (see WARNINGS).
drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin. Patients simultaneously After observing the response to initial therapy with naproxen sodium tablets, the dose and frequency should be adjusted to receiving naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.
suit an individual patient’s needs.
Naproxen and other nonsteroidal anti-inflammatory drugs can reduce the antihypertensive effect of propranolol and otherbeta-blockers.
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.
Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Although naproxen tablets, naproxen suspension, naproxen delayed-release tablets, and naproxen sodium tablets all circulate Drug/Laboratory Test Interaction
in the plasma as naproxen, they have pharmacokinetic differences that may affect onset of action. Onset of pain relief can Naproxen may decrease platelet aggregation and prolong bleeding time. This effect should be kept in mind when bleeding begin within 30 minutes in patients taking naproxen sodium and within 1 hour in patients taking naproxen. Because naproxen delayed-release tablets dissolve in the small intestine rather than in the stomach, the absorption of the drug is The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction delayed compared to the other naproxen formulations (see CLINICAL PHARMACOLOGY).
between the drug and/or its metabolites with m-di-nitrobenzene used in this assay. Although 17-hydroxy-corticosteroid The recommended strategy for initiating therapy is to choose a formulation and a starting dose likely to be effective for the measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be patient and then adjust the dosage based on observation of benefit and/or adverse events. A lower dose should be considered temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
in patients with renal or hepatic impairment or in elderly patients (see WARNINGS and PRECAUTIONS).
Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of A 2-year study was performed in rats to evaluate the carcinogenic potential of naproxen at rat doses of 8, 16, and naproxen is increased in the elderly. Caution is advised when high doses are required and some adjustment of dosage may 24 mg/kg/day (50, 100, and 150 mg/m2). The maximum dose used was 0.28 times the systemic exposure to humans at the be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose.
recommended dose. No evidence of tumorigenicity was found.
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
Reproduction studies have been performed in rats at 20 mg/kg/day (125 mg/m2/day, 0.23 times the human systemicexposure), rabbits at 20 mg/kg/day (220 mg/m2/day, 0.27 times the human systemic exposure), and mice at 275 mg (naproxen 250 mg with 25 mg sodium) twice daily 170 mg/kg/day (510 mg/m2/day, 0.28 times the human systemic exposure) with no evidence of impaired fertility or harm 550 mg (naproxen 500 mg with 50 mg sodium) twice daily to the fetus due to the drug. However, animal reproduction studies are not always predictive of human response. There areno adequate and well-controlled studies in pregnant women. Naproxen sodium should be used in pregnancy only if the During long-term administration, the dose of naproxen may be adjusted up or down depending on the clinical response of potential benefit justifies the potential risk to the fetus.
the patient. A lower daily dose may suffice for long-term administration. The morning and evening doses do not have to beequal in size and the administration of the drug more frequently than twice daily is not necessary.
Nonteratogenic EffectsThere is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor there is In patients who tolerate lower doses well, the dose may be increased to naproxen sodium 1650 mg/day for limited periods an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus and intracranial of up to 6 months when a higher level of anti-inflammatory/ analgesic activity is required. When treating such patients with hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary naproxen sodium 1650 mg/day, the physician should observe sufficient increased clinical benefits to offset the potential hypertension, renal dysfunction and abnormal prostaglandin E levels in preterm infants. Because of the known effects of increased risk. The morning and evening doses do not have to be equal in size and administration of the drug more nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy frequently than twice daily does not generally make a difference in response (see CLINICAL PHARMACOLOGY).
(particularly late pregnancy) should be avoided.
For the relief of juvenile arthritis, the recommended dose is approximately 10 mg/kg given orally in 2 divided doses
Labor and Delivery
(i.e., 5 mg/kg given twice a day). Naproxen sodium tablets are not well suited to this dosage so use of naproxen oral In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of suspension is recommended for this indication.
dystocia, delayed parturition, and decreased pup survival occurred. Naproxen-containing products are not recommendedin labor and delivery because, through its prostaglandin synthesis inhibitory effect, naproxen may adversely affect fetal Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis
circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage. The effects of naproxen sodium The recommended starting dose is 550 mg of naproxen sodium followed by 550 mg every 12 hours or 275 mg every 6 to on labor and delivery in pregnant women are unknown.
8 hours as required. The initial total daily dose should not exceed 1375 mg of naproxen sodium. Thereafter, the total dailydose should not exceed 1100 mg of naproxen sodium. Because the sodium salt of naproxen is more rapidly absorbed, Nursing Mothers
naproxen sodium tablets are recommended for the management of acute painful conditions when prompt onset of pain 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. Because of the possible adverse effects of prostaglandin-inhibiting drugs on Acute Gout
neonates, use in nursing mothers should be avoided.
The recommended starting dose is 825 mg of naproxen sodium tablets followed by 275 mg every 8 hours until the attack 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 Naproxen sodium tablets: Naproxen sodium 275 mg: blue, oval, film-coated tablets with ‘G 0’ engraved on one side and 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
Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction ofnaproxen is increased in the elderly. Caution is advised when high doses are required and some adjustment of dosage may Store at 15° to 30°C (59° to 86°F) in well-closed containers.
be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose.
Naproxen sodium tablets: Naproxen sodium 550 mg: blue colored, modified capsule shaped, biconvex, film-coated tablets Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of nonsteroidal with ‘G breakline 0’ engraved on one side and breakline on the other side.
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).
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 Store at 15° to 30°C (59° to 86°F) in well-closed containers.
for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration ofnonsteroidal anti-inflammatory drugs (see WARNINGS: Renal Effects).
Glenmark Generics Ltd.
Colvale-Bardez, Goa 403 513, India
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).
Glenmark Generics Inc., USA
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 wereincreased, 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,
Embargoed until 6:00 pm Eastern – October 3, 2012 NEWS RELEASE Violet Tsagkas; cell: 917/362‐2262 Suzanne Turner; cell: 202/744‐9161 [email protected] Office line: 202.466.9633 Hormone Therapy Has Many Favorable Effects in Newly Menopausal Women: Initial Findings of the Kronos Early Estrogen Prevention Study (KEEPS) PHOENIX, (October 3, 2012) –