Naprelan - Product Information
|Manufacture:||Sunovion Pharmaceuticals Inc.|
|Condition:||Osteoarthritis, Rheumatoid Arthritis|
|Class:||Nonsteroidal anti-inflammatory agents|
|Ingredients:||naproxen sodium, ammonio methacrylate copolymer Type A, ammonio methacrylate copolymer Type B, citric acid, crospovidone, magnesium stearate, methacrylic acid copolymer Type A, microcrystalline cellulose, povidone, and talc.|
Summary Product Information
|Dosage Form /
|Clinically Relevant Nonmedicinal
tablet/ 375 mg,
For a complete listing see Dosage Forms,
Composition and Packaging section.
Indications and Clinical Use
NAPRELAN (naproxen sodium) is indicated for the following:
- management of the signs and symptoms of rheumatoid arthritis and osteoarthritis.
Throughout this document, the term NSAIDs refers to both non-selective NSAIDs and selectiveCOX-2 inhibitor NSAIDs, unless otherwise indicated.
For patients with an increased risk of developing CV and/or GI adverse events, other management strategies that do NOT include the use of NSAIDs should be considered first. (See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS)
Use of NAPRELAN should be limited to the lowest effective dose for the shortest possible duration of treatment in order to minimize the potential risk for cardiovascular or gastrointestinal adverse events. (See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS)
NAPRELAN, as a NSAID, does NOT treat clinical disease or prevent its progression.
NAPRELAN, as a NSAID, only relieves symptoms and decreases inflammation for as long as the patient continues to take it.
Geriatrics (> 65 years of age)
Evidence from clinical studies and postmarket experience suggests that use in the geriatric population is associated with differences in safety (see WARNINGS AND PRECAUTIONS).
Pediatrics (< 18 years of age)
NAPRELAN is not recommended for use in patients under 18 years of age since safety andeffectiveness have not been established.
NAPRELAN is contraindicated in:
- the peri-operative setting of coronary artery bypass graft surgery (CABG). Although NAPRELAN has NOT been studied in this patient population, a selective COX-2 inhibitor NSAID studied in such a setting has led to an increased incidence of cardiovascular/thromboembolic events, deep surgical infections and sternal wound complications.
- the third trimester of pregnancy, because of risk of premature closure of the ductus arteriosus and prolonged parturition
- women who are breastfeeding, because of the potential for serious adverse reactions in nursing infants
- severe uncontrolled heart failure
- known hypersensitivity to naproxen or to any of the components/excipients
- history of asthma, urticaria, or allergic-type reactions after taking ASA or other NSAIDs (i.e. complete or partial syndrome of ASA-intolerance – rhinosinusitis, urticaria/ angioedema, nasal polyps, asthma). Fatal anaphylactoid reactions have occurred in such individuals. Individuals with the above medical problems are at risk of a severe reaction even if they have taken NSAIDs in the past without any adverse reaction. The potential for cross-reactivity between different NSAIDs must be kept in mind (see WARNINGS AND PRECAUTIONS – Hypersensitivity Reactions – Anaphylactoid Reactions).
- active gastric / duodenal / peptic ulcer, active GI bleeding.
- cerebrovascular bleeding or other bleeding disorders
- inflammatory bowel disease
- severe liver impairment or active liver disease
- severe renal impairment (creatinine clearance <30 mL/min or 0.5 mL/sec) or deteriorating renal disease (individuals with lesser degrees of renal impairment are at risk of deterioration of their renal function when prescribed NSAIDs and must be monitored) (see WARNINGS AND PRECAUTIONS – Renal)
- known hyperkalemia (see WARNINGS AND PRECAUTIONS – Renal – Fluid and Electrolyte Balance)
- children and adolescents less than 18 years of age
Warnings and Precautions
Risk of Cardiovascular (CV) Adverse Events: Ischemic Heart Disease, Cerebrovascular Disease, Congestive Heart Failure (NYHA II-IV) (See WARNINGS AND PRECAUTIONS – Cardiovascular).
NAPRELAN is a non-steroidal anti-inflammatory drug (NSAID). Use of some NSAIDs is associated with an increased incidence of cardiovascular adverse events (such as myocardial infarction, stroke or thrombotic events) which can be fatal. The risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.
Caution should be exercised in prescribing NAPRELAN to any patient with ischemic heart disease (including but NOT limited to acute myocardial infarction, history of myocardial infarction and/or angina), cerebrovascular disease (including but NOT limited to stroke, cerebrovascular accident, transient ischemic attacks and/or amaurosis fugax) and/or congestive heart failure (NYHA II-IV).
Use of NSAIDs, such as NAPRELAN, can promote sodium retention in a dose-dependent manner, through a renal mechanism, which can result in increased blood pressure and/or exacerbation of congestive heart failure. (see also WARNINGS AND PRECAUTIONS – Renal – Fluid and Electrolyte Balance)
Randomized clinical trials with NAPRELAN have not been designed to detect differences in cardiovascular events in a chronic setting. Therefore, caution should be exercised when prescribing NAPRELAN.
Risk of Gastrointestinal (GI) Adverse Events (See WARNINGS AND PRECAUTIONS – Gastrointestinal)
Use of NSAIDs, such as NAPRELAN, is associated with an increased incidence of gastrointestinal adverse events (such as peptic/duodenal ulceration, perforation, obstruction and gastrointestinal bleeding).
Frail or debilitated patients may tolerate side effects less well and therefore special care should be taken in treating this population. To minimize the potential risk for an adverse event, the lowest effective dose should be used for the shortest possible duration. As with other NSAIDs, caution should be used in the treatment of elderly patients who are more likely to be suffering from impaired renal, hepatic or cardiac function. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
NAPRELAN is NOT recommended for use with other NSAIDs, with the exception of low-dose ASA for cardiovascular prophylaxis, because of the absence of any evidence demonstrating synergistic benefits and the potential for additive adverse reactions. (See DRUG INTERACTIONS – Drug/Drug Interactions – Acetylsalicylic acid (ASA) or other NSAIDs)
NAPRELAN SHOULD NOT BE USED CONCOMITANTLY WITH OTHER NAPROXEN PRODUCTS SINCE THEY ALL CIRCULATE IN THE PLASMA AS THE NAPROXEN ANION.
NAPRELAN is a non-steroidal anti-inflammatory drug (NSAID). Use of some NSAIDs is associated with an increased incidence of cardiovascular adverse events (such as myocardial infarction, stroke or thrombotic events) which can be fatal. The risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.
Caution should be exercised in prescribing NAPRELAN to patients with risk factors for cardiovascular disease, cerebrovascular disease or renal disease, such as any of the following (NOT an exhaustive list):
- Dyslipidemia / Hyperlipidemia
- Diabetes Mellitus
- Congestive Heart Failure (NYHA I)
- Coronary Artery Disease (Atherosclerosis)
- Peripheral Arterial Disease
- Creatinine Clearance < 60 mL/min or 1 mL/sec
Use of NSAIDs, such as NAPRELAN, can lead to new hypertension or can worsen pre-existing hypertension, either of which may increase the risk of cardiovascular events as described above. Thus blood pressure should be monitored regularly. Consideration should be given to discontinuing NAPRELAN should hypertension either develop or worsen with its use.
Use of NSAIDs, such as NAPRELAN, can induce fluid retention and edema, and may exacerbate congestive heart failure, through a renally-mediated mechanism. (See WARNINGS AND PRECAUTIONS – Renal – Fluid and Electrolyte Balance).
For patients with a high risk of developing an adverse CV event, other management strategies that do NOT include the use of NSAIDs should be considered first. To minimize the potential risk for an adverse CV event, the lowest effective dose should be used for the shortest possible duration.
Endocrine and Metabolism
NAPRELAN (naproxen sodium) is NOT a substitute for corticosteroids. It does NOT treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. (see DRUG INTERACTIONS – Drug-Drug Interactions – Glucocorticoids)
Serious GI toxicity (sometimes fatal), such as peptic / duodenal ulceration, inflammation, perforation, obstruction and gastrointestinal bleeding, can occur at any time, with or without warning symptoms, in patients treated with NSAIDs, such as NAPRELAN. Minor upper GI problems, such as dyspepsia, commonly occur at any time. Health care providers should remain alert for ulceration and bleeding in patients treated with NAPRELAN, even in the absence of previous GI tract symptoms. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this population. To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest possible duration. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. (see WARNINGS AND PRECAUTIONS – Special Populations – Geriatrics)
Patients should be informed about the signs and/or symptoms of serious GI toxicity and instructed to discontinue using NAPRELAN and seek emergency medical attention if they experience any such symptoms. The utility of periodic laboratory monitoring has NOT been demonstrated, nor has it been adequately assessed. Most patients who develop a serious upper GI adverse event on NSAID therapy have no symptoms. Upper GI ulcers, gross bleeding or perforation, caused by NSAIDs, appear to occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue, thus increasing the likelihood of developing a serious GI event at some time during the course of therapy. Even short-term therapy has its risks.
GI adverse reactions reported with NAPRELAN were based on the results from two double-blind clinical trials of three months duration with an additional nine-month open-label extension. During these clinical trials upper GI ulcers and gross bleeding occurred with an incidence of less than 1% with naproxen (see ADVERSE REACTIONS). The risk continues beyond one year and possibly increases. The incidence of these complications increases with increasing dose.
Caution should be taken if prescribing NAPRELAN to patients with a prior history of peptic / duodenal ulcer disease or gastrointestinal bleeding as these individuals have a greater than 10-fold higher risk for developing a GI bleed when taking a NSAID than patients with neither of these risk factors. Other risk factors for GI ulceration and bleeding include the following: Helicobacter pylori infection, increased age, prolonged use of NSAID therapy, excess alcohol intake, smoking, poor general health status or concomitant therapy with any of the following:
- Anti-coagulants (e.g. warfarin)
- Anti-platelet agents (e.g. ASA, clopidogrel)
- Oral corticosteroids (e.g. prednisone)
- Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g. citalopram, fluoxetine, paroxetine, sertraline)
NAPRELAN endoscopic effects (see CLINICAL TRIALS, Special Studies, Endoscopic Effects)
Some NSAIDs are associated with persistent urinary symptoms (bladder pain, dysuria, urinary frequency), hematuria or cystitis. The onset of these symptoms may occur at any time after the initiation of therapy with an NSAID. Should urinary symptoms occur, in the absence of an alternate explanation, treatment with NAPRELAN should be stopped to ascertain if symptoms disappear. This should be done before urological investigations or treatments are carried out.
NSAIDs inhibiting prostaglandin biosynthesis interfere with platelet function to varying degrees; patients who may be adversely affected by such an action, such as those on anti-coagulants or suffering from haemophilia or platelet disorders should be carefully observed when NAPRELAN is administered.
Numerous studies have shown that the concomitant use of NSAIDs and anticoagulants increases the risk of bleeding. Concurrent therapy of NAPRELAN with warfarin requires close monitoring of the international normalized ratio (INR).
Even with therapeutic INR monitoring, increased bleeding may occur.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike acetylsalicylic acid (ASA), their effect on platelet function is quantitatively less, or of shorter duration, and is reversible.
NAPRELAN and other NSAIDs have no proven efficacy as anti-platelet agents and should NOT be used as a substitute for ASA or other anti-platelet agents for prophylaxis of cardiovascular thromboembolic diseases. Anti-platelet therapies (e.g. ASA) should NOT be discontinued. There is some evidence that use of NSAIDs with ASA can markedly attenuate the cardioprotective effects of ASA. (see DRUG INTERACTIONS – Drug-Drug Interactions – Acetylsalicylic Acid or other NSAIDs)
Concomitant administration of NAPRELAN with low dose ASA increases the risk of GI ulceration and associated complications
Blood dyscrasias (such as neutropenia, leukopenia, thrombocytopenia, aplastic anemia and agranulocytosis) associated with the use of NSAIDs are rare, but could occur with severe consequences.
Anemia is sometimes seen in patients receiving NSAIDs, including NAPRELAN. This may be due to fluid retention, GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including NAPRELAN, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss.
As with other NSAIDs, borderline elevations of one or more liver enzyme tests (AST, ALT, alkaline phosphatase) may occur in up to 15% of patients (less than 1% with naproxen, see ADVERSE REACTIONS). These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver function test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with this drug. Severe hepatic reactions including jaundice and cases of fatal hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes, have been reported with NSAIDs.
Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop (e.g. jaundice), or if systemic manifestations occur (e.g. eosinophilia, associated with rash, etc.), this drug should be discontinued.
During long-term therapy, liver function tests should be monitored periodically. If there is a need to prescribe this drug in the presence of impaired liver function, it must be done under strict observation.
Hepatic 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.
As with NSAIDs in general, anaphylactoid reactions have occurred in patients without known prior exposure to NAPRELAN. In post-marketing experience, rare cases of anaphylactic/anaphylactoid reactions and angioedema have been reported in patients receiving naproxen. NAPRELAN should NOT be given to patients with the ASA-triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking ASA or other NSAIDs (see CONTRAINDICATIONS).
NAPRELAN should NOT be given to patients with complete or partial syndrome of ASA-intolerance (rhinosinusitis, urticaria/angioedema, nasal polyps, asthma) in whom asthma, anaphylaxis, urticaria/angioedema, rhinitis or other allergic manifestations are precipitated by ASA or other NSAIDs. Fatal anaphylactoid reactions have occurred in such individuals. As well, individuals with the above medical problems are at risk of a severe reaction even if they have taken NSAIDs in the past without any adverse reaction (see CONTRAINDICATIONS).
Patients sensitive to one NSAID may be sensitive to any of the other NSAIDs as well.
Serious skin reactions
(See WARNINGS AND PRECAUTIONS – Skin)
(See WARNINGS AND PRECAUTIONS – Infection – Aseptic Meningitis)
NAPRELAN, in common with other NSAIDs, may mask signs and symptoms of an underlying infectious disease.
Rarely, with some NSAIDs, the symptoms of aseptic meningitis (stiff neck, severe headaches, nausea and vomiting, fever or clouding of consciousness) have been observed. Patients with autoimmune disorders (systemic lupus erythematosus, mixed connective tissue diseases, etc.) seem to be pre-disposed. Therefore, in such patients, the health care provider must be vigilant to the development of this complication.
Some patients may experience drowsiness, dizziness, blurred vision, vertigo, tinnitus, hearing loss, insomnia or depression with the use of NSAIDs, such as NAPRELAN. If patients experience such adverse reaction(s), they should exercise caution in carrying out activities that require alertness.
Blurred and/or diminished vision has been reported with the use of NSAIDs. In rare cases, adverse ocular disorders including papillitis, retrobulbar optic neuritis and papilledema have been reported in users of NSAIDs including naproxen, although a cause and effect relationship cannot be established. If such symptoms develop NAPRELAN should be discontinued and an ophthalmologic examination performed. Ophthalmologic examination should be carried out at periodic intervals in any patient receiving NAPRELAN for an extended period of time.
The use of NAPRELAN may cause photosensitivity. Exposure to sunlight or sunlamps may cause vision changes. Patients should be advised to contact their physician if they experience ophthalmologic reactions from exposure to the sun.
(See CONTRAINDICATIONS – Coronary Artery Bypass Graft Surgery)
(See WARNINGS AND PRECAUTIONS – Neurologic)
Long term administration of NSAIDs to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of acute interstitial nephritis, hematuria, low grade proteinuria and occasionally nephrotic syndrome.
Renal insufficiency due to NSAID use is seen in patients with pre-renal conditions leading to reduction in renal blood flow or blood volume. Under these circumstances, renal prostaglandins help maintain renal perfusion and glomerular filtration rate (GFR). In these patients, administration of a NSAID may cause a reduction in prostaglandin synthesis leading to impaired renal function. Patients at greatest risk of this reaction are those with pre-existing renal insufficiency (GFR < 60 mL/min or 1 mL/s), dehydrated patients, patients on salt restricted diets, those with congestive heart failure, cirrhosis, liver dysfunction, taking angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, cyclosporin, diuretics, and those that are elderly. Serious or life-threatening renal failure has been reported in patients with normal or impaired renal function after short term therapy with NSAIDs. Even patients at risk who demonstrate the ability to tolerate an NSAID under stable conditions may decompensate during periods of added stress (e.g. dehydration due to gastroenteritis). Assessment of renal function in these patients before and during therapy with naproxen is recommended. Discontinuation of NSAIDs is usually followed by recovery to the pretreatment state.
Caution should be used when initiating treatment with NSAIDs, such as NAPRELAN, in patients with considerable dehydration. Such patients should be rehydrated prior to initiation of therapy. Caution is also recommended in patients with pre-existing kidney disease.
NAPRELAN and its metabolites are eliminated primarily by the kidneys, therefore, the drug should be used with great caution in patients with impaired renal function. In these cases, utilization of lower doses of NAPRELAN should be considered and patients carefully monitored.
During long-term therapy, kidney function should be monitored periodically.
Advanced Renal Disease
Fluid and Electrolyte Balance
Use of NSAIDs, such as NAPRELAN, can promote sodium retention in a dose-dependent manner, which can lead to fluid retention and edema, and consequences of increased blood pressure and exacerbation of congestive heart failure. Thus, caution should be exercised in prescribing NAPRELAN in patients with a history of congestive heart failure, compromised cardiac function, hypertension, increased age or other conditions predisposing to fluid retention (see WARNINGS AND PRECAUTIONS – Cardiovascular).
Use of NSAIDs, such as NAPRELAN, can increase the risk of hyperkalemia, especially in patients with diabetes mellitus, renal failure, increased age, or those receiving concomitant therapy with adrenergic blockers, angiotensin-converting enzyme inhibitors, angiotensin-II receptor antagonists, cyclosporin, or some diuretics. Electrolytes should be monitored periodically (see CONTRAINDICATIONS).
NAPRELAN tablets contain 37.5 mg or 50 mg of sodium (1.5 mEq or 2.0 mEq respectively). This should be considered in patients whose overall intake of sodium must be severely restricted.
ASA-induced asthma is an uncommon but very important indication of ASA and NSAID sensitivity. It occurs more frequently in patients with asthma who have nasal polyps.
The use of NAPRELAN, as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, may impaired fertility and is not recommended in women attempting to conceive.
Therefore, in women who have difficulties conceiving, or who are undergoing investigation of infertility, withdrawal of NAPRELAN should be considered.
In rare cases, serious skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis and erythema multiforme have been associated with the use of some NSAIDs. Because the rate of these reactions is low, they have usually been noted during post-marketing surveillance in patients taking other medications also associated with the potential development of these serious skin reactions. Thus, causality is NOT clear. These reactions are potentially life threatening but may be reversible if the causative agent is discontinued and appropriate treatment instituted. Patients should be advised that if they experience a skin rash they should discontinue their NSAID and contact their physician for assessment and advice, including which additional therapies to discontinue.
The use of NAPRELAN may cause photosensitivity. Exposure to sunlight or sunlamps may cause sunburn, skin blisters, skin rash, redness, itching, or discoloration. Patients should be advised to contact their physician if they experience a reaction from exposure to sun.
Pregnant Women: NAPRELAN is CONTRAINDICATED for use during the third trimester of pregnancy because of risk of premature closure of the ductus arteriosus and the potential to prolong parturition (see TOXICOLOGY).
Caution should be exercised in prescribing NAPRELAN during the first and second trimesters of pregnancy (see TOXICOLOGY).
Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or the embryo-foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation after use of a prostaglandin synthesis inhibitor in early pregnancy.
In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period.
The naproxen anion has been found in the milk of lactating women at a concentration of approximately 1% of that found in the plasma. Because of the possible adverse effects of prostaglandin-inhibiting drugs on neonates, use in nursing mothers should be avoided (see CONTRAINDICATIONS).
No pediatric studies have been performed with NAPRELAN, thus safety of NAPRELAN in pediatric populations has not been established (see CONTRAINDICATIONS).
Geriatrics (> 65 years of age)
Patients older than 65 years (referred to in this document as older or elderly) and frail or debilitated patients are more susceptible to a variety of adverse reactions from NSAIDs. The incidence of these adverse reactions increases with dose and duration of treatment. In addition, these patients are less tolerant to ulceration and bleeding. Most reports of fatal GI events are in this population. Older patients are also at risk of lower esophageal injury including ulceration and bleeding. For such patients, consideration should be given to a starting dose lower than the one usually recommended, with individual adjustment when necessary and under close supervision.
Monitoring and Laboratory Tests
Patients on long-term treatment with NAPRELAN should have their blood pressure monitored regularly and an ophthalmologic examination should be carried out at periodic intervals (See WARNINGS AND PRECAUTIONS, Cardiovascular and Ophthalmologic).
Hemoglobin, hematocrit, red blood cells (RBCs), white blood cells (WBCs), and platelets should be checked in patients on long-term treatment with NAPRELAN. Additionally, concurrent therapy of NAPRELAN with warfarin requires close monitoring of the international normalized ratio (INR) (See WARNINGS AND PRECAUTIONS, Hematologic).
Serum transaminases and bilirubin should be monitored regularly during NAPRELAN therapy (See WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).
Serum creatinine, creatine clearance and serum urea should be checked in patients during therapy with NAPRELAN. Electrolytes, including serum potassium should be monitored periodically (See WARNINGS AND PRECAUTIONS, Renal).
When stopping or starting NAPRELAN therapy; monitoring of plasma lithium concentrations is advised.
Adverse Drug Reaction Overview
The most common adverse reactions encountered with nonsteroidal anti-inflammatory drugs are gastrointestinal, of which peptic ulcer, with or without bleeding, is the most severe. Fatalities have occurred particularly in the elderly.
As with all drugs in this class, the frequency and severity of adverse events depends on several factors: the dose of the drug and duration of treatment; the age, the sex, physical condition of the patient; any concurrent medical diagnoses or individual risk factors.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
The adverse reactions reported were based on the results from two double blind controlled clinical trials of three months duration with an additional nine month open label extension. Of these 542 patients, 232 received NAPRELAN tablets, 167 were initially treated with Naprosyn and 143 were initially treated with placebo.
The most frequent adverse events form the double blind and open label clinical trials were headache (15%), followed by dyspepsia (14%) and flu syndrome (10%).
Adverse Events (AEs) reported in combined rheumatoid arthritis (RA) and osteoarthritis (OA) clinical studies*
*Combined AEs regardless of causality and including AEs reported on active control and/or placebo
|Body as a Whole|
|urinary tract infection||3-9%||1-3%||3-9%|
|Body as a Whole|
|Central Nervous System|
|Metabolic and Nutritional|
|Body as a Whole||Abdomen enlarged, abscess, allergic reaction, carcinoma, cellulitis, edema general, LE|
syndrome, malaise, monilia, mucous membrane disorder, neck rigid, pain neck, pain
|Cardiovascular||Abnormal electrocardiogram (ECG), angina pectoris, aortic stenosis, arrhythmia,|
bundle branch block, coronary artery disease, deep thrombophlebitis, heart failure right,
hemorrhage, migraine, myocardial infarction, syncope, tachycardia, vascular anomaly,
|Amnesia, anxiety, confusion, co-ordination abnormal, depression, emotional lability,|
hematoma subdural, hypertonia, nervousness, neuralgia, neuritis, paralysis, vertigo
|Dermatologic||Acne, alopecia, dermatitis contact, dry skin, eczema, herpes simplex, herpes zoster, nail|
disorder, neoplasm skin, pruritus, subcutaneous nodule, ulcer skin, urticaria
|Gastrointestinal||Anorexia, cholecystitis, cholelithiasis, colitis, eructation, esophagitis, gastroenteritis, GI|
disorder, GI hemorrhage, hepatosplenomegaly, liver function abnormality, melena,
periodontal abscess, rectal disorder, rectal hemorrhage, stomatitis aphthous, stomatitis
ulcer, tooth disorder, ulcer esophagus, ulcer mouth, ulcer stomach, ulcerative stomatitis
|Hematologic||Abnormal red blood cell (RBC), abnormal white blood cell (WBC), bleeding time|
increased, eosinophilia, leukopenia, thrombocytopenia
|Albuminuria, alkalosis, blood urea nitrogen (BUN) increased, creatine increase,|
dehydration, edema, glucose tolerance decrease, glucosuria, hypercholesteremia,
hyperuricemia, hypokalemia, serum glutamic oxaloacetic transaminase (SGOT)
increase, serum glutamic pyruvic transaminase (SGPT) increase, weight decrease
|Musculoskeletal||Bone disorder, bone pain, bursitis, fibrotendinitis, myasthenia, ptosis, spasm general,|
spontaneous bone fracture
|Renal||Carcinoma breast, dysmenorrhea, dysuria, hematuria, kidney calculus, kidney failure,|
kidney function abnormality, menorrhagia, metrorrhagia, neoplasm breast,
nephrosclerosis, nocturia, pain kidney, prostate disorder, pyelonephritis, pyuria, urinary
frequency, urinary incontinence, urinary retention, urine abnormal, uterine spasm,
|Respiratory||Asthma, dyspnea, epistaxis, laryngitis, lung disorder, lung edema, pneumonia,|
respiratory disorder, respiratory distress
|Special Senses||Amblyopia, conjunctivitis, deaf, ear disorder, keratoconjunctivitis, lacrimation|
disorder, otitis media, pain eye, scleritis, cataract
|General||Angioneurotic edema, hypoglycemia|
Adverse Events (AEs) (Incidence between 1% and 9%) that have been reported in clinical trials with naproxen, but were not observed in those patients who received NAPRELAN during the controlled clinical trials described above. In view of the similarity of the two products, these events could potentially occur during the administration of NAPRELAN.
Congestive heart failure
Central Nervous System
Aseptic meningitis, cognitive dysfunction, diplopia, dream abnormalities, inability to concentrate, muscle weakness.
Angiodermatitis, epidermal necrolysis, epidermolysis bullosa, erythema multiforme, photosensitive dermatitis, photosensitivity reactions resembling porphyria cutaneous tarda, skin necrosis, Stevens-Johnson syndrome, sweating
Cardiospasm, hematemesis, jaundice, necrosis, non-peptic GI ulceration, pancreatitis
Agranulocytosis, aplastic anemia, granulocytopenia, hemolytic anemia
Glomerular nephritis, hyperkalemia, intersitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis
Anaphylactoid reactions, menstrual disorders, pyrexia (chills and fevers)
Serious Adverse Events (SAEs) (Incidence <1%) that have been reported in clinical trials with naproxen, but were not observed in patients who received NAPRELAN during the controlled clinical trials described above. In view of the similarity of the two products, these events could potentially occur during the administration of NAPRELAN.
Central Nervous System
Ecchymoses, purpura, skin eruptions
Hearing disturbances, tinnitus, visual disturbances
Prolonged concurrent use of acetaminophen with an NSAID may increase the risk of adverse renal effects. Therefore it is recommended that patients be under close medical supervision while receiving such combined therapy.
Acetylsalicylic acid (ASA) or other NSAIDs
The use of NAPRELAN in addition to any other NSAID, including over the counter ones (such as ASA and ibuprofen) for analgesic and/or antiinflammatory effect is NOT recommended because of the absence of any evidence demonstrating synergistic benefits and the potential for additive adverse reactions.
The exception is the use of low dose ASA for cardiovascular protection, when another NSAID is being used for its analgesic/anti-inflammatory effect, keeping in mind that combination NSAID therapy is associated with additive adverse reactions.
Some NSAIDs (e.g. ibuprofen) may interfere with the anti-platelet effects of low dose ASA, possibly by competing with ASA for access to the active site of cyclooxygenase-1.
In vitro studies have shown that the naproxen anion, because of its affinity for protein, may displace from their binding sites other drugs which are also albumin-bound (see ACTION AND CLINICAL PHARMACOLOGY – Pharmacokinetics).
Theoretically, the naproxen anion itself could likewise be displaced. Short-term controlled studies failed to show that taking the drug significantly affects prothrombin times when administered to individuals on coumarin-type anticoagulants. Caution is advised nonetheless, since interactions have been seen with other nonsteroidal agents of this class. Similarly, patients receiving the drug and a hydantoin, sulfonamide or sulfonylurea should be observed for signs of toxicity to these drugs.
Concomitant administration of naproxen and ASA is not recommended because naproxen is displaced from its binding sites during the concomitant administration of ASA, resulting in lower plasma concentrations and peak plasma levels.
The rate of absorption of naproxen can be altered (increased or decreased) by concomitant administration of antacids but is not adversely influenced by the presence of food.
(see WARNINGS AND PRECAUTIONS – Hematologic – Anti-coagulants)
Naproxen and other NSAIDs may diminish the anti-hypertensive effect of propranolol, other beta blockers and Angiotensin Converting Enzyme (ACE) inhibitors as well as other antihypertensive agents.
Combinations of ACE inhibitors, angiotensin-II antagonists, or diuretics with NSAIDs might have an increased risk for acute renal failure and hyperkalemia. Blood pressure and renal function (including electrolytes) should be monitored more closely in this situation, as occasionally there can be a substantial increase in blood pressure.
Anti-platelet Agents (including ASA)
There is an increased risk of bleeding, via inhibition of platelet function, when anti-platelet agents are combined with NSAIDs, such as NAPRELAN (see WARNINGS AND PRECAUTIONS – Hematologic – Anti-platelet Effects).
Concomitant administration of cholestyramine can delay the absorption of naproxen, but does not affect its extent.
Inhibition of renal prostaglandin activity by NSAIDs may increase the plasma concentration of cyclosporin and/or the risk of cyclosporin-induced nephrotoxicity. Patients should be carefully monitored during concurrent use.
Concomitant administration of an NSAID with digoxin can result in an increase in digoxin concentrations which may result in digitalis toxicity. Increased monitoring and dosage adjustments of digitalis glycosides may be necessary during and following concurrent NSAID therapy.
Clinical studies as well as post-marketing observations have shown that NSAIDs can reduce the effect of diuretics.
Some studies have shown that the concomitant use of NSAIDs and oral glucocorticoids increase the risk of GI adverse events such as ulceration and bleeding. This is especially the case in older (> 65 years of age) individuals.
Concurrent administration of NSAIDs with lithium may increase plasma lithium concentrations. Monitoring of plasma lithium concentrations is therefore advised when starting or stopping a NSAID.
Caution is advised in the concomitant administration of naproxen and methotrexate since naproxen and other non-steroidal anti-inflammatory agents have been reported to reduce the tubular secretion of methotrexate in an animal model, thereby possibly enhancing its toxicity.
Salicylate effectiveness may be impaired in women taking oral contraceptives. Women taking oral contraceptives may require higher or more frequent aspirin doses for desired clinical effects. Where maintenance of a specific plasma concentration is crucial, salicylate levels should be monitored when oral contraceptives are begun or discontinued.
Caution is advised in concomitant administration of salicylates and sulfonylureas. Some studies show salicylates reduce basal plasma glucose levels, increase glucose tolerances and augment acute insulin response.
Concurrent use of potassium supplements with an NSAID may increase the risk of gastrointestinal side effects including ulceration and hemorrhage.
Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Selective Serotonin Reuptake Inhibitors (SSRIs)
Concomitant administration of NSAIDs and SSRIs may increase the risk of gastrointestinal ulceration and bleeding (see Warnings and Precautions – Gastrointestinal).
Although this interaction has not been studied with NAPRELAN, co-administration of tacrolimus and any NSAID may increase the nephrotoxic effect of tacrolimus. Renal function should be monitored when NAPRELAN and tacrolimus are used in combination.
Interactions with food have not been established.
Interactions with herbal products have not been established.
Naproxen may decrease platelet aggregation and prolong bleeding time. This effect should be kept in mind when bleeding times are determined. Other laboratory tests in patients on naproxen therapy have shown sporadic abnormalities but no definite trend was seen that would indicate potential toxicity.
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. 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.
Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Concurrent use of alcohol with an NSAID may increase the risk of gastrointestinal side effects including ulceration and hemorrhage.
Dosage and Administration
- A lower dose should be considered in patients with renal or hepatic impairment or in elderly patients (see WARNINGS AND PRECAUTIONS).
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.
Recommended Dose and Dosage Adjustment
The lowest effective dose of NAPRELAN should be used in every patient. NAPRELAN like other NSAIDs show considerable variation in response. The recommended starting dose of NAPRELAN in adults is two NAPRELAN 375 mg tablets (750 mg) once daily, or two NAPRELAN 500 mg tablets (1000 mg) once daily. Patients already taking naproxen 250 mg, 375 mg or 500 mg twice daily (morning and evening) may have their total daily dose replaced with NAPRELAN as a single daily dose.
During long-term administration, the dose of NAPRELAN may be adjusted depending on the clinical response of the patient.
In patients who tolerate lower doses of NAPRELAN well, the dose may be increased to three NAPRELAN 500 mg tablets (1500 mg) once daily for limited periods when a higher level of antiinflammatory activity is required. When treating patients, especially at the higher dose levels, the physician should observe sufficient increased clinical benefit to offset the potential increased risk (see CLINICAL TRIALS). Symptomatic improvement in arthritis usually begins within one week; however, treatment for two weeks may be required to achieve a therapeutic benefit.
Regardless of indication, the dosage should be individualized to achieve effective dose and minimize adverse events, however the maximum daily dose is three NAPRELAN 500 mg (1500 mg) once daily.
To lessen stomach upset, take this medicine after a meal or with food or milk.
If a dose of this medication is missed, it is not necessary to make up the missed dose. Skip the missed dose and continue with the next scheduled dose. Do not double doses.
To lessen stomach upset, take this medicine immediately after a meal or with food or milk.
Significant naproxen overdosage may be characterized by drowsiness, dizziness, disorientation, heartburn, indigestion, epigastric pain, abdominal discomfort, nausea, vomiting, transient alterations in liver function, hypoprothrombinemia, renal dysfunction, metabolic acidosis and apnea. Because naproxen sodium may be rapidly absorbed, high and early blood levels should be anticipated. A few patients have experienced seizures, but it is not clear whether or not these were drug-related. No evidence of toxicity or late sequelae have been reported five to 15 months after ingestion for three to seven days of doses up to 3000 mg of naproxen. One patient ingested a single dose of 25 g of naproxen and experience mild nausea and indigestion. It is not known what dose of the drug would be life threatening.
Should a patient ingest a large number of tablets, accidentally or purposefully, the stomach may be emptied and usual supportive care following a NSAID overdose should be employed. Emesis and/or activated charcoal may be indicated following overdose. Hemodialysis does not decrease the plasma concentration of naproxen because of the high degree of its protein binding. However, hemodialysis may still be appropriate in the management of renal failure.
|For management of a suspected drug overdose, contact your regional Poison Control Centre.|
Action and Clinical Pharmacology
Mechanism of Action
NAPRELAN contains naproxen sodium, a member of the arylacetic acid group of NSAIDs.
Naproxen has demonstrated anti-inflammatory, analgesic and antipyretic properties. As with other NSAIDs, its mode of action is not fully understood; however, its ability to inhibit prostaglandin synthesis may be involved in the anti-inflammatory effect.
(See DETAILED PHARMACOLOGY – Pharmacodynamics)
NAPRELAN uses the proprietary IPDAS (Intestinal Protective Drug Absorption System) technology. It is a rapidly disintegrating tablet system combining an immediate release component and a sustained release component of microparticles that are widely dispersed allowing absorption of the active ingredient throughout the GI tract, maintaining blood levels over 24 hours.
Although naproxen itself is well absorbed, the sodium salt form is more rapidly absorbed resulting in higher peak plasma levels for a given dose. Approximately 30% of the total naproxen sodium dose in NAPRELAN is present in the dosage form as an immediate release component. The remaining naproxen sodium is coated as microparticles to provide sustained release properties.
After oral administration, plasma levels of naproxen are detected within 30 minutes of dosing, with peak plasma levels occurring approximately 5 hours after dosing. The observed terminal elimination half-life of naproxen from both immediate release naproxen sodium and NAPRELAN is approximately 15 hours. Steady state levels of naproxen are achieved in 3 days and the degree of naproxen accumulation in the blood is consistent with this.
|naproxen 500 mg tablets
Q12h (1000 mg)/5 days
|NAPRELAN 2 x 500 mg tablets
(1000 mg) Q24h/5 days
Naproxen itself is rapidly and completely absorbed from the GI tract with an in vivo bioavailability of 95%. Based on the pharmacokinetic profile, the absorption phase of NAPRELAN occurs in the first 4-6 hours after administration. This coincides with disintegration of the tablet in the stomach, the transit of the sustained release microparticles through the small intestine and into the proximal large intestine. An in vivo imaging study has been performed in healthy volunteers which confirms rapid disintegration of the tablet matrix and dispersion of the microparticles.
The absorption rate from the sustained release particulate component of NAPRELAN is slower than that of conventional naproxen sodium tablets. It is this prolongation of drug absorption processes which maintains plasma levels and allows for once daily dosing.
No significant food effects were observed when twenty-four subjects were given a single dose of NAPRELAN 500 mg either after an overnight fast or 30 minutes after a meal. In common with conventional naproxen and naproxen sodium formulations, food causes a slight decrease in the rate of naproxen absorption following NAPRELAN administration.
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 a less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses. However the concentration of unbound naproxen continues to increase proportionally to dose. NAPRELAN exhibits similar dose proportional characteristics.
Naproxen is extensively metabolized to 6-O-desmethyl naproxen and neither the parent nor the metabolites induce metabolizing enzymes.
The elimination half-life of NAPRELAN and conventional naproxen is approximately 15 hours. Steady state conditions are attained after 2-3 doses of NAPRELAN. Most of the drug is excreted in the urine, primarily as unchanged naproxen (less than 1%), 6-O-desmethyl naproxen (less than 1%) and their glucuronide or other conjugates (66-92%). A small amount (<5%) of the drug is excreted in the feces. The rate of excretion has been found to coincide closely with the rate of clearance from the plasma.
Special Populations and Conditions
In patients with renal failure metabolites may accumulate.
Storage and Stability
Store at room temperature 15-30°C (59-86°F), in well-closed containers. Dispense in a well-closed container with a child-resistant closure.
Keep in a safe place out of the reach of children.
Dosage Forms, Composition and Packaging
NAPRELAN contains 412.5 mg or 550 mg of naproxen sodium, equivalent to 375 mg and 500 mg naproxen and 37.5 mg and 50 mg sodium, respectively. Each NAPRELAN tablet also contains the following inactive ingredients: ammonio methacrylate copolymer Type A, ammonio methacrylate copolymer Type B, citric acid, crospovidone, magnesium stearate, methacrylic acid copolymer Type A, microcrystalline cellulose, povidone, and talc. The tablet coating contains hydroxypropyl methylcellulose, polyethylene glycol, and titanium dioxide.
Availability of Dosage Forms
NAPRELAN Controlled-Release Tablets
NAPRELAN 375: white, capsule-shaped, film-coated tablets, debossed with N on one side, and “375” on the other. Packaged in light-resistant bottles of 75 tablets. Each tablet contains 412.5 mg naproxen sodium equivalent to 375 mg naproxen.
NAPRELAN 500: white, capsule-shaped, film-coated tablets, debossed with N on one side and “500” on the other. Packaged in light-resistant bottles of 60 tablets. Each tablet contains 550 mg naproxen sodium equivalent to 500 mg naproxen.