Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare.
A few patients have experienced seizures, but it is not clear whether or not these were drug-related. It is not known what dose of the drug would be life threatening.
Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Hemodialysis does not decrease the plasma concentration of naproxen because of the high degree of its protein binding. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.
For additional information about overdosage treatment contact a poison control center (1-800-2221222).
NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are contraindicated in the following patients:
- Hypersensitivity to any of the constituents.
- Since the potential exists for cross-sensitivity reactions, Nalgesin is contraindicated in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, nasal polyps, angioedema or urticaria) in response to ibuprofen, aspirin, or other non-steroidal anti-inflammatory drugs. These reactions have the potential of being fatal. Severe anaphylactic-like reactions to Nalgesin have been reported in such patients.
- - Special warnings and precautions for use).
- )
- A history of gastrointestinal bleeding or perforation related to previous NSAIDs therapy. Active, or history of peptic ulcer/or active gastrointestinal bleeding (two or more distinct episodes of proven ulceration or bleeding).
- In principle, Nalgesin must not be administered to patients with gastrointestinal ulcerations, congestive gastritis or atrophic gastritis, gastrointestinal bleeding or other bleeding such as cerebrovascular bleeding.
- Hemorrhoids or predisposition to rectal bleeding.
Nalgesin is contraindicated in the following patients:
Nalgesin Tablets, EC-Nalgesin, and ANAPROX DS are contraindicated in the following patients:
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
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. The following adverse reactions are divided into three parts based on frequency and whether or not the possibility exists of a causal relationship between drug usage and these adverse events. In those reactions listed as “Probable Causal Relationship” there is at least one case for each adverse reaction where there is evidence to suggest that there is a causal relationship between drug usage and the reported event. 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. A total of 542 patients received Nalgesin Tablets either in the double-blind period or in the nine month open-label extension. Of these 542 patients, 232 received Nalgesin Tablets, 167 were initially treated with Naprosyn® and 143 were initially treated with placebo. Adverse reactions reported by patients who received Nalgesin Tablets are shown by body system. Those adverse reactions observed with naproxen but not reported in controlled trials with Nalgesin Tablets are italicized.
The most frequent adverse events from the double-blind and open-label clinical trials were headache (15%), followed by dyspepsia (14%), and flu syndrome (10%). The incidence of other adverse events occurring in 3% to 9% of the patients are marked with an asterisk.
Those reactions occurring in less than 3% of the patients are unmarked.
Incidence greater Than 1% (Probable Causal Relationship)Body as a Whole - Pain (back)*, pain*, infection*, fever, injury (accident), asthenia, pain chest, headache (15%), flu syndrome (10%).
Gastrointestinal - Nausea*, diarrhea*, constipation*, abdominal pain*, flatulence, gastritis, vomiting, dysphagia, dyspepsia (14%), heartburn*, stomatitis.
Hematologic - Anemia, ecchymosis.
Respiratory - Pharyngitis*, rhinitis*, sinusitis*, bronchitis, cough increased.
Renal - Urinary tract infection*, cystitis.
Dermatologic - Skin rash*, skin eruptions*, ecchymoses*, purpura.
Metabolic and Nutrition - Peripheral edema, hyperglycemia.
Central Nervous System - Dizziness, paresthesia, insomnia, drowsiness*, lightheadedness.
Cardiovascular - Hypertension, edema*, dyspnea*, palpitations.
Musculoskeletal - Cramps (leg), myalgia, arthralgia, joint disorder, tendon disorder.
Special Senses - Tinnitus*, hearing disturbances, visual disturbances.
General - Thirst.
Incidence Less Than 1% (Probable Causal Relationship)Body as a Whole - Abscess, monilia, neck rigid, pain neck, abdomen enlarged, carcinoma, cellulitis, edema general, LE syndrome, malaise, mucous membrane disorder, allergic reaction, pain pelvic.
Gastrointestinal - Anorexia, cholecystitis, cholelithiasis, eructation, GI hemorrhage, rectal hemorrhage, stomatitis aphthous, stomatitis ulcer, ulcer mouth, ulcer stomach, periodontal abscess, cardiospasm, colitis, esophagitis, gastroenteritis, GI disorder, rectal disorder, tooth disorder, hepatosplenomegaly, liver function abnormality, melena, ulcer esophagus, hematemesis, jaundice, pancreatitis, necrosis.
Renal - Dysmenorrhea, dysuria, kidney function abnormality, nocturia, prostate disorder, pyelonephritis, carcinoma breast, urinary incontinence, kidney calculus, kidney failure, menorrhagia, metrorrhagia, neoplasm breast, nephrosclerosis, hematuria, pain kidney, pyuria, urine abnormal, urinary frequency, urinary retention, uterine spasm, vaginitis, glomerular nephritis, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis.
Hematologic - Leukopenia, bleeding time increased, eosinophilia, abnormal RBC, abnormal WBC, thrombocytopenia, agranulocytosis, granulocytopenia.
Central Nervous System - Depression, anxiety, hypertonia, nervousness, neuralgia, neuritis, vertigo, amnesia, confusion, co-ordination, abnormal diplopia, emotional lability, hematoma subdural, paralysis, dream abnormalities, inability to concentrate, muscle weakness.
Dermatologic: Angiodermatitis, herpes simplex, dry skin, sweating, ulcer skin, acne, alopecia, dermatitis contact, eczema, herpes zoster, nail disorder, skin necrosis, subcutaneous nodule, pruritus, urticaria, neoplasm skin, photosensitive dermatitis, photosensitivity reactions resembling porphyria cutaneous tarda, epidermolysis bullosa.
Special Senses - Amblyopia, scleritis, cataract, conjunctivitis, deaf, ear disorder, keratoconjunctivitis, lacrimation disorder, otitis media, pain eye.
Cardiovascular - Angina pectoris, coronary artery disease, myocardial infarction, deep thrombophlebitis, vasodilation, vascular anomaly, arrhythmia, bundle branch block, abnormal ECG, heart failure right, hemorrhage, migraine, aortic stenosis, syncope, tachycardia, congestive heart failure.
Respiratory - Asthma, dyspnea, lung edema, laryngitis, lung disorder, epistaxis, pneumonia, respiratory distress, respiratory disorder, eosinophilic pneumonitis.
Musculoskeletal - Myasthenia, bone disorder, spontaneous bone fracture, fibrotendinitis, bone pain, ptosis, spasm general, bursitis.
Metabolic and Nutrition - Creatinine increase, glucosuria, hypercholesteremia, albuminuria, alkalosis, BUN increased, dehydration, edema, glucose tolerance decrease, hyperuricemia, hypokalemia, SGOT increase, SGPT increase, weight decrease.
General - Anaphylactoid reactions, angioneurotic edema, menstrual disorders, hypoglycemia, pyrexia (chills and fevers).
Incidence Less Than 1% (Causal Relationship Unknown)Other adverse reactions listed in the naproxen package label, but not reported by those who received Nalgesin Tablets are shown in italics. These observations are being listed as alerting information to the physician.
Hematologic - Aplastic anemia, hemolytic anemia.
Central Nervous System - Aseptic meningitis, cognitive dysfunction.
Dermatologic - Epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome.
Gastrointestinal - Non-peptic GI ulceration, ulcerative stomatitis.
Cardiovascular - Vasculitis.
There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
Carcinogenicity
Nalgesin was administered with food to Sprague-Dawley rats for 24 months at doses of 8, 16 and 24mg/kg/day. Nalgesin was not carcinogenic in rats.
Mutagenicity
Mutagenicity was not seet in Salmonella typhimurium (5 cell lines), Sachharomyces cerevisisae (1 cell line), and mouse lymphoma tests.
Fertility
Nalgesin did not affect the fertility of rats when administered orally at doses of 30mg/kg/day to males and 20mg/kg/day to females.
Teratogenicity
Nalgesin was not teratogenic when administered orally at dose of 20mg/kg/day during organogenesis to rats and rabbits.
Perinatal/Postnatal Reproduction
Oral administration of Nalgesin to pregnant rats at doses of 2, 10 and 20mg/kg/day during the third trimester of pregnancy resulted in difficult labour. These are known effects of this class of compounds and were demonstrated in pregnant rats with aspirin and indometacin.
Nalgesin has analgesic, anti-inflammatory and anti-pyretic actions.
Nalgesin is a non-steroidal anti-inflammatory analgesic compound with antipyretic properties as has been demonstrated in classical animal test systems. Nalgesin exhibits its anti-inflammatory effect even in adrenalectomised animals, indicating that its action is not mediated through the pituitary-adrenal axis.
Nalgesin inhibits prostaglandin synthetase (as do other NSAIDs). As with other NSAIDs, however, the exact mechanism of its anti-inflammatory action is not known.
Naproxen and naproxen sodium are rapidly and completely absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%. The different dosage forms of NAPROSYN are bioequivalent in terms of extent of absorption (AUC) and peak concentration (Cmax); however, the products do differ in their pattern of absorption. These differences between naproxen products are related to both the chemical form of naproxen used and its formulation. Even with the observed differences in pattern of absorption, the elimination half-life of naproxen is unchanged across products ranging from 12 to 17 hours. Steady-state levels of naproxen are reached in 4 to 5 days, and the degree of naproxen accumulation is consistent with this half-life. This suggests that the differences in pattern of release play only a negligible role in the attainment of steady-state plasma levels.
AbsorptionNAPROSYN Tablets/ANAPROX DS: After administration of NAPROSYN Tablets, peak plasma levels are attained in 2 to 4 hours. After oral administration of ANAPROX DS, peak plasma levels are attained in 1 to 2 hours. The difference in rates between the two products is due to the increased aqueous solubility of the sodium salt of naproxen used in ANAPROX DS.
EC-NAPROSYN: EC-NAPROSYN is designed with a pH-sensitive coating to provide a barrier to disintegration in the acidic environment of the stomach and to lose integrity in the more neutral environment of the small intestine. The enteric polymer coating selected for EC-NAPROSYN dissolves above pH 6. When EC-NAPROSYN was given to fasted subjects, peak plasma levels were attained about 4 to 6 hours following the first dose (range: 2 to 12 hours). An in vivo study in man using radiolabeled ECNAPROSYN tablets demonstrated that EC-NAPROSYN dissolves primarily in the small intestine rather than in the stomach, so the absorption of the drug is delayed until the stomach is emptied.
When EC-NAPROSYN and NAPROSYN Tablets were given to fasted subjects (n=24) in a crossover study following 1 week of dosing, differences in time to peak plasma levels (Tmax) were observed, but there were no differences in total absorption as measured by Cmax and AUC:
| EC-NAPROSYN* 500 mg bid | NAPROSYN* 500 mg bid | |
| Cmax (μg/mL) | 94.9 (18%) | 97.4 (13%) |
| Tmax (hours) | 4 (39%) | 1.9 (61%) |
| AUC0-12 hr (μg•hr/mL) | 845 (20%) | 767 (15%) |
| *Mean value (coefficient of variation) |
Antacid Effects
When EC-NAPROSYN was given as a single dose with antacid (54 mEq buffering capacity), the peak plasma levels of naproxen were unchanged, but the time to peak was reduced (mean Tmax fasted 5.6 hours, mean Tmax with antacid 5 hours), although not significantly.
Food Effects
When EC-NAPROSYN was given as a single dose with food, peak plasma levels in most subjects were achieved in about 12 hours (range: 4 to 24 hours). Residence time in the small intestine until disintegration was independent of food intake. The presence of food prolonged the time the tablets remained in the stomach, time to first detectable serum naproxen levels, and time to maximal naproxen levels (Tmax), but did not affect peak naproxen levels (Cmax).
DistributionNaproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough Css 36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma.
EliminationMetabolism
Naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen, and both parent and metabolites do not induce metabolizing enzymes. Both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective acylglucuronide conjugated metabolites.
Excretion
The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen ( < 1%), 6-0-desmethyl naproxen ( < 1%) or their conjugates (66% to 92%). The plasma half-life of the naproxen anion in humans ranges from 12 to 17 hours. The corresponding half-lives of both naproxen's metabolites and conjugates are shorter than 12 hours, and their rates of excretion have been found to coincide closely with the rate of naproxen clearance from the plasma. Small amounts, 3% or less of the administered dose, are excreted in the feces. In patients with renal failure metabolites may accumulate.
Nalgesin is readily absorbed from the gastro-intestinal tract and peak plasma levels are reached in 2 to 4 hours. Nalgesin is present in the blood mainly as unchanged drug. It is extensively bound to plasma proteins and has a half-life of about 15 hours. enabling a steady state to be achieved within 3 days of initiation of therapy on a twice daily dose regimen. The degree of absorption is not significantly affected by either foods or most antacids. Excretion is almost entirely via the urine, mainly as conjugated Nalgesin, with some unchanged drug. Metabolism in children is similar to that in adults. Chronic alcoholic liver disease reduces the total plasma concentration of Nalgesin but the concentration of unbound Nalgesin increases. In the elderly, the unbound plasma concentration of Nalgesin is increased although total plasma concentration is unchanged.About half of the dose is excreted in the urine in 24 hours and about 94% in 5 days largely as the glucuronide.
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 Nalgesin Tablets 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 Nalgesin Tablets 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.
Plasma Naproxen Concentrations Mean of 24 Subjects (+/-2SD) (Steady State, Day 5)
Pharmacokinetic Parameters at Steady State Day 5 (Mean of 24 Subjects)
| Parameter (units) | naproxen 500 mg Q12h/5 days (1000 mg) | Nalgesin 2 x 500 mg tablets (1000 mg) Q24h/5 days | ||||
| Mean | SD | Range | Mean | SD | Range | |
| AUC 0-24 (mcgxh/mL) | 1446 | 168 | 1167 - 1858 | 1448 | 145 | 1173 - 1774 |
| Cmax (mcg/mL) | 95 | 13 | 71 - 117 | 94 | 13 | 74 - 127 |
| Cava (mcg/mL) | 60 | 7 | 49 -77 | 60 | 6 | 49 -74 |
| Cmin (mcg/mL) | 36 | 9 | 13 - 51 | 33 | 7 | 23 -48 |
| Tmax (hrs) | 3 | 1 | 1 -4 | 5 | 2 | 2-10 |
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 Nalgesin Tablets occurs in the first 4 to 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 that confirms rapid disintegration of the tablet matrix and dispersion of the microparticles.
The absorption rate from the sustained release particulate component of Nalgesin Tablets is slower than that for conventional naproxen sodium tablets. It is this prolongation of drug absorption processes that maintains plasma levels and allows for once daily dosing.
Food Effects
No significant food effects were observed when twenty-four subjects were given a single dose of Nalgesin Tablets 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 Nalgesin Tablets administration.
DistributionNaproxen 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. Nalgesin Tablets exhibit similar dose proportional characteristics.
EliminationMetabolism
Naproxen is extensively metabolized to 6-0-desmethyl naproxen and both parent and metabolites do not induce metabolizing enzymes.
Excretion
The elimination half-life of Nalgesin Tablets and conventional naproxen is approximately 15 hours. Steady state conditions are attained after 2 to 3 doses of Nalgesin Tablets. Most of the drug is excreted in the urine, primarily as unchanged naproxen (less than 1%), 6-0-desmethyl naproxen (less than 1%) and their glucuronide or other conjugates (66 to 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. In patients with renal failure, metabolites may accumulate.
Naproxen and naproxen sodium are rapidly and completely absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%. The different dosage forms of Nalgesin are bioequivalent in terms of extent of absorption (AUC) and peak concentration (Cmax); however, the products do differ in their pattern of absorption. These differences between naproxen products are related to both the chemical form of naproxen used and its formulation. Even with the observed differences in pattern of absorption, the elimination half-life of naproxen is unchanged across products ranging from 12 to 17 hours. Steady-state levels of naproxen are reached in 4 to 5 days, and the degree of naproxen accumulation is consistent with this half-life. This suggests that the differences in pattern of release play only a negligible role in the attainment of steady-state plasma levels.
AbsorptionNalgesin Tablets/ANAPROX DS: After administration of Nalgesin Tablets, peak plasma levels are attained in 2 to 4 hours. After oral administration of ANAPROX DS, peak plasma levels are attained in 1 to 2 hours. The difference in rates between the two products is due to the increased aqueous solubility of the sodium salt of naproxen used in ANAPROX DS.
EC-Nalgesin: EC-Nalgesin is designed with a pH-sensitive coating to provide a barrier to disintegration in the acidic environment of the stomach and to lose integrity in the more neutral environment of the small intestine. The enteric polymer coating selected for EC-Nalgesin dissolves above pH 6. When EC-Nalgesin was given to fasted subjects, peak plasma levels were attained about 4 to 6 hours following the first dose (range: 2 to 12 hours). An in vivo study in man using radiolabeled ECNalgesin tablets demonstrated that EC-Nalgesin dissolves primarily in the small intestine rather than in the stomach, so the absorption of the drug is delayed until the stomach is emptied.
When EC-Nalgesin and Nalgesin Tablets were given to fasted subjects (n=24) in a crossover study following 1 week of dosing, differences in time to peak plasma levels (Tmax) were observed, but there were no differences in total absorption as measured by Cmax and AUC:
| EC-Nalgesin* 500 mg bid | Nalgesin* 500 mg bid | |
| Cmax (μg/mL) | 94.9 (18%) | 97.4 (13%) |
| Tmax (hours) | 4 (39%) | 1.9 (61%) |
| AUC0-12 hr (μg•hr/mL) | 845 (20%) | 767 (15%) |
| *Mean value (coefficient of variation) |
Antacid Effects
When EC-Nalgesin was given as a single dose with antacid (54 mEq buffering capacity), the peak plasma levels of naproxen were unchanged, but the time to peak was reduced (mean Tmax fasted 5.6 hours, mean Tmax with antacid 5 hours), although not significantly.
Food Effects
When EC-Nalgesin was given as a single dose with food, peak plasma levels in most subjects were achieved in about 12 hours (range: 4 to 24 hours). Residence time in the small intestine until disintegration was independent of food intake. The presence of food prolonged the time the tablets remained in the stomach, time to first detectable serum naproxen levels, and time to maximal naproxen levels (Tmax), but did not affect peak naproxen levels (Cmax).
DistributionNaproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough Css 36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma.
EliminationMetabolism
Naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen, and both parent and metabolites do not induce metabolizing enzymes. Both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective acylglucuronide conjugated metabolites.
Excretion
The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen ( < 1%), 6-0-desmethyl naproxen ( < 1%) or their conjugates (66% to 92%). The plasma half-life of the naproxen anion in humans ranges from 12 to 17 hours. The corresponding half-lives of both naproxen's metabolites and conjugates are shorter than 12 hours, and their rates of excretion have been found to coincide closely with the rate of naproxen clearance from the plasma. Small amounts, 3% or less of the administered dose, are excreted in the feces. In patients with renal failure metabolites may accumulate.
Included as part of the PRECAUTIONS section.
PRECAUTIONS Cardiovascular Thrombotic EventsClinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.
To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as naproxen, increases the risk of serious gastrointestinal (GI) events.
Status Post Coronary Artery Bypass Graft (CABG) SurgeryTwo large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG.
Post-MI PatientsObservational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.
Avoid the use of NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS are used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
Gastrointestinal Bleeding, Ulceration, And PerforationNSAIDs, including naproxen, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs.
Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.
Risk Factors For GI Bleeding, Ulceration, And PerforationPatients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.
Strategies To Minimize The GI Risks In NSAID-treated PatientsElevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported.
Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including naproxen.
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue NAPROSYN Tablets, ECNAPROSYN, or ANAPROX DS immediately, and perform a clinical evaluation of the patient.
HypertensionNSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs.
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.
Heart Failure And EdemaThe Coxib and traditional NSAID Trialists' Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.
Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of naproxen may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]).
Avoid the use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.
Since each ANAPROX DS tablet contains 50 mg of sodium (about 2 mEq per each 500 mg of naproxen), this should be considered in patients whose overall intake of sodium must be severely restricted.
Renal Toxicity And Hyperkalemia Renal ToxicityLong-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
No information is available from controlled clinical studies regarding the use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS in patients with advanced renal disease. The renal effects of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS may hasten the progression of renal dysfunction in patients with preexisting renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS. Avoid the use of NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.
HyperkalemiaIncreases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.
Anaphylactic ReactionsNaproxen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to naproxen and in patients with aspirin-sensitive asthma.
Seek emergency help if an anaphylactic reaction occurs.
Exacerbation Of Asthma Related To Aspirin SensitivityA subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs.
Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are contraindicated in patients with this form of aspirin sensitivity. When NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
Serious Skin ReactionsNSAIDs, including naproxen, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS at the first appearance of skin rash or any other sign of hypersensitivity. NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are contraindicated in patients with previous serious skin reactions to NSAIDs.
Premature Closure Of Fetal Ductus ArteriosusNaproxen may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, in pregnant women starting at 30 weeks of gestation (third trimester).
Hematologic ToxicityAnemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin and other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding.
Masking Of Inflammation And FeverThe pharmacological activity of NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.
Long-Term Use And Laboratory MonitoringBecause serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically.
Patients with initial hemoglobin values of 10g or less who are to receive long-term therapy should have hemoglobin values determined periodically.
Because of adverse eye findings in animal studies with drugs of this class, it is recommended that ophthalmic studies be carried out if any change or disturbance in vision occurs.
Patient Counseling InformationAdvise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS and periodically during the course of ongoing therapy.
Cardiovascular Thrombotic EventsAdvise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately.
Gastrointestinal Bleeding, Ulceration, And PerforationAdvise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding.
HepatotoxicityInform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS and seek immediate medical therapy.
Heart Failure And EdemaAdvise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur.
Anaphylactic ReactionsInform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur.
Serious Skin ReactionsAdvise patients to stop NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS immediately if they develop any type of rash and to contact their healthcare provider as soon as possible.
Female FertilityAdvise females of reproductive potential who desire pregnancy that NSAIDs, including NAPROSYN Tablets, ECNAPROSYN, and ANAPROX DS, may be associated with a reversible delay in ovulation (see Use in Specific Populations.)
Fetal ToxicityInform pregnant women to avoid use of NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus.
Avoid Concomitant Use Of NSAIDsInform patients that the concomitant use of NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.
Use Of NSAIDS And Low-Dose AspirinInform patients not to use low-dose aspirin concomitantly with NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS until they talk to their healthcare provider.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility CarcinogenesisA 2-year study was performed in rats to evaluate the carcinogenic potential of naproxen at rat doses of 8, 16, and 24 mg/kg/day (0.05, 0.1, and 0.16 times the maximum recommended human daily dose [MRHD] of 1500 mg/day based on a body surface area comparison). No evidence of tumorigenicity was found.
MutagenesisNaproxen tested positive in the in vivo sister chromatid exchange assay for but was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test).
Impairment Of FertilityMale rats were treated with 2, 5, 10, and 20 mg/kg naproxen by oral gavage for 60 days prior to mating and female rats were treated with the same doses for 14 days prior to mating and for the first 7 days of pregnancy. There were no adverse effects on fertility noted (up to 0.13 times the MRDH based on body surface area).
Use In Specific Populations Pregnancy Risk SummaryUse of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, in pregnant women starting at 30 weeks of gestation (third trimester).
There are no adequate and well-controlled studies of NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. In animal reproduction studies in rats, rabbits, and mice no evidence of teratogenicity or fetal harm when naproxen was administered during the period of organogenesis at doses 0.13, 0.26, and 0.6 times the maximum recommended human daily dose of 1500 mg/day, respectively. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen, resulted in increased pre-and post-implantation loss.
Clinical ConsiderationsLabor or Delivery
There are no studies on the effects of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS during labor or delivery. In animal studies, NSAIDS, including naproxen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.
DataHuman Data
There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor, there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus, and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction, and abnormal prostaglandin E levels in preterm infants. Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly starting at 30-weeks of gestation, or third trimester) should be avoided.
Animal data
Reproduction studies have been performed in rats at 20 mg/kg/day (0.13 times the maximum recommended human daily dose of 1500 mg/day based on body surface area comparison), rabbits at 20 mg/kg/day (0.26 times the maximum recommended human daily dose, based on body surface area comparison), and mice at 170 mg/kg/day (0.6 times the maximum recommended human daily dose based on body surface area comparison) with no evidence of impaired fertility or harm to the fetus due to the drug. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen, resulted in increased pre-and post-implantation loss.
Lactation Risk SummaryThe naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and any potential adverse effects on the breastfed infant from the NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS or from the underlying maternal condition.
Females And Males Of Reproductive Potential InfertilityFemales
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including NAPROSYN Tablets, ECNAPROSYN, and ANAPROX DS, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS, in women who have difficulties conceiving or who are undergoing investigation of infertility.
Pediatric UseSafety and effectiveness in pediatric patients below the age of 2 years have not been established. Pediatric dosing recommendations for polyarticular juvenile idiopathic arthritis are based on well-controlled studies. There are no adequate effectiveness or dose-response data for other pediatric conditions, but the experience in polyarticular juvenile idiopathic arthritis and other use experience have established that single doses of 2.5 to 5 mg/kg as naproxen suspension, , with total daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients over 2 years of age.
Geriatric UseThe hepatic and renal tolerability of long-term naproxen administration was studied in two double-blind clinical trials involving 586 patients. Of the patients studied, 98 patients were age 65 and older and 10 of the 98 patients were age 75 and older. NAPROXEN was administered at doses of 375 mg twice daily or 750 mg twice daily for up to 6 months. Transient abnormalities of laboratory tests assessing hepatic and renal function were noted in some patients, although there were no differences noted in the occurrence of abnormal values among different age groups.
Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects.
Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose.
Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of nonsteroidal anti-inflammatory drugs. Elderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most spontaneous reports of fatal GI events are in the geriatric population.
Naproxen is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of nonsteroidal anti-inflammatory drugs.
Hepatic ImpairmentCaution is advised when high doses are required and some adjustment of dosage may be required in these patients. It is prudent to use the lowest effective dose.
Renal ImpairmentNaproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance < 30 mL/min).
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- A history of gastrointestinal bleeding or perforation related to previous NSAIDs therapy. Active, or history of peptic ulcer/or active gastrointestinal bleeding (two or more distinct episodes of proven ulceration or bleeding).
- In principle, Nalgesin must not be administered to patients with gastrointestinal ulcerations, congestive gastritis or atrophic gastritis, gastrointestinal bleeding or other bleeding such as cerebrovascular bleeding.
- Hemorrhoids or predisposition to rectal bleeding.
4.4 Special warnings and precautions for useIn all patients:
Patients treated with NSAIDs long-term should undergo regular medical supervision to monitor for adverse events.
Elderly:
- Posology and administration). Prolonged use of NSAIDs in these patients is not recommended. Where prolonged therapy is required patients should be reviewed regularly.Severe gastrointestinal side effects may occur in patients who use prostaglandin synthetase inhibitors. The risk of developing gastrointestinal ulcers or bleeding increases with the duration of use and dose of Nalgesin. This risk is not limited to a specific patient population, but the elderly and debilitated individuals exhibit poorer tolerance to gastrointestinal ulceration or bleeding than others. The majority of fatal gastrointestinal effects attributed to prostaglandin synthetase inhibitors occurred in this population.
The antipyretic and anti-inflammatory activities of Nalgesin may reduce fever and inflammation, thereby diminishing their utility as diagnostic signs.
Respiratory disorders:
Caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.
Nalgesin decreases platelet aggregation and prolongs bleeding time. This effect should be kept in mind when bleeding times are determined.
Renal and Hepatic Impairment:
There have been reports of impaired renal function, renal failure, acute interstitial nephritis, haematuria, proteinuria, renal papillary necrosis and occasionally nephrotic syndrome associated with Nalgesin.
Renal failure linked to reduced prostaglandin production
The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure.-Contraindications).
Use in patients with impaired renal function
As Nalgesin is eliminated to a large extent (95%) by urinary excretion via glomerular filtration, it should be used with great caution in patients with impaired renal function and the monitoring of serum creatinine and/or creatinine clearance is advised and patients should be adequately hydrated. Nalgesin is contraindicated in patients having a baseline creatinine clearance of less than 30ml/minute.
Haemodialysis does not decrease the plasma concentration of Nalgesin because of the high degree of protein binding.
Certain patients, specifically those whose renal blood flow is compromised, such as in extracellular volume depletion, cirrhosis of the liver, sodium restriction, congestive heart failure, and pre-existing renal disease, should have renal function assessed before and during Nalgesin therapy. Some elderly patients in whom impaired renal function may be expected, as well as patients using diuretics, may also fall within this category. A reduction in daily dosage should be considered to avoid the possibility of excessive accumulation of Nalgesin metabolites in these patients.
Use in patients with impaired liver function
Care should also be exercised in patients with hepatic insufficiency.
Caution is advised when high doses of Nalgesin are administered to elderly patients, because there are indications that the quantity of non-protein-bound Nalgesin increases in such patients. Since Nalgesin has an anti-inflammatory, analgesic and antipyretic effect, certain symptoms of infection can therefore be masked.
Chronic alcoholic liver disease and probably also other forms of cirrhosis reduce the total plasma concentration of Nalgesin, but the plasma concentration of unbound Nalgesin is increased. The implication of this finding for Nalgesin dosing is unknown but it is prudent to use the lowest effective dose.
As with other non-steroidal anti-inflammatory drugs, elevations of one or more liver function tests may occur. Hepatic abnormalities may be the result of hypersensitivity rather than direct toxicity. Severe hepatic reactions, including jaundice and hepatitis (some cases of hepatitis have been fatal) have been reported with this drug as with other non-steroidal anti-inflammatory drugs. Cross reactivity has been reported.
Gastrointestinal bleeding, ulceration and perforation:
GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events.
The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation , when used with alcohol, in smoking and in the elderly. These patients should commence treatment on the lowest dose available.
Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.
Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroid, or anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin. If a corticosteroid is replaced by Nalgesin and the substitution occurs partially or fully, the usual precautions which come into consideration when discontinuing corticosteroid treatment should be applied.
When GI bleeding or ulceration occurs in patients receiving Nalgesin, the treatment should be withdrawn.
- Undesirable effects)Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk.
Haematological
Patients who have coagulation disorders or are receiving drug therapy that interferes with haemostasis should be carefully observed if Nalgesin-containing products are administered.
Patients at high risk of bleeding or those on full anti-caogulation therapy, e.g. who use coumarin derivatives or heparin alongside Nalgesin have an increased risk of bleeding. The benefits in that case should be weighed up against the risks. In any case concomitant use of Nalgesin with a high dose of heparin (or derivatives thereof) is not recommended.
Anaphylactic (anaphylactoid) reactions
Hypersensitivity reactions may occur in susceptible individuals. Anaphylactic (anaphylactoid) reactions may occur both in patients with and without a history of hypersensitivity or exposure to aspirin, other non-steroidal anti-inflammatory drugs or Nalgesin-containing products. They may also occur in individuals with a history of angio-oedema, bronchospastic reactivity (e.g. asthma), rhinitis and nasal polyps.
Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome.
Steroids
If steroid dosage is reduced or eliminated during therapy, the steroid dosage should be reduced slowly and the patients must be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis.
Ocular effects
Studies have not shown changes in the eye attributable to Nalgesin administration. In rare cases, adverse ocular disorders including papillitis, retrobulbar optic neuritis and papilloedema, have been reported in users of NSAIDs including Nalgesin, although a cause-and-effect relationship cannot be established; accordingly, patients who develop visual disturbances during treatment with Nalgesin-containing products should have an ophthalmological examination.
Cardiovascular and cerebrovascular effects
Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.
Mild peripheral oedema has been observed in a few patients receiving Nalgesin. Although sodium retention has not been reported in metabolic studies, it is possible that patients with questionable or compromised cardiac function may be at a greater risk when taking Nalgesin.
Clinical trial and epidemiological data suggest that use of coxibs and some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Although data suggest that the use of Nalgesin (1000mg daily) may be associated with a lower risk, some risk cannot be excluded.
Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with Nalgesin after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).
Dermatological
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens- Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reactions occurring in the majority of cases within the first month of treatment. Nalgesin should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. If the skin becomes delicate or in the event of blistering or other symptoms of pseudoporphyria, treatment should be discontinued and the patient should be carefully monitored.
Combination with other NSAIDs including cyclooxygenase-2 selective inhibitors
The combination of Nalgesin-containing products and other NSAIDs, including cyclooxygenase-2 selective inhibitors, is not recommended, because of the cumulative risks of inducing serious NSAID-related adverse events.
SLE and mixed connective tissue disease:
- Undesirable effects).Female fertility:
The use of Nalgesin, as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of Nalgesin should be considered.
Interference in tests:
It is suggested that Nalgesin therapy be temporarily discontinued 48 hours before adrenal function tests are performed, because Nalgesin may artifactually interfere with some tests for 17-ketogenic steroids. Similarly, Nalgesin may interfere with some assays of urinary 5-hydroxyindoleacetic acid.
Sporadic abnormalities in laboratory tests (e.g. liver function test) have occurred in patients on Nalgesin therapy, but no definite trend was seen in any test indicating toxicity.
Contains Lactose:
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiencyor glucose-galactose malabsorption should not take this medicine.
WARNINGSIncluded as part of the PRECAUTIONS section.
PRECAUTIONS Cardiovascular Thrombotic EventsClinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.
To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as naproxen, increases the risk of serious gastrointestinal (GI) events.
Status Post Coronary Artery Bypass Graft (CABG) SurgeryTwo large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG.
Post-MI PatientsObservational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.
Avoid the use of Nalgesin in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If Nalgesin is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
Gastrointestinal Bleeding, Ulceration, And PerforationNSAIDs, including naproxen, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.
Risk Factors For GI Bleeding, Ulceration, And PerforationPatients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.
Strategies To Minimize The GI Risks In NSAID-Treated PatientsElevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported.
Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including naproxen.
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue Nalgesin immediately, and perform a clinical evaluation of the patient.
HypertensionNSAIDs, including Nalgesin, can lead to new onset or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs.
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.
Heart Failure And EdemaThe Coxib and traditional NSAID Trialists' Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.
Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of naproxen may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]).
Avoid the use of Nalgesin in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If Nalgesin is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.
Renal Toxicity And Hyperkalemia Renal ToxicityLong-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
No information is available from controlled clinical studies regarding the use of Nalgesin in patients with advanced renal disease. The renal effects of Nalgesin may hasten the progression of renal dysfunction in patients with preexisting renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating Nalgesin. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of Nalgesin. Avoid the use of Nalgesin in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If Nalgesin is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.
HyperkalemiaIncreases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.
Anaphylactic ReactionsNaproxen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to naproxen and in patients with aspirin-sensitive asthma.
Seek emergency help if an anaphylactic reaction occurs.
Exacerbation Of Asthma Related To Aspirin SensitivityA subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, Nalgesin is contraindicated in patients with this form of aspirin sensitivity. When Nalgesin is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
Serious Skin ReactionsNSAIDs, including naproxen can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of Nalgesin at the first appearance of skin rash or any other sign of hypersensitivity.
Nalgesin is contraindicated in patients with previous serious skin reactions to NSAIDs.
Premature Closure Of Fetal Ductus ArteriosusNaproxen may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Nalgesin, in pregnant women starting at 30 weeks of gestation (third trimester).
Hematologic ToxicityAnemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with Nalgesin has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including Nalgesin, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders, concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding.
Masking Of Inflammation And FeverThe pharmacological activity of Nalgesin in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.
Laboratory MonitoringBecause serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically.
Patient Counseling InformationAdvise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with Nalgesin and periodically during the course of ongoing therapy.
Cardiovascular Thrombotic EventsAdvise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately.
Gastrointestinal Bleeding, Ulceration, And PerforationNalgesin, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding.
HepatotoxicityInform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop Nalgesin and seek immediate medical therapy.
Heart Failure And EdemaAdvise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur.
Anaphylactic ReactionsInform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur.
Serious Skin ReactionsNalgesin, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death. Advise patients to stop Nalgesin immediately if they develop any type of rash and to contact their healthcare provider as soon as possible.
Female FertilityAdvise females of reproductive potential who desire pregnancy that NSAIDs, including Nalgesin, may be associated with a reversible delay in ovulation.
Fetal ToxicityInform pregnant women to avoid use of Nalgesin and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus.
Avoid Concomitant Use Of NSAIDsInform patients that the concomitant use of Nalgesin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.
Use Of NSAIDS And Low-Dose AspirinInform patients not to use low-dose aspirin concomitantly with Nalgesin until they talk to their healthcare provider.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility CarcinogenesisA two year study was performed in rats to evaluate the carcinogenic potential of naproxen at doses of 8 mg/kg/day, 16 mg/kg/day, and 24 mg/kg/day (0.05, 0.1, and 0.16 times the maximum recommended human daily dose of 1,500 mg/day based on a body surface area comparison). No evidence of tumorigenicity was found.
MutagenesisStudies to evaluate the mutagenic potential of Naprosyn Suspension have not been completed.
Impairment Of FertilityStudies to evaluate the impact of naproxen on male or female fertility have not been completed.
Use In Specific Populations Pregnancy Risk SummaryUse of NSAIDs, including Nalgesin, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Nalgesin, in pregnant women starting at 30 weeks of gestation (third trimester).
There are no adequate and well-controlled studies of Nalgesin in pregnant women.
Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations, and 15 to 20% for pregnancy loss. In animal reproduction studies in rats, rabbit, and mice no evidence of teratogenicity or fetal harm when naproxen was administered during the period of organogenesis at doses 0.13, 0.26, and 0.6 times the maximum recommended human daily dose of 1,500 mg/day, respectively. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen sodium resulted in increased pre-and post-implantation loss.
Clinical ConsiderationsLabor Or Delivery
There are no studies on the effects of Nalgesin during labor or delivery. In animal studies, NSAIDS, including naproxen sodium, inhibit prostaglandin synthesis, cause delayed parturition, increase incidence of dystocia and increase the incidence of stillbirth.
DataHuman Data
There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor, there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus, and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction, and abnormal prostaglandin E levels in preterm infants. Because of the known effect of drugs of this class on the human fetal cardiovascular system (closure of the ductus arteriosus), use during third trimester should be avoided.
Animal data
Reproduction studies have been performed in rats at 20 mg/kg/day (0.13 times the maximum recommended human daily dose of 1,500 mg/day based on body surface area comparison) rabbits at 20 mg/kg/day (0.26 times the maximum recommended human daily dose, based on body surface area comparison), and mice at 170 mg/kg/day (0.6 times the maximum recommended human daily dose based on body surface area comparison) with no evidence of impaired fertility or harm to the fetus due to the drug. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen sodium resulted in increased preand post-implantation loss.
Lactation Risk SummaryThe naproxen anion has been found in the milk of lactating women at a concentration of approximately 1% of that found in the plasma. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Nalgesin and any potential adverse effects on the breastfed infant from the Nalgesin or from the underlying maternal condition.
Females And Males Of Reproductive Potential InfertilityFemales
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including Nalgesin, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including Nalgesin, in women who have difficulties conceiving or who are undergoing investigation of infertility.
Pediatric UseThe safety and effectiveness of Nalgesin in pediatric populations has not been established.
Geriatric UseElderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects.
Naproxen and its metabolites are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, use caution in this patient population, and it may be useful to monitor renal function
WARNINGSIncluded as part of the PRECAUTIONS section.
PRECAUTIONS Cardiovascular Thrombotic EventsClinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.
To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as naproxen, increases the risk of serious gastrointestinal (GI) events.
Status Post Coronary Artery Bypass Graft (CABG) SurgeryTwo large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG.
Post-MI PatientsObservational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.
Avoid the use of Nalgesin Tablets, EC-Nalgesin, and ANAPROX DS in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If Nalgesin Tablets, EC-Nalgesin and ANAPROX DS are used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
Gastrointestinal Bleeding, Ulceration, And PerforationNSAIDs, including naproxen, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs.
Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.
Risk Factors For GI Bleeding, Ulceration, And PerforationPatients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.
Strategies To Minimize The GI Risks In NSAID-treated PatientsElevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported.
Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including naproxen.
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue Nalgesin Tablets, ECNalgesin, or ANAPROX DS immediately, and perform a clinical evaluation of the patient.
HypertensionNSAIDs, including Nalgesin Tablets, EC-Nalgesin, and ANAPROX DS, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs.
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.
Heart Failure And EdemaThe Coxib and traditional NSAID Trialists' Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.
Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of naproxen may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]).
Avoid the use of Nalgesin Tablets, EC-Nalgesin, or ANAPROX DS in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If Nalgesin Tablets, EC-Nalgesin, or ANAPROX DS is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.
Since each ANAPROX DS tablet contains 50 mg of sodium (about 2 mEq per each 500 mg of naproxen), this should be considered in patients whose overall intake of sodium must be severely restricted.
Renal Toxicity And Hyperkalemia Renal ToxicityLong-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
No information is available from controlled clinical studies regarding the use of Nalgesin Tablets, EC-Nalgesin, or ANAPROX DS in patients with advanced renal disease. The renal effects of Nalgesin Tablets, EC-Nalgesin, or ANAPROX DS may hasten the progression of renal dysfunction in patients with preexisting renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating Nalgesin Tablets, EC-Nalgesin, or ANAPROX DS. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of Nalgesin Tablets, EC-Nalgesin, and ANAPROX DS. Avoid the use of Nalgesin Tablets, EC-Nalgesin, and ANAPROX DS in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If Nalgesin Tablets, EC-Nalgesin, or ANAPROX DS is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.
HyperkalemiaIncreases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.
Anaphylactic ReactionsNaproxen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to naproxen and in patients with aspirin-sensitive asthma.
Seek emergency help if an anaphylactic reaction occurs.
Exacerbation Of Asthma Related To Aspirin SensitivityA subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs.
Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, Nalgesin Tablets, EC-Nalgesin, and ANAPROX DS are contraindicated in patients with this form of aspirin sensitivity. When Nalgesin Tablets, EC-Nalgesin, or ANAPROX DS is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
Serious Skin ReactionsNSAIDs, including naproxen, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of Nalgesin Tablets, EC-Nalgesin, or ANAPROX DS at the first appearance of skin rash or any other sign of hypersensitivity. Nalgesin Tablets, EC-Nalgesin, and ANAPROX DS are contraindicated in patients with previous serious skin reactions to NSAIDs.
Premature Closure Of Fetal Ductus ArteriosusNaproxen may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Nalgesin Tablets, EC-Nalgesin, and ANAPROX DS, in pregnant women starting at 30 weeks of gestation (third trimester).
Hematologic ToxicityAnemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with Nalgesin Tablets, EC-Nalgesin, or ANAPROX DS has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including Nalgesin Tablets, EC-Nalgesin, and ANAPROX DS, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin and other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding.
Masking Of Inflammation And FeverThe pharmacological activity of Nalgesin Tablets, EC-Nalgesin, and ANAPROX DS in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.
Long-Term Use And Laboratory MonitoringBecause serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically.
Patients with initial hemoglobin values of 10g or less who are to receive long-term therapy should have hemoglobin values determined periodically.
Because of adverse eye findings in animal studies with drugs of this class, it is recommended that ophthalmic studies be carried out if any change or disturbance in vision occurs.
Patient Counseling InformationAdvise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with Nalgesin Tablets, EC-Nalgesin or ANAPROX DS and periodically during the course of ongoing therapy.
Cardiovascular Thrombotic EventsAdvise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately.
Gastrointestinal Bleeding, Ulceration, And PerforationAdvise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding.
HepatotoxicityInform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop Nalgesin Tablets, EC-Nalgesin or ANAPROX DS and seek immediate medical therapy.
Heart Failure And EdemaAdvise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur.
Anaphylactic ReactionsInform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur.
Serious Skin ReactionsAdvise patients to stop Nalgesin Tablets, EC-Nalgesin or ANAPROX DS immediately if they develop any type of rash and to contact their healthcare provider as soon as possible.
Female FertilityAdvise females of reproductive potential who desire pregnancy that NSAIDs, including Nalgesin Tablets, ECNalgesin, and ANAPROX DS, may be associated with a reversible delay in ovulation (see Use in Specific Populations.)
Fetal ToxicityInform pregnant women to avoid use of Nalgesin Tablets, EC-Nalgesin or ANAPROX DS and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus.
Avoid Concomitant Use Of NSAIDsInform patients that the concomitant use of Nalgesin Tablets, EC-Nalgesin and ANAPROX DS with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.
Use Of NSAIDS And Low-Dose AspirinInform patients not to use low-dose aspirin concomitantly with Nalgesin Tablets, EC-Nalgesin and ANAPROX DS until they talk to their healthcare provider.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility CarcinogenesisA 2-year study was performed in rats to evaluate the carcinogenic potential of naproxen at rat doses of 8, 16, and 24 mg/kg/day (0.05, 0.1, and 0.16 times the maximum recommended human daily dose [MRHD] of 1500 mg/day based on a body surface area comparison). No evidence of tumorigenicity was found.
MutagenesisNaproxen tested positive in the in vivo sister chromatid exchange assay for but was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test).
Impairment Of FertilityMale rats were treated with 2, 5, 10, and 20 mg/kg naproxen by oral gavage for 60 days prior to mating and female rats were treated with the same doses for 14 days prior to mating and for the first 7 days of pregnancy. There were no adverse effects on fertility noted (up to 0.13 times the MRDH based on body surface area).
Use In Specific Populations Pregnancy Risk SummaryUse of NSAIDs, including Nalgesin Tablets, EC-Nalgesin, and ANAPROX DS, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Nalgesin Tablets, EC-Nalgesin, and ANAPROX DS, in pregnant women starting at 30 weeks of gestation (third trimester).
There are no adequate and well-controlled studies of Nalgesin Tablets, EC-Nalgesin or ANAPROX DS in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. In animal reproduction studies in rats, rabbits, and mice no evidence of teratogenicity or fetal harm when naproxen was administered during the period of organogenesis at doses 0.13, 0.26, and 0.6 times the maximum recommended human daily dose of 1500 mg/day, respectively. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen, resulted in increased pre-and post-implantation loss.
Clinical ConsiderationsLabor or Delivery
There are no studies on the effects of Nalgesin Tablets, EC-Nalgesin, or ANAPROX DS during labor or delivery. In animal studies, NSAIDS, including naproxen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.
DataHuman Data
There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor, there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus, and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction, and abnormal prostaglandin E levels in preterm infants. Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly starting at 30-weeks of gestation, or third trimester) should be avoided.
Animal data
Reproduction studies have been performed in rats at 20 mg/kg/day (0.13 times the maximum recommended human daily dose of 1500 mg/day based on body surface area comparison), rabbits at 20 mg/kg/day (0.26 times the maximum recommended human daily dose, based on body surface area comparison), and mice at 170 mg/kg/day (0.6 times the maximum recommended human daily dose based on body surface area comparison) with no evidence of impaired fertility or harm to the fetus due to the drug. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen, resulted in increased pre-and post-implantation loss.
Lactation Risk SummaryThe naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Nalgesin Tablets, EC-Nalgesin, or ANAPROX DS and any potential adverse effects on the breastfed infant from the Nalgesin Tablets, EC-Nalgesin, or ANAPROX DS or from the underlying maternal condition.
Females And Males Of Reproductive Potential InfertilityFemales
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including Nalgesin Tablets, ECNalgesin, and ANAPROX DS, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including Nalgesin Tablets, EC-Nalgesin and ANAPROX DS, in women who have difficulties conceiving or who are undergoing investigation of infertility.
Pediatric UseSafety and effectiveness in pediatric patients below the age of 2 years have not been established. Pediatric dosing recommendations for polyarticular juvenile idiopathic arthritis are based on well-controlled studies. There are no adequate effectiveness or dose-response data for other pediatric conditions, but the experience in polyarticular juvenile idiopathic arthritis and other use experience have established that single doses of 2.5 to 5 mg/kg as naproxen suspension, , with total daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients over 2 years of age.
Geriatric UseThe hepatic and renal tolerability of long-term naproxen administration was studied in two double-blind clinical trials involving 586 patients. Of the patients studied, 98 patients were age 65 and older and 10 of the 98 patients were age 75 and older. NAPROXEN was administered at doses of 375 mg twice daily or 750 mg twice daily for up to 6 months. Transient abnormalities of laboratory tests assessing hepatic and renal function were noted in some patients, although there were no differences noted in the occurrence of abnormal values among different age groups.
Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects.
Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose.
Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of nonsteroidal anti-inflammatory drugs. Elderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most spontaneous reports of fatal GI events are in the geriatric population.
Naproxen is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of nonsteroidal anti-inflammatory drugs.
Hepatic ImpairmentCaution is advised when high doses are required and some adjustment of dosage may be required in these patients. It is prudent to use the lowest effective dose.
Renal ImpairmentNaproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance < 30 mL/min).
Undesirable effects such as dizziness, vertigo, insomnia, drowsiness, fatigue and visual disturbances or depression are possible after taking Nalgesin. If patient experiences these or similar undesirable effects, they should not drive or operate machinery.
None stated
