Source: Health Products and Food Branch (CA) Revision Year: 2021
Naproxen sodium is contraindicated in patients
sodium) or any of the excipients in the tablets. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph
Patients who are taking any other analgesic or anti-inflammatory drugs (including naproxen or naproxen sodium), steroids, diuretics or drugs that influence hemostasis.
Patients with severe cardiac impairment and a history of hypertension.
Naproxen may attenuate acetylsalicylic acid’s antiplatelet effect. Patients should talk to their doctor if they are on an acetylsalicylic acid regimen and plan to take naproxen sodium (see the Drug-Drug Interactions section of the product monograph).
Patients with a medical history of gastrointestinal disease including peptic ulceration. Pain of gastrointestinal origin is not an indication for naproxen sodium.
Patients with coagulation disturbances. Numerous studies have shown that concomitant use of NSAIDs and anti-coagulants increases the risk of bleeding. Concurrent therapy of ALEVE with warfarin requires close monitoring of the international normalized ratio (INR). Even with therapeutic INR monitoring, increased bleeding may occur.
Some patients may experience drowsiness, dizziness, blurred vision vertigo, tinnitus, hearing loss, insomnia or depression with the use of NSAIDs such as ALEVE. If patients experience such adverse reactions, they should exercise caution in carrying out activities that require alertness, like driving or using machinery.
Patients with a medical history of asthma, rhinitis or nasal polyps.
Patients with a medical history of urticaria and angioedema.
Naproxen, 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 difficulty conceiving or who are undergoing investigation of infertility, withdrawal of naproxen should be considered.
Patients older than 65 years and frail or debilitated patients are more susceptible to a variety of adverse reactions from NSAIDs. The incidence of these adverse reactions increases with dose and duration of treatment. In addition, these patients are less tolerant to ulceration and bleeding. Most reports of fatal GI events are in this population. Older patients are also at risk of lower esophageal injury including ulceration and bleeding.
Caution should be exercised in prescribing ALEVE during the first and second trimesters of pregnancy. As with other drugs of this type, naproxen sodium produces delay in parturition in animals and also affects the human fetal cardiovascular system (closure of the ductus arteriosus). Therefore, naproxen sodium should not be used unless clearly needed and when directed to do so by a doctor. The use of naproxen sodium in the first and second trimesters of pregnancy requires cautious balancing of the possible benefits and risks to the mother and fetus, especially during the first trimester.
Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or the embryo/fetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation after use of a prostaglandin synthesis inhibitor in early pregnancy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-fetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period.
Naproxen has been found in the milk of lactating mothers. The use of naproxen sodium should therefore be avoided in women who are breast feeding unless clearly needed and directed to do so by a doctor.
Children under 12 should not take this drug, unless directed by a doctor. The safety in pediatric use has not been established.
One tablet contains 20 mg sodium, which is classified as low in sodium. A variety of Health Canada guidelines suggest that a diet low in sodium should be restricted to 2 g per day while the Sodium Collaborative Research group suggests that a low-sodium diet should be restricted to ≤1.2 g (50 mmol) per day.
Naproxen sodium causes transient, dose-dependent modestly increased bleeding times. However, these values often do not exceed the upper limit of the reference range. Naproxen sodium may theoretically interfere with the urinary analyses of 17-ketogenic steroids and 5-hydroxy indoleacetic acid (5 HIAA).
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
The safety profile of ALEVE was analysed through a meta-analysis of the clinical trials which were performed in the course of the ALEVE clinical development program. The meta-analysis included a total of 46 studies, which satisfied the criteria of being randomized, placebo controlled, double-blind and used ALEVE in single (SD, 220 mg or 440 mg pooled data), multiple (MD, 440 mg/day and 880 mg/day) or PRN (up to 880 mg/day) doses. In total 4623 subjects were treated with ALEVE while 2659 took placebo. Fifty-two percent of subjects participated in SD trials, 20% in MD trials all lasting for 7 days and the remaining 28% in PRN trials. They were predominantly Caucasian, slightly more women with a mean age between the 20s and 30s with exception of 422 patients from the arthritis studies with a mean age in the low 60s. The occurrence of all adverse events did not differ between ALEVE and placebo, in the SD, MD or PRN trials. Moderate and severe events tended to occur less frequently in the subjects treated with ALEVE MD compared to placebo, presumably due to concomitant treatment of naturally occurring headache. The data in table 1 shows the frequencies of adverse events that are >1% from the meta-analysis. A thorough evaluation of gastrointestinal adverse events showed no difference between ALEVE and placebo. There was no serious gastrointestinal adverse event (bleeding or perforation) or any case of anaphylaxis.
Table 1. Adverse events that occurred with ALEVE (low dose short duration) with a frequency >1% in clinical trials:
| ALEVE n=4623 (%) | Placebo n=2659 (%) | |
|---|---|---|
| Gastrointestinal | ||
| Dyspepsia | 1.9% | 1.8% |
| Nausea | 4.4% | 4.8% |
| Vomiting | 1.8% | 2.4% |
| Nervous System | ||
| Dizziness | 2.0% | 2.1% |
| Headache | 4.9% | 6.8% |
| Somnolence | 2.4% | 1.5% |
Gastrointestinal: Constipation, Diarrhea
Other: Allergic reactions, Edema, Rash/pruritus
Table 2. The following post-marketing adverse drug reactions have been observed for OTC naproxen sodium and/or solely for prescription dosages (higher dose and/or longer duration) of naproxen/naproxen sodium:
| Immune system disorders | Very rare <0.01% and isolated reports | Anaphylaxis/anaphylactoid reactions |
| Blood and the lymphatic system disorders | Very rare <0.01% and isolated reports | hematopoietic disturbances (leukopenia, thrombocytopenia, agranulocytosis, aplastic anemia, eosinophilia, hemolytic anemia) |
| Psychiatric disorders | Very rare <0.01% and isolated reports | psychiatric disorders |
| Nervous system disorders | Common ≥1% - <10% | dizziness, headache, lightheadedness |
| Uncommon ≥0.1% - <1% | drowsiness, insomnia, somnolence | |
| Very rare <0.01% and isolated reports | aseptic meningitis, cognitive dysfunction, convulsions | |
| Eye disorders | Very rare <0.01% and isolated reports | visual disturbance, corneal opacity, papillitis, retrobulbar optic neuritis, papilledema |
| Ear & labyrinth disorders | Uncommon ≥0.1% - <1% | vertigo |
| Very rare <0.01% and isolated reports | hearing impairment, tinnitus | |
| Cardiac disorders | Very rare <0.01% and isolated reports | congestive heart failure, hypertension, pulmonary edema |
| Vascular disorders | Very rare <0.01% and isolated reports | vasculitis |
| Respiratory, Thoracic and Mediastinal disorders | Very rare <0.01% and isolated reports | dyspnea, asthma, eosinophilic pneumonitis |
| Gastrointestinal disorders | Common ≥1% - <10% | dyspepsia, nausea, heartburn, abdominal pain |
| Uncommon ≥0.1% - <1% | diarrhea, constipation, vomiting | |
| Rare ≥0.01% - <0.1% | peptic ulcers without or with bleeding or perforation, gastrointestinal bleeding, hematemesis, melena | |
| Very rare <0.01% and isolated reports | pancreatitis, colitis, aphthous ulcers, stomatitis, esophagitis, intestinal ulcerations | |
| Hepatobiliary disorders | Very rare <0.01% and isolated reports | Hepatitis, icterus |
| Skin & subcutaneous tissue disorders | Uncommon ≥0.1% - <1% | exanthema (rash), pruritus, urticaria |
| Rare ≥0.01% - <0.1% | angioneurotic edema | |
| Very rare <0.01% and isolated reports | alopecia (usually reversible), photosensitivity, porphyria, exudative erythema multiforme, epidermal necrolysis, erythema nodosum, fixed drug eruption, lichen planus, pustular reaction, skin rashes, Systemic Lupus Erythematosus, Stevens-Johnson syndrome, photosensitivity reactions including porphyria cutanea tarda (“pseudoporphyria”) or epidermolysis bullosa | |
| Renal & urinary disorders | Rare ≥0.01% - <0.1% | renal impairment |
| Very rare <0.01% and isolated reports | interstitial nephritis, renal papillary necrosis, nephrotic syndrome, renal failure, renal disease | |
| Pregnancy | Very rare <0.01% and isolated reports | Induction of labour |
| Congenital | Very rare <0.01% and isolated reports | Closure of ductus arteriosus, orofacial clefts as an isolated report |
| Reproductive system and breast disorders | Very rare <0.01% and isolated reports | female infertility |
| General disorders | Rare ≥0.01% - <0.1% | peripheral edema, particular in patients with hypertension or kidney failure, pyrexia |
| Investigations | Very rare <0.01% and isolated reports | raised serum creatinine, abnormal liver function test |
Severe allergic ADRs are very rare events, which are more likely to occur in subjects who have experienced allergic reactions previously. In short term use of naproxen sodium occurrence of GI ulcers/bleeding/perforation are rare events.
The adverse drug reactions seen during short term use of naproxen sodium are normally mild and disappear after discontinuing the drug. The most common ADRs for OTC naproxen sodium and/or solely for prescription doses (higher dose and or longer duration) are dizziness, headache, light-headedness, dyspepsia, nausea, heartburn, and abdominal pain. Uncommonly drowsiness, insomnia, and skin rashes are encountered. Peripheral edemas are rare events. Other ADRs are very rare and/or observed through isolated reports only. The adverse events are common to all NSAIDs as a class; there is no adverse event that is specific for naproxen alone.
During short term use of naproxen sodium, interactions with the following medications could be of clinical significance.
The drugs listed in table 3 are based on either drug interaction case reports or studies.
Table 3. Established or Potential Drug-Drug Interactions:
| Proper Name | Effect | Clinical comment |
|---|---|---|
| Cyclosporine | cyclosporin concentrations may increase, which could induce nephrotoxicity | These patients should be monitored adequately. |
| Lithium | in some patients lithium concentrations may increase, which could induce nausea, polydipsia, polyuria, tremor, confusion | These patients should be monitored adequately |
| Methotrexate | if weekly methotrexate intake exceeds 15 mg, methotrexate concentrations may increase which could induce blood dyscrasia, nephrotoxicity, mucosal ulcerations | These patients should be monitored adequately |
| NSAIDs | adds to the risk of gastro-intestinal bleeding | Should be avoided; however, effects may be minimised by using the lowest effective dose for the shortest duration necessary. |
| Low dose ASA (81mg to 325mg daily, for cardiovascular protection e.g. ASPIRIN 81mg) | Can add to the risk of gastro-intestinal bleeding and may attenuate the irreversible platelet inhibition induced by acetylsalicylic acid | These patients should be monitored adequately. |
| Anticoagulants | adds to the risk of gastro-intestinal bleeding | These patients should be monitored adequately. |
| Glucocorticoids | adds to the risk of gastro-intestinal bleeding | These patients should be monitored adequately. |
| Diuretics, antihypertensive drugs including ACE Inhibitors, β blockers | the diuretic and antihypertensive efficacy, particular in patients with pre-existing nephropathy, may be reduced | These patients should be monitored adequately. Concomitant use with diuretics may increase risk of congestive heart failure. |
In a recent (2005) American case-control study, labelled, short term use of OTC naproxen or OTC ibuprofen was not associated with GI risk nor was there any detectable interaction with ASA at this dose level; furthermore there was no difference between OTC naproxen or OTC ibuprofen. An increased risk could be attributed with concomitant use of ASA and high dose NSAIDs; however, the numbers of exposed cases were small.
Another recent (2006) American retrospective database study found an odds ratio of 2.07 (1.23–3.49) for GI complications with concomitant use of low dose ASA and OTC-dose naproxen; for comparison, this ratio was 3.36 (2.36–4.80) in subjects taking OTC-dose ibuprofen and low dose ASA; the corresponding ratio for naproxen as mono-therapy was 1.54 (1.04-2.28) which is not significantly different from the combined therapy. The corresponding ratio for ibuprofen as mono-therapy was 1.38 (1.07-1.78) which is significantly lower than the combined therapy of ibuprofen and low dose ASA therapy.
Due to the nature of the study, information regarding the duration of naproxen and ibuprofen intake could not be collected. The findings are consistent with previous study results indicating ncreased GI risk in patients taking OTC-NSAIDS for longer terms or prescription NSAIDs while on low dose ASA.
Labelled, short term use of OTC naproxen together with low dose ASA was not associated with a detectable GI-risk; longer term use (mainly >10 days) of NSAIDs in OTC doses and concomitant ASA can increase the relative risk a little, adding however only very little absolute risk.
Naproxen may attenuate the irreversible platelet inhibition induced by acetylsalicylic acid. Clinical pharmacodynamic data suggest that concurrent (same day) naproxen sodium usage for more than one day consecutively inhibits the effect of low-dose acetylsalicylic acid on platelet activity and this inhibition may persist for up to several days after stopping naproxen sodium therapy. The clinical relevance of this interaction is not known. Treatment with naproxen sodium in patients with increased cardiovascular risk may limit the cardiovascular protection of acetylsalicylic acid.
During short term use of naproxen sodium interactions of clinical significance do not seem to be relevant for the following medications: antacids, antidiabetics, hydantoines, probenecid, zidovudine.
ALEVE Caplets: The absorption may be slightly delayed with a meal ALEVE Liquid Gels and ALEVE Back and Body Pain (Capsules): Peak naproxen levels were reached at 1.4 hours on an empty stomach and at 3.7 hours with a meal.
Interactions with herbal products have not been established
Naproxen sodium causes transient, dose-dependent modestly increased bleeding times. However, these values often do not exceed the upper limit of the reference range. Naproxen sodium may theoretically interfere with the urinary analyses of 17-ketogenic steroids and 5-hydroxy indoleacetic acid (5 HIAA).
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