Source: Health Products and Food Branch (CA) Revision Year: 2021
Naproxen like all other nonsteroidal anti-inflammatory drugs (NSAIDs) is an analgesic, antipyretic and anti-inflammatory medication. ALEVE works at both the site of pain and centrally. The principle mechanism of action relies on the inhibition of prostaglandin synthesis. Prostaglandins are naturally occurring fatty acids derivates that are widely distributed in the tissues, and are involved in the production of pain, fever and inflammation. NSAIDs inhibit prostaglandin synthesis through inhibition of the cyclo-oxygenase enzymes. The antiinflammatory and analgesic activity of these drugs is based on the concept that prostaglandins sensitize the tissues to pain- and inflammation-producing mediators and the antipyretic activity is assumed to be due to inhibition of prostaglandin synthesis in the hypothalamus induced by infectious states such as the common cold.
In low dose, that is ≤660 mg naproxen sodium daily, the analgesic and anti-pyretic activities prevail, while higher doses mostly are necessary for a full anti-inflammatory activity response. Significant naproxen plasma levels and onset of pain relief can be obtained within 20 minutes of intake.
Table 4. Summary of naproxen sodium’s pharmacokinetic parameters in healthy subjects:
| Single dose | Cmax μg/ml | t½ hours | AUC0-∞ μg/ml.h | Clearance l/h | Volume of distribution (l) |
|---|---|---|---|---|---|
| 220 mg | 35 | 18 | 546 | 0.4 | 10.0 |
| 440 mg | 66 | 18 | 1021 | 0.4 | 10.6 |
| 2 × 220 mg | 53 | 18.6 | 852 | 0.5 | 14.1 |
Naproxen sodium promptly dissolves in the gastric juice to sodium and fine particles of naproxen. Naproxen is rapidly and completely absorbed from the gastrointestinal tract. The peak plasma level (Cmax) of 53-66 g/ml is reached approximately 1-1½ hours after intake of 440mg naproxen sodium. For ALEVE Caplets, food can slightly delay naproxen absorption but not the extent, and for ALEVE Liquid Gels and ALEVE Back and Body Pain (Capsules), food delays naproxen absorption. The kinetics are dose linear up to 550 mg naproxen sodium twice daily. Plasma concentrations of un-bound circulating naproxen, the active component, of about 10 ng/ml exert analgesic action and correspond to a total naproxen plasma concentration of 15 g/ml.
The volume of distribution of naproxen is small, about 0.1 l/kg. Steady-state concentrations are obtained in two days, and no significant accumulation has been observed. More than 99% of the circulating naproxen is albumin-bound.
Naproxen is either metabolised (cytochrome P450) to 6-0-desmethyl naproxen (6-DMN) and conjugated to glucuronides or left un-metabolised. Naproxen does not induce metabolizing enzymes.
Naproxen and its metabolites are primarily excreted via the kidneys (>95%). The elimination half-life of naproxen is about 14 hours. The rate of excretion has been found to coincide closely with the rate of drug disappearance from plasma.
There is no evidence of differential metabolism or excretion in the elderly.
There is no evidence of differential metabolism or excretion between genders.
In case of severe hepatic insufficiency circulating albumin is decreased giving rise to increased fractions of free and unbound naproxen.
In case of severe renal insufficiency protein binding is lower giving rise to increased fractions of free and unbound naproxen. In patients with severely reduced glomerular filtration, the rate of urinary excretion may be reduced. Naproxen, in contrast to its non-active metabolite 6-DMN, is not cleared from the body during haemodialysis.
Please refer to Action and Clinical Pharmacology section above.
N/A
The oral LD50 of the drug is 543 mg/kg in rats, 1234 mg/kg in mice, 4110 mg/kg in hamsters and greater than 1000 mg/kg in dogs. No carcinogenic or embryotoxic properties were detected and since the launch of naproxen in the beginning of the 1970’s no experience or information has been obtained that could indicate such properties.
In subacute and chronic oral studies with naproxen in a variety of species, the principle pathologic effect was gastrointestinal irritation and ulceration. The lesions seen were predominantly in the small intestine and ranged from hyperaemia to perforation and peritonitis. Similar results have been reported with other non-steroidal anti-inflammatory agents such as ibuprofen, phenylbutazone, ASA, indomethacin and mefenamic acid.
Nephropathy was seen occasionally in acute and subacute studies in rats, mice and rabbits at high-dose levels of naproxen, but not in rhesus monkeys, miniature pigs or dogs. In the affected species the pathologic changes occurred in the cortex and papilla. Some rats examined 14 days after single oral doses of 230 mg/kg or more of naproxen evidenced necrotic areas of cortical and papillary tissue. Tubular dilation (ectasia) occurred in rabbits dosed orally for 14 days with 200mg/kg/day or more of naproxen. An examination of unfixed renal tissue from rabbits sotreated was conducted and revealed the presence of diffraction patterns similar to that of crystalline naproxen. This suggests that the ectasia observed was a physical response to deposition of excreted naproxen within the tubules.
In mice given oral doses of 120 mg/kg/day or more of naproxen for 6 months, the kidneys were characterized by a low but non-dosage-related incidence of cortical sclerosis and papillary tip necrosis. Chronic administration of high doses of naproxen to mice appears to be associated with exacerbation of spontaneous murine nephropathy.
Rhesus monkeys were administered daily doses of 7, 20, or 60 mg/kg and the monkeys received these daily doses for the next six months. No evidence of drug-related pathology was seen in this study. In a 1 year study in rhesus monkeys at daily doses of 100, 140, 180 mg/kg renal lesions consistent with those described for analgesic nephropathy were observed. The severity of the lesions was generally dose related.
A similar catalogue of renal responses has been reported in the laboratory animals treated with a variety of non-steroidal anti-inflammatory agents.
A wide range of susceptibility to gastrointestinal lesions from administration of naproxen was evident in the various species tested. For example, 30mg/kg/day was tolerated well by rats for 90 days, but the same dose was ulcerogenic when administered for 6 months. Rhesus monkeys and miniature swine exhibited no significant pathology when dosed with naproxen at 45 mg/kg/day for 30 days. This dose of naproxen was also tolerated by miniature swine without obvious evidence of adverse effects when administered daily for 1 year. In rhesus monkeys doses as high as 120 mg/kg/day (60 mg/kg b.i.d.) for 6 months produced no clinical or histopathological evidence of gastrointestinal irritation although occult blood in the feces occurred more frequently in these animals compared to controls. Daily administration of naproxen to rhesus monkeys for one year was associated with mild gastric irritation in a few animals receiving 100, 140 or 180 mg/kg. In rabbits the maximum tolerated repeated oral dose is 80 to 100 mg/kg/day. Mice survived oral daily doses of 240 mg/kg/day for 6 months. In dogs, on the other hand, 5.0 mg/kg/day approaches the maximum tolerated dose. This peculiar canine susceptibility to gastrointestinal effects of non-steroidal anti-inflammatory agents has also been shown with indomethacin and ibuprofen.
In dogs naproxen exhibits a considerably longer plasma half-life than it does in rats, guinea pigs; miniature swine, monkeys, and man. The same observation has been made with ibuprofen in dogs compared to rats and man. In addition, in the species listed, only the dog excretes significant amounts of administered naproxen in the feces (50%). In the rat, guinea pigs, miniature swine, monkey and man, 86-90% of the administered drug is excreted in the urine. The suggested enteroheptic circulation of naproxen in the dog (as judged by fecal excretion) most likely is a major factor in the susceptibility of the dog to gastrointestinal irritation by this compound.
In subacute and chronic toxicity studies, other pathological changes were often seen which were considered to be clearly secondary to the effects of naproxen on the gastrointestinal tract. These consisted of peritoneal inflammation and adhesions, mesenteric lymphadenopathy, decreased haemoglobin and hematocrit levels, leucocytosis, evidence of stimulated hematopoeisis and elevated plasma glutamic oxaloacetic transaminase.
As noted above, gastrointestinal pathology in laboratory animals is a finding common to nonsteroidal anti-inflammatory agents.
Ophthalmic examinations were made in the two year rat study and the one year monkey study. No eye changes considered to be drug related were noted except for the observation of pale irides in the rats. This was secondary to anemia as a result of gastrointestinal blood loss and did not represent a toxic effect of naproxen on the eye.
Plasma levels of naproxen were measured in monkeys dosed for one year with 100, 140 or 180 mg/kg/day naproxen. Plasma levels after 1 week of dosing were not significantly different form those after 12 months of dosing. As judged by these results there was no evidence of tachyphylaxis or accumulation over the 1 year dosing period.
Moderate weight loss of the male secondary sex glands occurred in some studies in naproxentreated rats and dogs. Histopathologically the affected glands in some instances exhibited atrophic and/or hypoplastic changes characterized by decreased secretory material. A possible estrogenic action of naproxen as a causative factor seems highly unlikely since in standard bioassay procedures the drug exhibited no estrogenic activity.
Daily doses of naproxen as high as 30 mg/kg administered for 60 days before mating had no effect on fertility and reproductive performance of male rats. These results reflect the physiological integrity of the entire male reproductive apparatus after administration of naproxen throughout the spermatogenic cycle.
In embryotoxicity studies no skeletal or visceral anomalies or pathologic changes were induced in the fetuses of pregnant rats and rabbits treated during organogenesis with daily oral doses of naproxen up to 20 mg/kg nor in mice similarly treated with 30 or 50 mg/kg. In these studies there were also no significant differences from controls in the number of live fetuses, resorptions, fetal weights or ano-genital distances. In another mouse study no malformations were observed with administration of 60 or 120 mg/kg of naproxen although there was a slight reduction in numbers of live fetuses in both dose groups and in fetal body weight in the high dose group.
Daily oral administration of 15, 30 or 60 mg/kg of naproxen to female rabbits from 2 weeks before mating until day 20 of pregnancy did not affect fertility, gestation, or the numbers of live fetuses.
In a peri- and post-natal study in rats, oral doses of naproxen up to 20 mg/kg administered daily during the last part of pregnancy through weaning did not result in adverse effects in viability of pups, lactation index, sex ratio or weight gain of offspring. However, there was a slight increase in gestation length at the 10 and 20 mg/kg dose levels; and, at the 10 mg/kg dose level, there was a significant increase in stillbirths.
The mechanism of this phenomenon in the rats is not entirely clear at present. It is possible that difficulties in delivery in naproxen-treated rats reflect a general underlying maternal debility induced by increased susceptibility of the pregnant animals to gastrointestinal ulceration and subsequent peritonitis. Such an observation has been reported with ibuprofen. Pregnant animals were reported to be 9 times more susceptible to the ulcerogenic effects of that compound than were non-pregnant animals. Similarly, with naproxen, gastrointestinal lesions in non-pregnant paired drug-treated controls were found to occur less frequently and were less extensive than those in pregnant rates treated daily from day 15 of pregnancy through term.
More recent evidence, however, suggests that inhibition of prostaglandin synthesis by nonsteroidal anti-inflammatory compounds may be related to decreased uterine contractility. Thus, the onset of labour in a rat model system can be delayed with naproxen administration without causing maternal or fetal deaths in excess of that seen in controls. Since it has been shown that naproxen inhibits prostaglandin synthesis in vitro, it has been suggested that the effects of naproxen on uterine contractility are mediated through that mechanism.
Maternal and fetal deaths seen in naproxen-treated rats were, therefore, apparently related to dystocia rather than to a direct toxic effect of the compound. Naproxen is not unique in this regard since comparable results were obtained in the rat with other commonly used non-steroidal anti-inflammatory agents (ASA, indomethacin, mefenamic acid and phenylbutazone). Similar results have been suggested in reports of other animal studies with ibuprofen.
In a fertility and reproduction study in mice, the dams were dosed daily with 12, 36 or 108 mg/kg from 14 days prior to mating through weaning. At the highest dose level, there was an increase in maternal deaths which was reflected in decreased 21 day survival and lactation indices. There were no other changes in the parameters examined. In a similar study in rats, daily doses were 2, 10 or 20 mg/kg from 14 days before mating through weaning. Other than decreased survival to weaning which appeared due to poor maternal care in pups born to high dose dams, there were no differences between control and treated groups. One mid and one high dose dam died during labour due to delayed parturition.
The toxicity of naproxen in juvenile animals was compared to that in adult animals. The results of single oral dose LD50 studies in weanling rats and mice, run simultaneously with studies in adult animals, revealed no significant differences in the values obtained with mature and immature animals of both species.
An additional study with juvenile mice consisted of two parts. Weaning animals were treated daily for one month wit a pediatric formulation of naproxen. At the end of the treatment period a portion of the animals were examined for pathologic changes. The remaining animals were allowed to reach maturity and breed.
The usual gastroenteropathy characteristic for non-steroidal anti-inflammatory agents was observed in some high dose (135 mg/kg) mice. Naproxen administration for the first post-weaning month of life did not compromise in any way the later fertility or reproductive capacity of mice so-treated.
Mutagenicity tests were performed with naproxen using 5 strains of bacteria and one of yeast. The test was carried out with and without mammalian microsomal activation. Naproxen was also tested in the mouse lymphoma assay. Naproxen was not mutagenic.
To evaluate the carcinogenic potential of naproxen, the compound was administered in the feed to rats for up to 2 years. Naproxen did not reveal any carcinogenic potential in rats.
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