NAPROXEN

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) Naproxen
2) Propionic acid, 2-(6-methoxy-2-naphthyl)-,(+)
3) MNPA
4) CAS 22204-53-1

1.2.1) MOLECULAR FORMULA
1) NAPROXEN: C14H14O3
2) NAPROXEN SODIUM: C14H13NaO3

Available Forms Sources

1) NAPROXEN: Naproxen is available as 25 mg/mL and 125 mg/5 mL oral suspension, 250 mg, 375 mg, and 500 mg oral tablets, and 375 mg, and 500 mg oral enteric coated tablets (Prod Info NAPROSYN(R) oral tablets, oral suspension, 2008; Prod Info naproxen oral delayed release tablets, 2010; Prod Info naproxen oral tablets, 2005).
2) NAPROXEN SODIUM: Naproxen sodium is available as 220 mg, 275 mg, and 550 mg oral tablets, 375 mg, 500 mg, and 750 mg extended-release tablets, and 220 mg oral liquid filled capsule (Prod Info NAPRELAN(R) oral controlled-release tablets, 2011; Prod Info naproxen sodium oral film coated tablets, 2011; Prod Info ALEVE(R) oral caplets, 2006; Prod Info naproxen oral tablets, 2005).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) used as a pain medication and in various inflammatory conditions.
B) PHARMACOLOGY: Naproxen is a nonselective inhibitor of cyclooxygenases (COX-1 and COX-2), leading to decreased synthesis of prostanoids. Naproxen, like other NSAIDs, has anti-inflammatory, analgesic, and antipyretic properties.
C) TOXICOLOGY: Prostaglandin inhibition is responsible for the gastrointestinal irritant effects and nephrotoxicity.
D) EPIDEMIOLOGY: Poisoning with NSAIDs is not uncommon but rarely severe. Naproxen overdose is uncommon in the United States since other NSAIDs are used more often.
E) WITH THERAPEUTIC USE

1) CNS effects include drowsiness, headache, fatigue, and cognition disturbances, especially in the elderly. Gastrointestinal effects (eg, dyspepsia, ulceration, bleeding) are as common as with other NSAIDs. Renal dysfunction, especially in the elderly population, may be seen. Instances of agranulocytosis, thrombocytopenia, and pancreatitis have been reported. Hepatotoxicity is rare.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE POISONING: Gastrointestinal effects (eg, dyspepsia, ulceration, bleeding) are most commonly encountered. Renal dysfunction, most often in elderly patients, may occur. Mild CNS effects include altered cognition, drowsiness, headache, and mood changes, especially in the elderly population.
2) SEVERE POISONING: Severe poisoning is rare but can include CNS depression, hallucinations, seizures, renal failure, gastrointestinal bleeding, and metabolic acidosis.

0.2.6)

A) WITH THERAPEUTIC USE

1) Pulmonary infiltrates with eosinophilia has occurred with chronic therapeutic use. Bronchoconstriction and asthma have been reported after initial dosing.

B) WITH POISONING/EXPOSURE

1) Apnea has developed secondary to seizures following overdose.

0.2.7)

A) WITH THERAPEUTIC USE

1) Aseptic meningitis has been associated with naproxen.

B) WITH POISONING/EXPOSURE

1) CNS depression including coma can develop following overdose. Seizures (focal and generalized) have been observed following overdose.
2) Dizziness and dystonic movement disorders have also been reported.

0.2.8)

A) WITH THERAPEUTIC USE

1) Nausea, indigestion, vomiting, epigastric pain, and gastrointestinal bleeding have been associated with therapeutic and overdoses of naproxen. Ulcerative esophagitis has been reported in one case at therapeutic doses.

B) WITH POISONING/EXPOSURE

1) Nausea, indigestion, vomiting, epigastric pain, gastrointestinal bleeding, and pancreatitis have been associated with overdose of naproxen, as well as with therapeutic use.

0.2.9)

A) WITH THERAPEUTIC USE

1) Hepatotoxicity and jaundice have been reported with therapeutic use.

0.2.10)

A) WITH THERAPEUTIC USE

1) Acute renal failure, azotemia, and nephrotic syndrome have occurred with chronic ingestion of naproxen.

B) WITH POISONING/EXPOSURE

1) Acute renal failure may occur in overdose.

0.2.11)

A) WITH POISONING/EXPOSURE

1) Metabolic acidosis has been reported following overdose.

0.2.13)

A) WITH THERAPEUTIC USE

1) Neutropenia, agranulocytosis, and hemolytic anemia have been reported.

B) WITH POISONING/EXPOSURE

1) Hypoprothrombinemia has been seen in overdose.

0.2.19)

A) WITH THERAPEUTIC USE

1) Anaphylactoid reactions have been associated with naproxen.

0.2.20)

A) Naproxen is classified as FDA pregnancy category C. LATE PREGNANCY: However, in late pregnancy, as well with other NSAIDs, naproxen products (ie, immediate release, extended release, suspension) should be NOT be used because of the risk of premature closure of the ductus arteriosus. LABOR AND DELIVERY: Naproxen products are also NOT recommended during labor and delivery because its prostaglandin synthesis inhibitory effect may affect fetal circulation and inhibit uterine contractions, which could increase the risk of uterine hemorrhage. COMBINATION PRODUCTS: Starting at week 30 of gestation, the combination of naproxen and esomeprazole is classified as FDA pregnancy category D due to the potential for premature closure of the ductus arteriosus from the naproxen component. Esomeprazole magnesium/naproxen is, therefore, contraindicated during the late stage of pregnancy. NURSING MOTHERS: A concentration approximately equivalent to 1% of the maximum naproxen plasma concentration has been detected in the milk of lactating mothers. Due to the possible adverse effects of prostaglandin-inhibiting drugs on neonates, naproxen should be avoided in nursing mothers.

0.2.21)

A) At the time of this review, the manufacturer does not report any carcinogenic potential.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Primarily supportive care; activated charcoal may not be necessary given the fast gastrointestinal absorption of the drug and anticipated mild toxicity. Give benzodiazepines titrated to effect for anxiety and seizures.

B) MANAGEMENT OF SEVERE TOXICITY

1) If significant CNS depression occurs, consider orotracheal intubation for airway protection before giving charcoal. Give benzodiazepines for anxiety, agitation, delirium, and seizures. Be aware of the risk of acute renal failure and gastrointestinal bleeding. Avoid nephrotoxic drugs.

C) DECONTAMINATION

1) PREHOSPITAL: Not recommended because of potential for somnolence and seizures.
2) HOSPITAL: Consider activated charcoal if patients present early after a substantial ingestion. However, be aware of fast drug absorption and the potential for significant CNS toxicity early in the clinical course.

D) AIRWAY MANAGEMENT

1) Early orotracheal intubation in patients with signs of severe intoxication with CNS depression, seizures, or agitation.

E) ANTIDOTE

1) None.

F) ENHANCED ELIMINATION

1) There is no role for repeat-dose activated charcoal. Hemodialysis is unlikely to be useful given its high protein binding (greater than 99%).

G) PATIENT DISPOSITION

1) HOME CRITERIA: Asymptomatic children and adults with inadvertent ingestions can be managed at home.
2) OBSERVATION CRITERIA: Symptomatic patients and those with deliberate overdose should be sent to a health care facility for evaluation.
3) ADMISSION CRITERIA: Patients with serious CNS depression, agitation or seizures, renal failure, significant metabolic acidosis, and severe gastrointestinal toxicity (ie, bleeding) require admission.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.

H) PITFALLS

1) Many patients confuse over-the-counter pain medications with one another; rule out acetaminophen and salicylate ingestions in patients with a naproxen overdose.

I) PHARMACOKINETICS

1) Naproxen is rapidly and almost completely absorbed from the gastrointestinal tract. Protein binding is greater than 99%, and volume of distribution is 0.16 L/kg. Naproxen is mainly metabolized to inactive 6-O-desmethylnaproxen by the liver. Elimination mainly occurs, via the renal route, as unchanged naproxen (less than 1%), 6-O-desmethyl naproxen (less than 1%) or their conjugates (66% to 92%). The elimination half-life is 12 to 17 hours.

J) PREDISPOSING CONDITIONS

1) The elderly and patients with CHF, cirrhosis, dehydration or preexisting renal insufficiency are at greater risk for developing renal failure. Anticoagulated patients are at greater risk for developing severe gastrointestinal bleeding.

K) DIFFERENTIAL DIAGNOSIS

1) Differential diagnosis is wide given the unspecific signs and symptoms in a naproxen ingestion, and includes ingestion of other NSAIDs, salicylates, or iron. Rule out aspirin and acetaminophen poisoning. In case of CNS toxicity, consider other CNS affecting drugs. If metabolic acidosis is present, rule out other causes.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Cardiovascular

3.5.2)

A) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Severe metabolic acidosis (pH 7.23, PaCO2 49 mm Hg, PaO2 118 mm Hg, bicarbonate 19.9 mEq/L and a base deficit of -7.7 mEq/L) developed in a 15-year-old boy after intentionally ingesting 150 naproxen 220 mg tablets (total dose: 33 g) and 50 ibuprofen 200 mg tablets (total dose: 10 g). Shortly after admission, the patient became obtunded and hypotensive (range, 66/39 to 84/36 mmHg) and was electively intubated. Early treatment included normal saline, sodium bicarbonate and dopamine infusions with minimal clinical improvement. Vasopressors (epinephrine and vasopressin) were added for refractory hypotension. Metabolic acidosis gradually improved but hypotension persisted. A random cortisol level was 7.73 mcg/dL (normal greater than or equal to 25 mcg/dL) and the patient was started on hydrocortisone 100 mg followed by 50 mg every 6 hours and gradually tapered over 7 days. Hypotension resolved and he was successfully extubated 24 hours after admission. The patient recovered completely (Akingbola et al, 2015).
b) CASE REPORT: A 28-year-old man, with a history of depression and a previous suicide attempt, intentionally ingested 70.4 g (approximately 320 tablets of naproxen 220 mg) of naproxen and an unknown amount of alcohol and was admitted to the ED about 90 minutes after ingestion with only mild drowsiness and lethargy. Initial laboratory studies included a serum naproxen concentration of 1580 mg/L (therapeutic range, 25 to 75 mg/L) and an ethanol concentration of 166 mg/L. Drugs of abuse, acetaminophen and aspirin were not detected. One hour after admission he developed a tonic-clonic seizure and was intubated and sedated after a second seizure. His clinical course was further complicated by hypotension requiring a norepinephrine drip, metabolic acidosis (pH 7.14, HCO3 10 mmol/L and lactate 16.7 mmol/L) and anuria (creatinine increased to 1.72 mg/dL) about 5 hours after admission. Low efficiency dialysis was started followed by venovenous hemofiltration for 60 hours. His creatine kinase (CK) peaked at 10,000 Units/L. Repeat lactate levels trended down to 8.6 mmol/L and 2.3 mmol/L. By day 3, the patient was successfully extubated and his acidosis and creatinine were normalized. By day 7, he was clinically stable and was transferred for further psychiatric care. The authors suggested that further studies were indicated to determine if hemodialysis and renal replacement therapy are effective in the clearance of naproxen (Al-Abri et al, 2015).

B) HYPERTENSIVE DISORDER

1) WITH POISONING/EXPOSURE

a) Hypertension, acute renal failure, respiratory depression and coma may develop following overdose of naproxen, but these occurrences are rare (Prod Info naproxen oral delayed release tablets, 2010).

Respiratory

3.6.1)

A) WITH THERAPEUTIC USE

1) Pulmonary infiltrates with eosinophilia has occurred with chronic therapeutic use. Bronchoconstriction and asthma have been reported after initial dosing.

B) WITH POISONING/EXPOSURE

1) Apnea has developed secondary to seizures following overdose.

3.6.2)

A) APNEA

1) WITH POISONING/EXPOSURE

a) Apnea secondary to a generalized seizure occurred following an ingestion of 13.75 g of naproxen sodium (Martinez et al, 1989).

B) DECREASED RESPIRATORY FUNCTION

1) WITH POISONING/EXPOSURE

C) ALLERGIC PNEUMONIA

1) WITH THERAPEUTIC USE

a) Pulmonary infiltrates with eosinophilia (PIE) which improved with discontinuance of naproxen has occurred with chronic therapeutic use (Goodwin & Glenny, 1992; Buscaglia et al, 1984; Nader & Schillaci, 1983) .

1) Rechallenge with naproxen resulted in recurrence of PIE (Nader & Schillaci, 1983).

D) PNEUMONITIS

1) WITH THERAPEUTIC USE

a) Eosinophilic pneumonitis has been reported infrequently in patients receiving therapeutic doses of naproxen (Prod Info NAPRELAN(R) oral controlled-release tablets, 2011)
b) A patient treated with naproxen and gold for rheumatoid arthritis developed restrictive lung disease and blood eosinophilia 4 weeks after gold therapy had been discontinued.

1) Gold pneumonitis was suspected, but the symptoms did not resolve until the naproxen therapy was discontinued 1 week later (McFadden et al, 1989).

E) BRONCHOSPASM

1) WITH THERAPEUTIC USE

a) A patient with history of asthma was admitted with severe shortness of breath and wheezing 25 minutes after ingesting a single dose of naproxen. The patient had experienced a severe episode of wheezing following ingestion of aspirin 1 year prior to this incident (Salberg & Simon, 1980).

F) ACUTE LUNG INJURY

1) WITH THERAPEUTIC USE

a) Pulmonary edema, jaundice, and renal insufficiency developed in a 51-year-old man taking naproxen 250 mg twice daily (Reeve et al, 1987).

G) ASTHMA

1) WITH THERAPEUTIC USE

a) Asthma has been reported infrequently in patients receiving therapeutic doses of naproxen (Prod Info NAPRELAN(R) oral controlled-release tablets, 2011)

Neurologic

3.7.1)

A) WITH THERAPEUTIC USE

1) Aseptic meningitis has been associated with naproxen.

B) WITH POISONING/EXPOSURE

3.7.2)

A) SEIZURE

1) WITH POISONING/EXPOSURE

a) SUMMARY: Seizure activity has been reported infrequently following naproxen overdose (Al-Abri et al, 2015; Martinez et al, 1989)
b) CASE REPORT: A 28-year-old man, with a history of depression and a previous suicide attempt, intentionally ingested 70.4 g (approximately 320 tablets of naproxen 220 mg) of naproxen and an unknown amount of alcohol and was admitted to the ED about 90 minutes after ingestion with only mild drowsiness and lethargy. Initial laboratory studies included a serum naproxen concentration of 1580 mg/L (therapeutic range, 25 to 75 mg/L) and an ethanol concentration of 166 mg/L. Drugs of abuse, acetaminophen and aspirin were not detected. One hour after admission he developed a tonic-clonic seizure and was intubated and sedated after a second seizure. His clinical course was further complicated by hypotension requiring a norepinephrine drip, metabolic acidosis (pH 7.14, HCO3 10 mmol/L and lactate 16.7 mmol/L) and anuria (creatinine increased to 1.72 mg/dL) about 5 hours after admission. Low efficiency dialysis was started followed by venovenous hemofiltration for 60 hours. His creatine kinase (CK) peaked at 10,000 Units/L. Repeat lactate levels trended down to 8.6 mmol/L and 2.3 mmol/L. By day 3, the patient was successfully extubated and his acidosis and creatinine were normalized. By day 7, he was clinically stable and was transferred for further psychiatric care. The authors suggested that further studies were indicated to determine if hemodialysis and renal replacement therapy are effective in the clearance of naproxen (Al-Abri et al, 2015).
c) CASE REPORT: Focal seizures leading to 3 to 4 minutes of generalized seizure activity occurred in a 15-year-old girl following ingestion of 13.75 g of naproxen sodium. Midazolam was effective in controlling the seizure. The patient later developed episodic seizure activity unresponsive to diazepam but controlled by phenytoin (Martinez et al, 1989).
d) One case reported to the National Poison Information Service in England described a patient who ingested 35 g of naproxen presenting with a epileptic episode which responded to IV diazepam (Court & Volans, 1984).

B) DYSTONIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 15-year-old girl developed clenched fists, extended legs with feet in plantar flexion, head movement side to side, and contorted mouth within 30 minutes of ingestion of 13.75 g of naproxen sodium. The patient later developed seizures (Martinez et al, 1989).

C) MENINGITIS

1) WITH THERAPEUTIC USE

a) Aseptic meningitis has been reported infrequently with naproxen therapy (Prod Info NAPRELAN(R) oral controlled-release tablets, 2011).
b) A patient was admitted with severe headaches 3 weeks after starting naproxen for neck pain. Physical and laboratory findings were consistent with aseptic meningitis. Naproxen was discontinued 3 days after admission, and symptoms resolved within 4 days (Sylvia et al, 1988).
c) Recurrent aseptic meningitis related to prolonged naproxen therapy was reported in a 38-year-old woman with systemic lupus erythematosus. Two years after starting naproxen, she experienced 3 episodes of meningitis. Discontinuation of naproxen was followed by prompt recovery in each episode (Weksler & Lehany, 1991).

D) TOXIC ENCEPHALOPATHY

1) WITH POISONING/EXPOSURE

a) Acute encephalopathy, along with the development of triphasic waves on EEG, occurred in a 36-year-old man following intentional ingestion of 180 naproxen 500 mg tablets. Signs and symptoms resolved within 48 hours following correction of metabolic acidosis, and the patient recovered (Bortone et al, 1998).

E) COMA

1) WITH POISONING/EXPOSURE

Gastrointestinal

3.8.1)

A) WITH THERAPEUTIC USE

B) WITH POISONING/EXPOSURE

1) Nausea, indigestion, vomiting, epigastric pain, gastrointestinal bleeding, and pancreatitis have been associated with overdose of naproxen, as well as with therapeutic use.

3.8.2)

A) GASTROINTESTINAL TRACT FINDING

1) WITH THERAPEUTIC USE

a) SUMMARY: Nausea, dyspepsia, abdominal and epigastric pain, diarrhea, constipation, and stomatitis have occurred with therapeutic use of naproxen. Other potential gastrointestinal events reported in patients taking NSAIDs include flatulence, gross bleeding/perforation, GI ulcers (gastric/duodenal), and vomiting (Prod Info NAPRELAN(R) oral controlled-release tablets, 2011).

B) GASTRITIS

1) WITH THERAPEUTIC USE

a) Gastritis is common at therapeutic doses, due to the suppression of gastric mucosal prostaglandin production (Laine et al, 1995).

2) WITH POISONING/EXPOSURE

a) Mild and transient gastrointestinal distress (ie, nausea and indigestion) was reported in a case of a 25 g overdose (Fredell & Strand, 1977).
b) Mild epigastric pain was experienced by 1 subject (out of 16) ingesting a 3 g single dose (Runkel et al, 1976).

C) NAUSEA AND VOMITING

1) WITH POISONING/EXPOSURE

a) Nausea, abdominal pain, and vomiting were the initial symptoms of a naproxen sodium overdose of 13.75 g. (Martinez et al, 1989).

D) GASTROINTESTINAL HEMORRHAGE

1) WITH POISONING/EXPOSURE

a) Gastrointestinal bleeding can develop in overdose (Prod Info naproxen oral delayed release tablets, 2010).

E) ULCER OF ESOPHAGUS

1) WITH THERAPEUTIC USE

a) One case of ulcerative esophagitis has been reported in an elderly woman with esophageal dysmotility treated with therapeutic doses of naproxen (Ecker & Karsh, 1992).

F) PANCREATITIS

1) WITH THERAPEUTIC USE

a) Pancreatitis occurred after 2 therapeutic doses of naproxen for dysmenorrhea. Symptoms resolved within 2 days, with laboratory pertubations persisting for 4 days (Du Ville et al, 1993).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: A 20-year-old man developed acute pancreatitis after ingesting 10 naproxen sodium 550 mg tablets. Laboratory results showed hyperamylasemia of 1050 international units/L (normal range 25 to 125 international units/L) in the blood and 2480 international units/L (normal range 0 to 900 international units/L) in the urine and elevated serum lipase level of 151 international units/L (normal range 8 to 78 international units/L) in the blood. Abdominal ultrasound and CT scan revealed a homogenous pancreas and a normal gallbladder and biliary tree. Following symptomatic treatment, his symptoms resolved within a day, with laboratory findings persisting for 3 days (Aygencel et al, 2006).

Hepatic

3.9.1)

A) WITH THERAPEUTIC USE

1) Hepatotoxicity and jaundice have been reported with therapeutic use.

3.9.2)

A) JAUNDICE

1) WITH THERAPEUTIC USE

a) Jaundice has been observed infrequently in patients receiving therapeutic doses of naproxen (Prod Info VIMOVO(R) oral delayed release tablets, 2015).
b) A patient with arthritis was treated with naproxen twice a day. After 1 week, abdominal pain and jaundice occurred. The liver was enlarged and liver function tests were elevated. Jaundice resolved 4 weeks after discontinuing naproxen (Law & Knight, 1976).
c) A patient presented with breathlessness, swollen legs, jaundice, and pulmonary congestion 10 days after beginning therapy with naproxen. The patient recovered with supportive therapy (Reeve et al, 1987).

B) TOXIC HEPATITIS

1) WITH THERAPEUTIC USE

a) Transient, asymptomatic elevations of serum aminotransferases have occurred with naproxen therapeutic use. One case reported a patient with acute icteric hepatitis (Andrejak et al, 1987).
b) Occasional transient abnormalities of hepatic laboratory tests have been reported with naproxen (Turner, 1988).

Genitourinary

3.10.1)

A) WITH THERAPEUTIC USE

1) Acute renal failure, azotemia, and nephrotic syndrome have occurred with chronic ingestion of naproxen.

B) WITH POISONING/EXPOSURE

1) Acute renal failure may occur in overdose.

3.10.2)

A) ABNORMAL RENAL FUNCTION

1) WITH THERAPEUTIC USE

a) Chronic therapeutic use may result in renal impairment including renal papillary necrosis (Prod Info EC-NAPROSYN(R), NAPROSYN(R), ANAPROX(R)/ANAPROX(R)DS oral delayed-release tablets, oral tablets, suspension, 2008).
b) Various renal syndromes have been associated with the entire class of NSAIDs (Clive & Stoff, 1984).

B) ACUTE RENAL FAILURE SYNDROME

1) WITH THERAPEUTIC USE

a) Rapid development of acute renal failure has occurred with therapeutic doses. Renal function will usually return to normal upon discontinuation of naproxen (Ezra et al, 1986).
b) Acute renal impairment (serum creatinine 2.6 and 3.8 mg/dL) was reported in 2 adults following relatively small doses (5 g and 3.75 g, respectively) of naproxen . Both received supportive care and fully recovered within 2 months (Kulling et al, 1995).
c) A fatality due to renal failure was reported in an 85-year-old woman following a 5-week course of naproxen. The renal failure failed to remit spontaneously or after corticosteroids. The patient was managed with dialysis for 40 days prior to her demise (Wasser et al, 1982).
d) A patient developed acute renal failure (ie, interstitial nephritis associated with nephrotic syndrome) several weeks after taking naproxen (1 g/day for 4 days) with concurrent amoxicillin and N-acetylcysteine treatment of acute pneumonia. The patient progressed to end-stage renal failure (Nortier et al, 1991).

2) WITH POISONING/EXPOSURE

a) SUMMARY: Hypertension, acute renal failure, respiratory depression and coma may develop following overdose of naproxen, but these occurrences are rare (Prod Info naproxen oral delayed release tablets, 2010).
b) CASE REPORT: A 28-year-old man, with a history of depression and a previous suicide attempt, intentionally ingested 70.4 g (approximately 320 tablets of naproxen 220 mg) of naproxen and an unknown amount of alcohol and was admitted to the ED about 90 minutes after ingestion with only mild drowsiness and lethargy. Initial laboratory studies included a serum naproxen concentration of 1580 mg/L (therapeutic range, 25 to 75 mg/L) and an ethanol concentration of 166 mg/L. Drugs of abuse, acetaminophen and aspirin were not detected. One hour after admission he developed a tonic-clonic seizure and was intubated and sedated after a second seizure. His clinical course was further complicated by hypotension requiring a norepinephrine drip, metabolic acidosis (pH 7.14, HCO3 10 mmol/L and lactate 16.7 mmol/L) and anuria (creatinine increased to 1.72 mg/dL) about 5 hours after admission. Low efficiency dialysis was started followed by venovenous hemofiltration for 60 hours. His creatine kinase (CK) peaked at 10,000 Units/L. Repeat lactate levels trended down to 8.6 mmol/L and 2.3 mmol/L. By day 3, the patient was successfully extubated and his acidosis and creatinine were normalized. By day 7, he was clinically stable and was transferred for further psychiatric care. The authors suggested that further studies were indicated to determine if hemodialysis and renal replacement therapy are effective in the clearance of naproxen (Al-Abri et al, 2015).

Acid-Base

3.11.1)

A) WITH POISONING/EXPOSURE

1) Metabolic acidosis has been reported following overdose.

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Severe metabolic acidosis (pH 7.23, PaCO2 49 mm Hg, PaO2 118 mm Hg, bicarbonate 19.9 mEq/L and a base deficit of -7.7 mEq/L) developed in a 15-year-old boy after intentionally ingesting 150 naproxen 220 mg tablets (total dose: 33 g) and 50 ibuprofen 200 mg tablets (total dose: 10 g). Shortly after admission, the patient became obtunded and hypotensive (range, 66/39 to 84/36 mmHg) and was electively intubated. Early treatment included normal saline, sodium bicarbonate and dopamine infusions with minimal clinical improvement. Vasopressors (epinephrine and vasopressin) were added for refractory hypotension. Metabolic acidosis gradually improved but hypotension persisted. A random cortisol level was 7.73 mcg/dL (normal greater than or equal to 25 mcg/dL) and the patient was started on hydrocortisone 100 mg followed by 50 mg every 6 hours and gradually tapered over 7 days. Hypotension resolved and he was successfully extubated 24 hours after admission. The patient recovered completely (Akingbola et al, 2015).
b) CASE REPORT: A 28-year-old man, with a history of depression and a previous suicide attempt, intentionally ingested 70.4 g (approximately 320 tablets of naproxen 220 mg) of naproxen and an unknown amount of alcohol and was admitted to the ER about 90 minutes after ingestion with only mild drowsiness and lethargy. Initial laboratory studies included a serum naproxen concentration of 1580 mg/L (therapeutic range, 25 to 75 mg/L) and an ethanol concentration of 166 mg/L. Drugs of abuse, acetaminophen and aspirin were not detected. One hour after admission he developed a tonic-clonic seizure and was intubated and sedated after a second seizure. His clinical course was further complicated by hypotension requiring a norepinephrine drip, metabolic acidosis (pH 7.14, HCO3 10 mmol/L and lactate 16.7 mmol/L) and anuria (creatinine increased to 1.72 mg/dL) about 5 hours after admission. Low efficiency dialysis was started followed by venovenous hemofiltration for 60 hours. His creatine kinase (CK) peaked at 10,000 Units/L. Repeat lactate levels trended down to 8.6 mmol/L and 2.3 mmol/L. By day 3, the patient was successfully extubated and his acidosis and creatinine were normalized. By day 7, he was clinically stable and was transferred for further psychiatric care. The authors suggested that further studies were indicated to determine if hemodialysis and renal replacement therapy are effective in the clearance of naproxen (Al-Abri et al, 2015).
c) CASE REPORT: A 15-year-old girl rapidly developed severe metabolic acidosis after a naproxen sodium overdose of 13.75 g. Acid/base balance returned to normal within 12 hours of admission. Authors suggested acidosis due to naproxen and metabolites (Martinez et al, 1989).
d) CASE REPORT: Metabolic acidosis (pH 7.19, bicarbonate 11.6 mmol/L, serum lactate 12.4 mmol/L {normal 0.5 to 1.5}) occurred in a 36-year-old man after ingesting 180 naproxen 500 mg tablets (total dose 90 g). Symptoms resolved within 48 hours of metabolic correction and the patient recovered (Bortone et al, 1998).

Hematologic

3.13.1)

A) WITH THERAPEUTIC USE

1) Neutropenia, agranulocytosis, and hemolytic anemia have been reported.

B) WITH POISONING/EXPOSURE

1) Hypoprothrombinemia has been seen in overdose.

3.13.2)

A) PROTHROMBIN TIME LOW

1) WITH POISONING/EXPOSURE

a) Transient prolongation of the prothrombin time (PT) was observed in a 10 g ingestion. The patient's PT returned to 80% of normal within 4 days upon treatment with IV vitamin K 10 mg/day (Waugh & Keatinge, 1983).

B) LEUKOPENIA

1) WITH THERAPEUTIC USE

a) A 6-month assessment of 62 osteoarthritis patients receiving naproxen 1.5 g/day reported 1 case of neutropenia (Berry & Nichols, 1985).

C) AGRANULOCYTOSIS

1) WITH THERAPEUTIC USE

a) A patient had been treated for 4 years with naproxen 250 mg twice a day. Upon a routine hospital admission, laboratory tests disclosed neutropenia. Within 3 days, the patient developed a fever, and laboratory tests revealed agranulocytosis. This resolved within 72 hours after discontinuing the naproxen (Nygard & Starkebaum, 1987).

D) HEMOLYTIC ANEMIA

1) WITH THERAPEUTIC USE

a) A patient was prescribed a 2-week course of naproxen 275 mg every 6 hours for relief of paresthesia. One week after discontinuing therapy, the patient was admitted with dizziness and episodes of loss of consciousness. The patient was found to be anemic with a hemoglobin of 5.3 g/dL. After transfusion of whole blood, the hemoglobin returned to within normal limits and anemia resolved (Hughes & Sudell, 1983).

Dermatologic

3.14.2)

A) DERMATOLOGICAL FINDING

1) WITH THERAPEUTIC USE

a) SUMMARY: Pruritus, skin eruptions, purpura, ecchymoses, and sweating are the most common dermatological findings associated with naproxen therapy (Prod Info VIMOVO(R) oral delayed release tablets, 2015).

B) PORPHYRIA CUTANEA TARDA

1) WITH THERAPEUTIC USE

a) Pseudoporphyria has been described in patients treated with naproxen. The condition may occur after 1 dose or after years of chronic use (Surez et al, 1990).

C) VASCULITIS

1) WITH THERAPEUTIC USE

a) A patient developed generalized palpable purpura followed by fever and migratory polyarthritis 72 hours after being started on naproxen 250 mg twice a day. Skin biopsy showed necrotizing vasculitis. Authors concluded naproxen was the determining factor in this patient developing fulminant cutaneous necrotizing vasculitis (Mordes et al, 1980).

Immunologic

3.19.1)

A) WITH THERAPEUTIC USE

1) Anaphylactoid reactions have been associated with naproxen.

3.19.2)

A) ANAPHYLACTOID REACTION

1) WITH THERAPEUTIC USE

a) Anaphylactoid reactions may occur upon initiation of naproxen therapy (Prod Info VIMOVO(R) oral delayed release tablets, 2015; Prod Info NAPRELAN(R) oral controlled-release tablets, 2011).

2) WITH POISONING/EXPOSURE

a) Anaphylactoid reactions may develop following a naproxen overdose (Prod Info VIMOVO(R) oral delayed release tablets, 2015).

Reproductive

3.20.1)

3.20.2)

A) PATENT DUCTUS ARTERIOSUS

1) Closure of the ductus arteriosus has been reported in fetuses with the use of prostaglandin synthetase inhibitors in late pregnancy. Naproxen may adversely affect fetal circulation and inhibit uterine contractions, which can increase the risk of uterine hemorrhage (Prod Info ANAPROX(R) DS oral tablets, 2013).
2) Three cases have been reported in which naproxen had been given to the mothers to delay parturition at 30 weeks gestation. All infants were born with severe hypoxemia due to persistent pulmonary hypertension and a closed ductus arteriosus. Umbilical cord blood levels of naproxen were measured in the twins with 59.5 mcg/mL and 68 mcg/mL reported. Due to the association of high naproxen levels in the cord blood and the presence of severe symptoms, naproxen does not appear to be a safe and effective means of delaying preterm labor (Wilkinson, 1980).

3.20.3)

A) BIRTH PREMATURE

1) One preterm infant developed severe hyponatremia and water retention associated with overdosage of mother 8 hours prior to delivery. The infant's condition was unremarkable for 60 hours after delivery and then developed peripheral edema, lethargy and weight gain. Within 12 hours the condition deteriorated with development of cerebral irritation, paralytic ileus and anuria. Recovery was complete with in 15 days and subsequent development unimpaired (Alun-Jones & Williams, 1986).

B) PREGNANCY CATEGORY

1) The manufacturer has classified naproxen as FDA pregnancy category C (Prod Info ANAPROX(R) DS oral tablets, 2013).
2) RISK SUMMARY

a) LATE PREGNANCY/LABOR AND DELIVERY: In late pregnancy, as well with other NSAIDs, naproxen products (ie, immediate release, extended release, suspension) should be NOT be used because of the risk of premature closure of the ductus arteriosus. Naproxen products are also NOT recommended during labor and delivery because its prostaglandin synthesis inhibitory effect may affect fetal circulation and inhibit uterine contractions, which could increase the risk of uterine hemorrhage (Prod Info ANAPROX(R) DS oral tablets, 2013).
b) NAPROXEN/ESOMEPRAZOLE: The fixed-dose combination product of naproxen esomeprazole has been classified as FDA pregnancy category D starting at 30 weeks gestation due to the potential for premature closure of the ductus arteriosus from the naproxen component of the combination. The combination is, therefore, contraindicated during the late stage of pregnancy (Prod Info VIMOVO(TM) delayed release oral tablets, 2010).
c) NAPROXEN/SUMATRIPTAN: The combination product naproxen sodium/sumatriptan succinate has been classified as FDA pregnancy category C during the first and second trimesters and as FDA pregnancy category X during the third trimester due to naproxen. As with other NSAIDs, inhibitors of prostaglandin synthesis (including naproxen) can cause premature closure of the ductus arteriosus in humans (Prod Info TREXIMET(R) oral tablets, 2015).

C) MISCARRIAGE

1) Use of NSAIDs during the first 20 weeks of pregnancy was associated with an 80% increased risk of miscarriage over non-use (hazard ratio (HR), 1.8; 95% confidence interval (CI), 1 to 3.2) in a study of 1055 women. Risk of miscarriage was highest when the drug was taken around the time of conception (HR, 5.6; 95% CI, 2.3 to 13.7) or used for more than a week (HR 8.1; 95% CI, 2.8 to 23.4). Absolute risk of NSAID-associated miscarriage was 10% for any use, 35% for use around time of conception, and 52% for use longer than one week (Li et al, 2003).

D) LACK OF EFFECT

1) In a prospective study of NSAID use in pregnancy and rheumatic disease, 23 pregnancies were exposed to naproxen (average daily dose, 560 mg). The patients who took NSAIDs (43 patients, 45 pregnancies) were compared with a control group who did not take any NSAIDs (45 patients, 49 pregnancies). NSAIDs were discontinued during the last 4 weeks of pregnancy. No statistically significant difference relative to the outcome of pregnancy was noted between the two groups (Ostensen & Ostensen, 1996).

3.20.4)

A) BREAST MILK

1) A concentration approximately equivalent to 1% of the maximum naproxen plasma concentration has been detected in the milk of lactating mothers. Due to the possible adverse effects of prostaglandin-inhibiting drugs on neonates, naproxen should be avoided in nursing mothers (Prod Info ANAPROX(R) DS oral tablets, 2013).
2) The distribution of naproxen into breast milk in a nursing mother and its intake by the infant has been evaluated. The mother initially received 2 consecutive 12-hour doses of naproxen 250 mg. Following ingestion of the drug, milk samples were taken at 0, 2, 4, 8, and 12 hours post-dosing. In addition, total urinary output by the mother over the same time period was collected. Three weeks later the dosage regimen was increased to 375 mg and milk and urine samples were taken as described above. With the 375-mg dosage regimen, the infant (5 months, 8 kg) breastfed at 1.2 and 5.5 hours post-dosing and total urinary output was collected for 12 hours. Maximum milk concentrations of naproxen appeared at 4 hours and were 0.114 to 0.125 mg/dL and 0.237 mg/dL following the 250- and 375-mg doses, respectively. The infant excreted 0.47 mg total intact and conjugated naproxen after the maternal 375-mg dose, or 0.26% of the mother's dose (Jamali & Stevens, 1983).
3) In a prospective study of mother-infant pairs exposed to various medications while breastfeeding, 20 mothers were treated with naproxen. Two infants were reported by their mothers to have drowsiness; one mother reported vomiting in her infant (Ito et al, 1993).

Carcinogenicity

3.21.2)

A) At the time of this review, the manufacturer does not report any carcinogenic potential.

3.21.4)

A) LACK OF EFFECT

1) RATS: There was no evidence of tumorigenicity when rats were given naproxen at doses up to 25 mg/kg/day (0.28 times the maximum recommended dose) in a 2-year study (Prod Info EC-NAPROSYN(R), NAPROSYN(R), ANAPROX(R)/ANAPROX(R)DS oral delayed-release tablets, oral tablets, suspension, 2008).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs and mental status.
B) Naproxen plasma levels are not clinically useful or readily available.
C) No specific lab work is needed in most patients. Obtain routine chemistry, blood gases, and CBC in case of severe toxicity.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) No specific lab work is needed in most patients. Obtain routine chemistry, blood gases, and CBC in case of severe toxicity.
2) Naproxen plasma levels are not clinically useful or readily available.

4.1.4)

A) OTHER

1) MONITORING

a) Monitor vital signs and mental status.

Methods

1) NSAIDs are difficult to detect and correctly identify using common screening procedures, and a negative tox screen does not rule out overdose of these agents. Toxicology screening may help rule out other drugs causing similar symptomatology.
2) Methods to assay blood or serum concentrations of these drugs are available, but not on a widespread basis. There is insufficient data correlating toxic effects and concentrations.

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with serious CNS depression, agitation or seizures, renal failure, significant metabolic acidosis, and severe gastrointestinal toxicity (ie, bleeding) require admission.

6.3.1.2) HOME CRITERIA/ORAL

A) Asymptomatic children and adults with inadvertent ingestions can be managed at home.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Symptomatic patients and those with deliberate overdose should be sent to a health care facility for evaluation.

Monitoring

Oral Exposure

6.5.1)

A) Prehospital decontamination is not recommended because of potential for somnolence and seizures.

6.5.2)

A) ACTIVATED CHARCOAL

1) Consider activated charcoal if patients present early after a substantial ingestion. However, be aware of fast drug absorption and the potential of significant CNS toxicity early in the clinical course.
2) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

3) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.3)

A) SUPPORT

1) MANAGEMENT OF MILD TO MODERATE TOXICITY

a) Primarily supportive care; activated charcoal may not be necessary given the fast gastrointestinal absorption of the drug and anticipated mild toxicity. Give benzodiazepines titrated to effect for anxiety and seizures.

2) MANAGEMENT OF SEVERE TOXICITY

a) If significant CNS depression occurs, consider orotracheal intubation for airway protection before giving charcoal. Give benzodiazepines for anxiety, agitation, delirium, and seizures. Be aware of the risk of acute renal failure and gastrointestinal bleeding. Avoid nephrotoxic drugs.

B) MONITORING OF PATIENT

1) Monitor vital signs and mental status. No specific lab work is needed in most patients.
2) Obtain routine chemistry, blood gases, renal function and CBC in case of severe toxicity.
3) Naproxen plasma levels may not be clinically useful or readily available.

C) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

D) GASTROINTESTINAL HEMORRHAGE

1) Monitor patients for signs and/or symptoms of gastrointestinal ulceration and/or hemorrhage (i.e., stool guaiac test). Antacids may be of some value in patients with gastrointestinal symptoms.

a) SUCRALFATE has been recommended as gastric protectant. Studies have shown that it protects the stomach and anterior small intestine, but not the posterior small intestine, where NSAIDs may still be in mucosal contact (Aabakken & Osnes, 1988).

E) ANAPHYLAXIS

1) SUMMARY

a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.

2) BRONCHOSPASM

a) ALBUTEROL

1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).

3) CORTICOSTEROIDS

a) Consider systemic corticosteroids in patients with significant bronchospasm.
b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).

4) MILD CASES

a) DIPHENHYDRAMINE

1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).

5) MODERATE CASES

a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).

6) SEVERE CASES

a) EPINEPHRINE

1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).

7) AIRWAY MANAGEMENT

a) OXYGEN: 5 to 10 liters/minute via high flow mask.
b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).

8) MONITORING

a) CARDIAC MONITOR: All complicated cases.
b) IV ACCESS: Routine in all complicated cases.

9) HYPOTENSION

a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.

1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).

10) H1 and H2 ANTIHISTAMINES

a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).

1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).

b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).

11) DYSRHYTHMIAS

a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.

12) OTHER THERAPIES

a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

Enhanced Elimination

1) There is no role for repeat-dose activated charcoal. Hemodialysis is not unlikely to be useful given its high protein binding (greater than 99%) (Prod Info naproxen oral delayed release tablets, 2010).

Abstracts

Case Reports

1) A preterm infant developed severe hyponatremia and water retention, associated with overdosage by the mother, 8 hours prior to delivery. The infant's condition was unremarkable for 60 hours after delivery; the infant then developed peripheral edema, lethargy, and weight gain. In the subsequent 12 hours, the infant's condition deteriorated with development of cerebral irritation, paralytic ileus, and anuria. Recovery was complete within 15 days and subsequent development unimpaired (Alun-Jones & Williams, 1986).

1) An adult man suffered only nausea and mild indigestion after ingesting 25 g of naproxen. Serum concentration was 414 mcg/mL 15 hours after the ingestion (Fredell & Strand, 1977).

1) A 15-year-old girl presented with severe acidosis and seizures following an acute naproxen ingestion of 13.75 g. Intubation and mechanical ventilation were required for 12 hours after admission with full recovery within 36 hours of admission (Martinez et al, 1989).
2) A 16-year-old girl ingested approximately 10 g of naproxen. Mild nausea was the only complaint. Prolonged prothrombin time (PT) was noted during the 4 days of hospitalization without any apparent physical signs. PT returned to 80% of normal by discharge after being treated with parenteral vitamin K 10 mg/day (Waugh & Keatinge, 1983).

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) ACUTE GOUT

1) NAPROXEN SODIUM: Initial dose is 825 mg; maintenance dose is 275 mg orally every 8 hours until symptoms subside (Prod Info NAPROSYN(R) oral tablets, oral suspension, 2013; Prod Info ANAPROX(R) DS oral tablets, 2013; Prod Info EC-NAPROSYN(R) oral delayed release tablets, 2013).
2) NAPROXEN: Recommended starting dose is 750 mg followed by 250 mg every 8 hours until symptoms subside (Prod Info NAPROSYN(R) oral tablets, oral suspension, 2013; Prod Info ANAPROX(R) DS oral tablets, 2013; Prod Info EC-NAPROSYN(R) oral delayed release tablets, 2013).

B) FEVER

1) OVER-THE-COUNTER DOSING (AGES 12 YEARS AND OLDER): Initial dose is 220 to 440 mg orally; maintenance dose is 220 mg orally every 8 to 12 hours as needed. Do not administer longer than 10 days unless directed by physician. Maximum dose is 440 mg in any 8 to 12 hour period, 660 mg per 24 hours (Prod Info ALEVE(R) oral caplets, 2006).

C) HEADACHE

D) PAIN MANAGEMENT (DYSMENORRHEA, TENDONITIS, BURSITIS)

1) NAPROXEN SODIUM: Initial dose is 550 mg orally; maintenance dose is 550 mg orally every 12 hours as needed or 275 mg orally every 6 to 8 hours as needed. The maximum initial dose is 1375 mg/day, then 1100 mg/day (Prod Info NAPROSYN(R) oral tablets, oral suspension, 2013; Prod Info ANAPROX(R) DS oral tablets, 2013; Prod Info EC-NAPROSYN(R) oral delayed release tablets, 2013).
2) OVER-THE-COUNTER DOSING (AGES 12 YEARS AND OLDER): Initial dose is 220 to 440 mg orally; maintenance dose is 220 mg orally every 8 to 12 hours as needed. Do not administer longer than 10 days unless directed by physician. Maximum dose is 440 mg in any 8 to 12 hour period, 660 mg per 24 hours (Prod Info ALEVE(R) oral caplets, 2006).

E) RHEUMATOID ARTHRITIS, OSTEOARTHRITIS, ANKYLOSING SPONDYLITIS

1) NAPROXEN SODIUM: Usual dose is 275 to 550 mg orally twice a day, up to a maximum of 1650 mg/day for up to 6 months (Prod Info NAPROSYN(R) oral tablets, oral suspension, 2013; Prod Info ANAPROX(R) DS oral tablets, 2013; Prod Info EC-NAPROSYN(R) oral delayed release tablets, 2013).
2) NAPROXEN: Usual dose is 250 mg to 500 mg twice daily (Prod Info NAPROSYN(R) oral tablets, oral suspension, 2013; Prod Info ANAPROX(R) DS oral tablets, 2013; Prod Info EC-NAPROSYN(R) oral delayed release tablets, 2013).
3) DELAYED-RELEASE NAPROXEN AND ESOMEPRAZOLE MAGNESIUM: Usual dose is naproxen 375 mg/esomeprazole 20 mg or naproxen 500 mg/esomeprazole 20 mg orally twice daily (Prod Info VIMOVO(R) oral delayed release tablets, 2014).
4) DELAYED-RELEASE NAPROXEN: Usual dose is 375 to 500 mg twice daily (Prod Info NAPROSYN(R) oral tablets, oral suspension, 2013; Prod Info ANAPROX(R) DS oral tablets, 2013; Prod Info EC-NAPROSYN(R) oral delayed release tablets, 2013).

F) NAPROXEN SODIUM/SUMATRIPTAN SUCCINATE

1) MIGRAINE HEADACHE

a) Recommended dose is 1 tablet (sumatriptan 85 mg/naproxen 500 mg) ORALLY; may repeat dose once after 2 hours MAX DOSE, 2 tablets (sumatriptan 170 mg/naproxen 1000 mg) in 24 hours (Prod Info TREXIMET(R) oral tablets, 2015).

7.2.2)

A) SUMMARY

1) CHILDREN YOUNGER THAN 2 YEARS: Safety and efficacy of naproxen have not been established in children younger than 2 years of age (Prod Info NAPROSYN(R) oral tablets, oral suspension, 2013; Prod Info ANAPROX(R) DS oral tablets, 2013; Prod Info EC-NAPROSYN(R) oral delayed release tablets, 2013).

B) FEVER

C) HEADACHE

D) JUVENILE RHEUMATOID ARTHRITIS

1) CHILDREN 2 YEARS OF AGE AND OLDER: Recommended dose of oral suspension is 10 mg/kg/day in 2 divided doses. Maximum dose should not exceed 15 mg/kg/day (Prod Info NAPROSYN(R) oral tablets, oral suspension, 2013; Prod Info ANAPROX(R) DS oral tablets, 2013; Prod Info EC-NAPROSYN(R) oral delayed release tablets, 2013).
2) SUSPENSION DOSING (Prod Info NAPROSYN(R) oral tablets, oral suspension, 2013; Prod Info ANAPROX(R) DS oral tablets, 2013; Prod Info EC-NAPROSYN(R) oral delayed release tablets, 2013):

1) 13 kg: 62.5 mg (2.5 mL) twice daily
2) 25 kg: 125 mg (5 mL) twice daily
3) 38 kg: 187.5 mg (7.5 mL) twice daily

E) PRIMARY DYSMENORRHEA

F) NAPROXEN SODIUM/SUMATRIPTAN SUCCINATE

1) MIGRAINE HEADACHE

a) CHILDREN 12 YEARS OF AGE AND OLDER: Recommended dose is 1 tablet (sumatriptan 10 mg/naproxen 60 mg) ORALLY. MAX DOSE, 1 tablet (sumatriptan 85 mg/naproxen 500 mg) in 24 hours (Prod Info TREXIMET(R) oral tablets, 2015)

Maximum Tolerated Exposure

1) ADULT

a) A 28-year-old man intentionally ingested 70 g of naproxen and an unknown amount of alcohol. Approximately 90 minutes later, his serum naproxen level was 1580 mg/L (therapeutic range, 25 to 75 mg/dL); no other drugs (including drugs of abuse) were detected. The patient was admitted with lethargy and within 4 hours metabolic acidosis developed. Mechanical ventilation and sedation were required for seizure activity. Additional therapy included sustained low efficiency dialysis and continuous venovenous hemofiltration (CVVH) for acute renal failure (creatine kinase peaked at 10,000 Units/L). Symptoms resolved and the patient recovered completely within 48 hours (Al-Abri et al, 2015).
b) A 20-year-old man developed mild acute pancreatitis after ingesting 10 naproxen sodium (550 mg) tablets. Following symptomatic treatment, his symptoms resolved within a day with laboratory findings persisting for 3 days (Aygencel et al, 2006).
c) Mild, transient gastrointestinal distress was reported following acute ingestion of 25 g in a man (Fredell & Strand, 1977).
d) A 36-year-old man developed acute encephalopathy following an intentional ingestion of 90 g naproxen. Signs and symptoms of metabolic acidosis resolved within 48 hours of supportive treatment (Bortone et al, 1998).

2) ADOLESCENT

a) Severe metabolic acidosis and profound hypotension developed in a 15-year-old boy after intentionally ingesting naproxen (total dose: 33 g) and ibuprofen (total dose: 10 g). He became obtunded and was electively intubated. Early treatment included normal saline, sodium bicarbonate and dopamine infusions with minimal clinical improvement. Vasopressors were added for refractory hypotension. Metabolic acidosis gradually improved but hypotension persisted. A random cortisol level was 7.73 mcg/dL (normal greater than or equal to 25 mcg/dL) and the patient was started on hydrocortisone 100 mg followed by 50 mg every 6 hours and gradually tapered over 7 days. Hypotension resolved and he recovered completely (Akingbola et al, 2015).
b) A 15-year-old girl developed severe metabolic acidosis, dystonia, seizures, and apnea requiring mechanical ventilation for 12 hours. With supportive care, the patient completely recovered within 36 hours after admission (Martinez et al, 1989).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) CONCENTRATION LEVEL

a) Peak plasma concentrations after single oral doses of 6.1 milligrams/kilogram tablets and 5.67 milligrams/kilogram suspension was measured in children. The peak plasma concentrations were reported as 68.5 milligrams/liter and 54.6 milligrams/liter respectively. Time to peak and half-life were 2.67 hours and 8.08 hours for the tablets and 2.16 hours and 9.63 hours for the suspension (Wells TG et al, 1994).
b) The therapeutic serum concentrations have been reported to range from 46 to 67 micrograms/milliliter in children dosed at 5 milligrams/kilogram of suspension (Brogden et al, 1975).
c) There does not appear to be a correlation between free naproxen serum concentration and clinical effect or adverse reactions. Free naproxen serum levels of 0.295 micrograms/milliliter (mean) with a range of 0.013 to 1.838 micrograms/milliliter were measured after 4 weeks of naproxen 750 milligrams/day (Hundal et al, 1991).

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CASE REPORTS

a) ADULT

1) A 15-year-old presented with severe acidosis and seizures following an acute naproxen ingestion of 13,750 milligrams. Serum concentration 14 hours after admission was 1290 milligrams/deciliter. Therapeutic range has been reported as 40 to 90 milligrams/deciliter (Martinez et al, 1989).
2) The serum concentration of naproxen was reported as 414 micrograms/milliliter 15 hours after ingestion of 25 g in a adult male. The patient suffered only nausea and indigestion (Fredell & Strand, 1977).

b) INFANT

1) The serum level in a 5-day-old was 78 micrograms/milliliter. The mother had ingested 5 g 8 hours prior to birth. Infant suffered severe hyponatremia and fluid retention (Alun-Jones & Williams, 1986).

c) OVERDOSE SERUM LEVEL STUDIES -

1) Pharmacokinetic studies have been done on large single doses. After the administration of 1, 2, 3 and 4 g single doses, the peak serum levels were 110, 155, 169 and 210 micrograms/milliliter respectively (Runkel et al, 1976).

Toxicity Information

7.7.1)

A) ANIMAL DATA

1) LD50- (ORAL)MOUSE:

a) 1200 mg/kg

2) LD50- (ORAL)RAT:

a) 500 mg/kg

Pharmacology Toxicology

Pharmacologic Mechanism

Toxicologic Mechanism

Physicochemical

Physical Characteristics

Ph

Molecular Weight

Animal Toxicology

Clinical Effects

11.1.3)

A) A 13-year-old Basenji was given 125 milligrams naproxen twice daily for 7 days by his owner. He was depressed and afebrile with pale mucous membranes, abdominal pain, and melena upon admission. Hematocrit was 22 percent with normal platelet and increased leukocyte counts.

1) Numerous granular and hyaline casts were found on urinalysis (specific gravity 1037). Two days after removal of the medication, the hematocrit was 29 percent and leukocyte count was normal, and three weeks later melena had resolved and the dog was completely recovered (Roudebush & Morse, 1981).

B) A 5-year-old male Dachshund experienced weakness, lethargy, anorexia, vomiting, and melena after being given 125 milligrams naproxen twice daily for 5 days.

1) Hematocrit was 14 percent; after two blood transfusions and supportive care, the dog recovered without sequelae (Smith, 1982).

C) A 9-year-old, 34-kilogram Samoyed was admitted with vomiting, weakness, tarry feces, and pale mucous membranes after being given 187.5 milligrams (5.6 milligrams/kilogram) naproxen daily for 7 days by the owner.

1) He had severe regenerative anemia, neutrophilia with left shift, negative Coombs' test, and increased creatinine and BUN levels. He was treated with fluids, one transfusion, and gastric protectants, and was almost completely recovered within eleven days (Gilmour & Walshaw, 1987).

Treatment

11.2.1)

A) GENERAL TREATMENT

1) Begin treatment immediately.
2) Keep animal warm and do not handle unnecessarily.
3) Sample vomitus, blood, urine, and feces for analysis.
4) Remove the patient and other animals from the source of contamination.
5) Treatment should always be done on the advice and with the consultation of a veterinarian. Additional information regarding treatment of poisoned animals may be obtained from a Board Certified (ABVT) Veterinary Toxicologist (check with nearest veterinary school or veterinary diagnostic laboratory) or the National Animal Poison Control Center.
6) ANIMAL POISON CONTROL CENTERS

a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.

11.2.2)

A) GENERAL

1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.

11.2.4)

A) GASTRIC DECONTAMINATION

1) DOGS/CATS

a) EMESIS AND LAVAGE - If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per mouth.

1) Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per mouth. Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram. Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage. Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).

b) ACTIVATED CHARCOAL - Administer activated charcoal 2 grams/kilogram per mouth or via stomach tube. Avoid aspiration by proper restraint, careful technique, and if necessary tracheal intubation.
c) CATHARTIC - Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per mouth for dilution.

2) RUMINANTS/HORSES/SWINE

a) EMESIS - Do not attempt to induce emesis in ruminants (cattle) or equidae (horses).
b) ACTIVATED CHARCOAL - Adult horses: administer 0.5 to 1 kilogram of activated charcoal in up to 1 gallon warm water via nasogastric tube. Neonates: administer 250 grams (one-half pound) activated charcoal in up to 2 quarts water.

1) Adult cattle: administer 2 to 9 grams/ kilogram of activated charcoal in a slurry of 1 gram charcoal/3 to 5 milliliters warm water via stomach tube. Sheep may be given 0.5 kilogram charcoal in slurry.

c) CATHARTIC - Administer an oral cathartic:

1) Mineral oil (small ruminants and swine, 60 to 200 milliliters; equidae and cattle, 0.5 to 1 gallon);
2) Magnesium sulfate (ruminants and swine, 1 to 2 grams/kilogram; equine, 0.2 to 0.9 gram/kilogram);
3) Or Milk of Magnesia (small ruminants, up to 0.25 gram/kilogram in 1 to 3 gallons warm water; adult cattle up to 1 gram/kilogram in 1 to 3 gallons warm water or 2 to 4 boluses MgOH per mouth). Give these solutions via stomach tube and monitor for aspiration.

11.2.5)

A) DOGS/CATS

1) MAINTAIN VITAL FUNCTIONS - as necessary.
2) SEIZURES -

a) DIAZEPAM - Dose of diazepam for DOGS & CATS: 0.5 milligram/kilogram intravenous bolus; may repeat dose every ten minutes for four total doses. Give slowly over 1 to 2 minutes.
b) PHENOBARBITAL may be used as adjunct treatment at 5 to 30 milligrams/kilogram over 5 to 10 minutes intravenously.
c) REFRACTORY SEIZURES - Consider anaesthesia or heavy sedation. Administer pentobarbital to DOGS & CATS at a dose of 3 to 15 milligrams/kilogram intravenously slowly to effect. May need to repeat in 4 to 8 hours. Be sure to protect the airway.

3) ANEMIA - Prior to running large amounts of fluids, check hematocrit. Blood transfusions may be necessary and clinical condition may be worsened by giving large amounts of fluids.

a) TRANSFUSION - Transfuse with whole blood, 25 milliliters/kilogram or fresh plasma, 9 milliliters/kilogram.
b) FLUIDS - Begin fluid therapy at maintenance doses (66 milliliters solution/kilogram body weight/day intravenously) or, in hypotensive patients, at high doses (up to shock dose 60 milliliters/kilogram/hour). Monitor for urine production and pulmonary edema.

1) One reported successful treatment included alternating treatment with Ringer's solution alternated with 10% dextrose (Spyridakis et al, 1986).

4) GASTROINTESTINAL TRACT IRRITATION - Observe patients with ingestion carefully for esophageal or laryngeal burns prior to inducing emesis. If burns are present, consider esophagoscopy to determine their extent.

a) SUCRALFATE - For relief of gastric irritation or ulceration, administer sucralfate as follows: DOGS (body weight less than 20 kilograms): 500 milligrams three to four times daily; (weight greater than 20 kilograms) one gram three to four times daily.

1) Give sucralfate one hour before feeding and wait two hours prior to cimetidine dosing.

b) CIMETIDINE - To decrease gastric acid, administer cimetidine. DOGS: 5 to 10 milligrams/kilogram per mouth, intravenously, or intramuscularly every 6 to 8 hours; CATS: 2.5 to 5 milligrams/kilogram per mouth, intravenously, or intramuscularly every 8 to 12 hours.

5) ACIDOSIS - Add sodium bicarbonate to the intravenous fluids if metabolic acidosis is suspected. (If using lactated Ringers solution and precipitate forms upon addition of bicarbonate, discard and substitute a different solution).

a) Formula for bicarbonate addition when blood gases are available: milliequivalents bicarb added = base deficit x 0.5 x body weight in kilograms.
b) Give one half of the determined dose slowly over 3 to 4 hours intravenously. Continue to dose based on blood gas determinations. When blood gases are not available, administer 1 to 4 milliequivalents/kilogram intravenously slowly over 4 to 8 hours (Beasley et al, 1991).

6) ALKALINE DIURESIS will speed elimination of many NSAIDs such as phenylbutazone and ibuprofen. Adding sodium bicarbonate to the IV fluids to maintain urine pH at 7 to 8 is advisable.
7) MONITOR for CBC changes and renal and hepatic damage. Provide good supportive care; treatment may need to be continued for several days.

B) RUMINANTS/HORSES/SWINE

1) MAINTAIN VITAL FUNCTIONS - Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.
2) SEIZURES may be controlled with diazepam. Doses of diazepam, given slowly intravenously: HORSES: 1 milligram/kilogram; CATTLE, SHEEP AND SWINE: 0.5 to 1.5 milligrams/kilogram.
3) FLUIDS - Administer electrolyte and fluid therapy as needed.

a) Maintenance dose of intravenous isotonic fluids is 10 to 20 milliliters/kilogram per day.
b) High dose for shock is 20 to 45 milliliters/kilogram/hour. Monitor for packed cell volume, adequate urine output and pulmonary edema. Goal is to maintain a urinary flow of 0.1 milliliter/kilogram/minute (2.4 liters/hour for an 880 pound horse).
c) Maintenance dose of intravenous isotonic fluids for calves and debilitated adult cattle: 140 milliliters/kilogram/day. Dose for rehydration: 50 to 100 milliliters/kilogram given over 4 to 6 hours.

Range Of Toxicity

11.3.1)

A) SPECIFIC TOXIN

1) NAPROXEN is dosed in horses intravenously at 5 mg/kg. It may also be fed orally for up to 14 days.

11.3.2)

A) SPECIFIC TOXIN

1) NAPROXEN - A dose of 125 milligrams/kilogram twice daily for seven days caused severe gastrointestinal irritation, bleeding, and pain and transient renal tubular damage in an adult Basenji dog (Roudebush & Morse, 1981).

a) CASE REPORT - A 5-year-old male Dachshund experienced weakness, lethargy, anorexia, vomiting, and melena after being given 125 milligrams naproxen twice daily for 5 days (Smith, 1982).
b) CONCLUSION - Doses greater than or equal to 5 milligrams/kilogram will cause severe gastrointestinal bleeding and transient renal damage in some dogs.

Continuing Care

11.4.1)

11.4.1.2) DECONTAMINATION/TREATMENT

A) GENERAL TREATMENT

11.4.2)

11.4.2.2) GASTRIC DECONTAMINATION

A) GASTRIC DECONTAMINATION

1) DOGS/CATS

a) EMESIS AND LAVAGE - If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per mouth.

2) RUMINANTS/HORSES/SWINE

c) CATHARTIC - Administer an oral cathartic:

11.4.3)

11.4.3.5) SUPPORTIVE CARE

A) GENERAL

1) Ongoing treatment is symptomatic and supportive.

11.4.3.6) OTHER

A) OTHER

1) GENERAL

a) LABORATORY--PREMORTEM - Monitor BUN, creatinine, and coagulation parameters.
b) LABORATORY--POSTMORTEM - Postmortem lesions commonly seen include ulcers of the gastric and intestinal mucosa and renal lesions including papillary necrosis.

Pharmacology Toxicology

1) Non-steroidal anti-inflammatory drugs interfere with prostaglandin synthesis via inhibition of the cyclooxygenase pathway. It is irritating to the mucosa of the gastrointestinal tract.
2) Dogs appear to be very sensitive to the proprionic acid group of NSAIDs (naproxen) and easily develop gastric ulcers and renal failure.

References

General Bibliography

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FeedBack

NAPROXEN

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Cardiovascular

Respiratory

Neurologic

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Hematologic

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Immunologic

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Carcinogenicity

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Monitoring Parameters Levels

Methods

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Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Toxicity Information

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Toxicologic Mechanism

Physical Characteristics

Ph

Molecular Weight

Clinical Effects

Treatment

Range Of Toxicity

Continuing Care

Pharmacology Toxicology

General Bibliography