IBUPROFEN

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) 2-(4-isobutylphenyl) propanoic acid
2) 2-(p-Isobutylphenyl) propionic acid
3) 4-Isobutylphenyl hydratropic acid
4) alpha-(4-isobutylphenyl) propionic acid
5) alpha-Methyl-4-(20methylpropyl)-
6) alpha-p-Isobutylphenylpropionic acid
7) Benzeneacetic acid
8) IB-82
9) p-Isobutylhydratropic acid
10) R.D. 13621
11) CAS 15687-27-1
12) 2-(4-ISOBUTYLPHENYL)PROPRIONIC ACID
13) RD 13621

1.2.1) MOLECULAR FORMULA
1) BASE - C13H1802
2) LYSINE - C19H32N2O4

Available Forms Sources

1) Ibuprofen is available as oral tablets (200 mg, 400 mg, 600 mg, 800 mg), oral capsules, oral liquid-filled capsules (200 mg), oral chewable tablets (50 mg, 100 mg), oral suspension (40 mg/mL, 50 mg/1.25 mL, 100 mg/5 mL), intravenous solution (100 mg/mL) (Prod Info CALDOLOR Intravenous, injection, 2009; Prod Info ibuprofen oral capsules, 2006; Prod Info ADVIL(R) oral suspension, 2003; Prod Info INFANT'S MOTRIN(R) concentrated oral suspension, 2002).
2) Ibuprofen lysine is available as intravenous solution (10 mg/mL) (Prod Info NeoProfen(R) intravenous injection, 2013).

1) Ibuprofen, or 2(4-isobutylphenyl) propionic acid, is a substituted phenylalkanoic acid with nonsteroidal anti-inflammatory, antipyretic, and analgesic properties (Adams & Buckler, 1979).

1) Ibuprofen is used as an anti-inflammatory in the treatment of fever, headache, migraine, osteoarthritis, pain, primary dysmenorrhea, and rheumatoid arthritis (Prod Info CALDOLOR Intravenous, injection, 2009; Prod Info ibuprofen oral capsules, 2006; Prod Info ADVIL(R) oral suspension, 2003; Prod Info INFANT'S MOTRIN(R) concentrated oral suspension, 2002).
2) Ibuprofen lysine is indicated to close a clinically significant patent ductus arteriosus (PDA) in premature infants weighing between 500 and 1500 g, who are no more than 32 weeks gestational age when usual medical management (eg, fluid restriction, diuretics, respiratory support, etc.) is ineffective (Prod Info NeoProfen(R) intravenous injection, 2013)

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Ibuprofen is used for fever and pain control and for the treatment of several rheumatologic conditions.
B) PHARMACOLOGY: Ibuprofen inhibits the cyclooxygenase enzyme, leading to decreased prostaglandin production and decreased pain and inflammation.
C) TOXICOLOGY: Gastrointestinal (GI) symptoms are due to both local irritant effects and the inhibition of prostaglandins (PG), which are responsible in part for maintaining the GI mucosal barrier. Inhibition of thromboxane A2 production in platelets prolongs bleeding time and contributes to gastrointestinal bleeding. Inhibition of PGI2 and PGE2, which have vasodilatory and natriuretic activity in the kidney, can be linked to sodium and water retention and occasional acute renal failure.
D) EPIDEMIOLOGY: Overdose is common; however, severe toxicity is very rare.
E) WITH THERAPEUTIC USE

1) ADVERSE EFFECTS: Gastrointestinal distress, nausea, and epigastric pain are the most common findings; upper GI bleeding may occur after acute or chronic ingestion. Angioedema, hives, itching, rash, and swelling have also been reported with therapeutic use. Fluid retention, interstitial nephritis, nephritic syndrome, and acute renal failure can develop. Hematologic effects include agranulocytosis, aplastic anemia, and thrombocytopenia. Headache, asthma exacerbation, aseptic meningitis, delirium, and anaphylactoid reactions have also been reported.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: In general, patients are asymptomatic or have mild GI upset (ie, nausea, vomiting, abdominal pain). Mild CNS depression (drowsiness, lethargy) and headache are common (incidence up to 30%). Nystagmus, diplopia, headache, tinnitus, and transient deafness may also occur following overdose.
2) SEVERE TOXICITY: With massive overdose, seizure, coma, acute renal failure, and, very rarely, cardiopulmonary arrest may occur. Upper GI bleeding may occur after acute or chronic ingestion. Elevated liver enzymes, hypoprothrombinemia, metabolic acidosis, hypokalemia, hypophosphatemia, hyponatremia, and hyperkalemia (associated with renal failure), hypotension, bradycardia, tachycardia, atrial fibrillation, dyspnea, aspiration pneumonia, rhabdomyolysis, and disseminated intravascular coagulation have also been observed in overdose. Transient episodes of apnea have been reported in young children following large ingestions. Acute pancreatitis has been reported.
3) ONSET: Symptoms typically occur within 4 to 6 hours of ingestion.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Apnea, tachycardia or bradycardia, hypotension, and hypothermia may develop after large overdose.

0.2.20)

A) Because of the potential for premature closure of the ductus arteriosus, avoid using ibuprofen in pregnant women starting at 30 weeks gestation. Advise patient of the potential risk to the fetus. Only use ibuprofen-containing products prior to 30 weeks gestation if the potential maternal benefit outweighs the fetal risk. The manufacturer has classified ibuprofen/oxycodone as FDA pregnancy category C prior to 30 weeks gestation and FDA pregnancy category D after 30 weeks gestation. The manufacturer has classified ibuprofen/hydrocodone as FDA pregnancy category C. There are no published reports linking ibuprofen with congenital defects. Other possible complications of use during the last trimester of pregnancy include delayed labor, complications during delivery, and postpartum bleeding.

0.2.21)

A) Studies evaluating the potential carcinogenic effects of the ibuprofen/famotidine combination are lacking.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Most ibuprofen toxicity resolves with supportive care. Otherwise healthy patients with a history of ibuprofen poisoning generally require only supportive care and fluid and electrolyte replacement.

B) MANAGEMENT OF SEVERE TOXICITY

1) Maintain an open airway and support ventilation. Treat seizures with benzodiazepines, hypotension with fluids and adrenergic vasopressors, and coma with intubation. Monitor ECG and arterial blood gases in patients with severe toxicity.

C) DECONTAMINATION

1) PREHOSPITAL: Activated charcoal can be given to patients with significant overdose (more than 200 mg/kg) who are alert and can protect their airway.
2) HOSPITAL: Activated charcoal binds ibuprofen and should be administered after significant overdose (more than 200 mg/kg). Gastric lavage is rarely, if ever, indicated, as this drug is absorbed rapidly and severe toxicity is exceedingly rare.

D) AIRWAY MANAGEMENT

1) Endotracheal intubation should be considered for patients who present with CNS depression (rare).

E) ANTIDOTE

1) None.

F) ENHANCED ELIMINATION

1) Ibuprofen is highly protein-bound; hemodialysis is unlikely to be effective. However, continuous veno-venous hemodialysis (CVVHD) was successfully used to treat a patient with refractory metabolic acidosis and hypotension after a massive ibuprofen overdose.

G) PATIENT DISPOSITION

1) HOME CRITERIA: Asymptomatic children with inadvertent ingestions of less than 200 mg/kg can be managed at home with milk or water dilution and observation.
2) OBSERVATION CRITERIA: Symptomatic children, adults with deliberate ingestion, and children ingesting more than 200 mg/kg should be referred to a health care facility for observation and treatment. Most patients who have ingested significant amounts of ibuprofen will manifest symptoms within 4 to 6 hours.
3) ADMISSION CRITERIA: Patients who develop CNS depression, hypotension, acidosis or gastrointestinal bleeding should be admitted.

H) PITFALLS

1) Although symptoms usually appear within 4 hours, there have been a few case reports of delayed symptoms. Severe toxicity is rare; very aggressive treatment is rarely warranted.

I) PHARMACOKINETICS

1) Ibuprofen is rapidly absorbed from the GI tract, with peak levels occurring within 1 to 2 hours. It has low water solubility; therefore, absorption of a large ingestion may be limited. The plasma half-life is approximately 2 hours; highly protein-bound to plasma proteins. In usual doses, the liver metabolizes more than 99%. Volume of distribution is approximately 0.12 L/kg.

J) DIFFERENTIAL DIAGNOSIS

1) Any poison that causes nausea, vomiting and metabolic acidosis: other NSAIDS, toxic alcohols, metformin or aspirin.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Apnea, tachycardia or bradycardia, hypotension, and hypothermia may develop after large overdose.

3.3.3)

A) WITH POISONING/EXPOSURE

1) HYPOTHERMIA has been reported following overdose (Holubek et al, 2007; Chelluri & Jastremski, 1986; Rittner & Eskin, 1998).

Heent

3.4.3)

A) ANIMAL STUDIES

1) CONJUNCTIVITIS: Ocular application of 5% cream to rabbits produced a strong but transient conjunctivitis (Gruber et al, 1983).

B) WITH THERAPEUTIC USE

1) VISUAL DISTURBANCES (CHRONIC USE): Blurred vision and visual acuity impairment have been noted occasionally with chronic therapy (Cuthbert, 1974).
2) IRIDOCYCLITIS: There has been 1 case report of a patient treated with 400 to 600 mg ibuprofen 4 times a day developing iridocyclitis and aseptic meningitis shortly after beginning the therapy for musculoskeletal pain and paresthesias (Kaplan et al, 1994).

C) WITH POISONING/EXPOSURE

1) NYSTAGMUS has been reported following acute overdose (Court et al, 1983; Hall et al, 1986).
2) BLURRED VISION has been reported following acute overdose (Court et al, 1983; Hall et al, 1986).
3) DIPLOPIA has been reported following acute overdose (Court et al, 1983; Hall et al, 1986).
4) MIOSIS has been reported in acute overdose (Perry et al, 1987).
5) OPTIC NEURITIS: A toxic optic neuritis has been reported with ibuprofen toxicity (Hamburger et al, 1984).

3.4.4)

A) WITH POISONING/EXPOSURE

1) TINNITUS and transient deafness have been reported following acute overdose (Court et al, 1983).

Cardiovascular

3.5.2)

A) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypotension and cardiovascular collapse may occur following acute overdose but is unusual (Christian & Thornton, 2015; Holubek et al, 2007; Marciniak et al, 2007; Wood et al, 2006; Hunt & Leigh, 1980; Hall et al, 1986; Chelluri & Jastremski, 1986; Perry et al, 1987; Le et al, 1994).
b) 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).
c) CASE REPORT: A 26-year-old woman was found comatose with hypotension (systolic BP 80 mg Hg) unresponsive to therapy following an estimated ingestion of ibuprofen 105 g sustained-release . The patient died of a ventricular tachycardia/ventricular fibrillation cardiac arrest approximately 10 hours after exposure, despite resuscitation efforts (Wood et al, 2006).
d) CASE SERIES: Cardiovascular effects were reported in 4.3% of cases in 1 prospective study of 329 cases of ibuprofen overdose (McElwee et al, 1990).
e) CASE REPORT: A 14-year-old boy developed cardiovascular collapse, an anion gap metabolic acidosis, elevated lactate concentrations and liver enzymes, and high-output renal failure after the ingestion of approximately 50 g of ibuprofen (ibuprofen concentration of 776 mcg/mL 5 to 10 hours postingestion; therapeutic range: 20 to 30 mcg/mL). Extracorporeal membrane oxygenation (ECMO) was used to treat hypotension unresponsive to pressor support with norepinephrine, phenylephrine, and vasopressin infusions. The patient's hemodynamic status improved and ECMO was discontinued on day 4 (Marciniak et al, 2007).

B) BRADYCARDIA

1) WITH POISONING/EXPOSURE

a) Bradycardia has been rarely described following overdose (Hall et al, 1986).

C) TACHYCARDIA

1) WITH POISONING/EXPOSURE

a) Tachycardia may occur in overdose (Levine et al, 2010; Marciniak et al, 2007; Jenkinson et al, 1988; Vale & Meredith, 1986; Halpern et al, 1993).

D) ATRIAL FIBRILLATION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Atrial fibrillation, with a ventricular rate of 170 to 180 beats per minute (bpm), was reported in a man with a history of mild mitral valve regurgitation following ingestion of ibuprofen 12 g (McCune & O'Brien, 1993).

E) VENTRICULAR TACHYCARDIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 26-year-old woman was found comatose and had an initial ECG that showed normal sinus rhythm with widespread myocardial ischemia following an estimated ingestion of ibuprofen 105 g sustained-release . The patient died of a ventricular tachycardia/ventricular fibrillation cardiac arrest approximately 10 hours after exposure, despite resuscitation efforts (Wood et al, 2006).

F) PROLONGED QT INTERVAL

1) WITH POISONING/EXPOSURE

a) Prolonged QT interval has been reported in patients with massive ibuprofen overdose (Holubek et al, 2007).

Respiratory

3.6.2)

A) APNEA

1) WITH POISONING/EXPOSURE

a) Transient episodes of apnea have been described in children aged 1 to 1.5 years after ingestion of 2.8 to 7.6 g (Hall et al, 1986; Linden & Townsend, 1987; Oker et al, 2000).
b) CASE REPORT: One case of respiratory arrest has been reported in an adult who ingested ibuprofen 400 mg , diclofenac 375 mg , and indomethacin 75 mg (Bright & McNulty, 1991).

B) PULMONARY ASPIRATION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Fatal aspiration pneumonia was reported in a 16-month-old who ingested 469 mg/kg (Hall et al, 1986).

C) BRONCHOSPASM

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Fatal bronchospasm was reported in a 65-year-old woman who had asthma but no known drug sensitivities and ingested ibuprofen 400 mg (Ayres et al, 1987).

D) DYSPNEA

1) WITH POISONING/EXPOSURE

a) CASE SERIES: Painful breathing and dyspnea were observed in 2.4% of cases in 1 prospective study (McElwee et al, 1990).

E) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 21-year-old female developed adult respiratory distress syndrome (ARDS) and disseminated intravascular coagulation following a massive overdose of ibuprofen; her ibuprofen level was 463.5 mcg/mL 25 hours after hospital admission (Stipetic et al, 1996). The patient had a complete recovery.
b) CASE REPORT: A 23-year-old male ingested ibuprofen 30 g and developed metabolic acidosis and acute renal failure followed by hypoxia and respiratory difficulty on hospital day 3 (Le et al, 1994). ARDS was diagnosed; the patient required ongoing outpatient hemodialysis for 1 week following discharge.
c) CASE REPORT: A case of ibuprofen-induced noncardiogenic pulmonary edema in a patient with human immunodeficiency virus was reported (Chetty et al, 1993).

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH POISONING/EXPOSURE

a) Lethargy and drowsiness are common in acute overdose (Hall et al, 1986; Hall & Rumack, 1988; Linden & Townsend, 1987).
b) CASE SERIES: In 1 prospective study of 329 cases of ibuprofen overdose, central nervous system depression occurred in 30% of cases (McElwee et al, 1990).
c) CASE SERIES: In a prospective study of 63 overdose cases ingesting between 1.2 and 60 g of ibuprofen, there were 10 cases of mild CNS depression reported in 26 symptomatic patients. The lowest dose causing any CNS depression was 3 g. Dizziness was seen in 5 patients (Hall et al, 1992).

B) COMA

1) WITH POISONING/EXPOSURE

a) INFANT/TODDLER

1) CASE REPORT: An 11-month-old female was responsive to painful stimuli only, approximately 1 hour after an accidental ibuprofen ingestion; a maximum dose of 10 to 12 g (1200 to 1500 mg/kg) was suspected with a serum level of 624 mg/L at 6 hours postingestion. Toxicological screening was negative for other agents. Progressive CNS depression improved with naloxone (total dose 0.9 mg/kg) boluses along with therapy to correct severe metabolic acidosis. The patient recovered without sequelae (Easley & Altemeier, 2000).

b) PEDIATRIC

1) Coma has been reported in children after ibuprofen overdose; coma generally only develops after ingestions involving large amounts of ibuprofen (Marciniak et al, 2007; Wiger & Gummin, 2002; Seifert et al, 2000; Hall & Rumack, 1988; Perry et al, 1987; Hall et al, 1986; Court et al, 1981).
2) CASE REPORT: Coma and CNS depression were described in a pediatric patient following 469 mg/kg (Hall et al, 1986), in a second child who ingested between 1.6 and 4.8 g (Perry et al, 1987).
3) CASE REPORT: A 15-year-old female intentionally ingested ibuprofen 100 g and developed coma, metabolic acidosis, and mild thrombocytopenia, which resolved with supportive care (Seifert et al, 2000). The patient was extubated at 8 hours and alert and oriented within 12 hours of overdose. Recovery was complete.
4) CASE REPORT: A 19-year-old man developed lactic acidosis, polyuria, and coma after ingesting over 90 grams (1200 mg/kg) of ibuprofen 3 hours after consuming 1180 mL of beer in a suicide attempt. The patient was successfully treated with aggressive supportive care, including mechanical ventilation and fluid resuscitation and regained consciousness approximately 24 hours after ingestion. No long term deficits were reported (Levine et al, 2010).
5) CASE REPORT: A 17-year-old developed coma after ingestion of 14 to 16 g of ibuprofen and unknown amounts of diazepam and ethanol (Court et al, 1981).
6) CASE REPORT: A 6-year-old male was found unresponsive after ingesting approximately 6 g of ibuprofen (Zuckerman & Uy, 1995). The child required aggressive supportive care including intubation and ventilation; he was discharged to home on hospital day 4.
7) CASE REPORT: A 17-year-old developed coma (gag reflex present, Glasgow coma score 6), lactic acidosis, and high output renal failure after ingesting approximately 14 g of ibuprofen (serum ibuprofen concentration on admission 962.6 mg/L). She recovered in 3 days with supportive care (Wiger & Gummin, 2002).

c) ADULT

1) CASE REPORT: A 26-year-old woman was found comatose and developed metabolic acidosis and hypotension (systolic BP 80 mg Hg) unresponsive to therapy following an estimated ingestion of ibuprofen 105 g sustained-release . The patient died of a ventricular tachycardia/ventricular fibrillation cardiac arrest approximately 10 hours after exposure (Wood et al, 2006).
2) CASE REPORT: A 50-year-old female developed coma after ingesting 40 to 60 ibuprofen 600 mg tablets; a 16-hour postingestion ibuprofen level was 270 mcg/mL (Chelluri & Jastremski, 1986).
3) CASE REPORT: A 70-year-old developed coma after ingesting 12 g of ibuprofen and an unknown amount of chlorpheniramine (Court et al, 1981).

C) SEIZURE

1) WITH POISONING/EXPOSURE

a) Seizures has been reported following acute massive ibuprofen overdose (Holubek et al, 2007).
b) CASE SERIES: Seizures have occurred in several pediatric patients (Oker et al, 2000; Hall et al, 1986) and appeared to be associated with ingestion of greater than 400 mg/kg.
c) CASE REPORT: A 21-month-old male developed tonic-clonic seizures 46 hours after ingestion of 20 ibuprofen 400 mg tablets (total 8 g) with no other known ingestants. The child was initially treated for acute renal failure (serum creatinine of 2.1 mg/dL, BUN 59 mg/dL, and potassium 6.3 mEq/L; treatment included furosemide and sodium polystyrene sulfonate) with severe metabolic acidosis (Al Harbi et al, 1997).
d) Seizure activity stopped after the child's hypocalcemia and hypomagnesemia were corrected (serum calcium 1.9 mEq/L, magnesium 1.4 mg/dL, and sodium 128 mEq/L); neurological activity slowly improved (Al Harbi et al, 1997).

D) HEADACHE

1) WITH POISONING/EXPOSURE

a) Headache has been reported following acute overdose (Court et al, 1983; Halpern et al, 1993).

E) MENINGITIS

1) WITH THERAPEUTIC USE

a) Aseptic meningitis has been reported with therapeutic use, especially in patients with systemic lupus erythematosus and other collagen vascular diseases; it is not dose-related (Katona et al, 1988; Durback et al, 1988). In 1 case report, aseptic meningitis occurred in an adult taking ibuprofen with a history of rheumatoid arthritis (Horn & Jarrett, 1997).

F) PSYCHOMOTOR AGITATION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 16-year-old ingested ibuprofen 40 g and was initially found unresponsive and hypothermic (rectal temperature 33.8 degrees C), and later developed severe agitation in the emergency department (ED) that required physical restraint (Rittner & Eskin, 1998). The patient did not respond to auditory stimuli or recognize family members. Approximately 12 hours after ingestion, following intensive supportive care, including mechanical ventilation, correction of metabolic acidosis and rewarming, the patient was alert and oriented.

Gastrointestinal

3.8.2)

A) ABDOMINAL PAIN

1) WITH THERAPEUTIC USE

a) Esophageal stricture has occurred in patients with GI reflux following ingestion with insufficient liquids (Heller et al, 1982).
b) CASE REPORT: An 82-year-old woman died of massive gastrointestinal bleeding secondary to hemorrhagic duodenitis and gastritis after taking ibuprofen 1200 mg daily for 10 days for flu-like symptoms (Stevenson et al, 2001).

2) WITH POISONING/EXPOSURE

a) Gastrointestinal distress, nausea, and epigastric pain are commonly reported following overdose (Joubert, 1982; Hall et al, 1986; Hall & Rumack, 1988).
b) Gastrointestinal disturbances were reported in 42% of cases in 1 prospective study of 329 cases of ibuprofen overdose (McElwee et al, 1990).
c) Gastrointestinal bleeding may occur (Chelluri & Jastremski, 1986).

B) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE

1) WITH THERAPEUTIC USE

a) Nausea, vomiting, diarrhea, and guaiac positive stools have been reported. Upper GI bleeding and activation of lower GI disease may occur (Marciniak et al, 2007; Cuthbert, 1974; Collins et al, 1989).
b) Small intestinal strictures, ulcerations, perforations, diarrhea, and villous atrophy have been reported (Kwo & Tremaine, 1995).
c) CASE REPORT: A 12-year-old girl with cystic fibrosis developed pyloric channel stricture after 1 month of taking high-dose ibuprofen (16.2 to 31.6 mg/kg/dose {mean 25.4}) to treat pulmonary symptoms (Bell et al, 1999). The authors suggested that the strictures developed as a result of healing antral/pyloric channel ulcers. Following dilatation and drug cessation, the patient remained asymptomatic.

C) ACUTE PANCREATITIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: An 18-year-old male developed acute pancreatitis after ingesting 7 ibuprofen 400 mg tablets (equivalent to 51.4 mg/kg) . The serum amylase was 493 International Units/L and urine amylase was 4786 International Units/L. Liver enzymes and the lipid panel results were all within normal limits. All laboratory values returned to normal within 3 days with conservative therapy (Magill et al, 2006).

Hepatic

3.9.2)

A) LIVER ENZYMES ABNORMAL

1) WITH THERAPEUTIC USE

a) Occasional abnormalities of liver enzymes may be noted during chronic therapeutic usage (Lee & Finkler, 1986).
b) CASE REPORT: Three patients with chronic hepatitis C developed a 5-fold elevation of liver transaminases levels following therapeutic ingestion of ibuprofen (Riley & Smith, 1998).
c) CASE REPORT: A 16-year-old boy presented with dark-colored urine and jaundice after 6 weeks of therapy with ibuprofen (1200 mg/day for 2 weeks followed by 200 to 400 mg/day sporadically for 4 weeks). Initial labs showed mild elevations in liver enzymes; all values continued to rise with no cause evident on CT. Viral and autoimmune etiologies were ruled out. On day 18 of illness, a liver biopsy revealed histology consistent with drug-induced livery injury.

1) Liver enzymes peaked 1 week later (total bilirubin 10.1 mg/dL, AST 51 Units/L, ALT 80 Units/L, alkaline phosphatase 510 Units/L), as well as an INR of 1.87. Total bilirubin and transaminase levels slowly declined to normal values over the next 3 months, with no sequelae (Bennett et al, 2009).

2) WITH POISONING/EXPOSURE

a) Elevated aminotransferases have been reported rarely after overdose (Marciniak et al, 2007; Lee & Finkler, 1986).

B) HEPATIC FAILURE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 55-year-old female with a history of alcohol abuse (100 g/day for 15 years) ingested ibuprofen 9.6 g and approximately 1 week later developed symptoms of jaundice, which progressed to subfulminant hepatitis (Laurent et al, 2000). Over the next 4 weeks, the patient's liver function continued to decline, resulting in stage III encephalopathy and complete liver failure requiring transplantation. The patient recovered uneventfully.

C) TOXIC LIVER DISEASE

1) WITH POISONING/EXPOSURE

a) Hepatotoxicity has been reported following acute massive ibuprofen overdose (Holubek et al, 2007).

Genitourinary

3.10.2)

A) ACUTE RENAL FAILURE SYNDROME

1) WITH THERAPEUTIC USE

a) CASE REPORT: Transient renal failure may have been caused by the concurrent use of maintenance ibuprofen therapy and intravenous aminoglycoside in an adult (Kovesi et al, 1998).
b) RISK FACTORS: Patients with coronary artery disease and elderly patients were found to be at risk for therapeutic dose ibuprofen-associated renal impairment in a study of 1908 patients treated with ibuprofen (Murray et al, 1990).
c) CASE REPORT: A 73-year-old diabetic woman who was taking metformin and lisinopril, presented with weakness, nausea, and decreased urination 5 days after taking ibuprofen (2400 mg initially and 2000 mg the next day) for fractured right humerus. Laboratory results revealed a potassium of 8.6 mmol/L and a serum creatinine of 6.99 mg/dL (baseline value: 0.94 mg/dL; baseline glomerular filtration rate: 59 mL/min per 1.73 m(2)). An ECG revealed a QRS duration of 186 ms. Following supportive care, including treatment with IV calcium gluconate and sodium bicarbonate and emergent hemodialysis, her condition improved and she was discharged 6 days after admission. On followup visit a year later, her serum creatinine was 0.95 mg/dL with an estimated glomerular filtration rate of 55 mL/min per 1.73 m(2) (Platts-Mills et al, 2013).
d) CASE REPORT/PEDIATRIC: Four children with cystic fibrosis developed acute renal failure that may have been caused by the concurrent use of an intravenous aminoglycoside while continuing on maintenance therapy with ibuprofen (Kovesi et al, 1998).
e) ADULTS: Mild reversible reduction in kidney function was observed in a patient with SLE receiving 2.4 g/day for 3 days (Kimberly et al, 1978) with elevated BUN, serum, creatinine and potassium. Similar effects occurred in an elderly patient following an increase in dose from 1.2 to 1.6 g/day (Poirier, 1984).
f) COMBINATION THERAPY: One of 7 patients presenting with acute renal failure, 1 of 4 patients with impaired renal functions or proteinuria, and 1 of 5 patients presenting with chronic renal failure due to nonsteroidal anti-inflammatory drugs were taking ibuprofen in combination with other nonsteroidal agents (Adams et al, 1986).
g) CHILD: Acute renal failure was reported in a 10-year-old child receiving 200 mg every 8 hours for 5 days for treatment of a subaponeurotic hematoma. Renal function rapidly improved following discontinuation (Van Biljon, 1989).

2) WITH POISONING/EXPOSURE

a) SUMMARY: Acute renal failure can occur in overdose (Holubek et al, 2007; Marciniak et al, 2007; Rogers & Venning, 1986; Le et al, 1994).
b) CASE REPORTS

1) ADULTS

a) Following ingestion of 9.6 to 16 g, an elderly male had an increased serum creatinine and BUN (Court et al, 1983).
b) Despite a massive overdose (72 g) of ibuprofen, a 44-year-old male experienced only transient renal insufficiency which did not require dialysis (Wolfe, 1995).
c) Mild transient asymptomatic elevation of BUN in 2 patients were the only abnormal renal findings in 50 cases of adult ibuprofen ingestion where renal function tests were obtained (Hall et al, 1992). Reversible elevations of BUN and creatinine occurred in another series, associated with transient hematuria in 1 case (Hall et al, 1986).
d) DOSE RELATIONSHIP: Acute oliguric renal failure has been reported after massive (range: 20 to 54 g) intentional ingestions (Bennett et al, 1985; Lee & Finkler, 1986; Hall & Rumack, 1988). Supportive treatment and hemodialysis resulted in survival of all patients.

1) In another study, renal toxicity was reported in 7 adults who ingested 3.6 to 40 g (Court et al, 1983)

e) A 50-year-old female developed acute nonoliguric renal failure after ingesting 40 to 60 ibuprofen 600 mg tablets. Her serum creatinine peaked at 2.7 mg/dL on day 2 and returned to baseline within a few days (Chelluri & Jastremski, 1986).
f) A 23-year-old male developed hypotension, metabolic acidosis, adult respiratory distress syndrome and acute oliguric renal failure necessitating hemofiltration for 7 days, then hemodialysis for 20 days (Le et al, 1994).
g) Reversible nonoliguric acute renal failure occurred with an overdose of greater than 18 g ibuprofen. The hospital course was unremarkable, with renal function returning to baseline by day 6 (Perazella & Buller, 1991).

2) PEDIATRICS

a) Acute renal failure developed in a 21-month-old following an ingestion of 20 ibuprofen 400 mg tablets (total 8 g); renal function returned to normal within 72 hours postingestion (Al Harbi et al, 1997).
b) Renal failure was described in a 26-month-old child who ingested up to 137 mg/kg (Pers Comm., 1984).
c) A 2-year-old boy developed reversible renal failure following ingestion of approximately 640 mg/kg of ibuprofen; renal function normalized by 72 hours postingestion (Kim et al, 1993).

3) OTHER

a) ALCOHOL USE: The concurrent use of ibuprofen in association with binge drinking has been associated with reversible acute deterioration in renal function (Elsasser et al, 1988; Wen et al, 1992; Johnson & Wen, 1995).

B) RENAL TUBULAR ACIDOSIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: Recurrent severe renal tubular acidosis developed in a 45-year-old patient after the repeated use of ibuprofen. The patient presented on several occasions with unexplained generalized weakness and acidemia (hyperchloremic, hypokalemic metabolic acidosis). Laboratory results from the last visit revealed a pH of 6.89, a bicarbonate of 5 mmol/L, a potassium level of 2.5 mmol/L, and a urine pH of 7.0 with a positive urine gap after fluid resuscitation. The patient recovered following discontinuation of ibuprofen and supportive care (Wu et al, 2015).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: A 28-year-old woman developed renal tubular acidosis, with severe hypokalemia (serum potassium 1.4 mmol/L), hypophosphatemia (serum phosphate 0.43 mmol/L), metabolic acidosis, prolonged QT intervals, and weakness after abusing a product containing ibuprofen 200 mg and codeine phosphate 12.8 mg per tablet (taking 40 to 60 tabs per day for several years) (Chetty et al, 2003).

C) INTERSTITIAL NEPHRITIS

1) WITH THERAPEUTIC USE

a) Interstitial nephritis may develop following a short course of ibuprofen in therapeutic doses (Marasco et al, 1987) McIntire et al, 1993; (Wattad et al, 1994).
b) CASE REPORT: Acute interstitial nephritis with a creatinine of 9.7 mg/dL and a BUN of 110 mg/dL developed in a patient with normal renal function who took 600 mg of ibuprofen daily for 2 days while volume depleted from influenza (Moss et al, 1986).

D) NEPHROTIC SYNDROME

1) WITH THERAPEUTIC USE

a) CASE REPORT: Two cases of nephrotic syndrome occurred after therapeutic courses of ibuprofen with durations of treatment greater than 6 months. Both cases resolved with discontinuation of ibuprofen (Morgenstern et al, 1989; Justiniani, 1986).

E) POLYURIA

1) WITH POISONING/EXPOSURE

a) A 19-year-old man developed lactic acidosis, polyuria, and coma after ingesting over 90 grams (1200 mg/kg) of ibuprofen 3 hours after consuming 1180 mL of beer in a suicide attempt. The patient was placed on mechanical ventilation and aggressive supportive care. Polyuria was noted approximately 7 hours after ingestion. The patient regained consciousness approximately 24 hours after ingestion. During the first two days of his treatment, the patient received a total of 11.23 L of IV fluids and had a measured output of 15.18 L of urine (Levine et al, 2010).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) SUMMARY

1) Elevated anion gap metabolic acidosis has been reported in children and adults after overdose (Holubek et al, 2007; Marciniak et al, 2007; Wood et al, 2006; Wiger & Gummin, 2002; Al Harbi et al, 1997; Wolfe, 1995; Le et al, 1994; Lee & Finkler, 1986; Hall & Rumack, 1988; Linden & Townsend, 1987; Chelluri & Jastremski, 1986; Menzies et al, 1989).

b) CASE REPORTS

1) ADULTS

a) A 19-year-old man developed lactic acidosis, polyuria, and coma after ingesting over 90 grams (1200 mg/kg) of ibuprofen 3 hours after consuming 1180 mL of beer in a suicide attempt. The patient was successfully treated with aggressive supportive care, including mechanical ventilation and fluid resuscitation and regained consciousness approximately 24 hours after ingestion. No long term deficits were reported (Levine et al, 2010).
b) A 26-year-old woman was found comatose with metabolic acidosis (pH 6.99, base excess -21), and hypotension unresponsive to therapy following an estimated ingestion of ibuprofen 105 g sustained-release . The patient died of cardiac arrest approximately 10 hours after exposure, despite resuscitation efforts (Wood et al, 2006).
c) A 33-year-old man developed severe metabolic acidosis (nadir pH 6.88) following ingestion of ibuprofen 60 g (about 800 mg/kg) and diclofenac 250 mg . Coingestion of ethanol, hypotension, and impaired respiratory compensation may have been contributing factors to the severity of acidosis (Downie et al, 1993).
d) A 23-year-old man developed hypotension, metabolic acidosis, adult respiratory distress syndrome, and acute oliguric renal failure necessitating ventilation and prolonged hemodialysis after a 30 g overdose (Le et al, 1994).
e) Recurrent severe renal tubular acidosis developed in a 45-year-old patient after the repeated use of ibuprofen. The patient presented on several occasions with unexplained generalized weakness and acidemia (hyperchloremic, hypokalemic metabolic acidosis). Laboratory results from the last visit revealed a pH of 6.89, a bicarbonate of 5 mmol/L, a potassium level of 2.5 mmol/L, and a urine pH of 7.0 with a positive urine gap after fluid resuscitation. The patient recovered following discontinuation of ibuprofen and supportive care (Wu et al, 2015).

2) ADOLESCENTS

a) A 16-year-old adolescent developed depressed mental status, requiring intubation, hypotension, and metabolic acidosis about 5 hours after ingesting an unknown amount of ibuprofen. Two empty bottles of ibuprofen 200 mg (originally contained 500 tablets in each bottle) were found in the house. Laboratory results obtained 10 hours postingestion revealed a pH of 6.93, pCO2 of 35, HCO3 of 11, lactic acid of 15.9, BUN of 10, serum creatinine of 1.18, and a serum ibuprofen concentration of 570 mcg/mL (normal 10 to 50 mcg/mL). He was treated with sodium bicarbonate and inotropic support, but his condition did not improve. At about 11 hours postingestion, he underwent continuous veno-venous hemodialysis (CVVHD) for 19 hours. Initially, his serum ibuprofen concentration decreased to 171 mcg/mL at 32 hours postingestion, but despite an increase in serum ibuprofen concentration (327 mcg/mL at 50 hours postingestion), his condition continued to improve and he was discharged without further sequelae (Christian & Thornton, 2015).
b) 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).
c) A 15-year-old girl developed metabolic acidosis (pH 7.16 preintubation), pCO2 27 mm Hg, and PO2 127 mm Hg (room air), coma, and mild thrombocytopenia following an overdose of 100 g of ibuprofen. The patient required 8 hours of mechanical ventilation with pharmacological correction of the acidosis. The patient was alert and oriented within 12 hours, and discharged to home at 63 hours postexposure with no long-term sequelae reported (Seifert et al, 2000).

3) INFANT/TODDLERS

a) A 21-month-old male developed severe metabolic acidosis, acute renal failure, and tonic-clonic seizures following the ingestion of 20 ibuprofen 400 mg tablets. Hypocalcemia and hypomagnesemia were also reported, which may have been attributable in part to the use of furosemide and sodium polystyrene sulfonate to treat the acute renal failure (Al Harbi et al, 1997).
b) An 18-month old male potentially ingested ibuprofen 7.2 g (600 mg/kg) and developed severe metabolic acidosis (initial ABG: pH 7.20, HCO3 15 mEq/L), and a single 30-second tonic-clonic seizure (Oker et al, 2000). A 4-hour postingestion ibuprofen serum level was 640 mcg/mL and 39 mcg/mL at 7.5 hours. The patient was given an initial 12 mEq bolus of sodium bicarbonate, followed by an infusion of D5W and 24 mEq/L sodium bicarbonate at 90 mL/hour for persistent acidosis. Respiratory intubation was required for apnea. The patient was successfully extubated within 24 hours, and mentation improved with complete recovery.

Hematologic

3.13.2)

A) PANCYTOPENIA

1) WITH THERAPEUTIC USE

a) Isolated cases of thrombocytopenia, agranulocytosis, hemolysis, lymphopenia, and pancytopenia have been reported after therapeutic use (Cuthbert, 1974; Korsager, 1978; Mamus et al, 1986; Lee & Finkler, 1986; Lindblad & Rodjer, 1991).

B) THROMBOCYTOPENIC DISORDER

1) WITH POISONING/EXPOSURE

a) Thrombocytopenia has been reported following acute massive ibuprofen overdose (Holubek et al, 2007).
b) CASE REPORT: Mild thrombocytopenia (platelet count 135 x 10(3)/mcg/L {normal 150-450}) and a slight drop in hemoglobin were reported in a 15-year-old female following a massive 100 g overdose of ibuprofen (Seifert et al, 2000). No hematemesis or melena developed. The platelet count returned to normal approximately 56 hours after exposure. The patient made a complete recovery.

C) DISSEMINATED INTRAVASCULAR COAGULATION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 21-year-old female developed disseminated intravascular coagulation and adult respiratory distress syndrome following a massive overdose of ibuprofen; her initial PT was 20.5 and initial PT-INR was 1.9 (Stipetic et al, 1996). Following supportive care, the patient had a complete recovery.
b) CASE REPORT: A 17-year-old developed disseminated intravascular coagulation and multiorgan system failure following a massive overdose (nearly 200 g) of ibuprofen . She died 9 days after admission (Holubek et al, 2007).

D) ACQUIRED HYPOPROTHROMBINEMIA

1) WITH POISONING/EXPOSURE

a) Asymptomatic hypoprothrombinemia occurred in a 17-year-old male following an intentional ingestion of ibuprofen 98 g and 10 diphenhydramine tablets (Keller, 1995). Despite reportedly vomiting within 1 hour of ingestion, the patient had an ibuprofen level of 572.5 mcg/mL. Two days after ingestion, peak coagulation studies were PT 17.8/11.4 (control) and INR 2.27. The patient had an uncomplicated recovery.

Musculoskeletal

3.15.2)

A) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Following a massive (72 g) ibuprofen overdose, a 44-year-old male experienced transient rhabdomyolysis (CK 1018 International Units/L) without developing permanent sequelae (Wolfe, 1995).

Endocrine

3.16.2)

A) ADRENAL CORTICAL HYPOFUNCTION

1) WITH THERAPEUTIC USE

a) CASE REPORT: A case of reversible hyporeninemic hypoaldosteronism causing hyperkalemia and cardiac arrest in a 59-year-old male with autonomic dysfunction was reported after a short course of ibuprofen (Masud et al, 1993).

Immunologic

3.19.2)

A) ANAPHYLACTOID REACTION

1) WITH THERAPEUTIC USE

a) CASE SERIES: Anaphylactoid reactions (respiratory distress, accompanied by circulatory collapse, angioedema, or pruritus) were described in 17 patients in a 1980 FDA report. Reactions occurred within 30 to 60 minutes and more commonly in patients with prior exposure to ibuprofen, aspirin, or both (Rossi & Knapp, 1982).

Reproductive

3.20.1)

3.20.2)

A) IBUPROFEN

1) In a prospective cohort study, ibuprofen use during pregnancy resulted in low birthweight when used during the second trimester and asthma in 18-month-old infants when used in the second and third trimesters; however, there was no significant difference in infant survival, congenital malformations, or structural heart defects in women taking NSAIDs during the first-trimester (Nezvalova-Henriksen et al, 2013).
2) The use of ibuprofen as a tocolytic agent was studied in 52 pregnant women up to 32 weeks gestation (Hennessy et al, 1992). No cases of oligohydramnios were observed; however, 3 cases of low-normal fluid occurred and resolved after discontinuation. A mild constriction of ductus arteriosus in 4 (7%) of the fetuses was observed, and 3 of these fetuses demonstrated ductal constriction within one week of starting ibuprofen. No relation between the dosage of ibuprofen used and the incidence of ductal constriction was noted. Another source reported a significant reduction of amniotic fluid with the use of ibuprofen as an oral tocolytic in a woman with triplet pregnancy (Wiggins & Elliott, 1990).

B) LACK OF EFFECT

1) There are no published reports linking ibuprofen with congenital defects. The article does contain several cases, prospective reviews, and surveillances that mention birth defects, but the data do not support an association with ibuprofen use during pregnancy (Briggs et al, 1998).

C) ANIMAL STUDIES

1) IBUPROFEN

a) Animals administered oral ibuprofen doses 0.912 times the maximum recommended human dose demonstrated an increased incidence of membranous ventricular septal defects (Prod Info CALDOLOR(R) intravenous injection, 2015).
b) No developmental abnormalities were observed in animals administered ibuprofen (Prod Info ibuprofen oral suspension, 2012; Prod Info ibuprofen oral tablets, 2014; Prod Info DUEXIS(R) oral tablets, 2014; Prod Info REPREXAIN(TM) oral film coated tablets, 2014).

2) IBUPROFEN/HYDROCODONE

a) An increased rate of major abnormalities and nonossified metacarpals was observed in animals administered ibuprofen doses up to 5.72 times the maximum clinical dose, based on body weight (Prod Info REPREXAIN(TM) oral film coated tablets, 2014).
b) No reproductive toxicity was observed in animals administered ibuprofen doses up to 10 times the maximum clinical dose, based on body weight and surface area (Prod Info REPREXAIN(TM) oral film coated tablets, 2014).

3) IBUPROFEN/OXYCODONE

a) No evidence of teratogenicity was observed in animals administered oral oxycodone:ibuprofen doses up to 3:240 mg/kg/day during gestation days 7 to 19; however, developmental toxicity (delayed ossification and reduced fetal body weights) was observed (Prod Info oxycodone HCl ibuprofen oral tablets, 2011).
b) No evidence teratogenicity or developmental toxicity were observed in animals administered oral oxycodone:ibuprofen doses equivalent to the maximum recommended human dose of up to 20:1600 mg/day, based on mg/m(2)) during gestation days 7 to 16 (Prod Info oxycodone HCl ibuprofen oral tablets, 2011).

3.20.3)

A) PREGNANCY CATEGORY

1) Because of the potential for premature closure of the ductus arteriosus, avoid using ibuprofen in pregnant women starting at 30 weeks gestation. Advise patient of the potential risk to the fetus (Prod Info CALDOLOR(R) intravenous injection, 2015; Levin, 1980; Needs & Brooks, 1985). Only use ibuprofen prior to 30 weeks gestation if the potential maternal benefit outweighs the fetal risk (Prod Info ibuprofen oral suspension, 2012; Prod Info ibuprofen oral tablets, 2014).
2) The manufacturer has classified ibuprofen/oxycodone as FDA pregnancy category C prior to 30 weeks gestation and FDA pregnancy category D after 30 weeks of gestation (Prod Info oxycodone HCl ibuprofen oral tablets, 2011).
3) The manufacturer has classified ibuprofen (oral), and ibuprofen/hydrocodone as FDA pregnancy category C (Prod Info ibuprofen oral suspension, 2012; Prod Info ibuprofen oral tablets, 2014; Prod Info REPREXAIN(TM) oral film coated tablets, 2014).
4) Administration of ibuprofen (oral suspension), ibuprofen/hydrocodone, or ibuprofen/oxycodone during labor and delivery is not recommended (Prod Info ibuprofen oral suspension, 2012; Prod Info oxycodone HCl ibuprofen oral tablets, 2011; Prod Info REPREXAIN(TM) oral film coated tablets, 2014).
5) There are no adequate and well-controlled studies of famotidine/ibuprofen use during pregnancy in humans. Because data are limited, famotidine/ibuprofen should only be used during pregnancy if the maternal benefit outweighs the fetal risk. The use of NSAIDs such as famotidine/ibuprofen during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus (Prod Info DUEXIS(R) oral tablets, 2016a).

B) ABORTION

1) Two reports of stillbirth without abnormalities, 2 reports of spontaneous abortion without abnormalities, and 5 abnormalities including anencephalic birth, fetal convulsions, cerebral palsy, and microphthalmia were reported (Barry et al, 1984).

C) HYPERTENSION PULMONARY

1) Prostaglandin synthetase inhibitor use during pregnancy may cause a constriction of the ductus arteriosus, pulmonary hypertension, or both (Briggs et al, 1998).

D) MISCARRIAGE

1) NSAID use during the first 20 weeks of pregnancy was associated with an 80% nonsignificant increased risk of miscarriage over nonuse. Risk of miscarriage was highest when the drug was taken around the time of conception or used for more than a week (a significant difference). 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).

E) PREGNANCY DISORDER

1) Possible complications of ibuprofen use during the last trimester of pregnancy include delayed labor, complications during delivery, and postpartum bleeding (Hussar & Hodge, 1985).
2) Ibuprofen has been used as a tocolytic agent. It has been associated with reduced amniotic fluid volume in the fetus (Briggs et al, 1998).
3) When ibuprofen was studied in pregnant women up to 32 weeks gestation (Hennessy et al, 1992), low-normal amniotic fluid occurred and resolved after discontinuation. A significant reduction of amniotic fluid with the use of ibuprofen as an oral tocolytic occurred in a woman with triplet pregnancy (Wiggins & Elliott, 1990).

F) RESPIRATORY DEPRESSION

1) Possible complications of ibuprofen use during the last trimester of pregnancy include respiratory depression in the newborn (Hussar & Hodge, 1985).

G) ANIMAL STUDIES

1) IBUPROFEN

a) Developmental abnormalities were not observed in animals administered ibuprofen (Prod Info CALDOLOR(R) intravenous injection, 2015; Prod Info DUEXIS(R) oral tablets, 2014; Prod Info REPREXAIN(TM) oral film coated tablets, 2014).
b) Animals administered ibuprofen experienced an increased incidence of stillbirth and an increased incidence of pre- and postimplantation loss (Prod Info CALDOLOR(R) intravenous injection, 2015).
c) An increased incidence of dystocia and delayed parturition occurred in animals (Prod Info CALDOLOR(R) intravenous injection, 2015; Prod Info Motrin(R), 1992).

2) IBUPROFEN/OXYCODONE

a) An increased mortality of pups was observed in animals administered an oxycodone:ibuprofen dose equivalent to 0.25 times the maximum recommended human dose (MRHD) , based on mg/m(2). There was also an increase in the number of stillborn pups and a decrease in mean pup weight at an oxycodone:ibuprofen dose of 0.5 times the MRHD (Prod Info oxycodone HCl ibuprofen oral tablets, 2011).

3.20.4)

A) BREAST MILK

1) IBUPROFEN

a) There are no adequate or well-controlled studies of the effect on ibuprofen administration on mothers, nursing infants, or milk production. In limited published literature, ibuprofen was detected in human breast milk at doses between 0.06% and 0.6% of the maternal weight-adjusted daily dose. No adverse effects were reported in breastfed infants (Prod Info CALDOLOR(R) intravenous injection, 2015).
b) Lactating women who took up to 2.4 grams of ibuprofen tablets daily experienced no measurable excretion of ibuprofen in breast milk (Townsend et al, 1984).
c) The manufacturer recommends considering the maternal benefit and potential harm to the nursing infant when deciding to administer ibuprofen (Prod Info CALDOLOR(R) intravenous injection, 2015); however, ibuprofen is considered compatible with breastfeeding by the American Academy of Pediatrics and the World Health Organization (Anon, 2001; Anon, 2002).

2) IBUPROFEN/FAMOTIDINE

a) It is unknown whether famotidine/ibuprofen or ibuprofen alone is excreted in human milk (Prod Info DUEXIS(R) oral tablets, 2016).

3.20.5)

A) ANIMAL STUDIES

1) IBUPROFEN

a) Ibuprofen may delay or prevent rupture of ovarian follicles, possibly associated with reversible infertility. Reversible delay in ovulation has also been reported in some studies. Animal studies have observed a disruption in prostaglandin-mediated follicular rupture (Prod Info CALDOLOR(R) intravenous injection, 2015).

2) IBUPROFEN/FAMOTIDINE

a) Animal studies showed that the administration of prostaglandin-mediated NSAIDs such as ibuprofen/famotidine may delay or prevent ovarian follicle rupture, a phenomenon that can be associated with reversible female infertility. Small studies in women reported the same findings (Prod Info DUEXIS(R) oral tablets, 2016).

3) IBUPROFEN/OXYCODONE

a) There was no evidence of impairment of fertility in male or female animals administered oxycodone hydrochloride and ibuprofen 0.5 times the maximum recommended human dose (Prod Info oxycodone HCl ibuprofen oral tablets, 2011).

Carcinogenicity

3.21.2)

A) Studies evaluating the potential carcinogenic effects of the ibuprofen/famotidine combination are lacking.

3.21.3)

A) LACK OF INFORMATION

1) IBUPROFEN/FAMOTIDINE: Studies evaluating the potential carcinogenic effects of the ibuprofen/famotidine combination are lacking (Prod Info DUEXIS(R) oral tablets, 2016).

Genotoxicity

Dermatologic

3.14.2)

A) ANGIOEDEMA

1) WITH POISONING/EXPOSURE

a) CASE SERIES: Angioedema, hives, itching, rash, and other swelling were noted in 1.8% of cases in a prospective study of 329 cases of ibuprofen overdose (McElwee et al, 1990).

B) DERMATITIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A case of dermatitis herpetiformis was reported within 48 hours of starting ibuprofen for polyarthralgia and myalgia (Tousignant et al, 1994). Following an unsuccessful trial of prednisone, the rash resolved with dapsone (100 mg/day).
b) CASE REPORT: One case of contact dermatitis to ibuprofen developed after chronic intermittent use of an ibuprofen-containing topical ointment (Veronesi et al, 1986).

C) BULLOUS ERUPTION

1) WITH THERAPEUTIC USE

a) Two cases of bullous lower extremity lesions after therapeutic ibuprofen use have been reported. The lesions resolved after discontinuation of ibuprofen (Laing et al, 1988).

D) SKIN FINDING

1) WITH THERAPEUTIC USE

a) CASE REVIEW: In a review of 2644 ibuprofen cutaneous adverse reaction reports, Halpern & Volans (1994) listed the following reactions to ibuprofen (Halpern, 1994):

1) Morbilliform rash 42.0%
2) Angioedema 21.4%
3) Urticaria 12.7%
4) Photosensitivity 5.3%
5) Hair and Nail disorders 3.7%
6) Pruritus (no rash) 3.1%
7) Erythema multiform/Stevens Johnson/Toxic epidermal necrolysis 3.0%
8) Bullous eruptions 2.5%
9) Erythema nodosum 0.1%
10) Vasculitis 0.1%

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Serum ibuprofen levels are not available in most hospital laboratories and are not necessary for clinical management.
B) Measure serum electrolytes, creatinine, and BUN. Monitor for gastrointestinal bleeding.
C) If significant CNS or respiratory toxicity present, assess acid-base status.
D) Obtain serum acetaminophen level.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Measure serum electrolytes, creatinine, and BUN.

B) ACID-BASE

1) If significant CNS or respiratory toxicity present, assess acid-base status.

C) HEMATOLOGIC

1) Monitor for gastrointestinal bleeding; obtain baseline hematocrit in patients with suspected bleed.

4.1.3)

A) URINALYSIS

1) Urinalysis to detect hematuria or proteinuria may be useful.

B) OTHER

1) Monitor urine output carefully.

4.1.4)

A) OTHER

1) FECAL

a) Stool guaiac test is recommended to detect gastrointestinal bleeding.

2) OTHER

a) If any VISUAL symptoms are present, an ocular exam is desirable.

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients who develop CNS depression, hypotension, acidosis, or gastrointestinal bleeding should be admitted.

6.3.1.2) HOME CRITERIA/ORAL

A) Asymptomatic children with inadvertent ingestions of less than 200 mg/kg can be managed at home with milk or water dilution and observation.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Symptomatic children, adults with deliberate ingestion, and children ingesting more than 200 mg/kg should be referred to a health care facility for observation and treatment. Most patients who have ingested significant amounts of ibuprofen will manifest symptoms within 4 to 6 hours.

Monitoring

Oral Exposure

6.5.1)

A) DILUTION

1) Amounts not likely to produce symptoms (less than 200 mg/kg) may be diluted with water or milk to minimize gastrointestinal (GI) upset. Excessive dilution is not recommended for larger amounts, as this may increase the amount of ibuprofen absorbed.
2) However, small amounts of fluid (less than 4 ounces) may be given to prevent esophageal lodging of tablets.

B) ACTIVATED CHARCOAL

1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

2) 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).

6.5.2)

A) SUMMARY

1) Aggressive decontamination is generally not necessary, as toxicity is usually limited.

B) DILUTION

1) Amounts not likely to produce symptoms (less than 200 mg/kg) may be diluted with water or milk to minimize GI upset. Excessive dilution is not recommended for larger amounts, as this may increase the amount of ibuprofen absorbed.
2) However, small amounts of fluid (less than 4 ounces) may be given to prevent esophageal lodging of tablets.

C) ACTIVATED CHARCOAL

1) 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.

2) CHARCOAL DOSE

b) ADVERSE EFFECTS/CONTRAINDICATIONS

6.5.3)

A) SUPPORT

1) Overdose treatment is symptomatic and supportive. Maintain an open airway and support ventilation. Treat seizures with benzodiazepines, hypotension with fluids and adrenergic vasopressors, and coma with intubation. Monitor ECG and arterial blood gases in patients with severe toxicity.

B) MONITORING OF PATIENT

1) Serum ibuprofen levels are not available in most hospital laboratories and are not necessary for clinical management. Measure serum electrolytes, creatinine, and BUN. If significant CNS or respiratory toxicity is present, assess acid-base status. Obtain serum acetaminophen level. Monitor for gastrointestinal bleeding.

C) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

4) EXTRACORPOREAL MEMBRANE OXYGENATION (ECMO): Marciniak et al (2007) reported the successful use of ECMO to treat a 14-year-old boy following an overdose of approximately 50 g of ibuprofen (ibuprofen concentration 776 mcg/mL 5 to 10 hours postingestion; therapeutic range: 20 to 30 mcg/mL). Venoarterial ECMO was started 7 hours after presentation when no clinical improvement was observed following pressor support, which included norepinephrine, phenylephrine, and vasopressin infusions. The patient's hemodynamic status improved, and ECMO was discontinued on day 4 (Marciniak et al, 2007).

D) ACIDOSIS

1) METABOLIC ACIDOSIS: Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate, 1 to 2 mEq/kg is a reasonable starting dose(Kraut & Madias, 2010). Monitor serum electrolytes and arterial or venous blood gases to guide further therapy.

E) NALOXONE

1) CASE REPORT

a) An 11-month-old female became comatose following accidental ibuprofen ingestion, which was successfully treated with naloxone; suspected ibuprofen dose was 10 to 12 g based on a serum level of 624 mg/L at 6 hours following ingestion. A total dose of 0.9 mg/kg naloxone was given as follows: 1 mg IV push, followed by another 1 mg, then 2 mg IV push, and finally 3 mg IV within a 40-minute period. Improvement in physical signs/symptoms and mental status were observed with appropriate response to stimuli. The infant made a complete recovery.

1) Although opioids were suspected, the toxicological screen was negative with the exception of ibuprofen. It was suggested that ibuprofen may share a common mechanism with opioids; however, the exact mechanism remains unknown (Easley & Altemeier, 2000).

F) 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).

Eye Exposure

6.8.1)

A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

6.9.1)

A) DERMAL DECONTAMINATION

1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

6.9.2)

A) DERMATITIS

1) Contact dermatitis developing after use of ibuprofen-containing topical agents should be treated by discontinuing use of the product and with corticosteroids if necessary.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

1) Ibuprofen is highly protein-bound; hemodialysis is unlikely to be effective.

1) URINE ALKALINIZATION with sodium bicarbonate is not expected to be of benefit (Hall et al, 1986). Although the manufacturer recommends alkaline diuresis because ibuprofen is acidic, ibuprofen is highly protein-bound (99%), resulting in minimal renal excretion of unchanged drug (1%).
2) HEMODIALYSIS: Pharmacokinetic studies of ibuprofen in hemodialysis patients have shown that dialysis does NOT enhance ibuprofen clearance (Antal et al, 1986). If renal failure occurs, dialysis may be required as general supportive care (Holubek et al, 2007; Bennett et al, 1985).

1) REFRACTORY METABOLIC ACIDOSIS: A 16-year-old adolescent developed depressed mental status, requiring intubation, hypotension, and metabolic acidosis about 5 hours after ingesting an unknown amount of ibuprofen. Two empty bottles of ibuprofen 200 mg (originally contained 500 tablets in each bottle) were found in the house. Laboratory results obtained 10 hours postingestion revealed a pH of 6.93, pCO2 of 35, HCO3 of 11, lactic acid of 15.9, BUN of 10, serum creatinine of 1.18, and a serum ibuprofen concentration of 570 mcg/mL (normal 10 to 50 mcg/mL). He was treated with sodium bicarbonate and inotropic support, but his condition did not improve. At about 11 hours postingestion, he underwent continuous veno-venous hemodialysis (CVVHD) for 19 hours. Initially, his serum ibuprofen concentration decreased to 171 mcg/mL at 32 hours postingestion, but despite an increase in serum ibuprofen concentration (327 mcg/mL at 50 hours postingestion), his condition continued to improve and he was discharged without further sequelae (Christian & Thornton, 2015).

Abstracts

Case Reports

1) DICLOFENAC SODIUM, INDOMETHACIN, AND IBUPROFEN: A 61-year-old female ingested diclofenac sodium 375 mg , indomethacin 75 mg, and ibuprofen 400 mg . She presented to ED incoherent and hallucinating; shortly following admission, the patient suffered respiratory arrest. Aggressive supportive therapy was instituted and the patient was awake and alert in less than 24 hours with no serious sequelae (Bright & McNulty, 1991).
2) Chelluri & Jastremski (1986) reported the case of a 50-year-old female who ingested between 24 and 36 g of ibuprofen. She recovered after experiencing CNS depression, acidosis, GI bleeding, and reversible renal failure (Chelluri & Jastremski, 1986).
3) A 73-year-old man, who had been taking ibuprofen 600 mg 1 to 4 times daily for several years, experienced severe pancytopenia, which completely resolved within 21 days of discontinuing ibuprofen therapy (Lindblad & Rodjer, 1991).
4) NITROGLYCERIN AND IBUPROFEN: A 23-year-old male ingested ibuprofen 30 g and an unknown quantity of nitroglycerin 0.4 mg sublingual tablets. The patient presented with nausea, vomiting, and abdominal cramps. Mild hypotension and metabolic acidosis were present, with the patient developing progressively worsening oliguric renal failure. Continuous hemofiltration was initiated 24 hours after admission. On day 3, the patient developed hypoxia and respiratory difficulty; a diagnosis of adult respiratory distress syndrome was made. Intubation and ventilation were required. Hemodialysis was initiated on day 10 and the patient was discharged after 20 days; hemodialysis continued until day 27 (Le et al, 1994).

1) Linden & Townsend (1987) reported 2 cases of ibuprofen overdose in children aged 1.5 and 2 years old. They ingested ibuprofen 560 to 666 mg/kg and fully recovered after supportive treatment for central nervous system depression and metabolic acidosis (Linden & Townsend, 1987).
2) Doizaki et al (1987) reported the case of a 12-month-old child who ingested ibuprofen 933 mg/kg and recovered after receiving supportive treatment for metabolic acidosis (Doizaki et al, 1987).
3) A 16-month-old child who ingested 6.8 g (469 mg/kg) died of aspiration pneumonia (Hall et al, 1986).

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) IBUPROFEN

1) OVER THE COUNTER

a) ORAL TABLETS, CAPLETS, GEL CAPLETS, AND CAPSULES: 1 or 2 tablets, caplets, or gel caplets (200 mg each) every 4 to 6 hours; MAX: 1200 mg (6 tablets, caplets, or gel caplets) (OTC Product Information, as posted to the DailyMed site 09/2014; OTC Product Information, as posted to the DailyMed site 09/2014a)

2) PRESCRIPTION

a) INTRAVENOUS: Varies by indication. 100 to 200 mg IV every 4 hours as necessary or 400 mg IV every 4 to 6 hours or 800 mg IV every 6 hours as necessary with infusion times no less than 30 minutes; MAX: 3200 mg daily (Prod Info CALDOLOR(R) intravenous injection, 2014).
b) ORAL TABLETS: Adult dose is 400 to 800 mg 3 or 4 times daily; maximum daily dose is 3200 mg (Prod Info MOTRIN(R) oral tablets, 2007).

B) IBUPROFEN/FAMOTIDINE

1) PRESCRIPTION

a) ORAL TABLETS: 800 mg ibuprofen/26.6 mg famotidine (1 tablet) orally 3 times daily (Prod Info DUEXIS(R) oral tablets, 2013).
b) Tablets should be swallowed whole and should not be chewed, divided, or crushed (Prod Info DUEXIS(R) oral tablets, 2013).

7.2.2)

A) IBUPROFEN

1) GENERAL ORAL DOSING

a) INFANTS AND CHILDREN (LESS THAN 60 KG): 5 to 10 mg/kg/dose orally every 6 to 8 hours as needed; maximum daily dose is 40 mg/kg/day(Prod Info MOTRIN(R) oral suspension, 2006; Kraemer & Rose, 2009; Drendel et al, 2009; Friday et al, 2009; Koller et al, 2007; Dlugosz et al, 2006; Goldman et al, 2004; Perrott et al, 2004; Kokki, 2003).

2) OVER THE COUNTER

a) 100 MG CHEWABLE TABLETS (CAREONE)

1) UNDER 2 YEARS (UNDER 11 KG): No dosing provided (OTC Product Information, as posted to the DailyMed site 08/2014)
2) 2 TO 3 YEARS (11 TO 16 KG): 100 mg (1 tablet) every 6 to 8 hours; MAX: 4 times daily (OTC Product Information, as posted to the DailyMed site 08/2014)
3) 4 TO 5 YEARS (GREATER THAN 16 TO 21 KG): 150 mg (1.5 tablets) every 6 to 8 hours; MAX: 4 times daily (OTC Product Information, as posted to the DailyMed site 08/2014)
4) 6 TO 8 YEARS (22 TO 27 KG): 200 mg (2 tablets) every 6 to 8 hours; MAX: 4 times daily (OTC Product Information, as posted to the DailyMed site 08/2014)
5) 9 TO 10 YEARS (GREATER THAN 27 TO 32 KG): 250 mg (2.5 tablets) every 6 to 8 hours; MAX: 4 times daily (OTC Product Information, as posted to the DailyMed site 08/2014)
6) 11 YEARS (33 TO 43 KG): 300 mg (3 tablets) every 6 to 8 hours; MAX: 4 times daily (OTC Product Information, as posted to the DailyMed site 08/2014)

b) ORAL TABLETS, CAPLETS, AND GEL CAPLETS

1) 12 YEARS AND OLDER: 1 or 2 tablets, caplets, or gel caplets (200 mg each) every 4 to 6 hours; MAX: 1200 mg (6 tablets, caplets, or gel caplets) (OTC Product Information, as posted to the DailyMed site 09/2014; OTC Product Information, as posted to the DailyMed site 09/2014a; Playfor et al, 2006; Greco & Berde, 2005)
2) UNDER 12 YEARS: No dosing provided (OTC Product Information, as posted to the DailyMed site 09/2014; OTC Product Information, as posted to the DailyMed site 09/2014a).

c) ORAL SUSPENSION

1) 50 MG SUSPENSION (7-ELEVEN AND MOTRIN)

a) UNDER 6 MONTHS: No dosing provided (OTC Product Information, as posted to the DailyMed site 06/2014; Prod Info Motrin(R), Ibuprofen, Children's formulas for OTC use, 2000).
b) 6 TO 11 MONTHS (5 TO 8 KG): 50 mg (1.25 mL) every 6 to 8 hours; MAX: 4 times daily (OTC Product Information, as posted to the DailyMed site 06/2014; Prod Info Motrin(R), Ibuprofen, Children's formulas for OTC use, 2000)
c) 12 TO 23 MONTHS (GREATER THAN 8 TO 10 KG): 75 mg (1.875 mL) every 6 to 8 hours; MAX: 4 times daily (OTC Product Information, as posted to the DailyMed site 06/2014; Prod Info Motrin(R), Ibuprofen, Children's formulas for OTC use, 2000)

2) 100 MG SUSPENSION (KROGER AND MOTRIN)

a) UNDER 2 YEARS: No dosing provided (OTC Product Information, as posted to the DailyMed site 08/2014a)
b) 2 TO 3 YEARS 11 TO 16 KG): 100 mg (5 mL or 1 teaspoonful) every 6 to 8 hours; MAX: 4 times daily (OTC Product Information, as posted to the DailyMed site 08/2014a; Prod Info Motrin(R), Ibuprofen, Children's formulas for OTC use, 2000)
c) 4 TO 5 YEARS (GREATER THAN 16 TO 21 KG): 150 mg (7.5 mL or 1.5 teaspoonfuls) every 6 to 8 hours; MAX: 4 times daily (OTC Product Information, as posted to the DailyMed site 08/2014a; Prod Info Motrin(R), Ibuprofen, Children's formulas for OTC use, 2000)
d) 6 TO 8 YEARS (22 TO 27 KG): 200 mg (10 mL or 2 teaspoonfuls) every 6 to 8 hours; MAX: 4 times daily (OTC Product Information, as posted to the DailyMed site 08/2014a; Prod Info Motrin(R), Ibuprofen, Children's formulas for OTC use, 2000)
e) 9 TO 10 YEARS (GREATER THAN 27 TO 32 KG): 250 mg (12.5 mL or 2.5 teaspoonfuls) every 6 to 8 hours; MAX: 4 times daily (OTC Product Information, as posted to the DailyMed site 08/2014a; Prod Info Motrin(R), Ibuprofen, Children's formulas for OTC use, 2000)
f) 11 YEARS (33 TO 43 KG): 300 mg (15 mL or 3 teaspoonfuls) every 6 to 8 hours; MAX: 4 times daily (OTC Product Information, as posted to the DailyMed site 08/2014a; Prod Info Motrin(R), Ibuprofen, Children's formulas for OTC use, 2000)

3) PRESCRIPTION

a) INTRAVENOUS

1) UNDER 17 YEARS: Safety and efficacy in pediatric patients have not been established (Prod Info CALDOLOR(R) intravenous injection, 2014).
2) 17 YEARS AND OLDER: Varies by indication. 100 to 200 mg IV every 4 hours as necessary or 400 mg IV every 4 to 6 hours or 800 mg IV every 6 hours as necessary with infusion times no less than 30 minutes; MAX: 3200 mg daily (Prod Info CALDOLOR(R) intravenous injection, 2014).
3) PREMATURE INFANTS - PATENT DUCTUS ARTERIOSUS: Initial, 10 mg/kg, followed by 2 doses of 5 mg/kg at 24 and 48 hours (Prod Info NeoProfen(R) intravenous injection, 2013; Ohlsson et al, 2013; Amoozgar et al, 2010).

b) ORAL

1) INFANTS AND CHILDREN (LESS THAN 60 KG): 5 to 10 mg/kg/dose orally every 6 to 8 hours as needed; maximum daily dose is 40 mg/kg/day(Prod Info MOTRIN(R) oral suspension, 2006; Kraemer & Rose, 2009; Drendel et al, 2009; Friday et al, 2009; Koller et al, 2007; Dlugosz et al, 2006; Goldman et al, 2004; Perrott et al, 2004; Kokki, 2003).
2) ADOLESCENTS (60 KG OR GREATER): 400 to 600 mg orally every 6 to 8 hours as needed. Doses up to 800 mg may be used; maximum daily dose 3200 mg/day (Playfor et al, 2006; Greco & Berde, 2005).
3) A therapeutic maximum dose of 3200 mg/day (800 mg/dose) has been documented in children with juvenile rheumatoid arthritis aged 1 year and older (Litalien & Jacqz-Aigrain, 2001; Rose & Doughty, 1992; Giannini et al, 1990; Steans et al, 1990; Prod Info MOTRIN(R) oral suspension, 2006).

B) IBUPROFEN/FAMOTIDINE

1) PRESCRIPTION

a) ORAL TABLETS: Safety and efficacy in pediatric patients have not been established (Prod Info DUEXIS(R) oral tablets, 2013).

Minimum Lethal Exposure

1) A 17-year-old girl presented unresponsive with a metabolic acidosis and hypothermia after ingesting nearly 200 g of ibuprofen (serum ibuprofen concentration of 352 mcg/mL). Despite aggressive supportive care and continuous veno-venous hemofiltration, she developed disseminated intravascular coagulation and multiorgan system failure. She died 9 days after admission (Holubek et al, 2007).
2) A 16-month-old child who ingested ibuprofen 6.8 g (469 mg/kg) died of aspiration pneumonia (Hall et al, 1986).

1) A 49-year-old man presented unresponsive and hypotensive, with a significant metabolic acidosis after ingesting up to 120 g of ibuprofen (serum ibuprofen concentration of 260 mcg/mL) and divalproex sodium (serum valproate concentration 250 mcg/mL). Despite aggressive supportive care and hemodialysis, he died 3 days after admission (Holubek et al, 2007).
2) A 26-year-old female died approximately 10 hours after ingesting an estimated 105 g of sustained-release ibuprofen. Despite supportive care and resuscitation efforts, the patient died of a ventricular tachycardia/ventricular fibrillation cardiac arrest (Wood et al, 2006).
3) An adult patient who ingested 24 g developed acute oliguric renal failure and sepsis and died (Hall & Rumack, 1988).
4) An 82-year-old female died of hemorrhagic duodenitis and gastritis after taking ibuprofen 1200 mg daily for 10 days for flu-like symptoms. Past medical history was significant for hypertension and chronic renal impairment secondary to renal artery stenosis; hemoglobin (lowest reading 5.8 g/dL) was the only value reported (Stevenson et al, 2001).

Maximum Tolerated Exposure

1) ABSENCE OF SYMPTOMS

a) Up to 2.4 g has resulted in no symptoms (Hall et al, 1986). The majority of symptoms in children have occurred with ingestions greater than 100 mg/kg.
b) None developed toxicity with less than 100 mg/kg (Hall et al, 1986; Hall & Rumack, 1988).
c) In a study that compared the efficacy of oral high-dose ibuprofen (20-10-10 mg/kg/day) with standard dose oral ibuprofen (10-5-5 mg/kg/day) for 3 days for the treatment of patent ductus arteriosus closure in 60 preterm infants, no gastrointestinal, renal or hematological adverse effects were observed (Pourarian et al, 2015).

2) SEVERE SYMPTOMS

a) CASE REPORTS: Children developed toxicity with a mean ingestion of 440 +/- 146 mg/kg, while none developed toxicity with less than 100 mg/kg in 2 large series (Hall et al, 1986; Hall & Rumack, 1988).
b) CASE REPORT: An 18-month-old developed severe metabolic acidosis following a potential ingestion of as much as 7.2 g of ibuprofen (600 mg/kg) (Oker et al, 2000). A 4-hour serum ibuprofen level was 640 mcg/mL. The patient developed severe metabolic acidosis and a single tonic-clonic seizure. Complete recovery was reported following pharmacological correction of the acidosis.
c) CASE REPORT: A 14-year-old boy developed cardiovascular collapse, an anion gap metabolic acidosis, elevated lactate levels, liver enzymes, and high-output renal failure after the ingestion of approximately 50 g of ibuprofen (ibuprofen concentration of 776 mcg/mL 5 to 10 hours postingestion; therapeutic range: 20 to 30 mcg/mL). Extracorporeal membrane oxygenation (ECMO) was used to treat hypotension unresponsive to pressor support with norepinephrine, phenylephrine and vasopressin infusion. The patient's hemodynamic status improved and ECMO was discontinued on day 4 (Marciniak et al, 2007).
d) CASE REPORT: 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).
e) CASE REPORT: A 16-year-old adolescent developed depressed mental status, requiring intubation, hypotension, and metabolic acidosis about 5 hours after ingesting an unknown amount of ibuprofen. Two empty bottles of ibuprofen 200 mg (originally contained 500 tablets in each bottle) were found in the house. He was treated with sodium bicarbonate and inotropic support, but his condition did not improve. He was successfully treated with continuous veno-venous hemodialysis (CVVHD) (Christian & Thornton, 2015).

1) A 19-year-old man developed lactic acidosis, polyuria, and coma after ingesting over 90 grams (1200 mg/kg) of ibuprofen 3 hours after consuming 1180 mL of beer in a suicide attempt. He recovered following supportive care (Levine et al, 2010).
2) A prospective study of 63 ibuprofen overdose cases (1.2 to 60 g) reported no serious or life-threatening toxicity. Thirty-seven patients were asymptomatic (1.2 to 48 g ingested), and 26 patients had minor toxicity reported (1.2 to 60 g ingested). The lowest dose causing CNS depression was 3 g (Hall et al, 1992).
3) An ingestion of 30 g of ibuprofen combined with an unknown quantity of sublingual nitroglycerin by a 23-year-old man resulted in severe multi-system toxicity (Le et al, 1994).
4) A 44-year-old man developed severe toxicity but survived an ingestion of 72 g of ibuprofen (Wolfe, 1995). No permanent sequelae were reported.
5) History of amount ingested does not correlate with toxicity in adult overdoses; plasma levels may be more helpful in assessing risk in these patients (Hall et al, 1986; Hall & Rumack, 1988; Hall et al, 1992).

1) A 17-year-old boy ingested 98 g of ibuprofen and 10 diphenhydramine tablets and recovered with minimal toxicity (Keller, 1995).
2) A 15-year-old girl developed coma, metabolic acidosis, and mild thrombocytopenia but improved rapidly with supportive care following a 100 g ibuprofen ingestion (Seifert et al, 2000).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) A 1-hour serum level of less than 100 mcg/mL is unlikely to produce toxicity (Hall et al, 1986) and indicates a 15% chance of mild gastrointestinal (GI) symptoms.
2) MILD SYMPTOMS (GI upset, lethargy) were observed at levels of 80 to 200 mcg/mL at 3 hours. Moderate to severe toxicity is possible with 1-hour levels of 100 to 200 mcg/mL (Hall et al, 1986) and indicates a 43% chance of moderate to severe toxicity.
3) SERIOUS SYMPTOMS (renal failure, hypotension, apnea, seizures, acidosis) have been described with 2-hour levels of 360 mcg/mL (Hall et al, 1986).

a) Levels as high as 725 mcg/mL at 1.5 hours have occurred with no symptoms (Barry et al, 1984).
b) Serious symptoms are likely with 1-hour serum levels of 200 mcg/mL or greater, with a 72% incidence of toxicity and 28% incidence of severe toxicity (Hall et al, 1986).

4) CASE REPORTS

a) ADULTS

1) A man who ingested over 90 grams (1200 mg/kg) of ibuprofen had an ibuprofen concentration of 739.2 mg/L 7 hours after ingestion. He developed lactic acidosis, polyuria, and coma, but recovered following supportive care (Levine et al, 2010).
2) One adult who ingested up to 120 g ibuprofen and divalproex sodium and had a 260 mcg/mL serum ibuprofen concentration died 3 days after admission (Holubek et al, 2007).
3) One fatality was described with a level of 440 mcg/mL, with a salicylate level of 240 mcg/mL (Court et al, 1983).
4) One adult ingesting only ibuprofen died with a level of 15.8 mcg/mL obtained at an unknown time, but greater than 12 hours after ingestion (Hall & Rumack, 1988).
5) A case of ingestion of 30 g ibuprofen combined with an unknown quantity of sublingual nitroglycerin by a 23-year-old male resulted in severe multisystem toxicity. The ibuprofen level at 18 hours after ingestion was 324 mcg/dL (Le et al, 1994).
6) In a report of 4 cases of acute ibuprofen overdose, 3 asymptomatic patients had ibuprofen plasma levels of "trace" amounts at 2 hours (200 mg/kg ingested), 37 mcg/mL at 4 hours (305 mg/kg ingested), and 38 mcg/mL at 5 hours (428 mg/kg ingested). The fourth patient developed central nervous system depression, hypoventilation requiring intubation, hypotension, and hypokalemia/hypophosphatemia. Ibuprofen levels were 320 mcg/mL at 4 hours, 124 mcg/mL at 6.5 hours, and 9.5 mcg/mL at 11.5 hours after ingestion (Harchelroad et al, 1988).
7) Postmortem tissue concentrations were obtained following an overdose of an unknown quantity of ibuprofen: heart blood (518 mcg/mL) and femoral blood (348.3 mcg/mL). Gastric contents had a total of 131 mg recovered (Kunsman & Rohrig, 1993).
8) In the case of a fatal ibuprofen and acetaminophen overdose, the following tissue concentrations of ibuprofen and metabolites were found (Steinmetz et al, 1987):

	IBUPROFEN	HYDROXYIBUPROFEN	CARBOXYIBUPROFEN
Liver (mcg/g)	238	115	225
Lung (mcg/g)	81.7	56.7	432
Kidney (mcg/g)	622	160	385
Serum (mcg/mL)	80.8	43	101

b) PEDIATRIC

1) A 17-year-old girl who ingested nearly 200 g ibuprofen and had a 352 mcg/mL serum ibuprofen concentration died 9 days after admission (Holubek et al, 2007).
2) An 18-month-old had a 4-hour serum ibuprofen level of 640 mcg/mL following a potential ingestion of as much as 7.2 g ibuprofen (600 mg/kg) (Oker et al, 2000). Despite severe metabolic acidosis and a single tonic-clonic seizure, the toddler made a complete recovery with supportive care.
3) A 14-year-old boy had an ibuprofen concentration of 776 mcg/mL (therapeutic range: 20 to 30 mcg/mL) 5 to 10 hours after the ingestion of approximately 50 g ibuprofen. Extracorporeal membrane oxygenation (ECMO) was used to treat hypotension unresponsive to pressor support, which included norepinephrine, phenylephrine, and vasopressin infusions. The patient's hemodynamic status improved, and ECMO was discontinued on day 4 (Marciniak et al, 2007).

Toxicity Information

7.7.1)

A) ANIMAL DATA

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 320 mg/kg (RTECS, 2006)

2) LD50- (ORAL)MOUSE:

a) 740 mg/kg (RTECS, 2006)

3) LD50- (SUBCUTANEOUS)MOUSE:

a) 395 mg/kg (RTECS, 2006)

4) LD50- (INTRAPERITONEAL)RAT:

a) 626 mg/kg (RTECS, 2006)

5) LD50- (ORAL)RAT:

a) 636 mg/kg (RTECS, 2006)

6) LD50- (SUBCUTANEOUS)RAT:

a) 740 mg/kg (RTECS, 2006)

Pharmacology Toxicology

Toxicologic Mechanism

Physicochemical

Physical Characteristics

Ph

Molecular Weight

Animal Toxicology

Clinical Effects

11.1.3)

A) SIGNS/SYMPTOMS

1) SUMMARY: Signs and symptoms include vomiting (sometimes prolonged for days), hematemesis, melena, central nervous system depression, ataxia, anorexia, weight loss, polydipsia, polyuria, acute renal failure, and collapse (Tempowski, 1989).
2) METABOLIC ACIDOSIS may also occur, leading to tachypnea and shock. Seizures or coma rarely occur (Beasley et al, 1990). Lethargy, incoordination, hemorrhagic gastritis, abdominal tenderness, and diarrhea have also been reported (Campbell, 1992).
3) RENAL DAMAGE: Ibuprofen has been responsible for severe renal toxicity in dogs who have overdosed on it (Poortinga & Hungerford, 1998). Be prepared for renal papillary necrosis, transient tubular damage, and acute renal failure. German Shepherds appear to be most susceptible and may need to be managed aggressively.
4) GASTRIC MUCOSAL DAMAGE may be severe enough to cause perforating ulcers when dogs are given even low doses chronically. Fatalities have been reported (Smith & Taylor, 1993).

B) ONSET of signs and symptoms is not well documented for dogs. In a review of 35 cases of canine ibuprofen ingestion, 7 dogs vomited shortly after exposure; 6 developed vomiting or hematemesis within 20 to 24 hours of exposure. Severe hemorrhagic gastroenteritis developed 48 hours after exposure in 1 case (Campbell, 1992).
C) INCIDENCE: Clinical signs were observed at the time of the call to an animal poison information center in 46 of 81 (56%) dogs following ingestion of a single dose of ibuprofen (mostly less than 100 mg/kg). Gastrointestinal signs were the most common (25 dogs, 30.8%). Renal signs (polyuria, pollakiuria) were reported in 5 dogs and respiratory signs (tachypnea, dyspnea, orthopnea) in 4 dogs (Jones et al, 1992).

1) Only 3 of 22 dogs remained asymptomatic after ibuprofen ingestion in 1 canine series (Campbell, 1992).

D) RISK FACTORS: Risk factors were characterized for gastrointestinal ulceration (GIU) and acute renal failure (ARF) subsequent to the acute ingestion of ibuprofen (Poortinga & Hungerford, 1998). The risk for GIU and ARF was lowest when the time of ingestion of ibuprofen was known. The risk for GIU and ARF was highest as the time increased from ingestion to intervention. Although a dose-response relationship could not be determined, there may be breed differences in susceptibility to GIU following ibuprofen ingestion.

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.
6) Additional information regarding treatment of poisoned animals may be obtained from a Board Certified Veterinary Toxicologist (ABVT) (check with nearest veterinary school or veterinary diagnostic laboratory) or the National Animal Poison Control Center.
7) 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 mL/kg syrup of ipecac via OS.

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

b) ACTIVATED CHARCOAL: Administer activated charcoal, 2 g/kg via OS 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 g/kg).

2) RUMINANTS/HORSES/SWINE

a) EMESIS: Do not attempt to induce emesis in ruminants (cattle) or equids (horses).
b) ACTIVATED CHARCOAL -

1) Adult horses: Administer 0.5 to 1 kg of activated charcoal in up to 1 gallon warm water via nasogastric tube.
2) Neonates: Administer 250 g (one-half pound) activated charcoal in up to 2 quarts water.
3) Adult cattle: Administer 2 to 9 g/kg of activated charcoal in a slurry of 1 g charcoal/3 to 5 mL warm water via stomach tube.
4) Sheep may be given 0.5 kg charcoal in slurry.

c) CATHARTIC: Administer an oral cathartic:

1) Mineral oil (small ruminants and swine: 60 to 200 mL; equids and cattle: 0.5 to 1 gallon)
2) Magnesium sulfate (ruminants and swine: 1 to 2 g/kg; equine,: 0.2 to 0.9 g/kg)
3) Milk of Magnesia (small ruminants: up to 0.25 g/kg in 1 to 3 gallons warm water; adult cattle: up to 1 g/kg in 1 to 3 gallons warm water or 2 to 4 boluses MgOH via OS).
4) 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 and CATS: 0.5 mg/kg intravenous bolus; may repeat dose every 10 minutes for 4 total doses. Give slowly over 1 to 2 minutes.
b) PHENOBARBITAL may be used as adjunct treatment at 5 to 30 mg/kg intravenously over 5 to 10 minutes .
c) REFRACTORY SEIZURES: Consider anaesthesia or heavy sedation. Administer pentobarbital to DOGS and CATS at a dose of 3 to 15 mg/kg 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 or plasma, 25 mL/kg.

4) FLUIDS: Begin fluid therapy at maintenance doses (66 mL solution/kg/day intravenously) or, in hypotensive patients, at high doses (up to shock dose 60 mL/kg/hr).

a) Monitor for urine production and pulmonary edema. One reported successful treatment included alternating treatment with Ringer's solution and with 10% dextrose (Spyridakis et al, 1986).

5) 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:

1) DOG: Give sucralfate 1 hour before feeding and wait 2 hours prior to cimetidine dosing.
2) Body weight less than 20 kg: 500 mg 3 to 4 times daily.
3) Body weight greater than 20 kg: 1 g 3 to 4 times daily.

b) CIMETIDINE: To decrease gastric acid, administer cimetidine (Campbell, 1992):

1) DOGS: 5 to 10 mg/kg via OS, intravenously, or intramuscularly every 6 to 8 hours
2) CATS: 2.5 to 5 mg/kg via OS, intravenously, or intramuscularly every 8 to 12 hours

6) ACIDOSIS: Add sodium bicarbonate to the intravenous fluids if metabolic acidosis is suspected. If using lactated Ringer's 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.
c) When blood gases are not available, administer 1 to 4 mEq/kg intravenously slowly over 4 to 8 hours (Beasley et al, 1991).

7) 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.
8) 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, are 1 mg/kg (HORSES); 0.5 to 1.5 mg/kg (CATTLE, SHEEP, AND SWINE).
3) FLUIDS: Administer electrolyte and fluid therapy as needed.

a) Maintenance dose of intravenous isotonic fluids: 10 to 20 mL/kg/day. High dose for shock: 20 to 45 mL/kg/hour. Monitor for packed cell volume, adequate urine output, and pulmonary edema.
b) Goal is to maintain a urinary flow of 0.1 mL/kg/min (2.4 L/hr for an 880 pound horse).
c) Administer electrolyte and fluid therapy, orally or parenterally as needed.
d) Maintenance dose of intravenous isotonic fluids for calves and debilitated adult cattle: 140 mL/kg/day. Dose for rehydration: 50 to 100 mL/kg given over 4 to 6 hours.

Range Of Toxicity

11.3.1)

A) SPECIFIC TOXIN

1) Ibuprofen is not recommended for use in animals.

11.3.2)

A) ACUTE OVERDOSE

1) DOG

a) A single dose of ibuprofen 100 mg /kg is acutely toxic to dogs (Beasley et al, 1990; Villar & Buck, 1998).
b) After ingestion of 6 g ibuprofen, an 18 kg Labrador retriever developed serious CNS depression and polyuria/polydipsia that persisted for 2 months following ingestion (Spyridakis et al, 1986).
c) Acute ingestion of ibuprofen, with most doses less than 100 mg/kg, produced signs of toxicity in 56% of 81 dogs (Jones et al, 1992). In another series of 28 dogs, 10 of 15 dogs who ingested 800 to 6000 mg of ibuprofen developed prolonged vomiting (Tempowski, 1989).
d) At doses of greater than or equal to 175 to 200 mg/kg, acute renal failure due to ischemia has been reported (Villar & Buck, 1998).
e) Single acute exposures of 70 mg/kg do not usually cause toxicity. Vomiting, diarrhea, frequent urination, melena, and abdominal pain develop at doses of greater than 100 to 125 mg/kg (Villar & Buck, 1998).

2) CAT

a) Cats are more susceptible to the toxic effects at half the dose of dogs (Villar & Buck, 1998). Induction of emesis at home may be preferable to delaying emesis. These drugs should NOT be used in cats.

B) CHRONIC OVERDOSE

1) DOG

a) Dogs have developed gastric ulcers after being fed ibuprofen at levels as low as 8 mg/kg for 30 days (Nash et al, 1987; Villar & Buck, 1998).
b) CASE REPORT: A dog given ibuprofen 3 mg/kg every other day for 6 weeks developed a perforated gastric ulcer and died (Smith & Taylor, 1993).
c) CASE REPORT: A dog experienced vomiting, diarrhea, melena, and weight loss when given a dose of ibuprofen 16 mg/kg/day for 8 weeks, and subsequently died. Gastric ulcers were evident at postmortem examination (Villar & Buck, 1998).

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 mL/kg syrup of ipecac via OS.

2) RUMINANTS/HORSES/SWINE

a) EMESIS: Do not attempt to induce emesis in ruminants (cattle) or equids (horses).
b) ACTIVATED CHARCOAL -

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

1) Monitor BUN, creatinine, and coagulation parameters.

b) LABORATORY-POSTMORTEM

1) Postmortem lesions commonly seen include ulcers of the gastric and intestinal mucosa and renal lesions, including papillary necrosis.

Kinetics

11.5.1)

A) LACK OF INFORMATION

1) There was no specific information on absorption at the time of this review.

11.5.2)

A) SPECIFIC TOXIN

1) Ibuprofen is 99% protein-bound in humans (Beasley et al, 1990).

Pharmacology Toxicology

1) Ibuprofen interferes 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 (ibuprofen) and easily develop gastric ulcers and renal failure.

References

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FeedBack

IBUPROFEN

Classification | Detailed evidence-based information

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Available Forms Sources

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Toxicity Information

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Ph

Molecular Weight

Clinical Effects

Treatment

Range Of Toxicity

Continuing Care

Kinetics

Pharmacology Toxicology

General Bibliography