NONSTEROIDAL ANTIINFLAMMATORY DRUGS

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) Antiinflammatory agents, nonsteroidal
2) Nonsteroidal antiinflammatory agents
3) NSAIDs (abbreviation for nonsteroidal antiinflammatory agents)

1) Benoxaprofen*
2) Carprofen
3) Fenbufen
4) Fenoprofen
5) Flurbiprofen
6) Indoprofen
7) Ketorolac
8) Loxoprofen*
9) Oxaprozin
10) Pirprofen
11) Suprofen*
12) Tiaprofenic acid

1) Aceclofenac
2) Acemetacin
3) Bromfenac
4) Diclofenac
5) Etodolac
6) Nabumetone
7) Sulindac
8) Sulindac sulphide
9) Tolmetin
10) Zomepirac

1) Floctafenine
2) Flufenamic acid
3) Meclofenamate

1) Isoxicam
2) Lornoxicam
3) Meloxicam
4) Piroxicam
5) Sudoxicam

1) Azapropazone
2) Fenprazone
3) Oxyphenbutazone

1.2.1) MOLECULAR FORMULA
1) BROMFENAC SODIUM: C15H11BrNNaO3-1.5H2O
2) DICLOFENAC: C14H11Cl2NO2
3) DICLOFENAC EPOLAMINE: C20H24Cl2N2O3
4) DICLOFENAC POTASSIUM: C14H10Cl2NKO2
5) DICLOFENAC SODIUM: C14H10Cl2NNaO2
6) KETOROLAC TROMETHAMINE: C19H24N2O6
7) NABUMETONE: C15H16O2
8) NEPAFENAC: C15H14N2O2

Available Forms Sources

1) Bromfenac: Ophthalmic Solution: 0.09%
2) Diclofenac Potassium:

a) Capsule: 25 mg
b) Oral Powder for Solution: 50 mg
c) Tablet: 50 mg

3) Diclofenac Sodium:

a) Ophthalmic Solution 0.1%;
b) Tablet, Enteric Coated: 25 mg, 50 mg, 75 mg;
c) Tablet, Extended Release: 75 mg, 100 mg
d) Topical Gel: 1%, 3%,

4) Diclofenac Sodium/Misoprostol:

a) Tablet, Enteric Coated: 50 mg (Diclofenac sodium)/0.2 mg (Misoprostol)
b) Tablet, Enteric Coated: 75 mg (Diclofenac sodium)/0.2 mg (Misoprostol)

5) Diclofenac Epolamine: Topical Patch, Extended Release: 1.3%
6) Etodolac

a) Capsule: 200 mg, 300 mg
b) Tablet: 400 mg, 500 mg
c) Tablet, Extended Release: 400 mg, 500 mg, 600 mg

7) Fenoprofen Calcium:

a) Capsule: 200 mg, 300 mg, 400 mg
b) Tablet: 600 mg

8) Flurbiprofen: Tablet: 50 mg, 100 mg
9) Ketorolac:

a) Injection Solution: 15 mg/mL, 30 mg/mL
b) Intramuscular Solution: 15 mg/mL, 30 mg/mL
c) Intravenous Solution: 15 mg/mL, 30 mg/mL
d) Ophthalmic Solution: 0.4%, 0.45%, 0.5%
e) Tablet: 10 mg

10) Meloxicam:

a) Oral Suspension: 7.5 mg/mL
b) Tablet: 7.5 mg, 15 mg

11) Nabumetone: Tablet: 500 mg, 750 mg
12) Oxaprozin: Tablet: 600 mg
13) Piroxicam: Capsule: 10 mg, 20 mg
14) Sulindac: Tablet: 150 mg, 200 mg
15) Tolmetin:

a) Capsule: 400 mg
b) Tablet: 200 mg, 600 mg

a) NOT AVAILABLE: UNITED STATES

1) BENZYDAMINE: Is not available in the US, but is widely used in Europe. It is available as a topical cream or gel at 3% to 6%; it is found in mouthwashes in concentrations of 0.15% for the topical treatment of mild oropharyngeal infections; and is also used in vaginal preparations by dissolving 500 mg of the powder formulation in one liter of water (Ballesteros et al, 2009).
2) FLOCTAFENINE: Is not available in the US.

b) WITHDRAWN FROM MARKET

1) BROMFENAC: Long-term use of bromfenac has caused severe hepatotoxicity, including hepatitis and liver failure, and the manufacturer has voluntarily withdrawn bromfenac from the market as of June 1998.
2) OTHERS: The items with an "*" in the list above have been withdrawn from the US Market and include: benoxaprofen, loxoprofen, meclofenamate, and suprofen.

1) DELIBERATE MISUSE

a) GREAT BRITAIN: A review of deliberate self-poisoning overdoses seen in West Fife found that almost 50% of these cases involved NSAID agents. The study found that the use of mefenamic acid for misuse rose exponentially in the 15-year period studied (McMurray et al, 1987).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Nonsteroidal antiinflammatory drugs (NSAIDs) are used acutely for fever and pain control and for the treatment of several rheumatologic conditions. NOTE: Salicylates, ibuprofen, naproxen, indomethacin, phenylbutazone, mefenamic acid, ketoprofen, and the COX-2 inhibitors (celecoxib, meloxicam, rofecoxib , valdecoxib) are covered under separate managements.
B) PHARMACOLOGY: NSAIDs include at least 20 drugs that share the cyclooxygenase enzyme inhibition leading to decreased prostaglandin production and decreased pain and inflammation.
C) TOXICOLOGY: NSAIDs cause gastrointestinal irritation directly, and by inhibiting cyclooxygenase 1 (COX-1), which is necessary for the formation of the prostaglandins PG12 and PGE2; decrease in these prostaglandins results in decreased tissue mucus and bicarbonate secretion, increased hydrochloride secretion, and decreased gastric blood flow. The acidosis associated with severe NSAID overdose appears to result from the formation acidic metabolites, and mild hypotension. Prostaglandin inhibition by NSAIDs also causes renal arteriolar constriction, reduced renal blood flow and subsequent renal insufficiency in patients with conditions characterized by high angiotensin and low intravascular volume (eg, congestive heart failure, cirrhosis, hypovolemia). COX-1 inhibition also decreases the formation of thromboxane A2 which is necessary for platelet aggregation, predisposing patients to bleeding.
D) EPIDEMIOLOGY: NSAID overdose is common, but severe toxicity and deaths are very rare.
E) WITH THERAPEUTIC USE

1) ADVERSE EFFECTS: Dyspepsia, ulceration perforation, gastrointestinal hemorrhage, acute renal failure, fluid retention, interstitial nephritis, nephrotic syndrome, asthma exacerbation, headache and aseptic meningitis may develop. Agranulocytosis, aplastic anemia, and thrombocytopenia have developed, but appear to be idiosyncratic reactions.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Most patients with an NSAID overdose are asymptomatic or have mild gastrointestinal upset (ie, nausea, vomiting, abdominal pain), and sometimes hematemesis.
2) SEVERE TOXICITY: Massive overdose can cause seizures, delirium, coma, hypotension, renal failure, hepatic dysfunction, hypoprothrombinemia, gastrointestinal bleeding, hyperkalemia and metabolic acidosis.
3) VETERINARY/FLURBIPROFEN: Pets exposed to topical pain medications containing flurbiprofen may be at risk of developing significant illness and death. The FDA has received reports of severe illness in several households where pet owners applied the topical medication to themselves (ie, neck and feet). In these cases, it was unclear how the cats became exposed. However, 2 cats in one household developed renal failure and recovered with supportive care and 2 cats in another household developed lethargy, vomiting, melena, and anemia and died despite care.

0.2.3)

A) Low grade fever, hypotension, and sinus tachycardia have been noted in both overdose and therapeutic use of NSAIDs.

0.2.4)

A) Various ocular adverse reactions and tinnitus are frequently reported following NSAID overdoses. Bullous and erosive stomatitis has occurred in a patient taking nimesulide and diclofenac.

0.2.5)

A) Although rare, hypotension, bradycardia and tachycardia have been reported following an NSAID overdose.

0.2.6)

A) Although rare, respiratory arrest has been reported. Pulmonary fibrosis has been associated with therapeutic use.

0.2.7)

A) Drowsiness, delirium, lethargy, seizures, dizziness, disorientation, loss of consciousness, tinnitus, headache, hallucinations, and encephalopathy have been associated with therapeutic dosing and/or overdose of NSAIDs. Coma has been reported following severe NSAID overdose. Myoclonic twitching as been reported for several days after an overdose of piroxicam and fentiazac.

0.2.8)

A) Nausea, vomiting, epigastric pain, erosive esophagitis, pancreatitis, gastrointestinal bleeding, and intestinal stenosis have been associated with therapeutic use and/or overdose of nonsteroidal antiinflammatory drugs.

0.2.9)

A) Hepatotoxicity has been reported following chronic therapeutic use, especially with sulindac and bromfenac, and in one piroxicam overdose.

0.2.10)

A) Acute renal failure, azotemia, and nephrotic syndrome have occurred with both acute overdose and chronic ingestion of most NSAIDs.

0.2.11)

A) Metabolic acidosis occurs rarely in overdose, usually in conjunction with seizures.

0.2.12)

A) Severe fluid and electrolyte imbalance has been described with piroxicam overdose in a child. Hyperkalemia has been reported with ketorolac.

0.2.13)

A) There are reports of granulocytosis, pancytopenia, coagulopathy, and prolonged prothrombin time with overdose; thrombocytopenia, aplastic anemia, neutropenia, and increased bleeding times have occurred with therapeutic use.

0.2.14)

A) Photosensitivity, toxic epidermal necrolysis, erythema multiforme, and phototoxicity have been reported with therapeutic use.

0.2.19)

A) Anaphylactoid reactions have been associated with therapeutic ingestion of tolmetin, zomepirac, sulindac, ketorolac, fenoprofen, naproxen, mefenamic acid, and meclofenamate sodium, but have not been reported following acute overdose.

0.2.20)

A) Diclofenac, diclofenac potassium (oral solution, oral capsule), diclofenac epolamine (topical patch), ketorolac tromethamine, and piroxicam are classified as FDA pregnancy category C prior to 30 weeks gestation and FDA pregnancy category D starting at 30 weeks gestation. Diclofenac sodium (topical gel 1%, ophthalmic solution 0.1%, extended-release oral tablets, delayed-release oral tablets), diclofenac potassium (immediate-release tablet), fenoprofen, ketorolac phenylephrine (ophthalmic solution), meloxicam, sulindac, and tolmetin are classified as FDA pregnancy category C. Diclofenac sodium (topical gel 3%) is classified as FDA pregnancy category B. Inhibition of prostaglandin synthesis may cause closure of the ductus arteriosus. NSAIDs may prolong pregnancy if taken before the onset of labor, especially during the third trimester.

0.2.21)

A) DICLOFENAC SODIUM: At the time of this review, the manufacturer does not report any carcinogenic potential.
B) PIROXICAM: At the time of this review, the manufacturer does not report any carcinogenic potential.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Most toxicity related to NSAID exposure resolves with supportive care; otherwise, healthy patients with a history of NSAID poisoning generally require only gastrointestinal decontamination with activated charcoal, and fluid and electrolyte replacement.

B) MODERATE TOXICITY

1) Endotracheal intubation and mechanical ventilation may be necessary in patients with CNS depression or recurrent seizures. Treat seizures with benzodiazepines, and hypotension with fluids, adding adrenergic vasopressors, if necessary.

C) DECONTAMINATION

1) PREHOSPITAL: Activated charcoal can be given after a large overdose.
2) HOSPITAL: Activated charcoal binds NSAIDs, but is usually not required as severe toxicity is rare. Charcoal should be administered after a large, recent overdose. Gastric lavage is generally not indicated as life threatening toxicity is very rare.

D) AIRWAY MANAGEMENT

1) Intubation and mechanical ventilation should be considered for patients who present with CNS depression.

E) ANTIDOTE

1) None.

F) ENHANCED ELIMINATION

1) NSAIDs are highly protein bound and extensively metabolized; therefore, hemodialysis is unlikely to be effective.

G) PATIENT DISPOSITION

1) HOME CRITERIA: Inadvertent exploratory ingestions in asymptomatic children can generally be managed with dilution and observation at home.
2) OBSERVATION CRITERIA: Patients with large or deliberate ingestions should be observed for 4 to 6 hours. If they remain asymptomatic with normal laboratory evaluation they may be discharged after appropriate psychiatric evaluation.
3) ADMISSION CRITERIA: Patients who may have ingested a large dose of NSAIDs and who present with CNS or cardiovascular toxicity or metabolic acidosis, or who have a known risk factor for organ system toxicity associated with NSAIDs should be considered at higher risk of complications and warrant admission.

H) PITFALLS

1) Symptoms usually appear within 4 hours; however, there have been a few case reports of delayed symptoms. Many patients confuse over-the-counter pain medications with one another; rule out acetaminophen and salicylate ingestions in patients with a NSAID overdose.

I) PREDISPOSING CONDITIONS

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

J) PHARMACOKINETICS

1) NSAIDs are rapidly absorbed from the gastrointestinal tract, with a peak concentration occurring within 2 hours of oral administration for most drugs. Sustained-release and enteric-coated tablets require 2 to 5 hours to reach peak concentrations. All of the drugs are weakly acidic and highly protein bound, with a volume of distribution of approximately 0.1 to 0.2 L/kg.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.1)

A) Low grade fever, hypotension, and sinus tachycardia have been noted in both overdose and therapeutic use of NSAIDs.

3.3.3)

A) FEVER: Low grade fever has been reported in a fenoprofen overdose (Appleby, 1981) and in a case of therapeutic use presenting with a maculopapular rash (Neufeld & Korczyn, 1986).

3.3.4)

A) WITH POISONING/EXPOSURE

1) HYPOTENSION has been reported in severe NSAID overdose, but is not common (Appleby, 1981; Kolodzik et al, 1990; Meredith & Vale, 1986).

3.3.5)

A) WITH POISONING/EXPOSURE

1) TACHYCARDIA has been reported following an overdose:

a) CASE REPORT: Sinus tachycardia of 150 beats per minute has been reported in a case of fenoprofen overdose. ECG was otherwise normal (Appleby, 1981).

Heent

3.4.1)

A) Various ocular adverse reactions and tinnitus are frequently reported following NSAID overdoses. Bullous and erosive stomatitis has occurred in a patient taking nimesulide and diclofenac.

3.4.3)

A) WITH POISONING/EXPOSURE

1) OCULAR TOXICITY: Nystagmus, diplopia, and blurred vision have been reported following NSAID overdose.

3.4.4)

A) TINNITUS may occur following therapeutic use or overdose of most NSAIDs (Meredith & Vale, 1986). Hearing loss has also been reported (Chapman, 1982) Morley, 1982; (Otti et al, 1997). With therapeutic doses of tolmetin, tinnitus occurred more frequently than in 1 in 100 patients (Prod Info Tolectin(R), 1995).

3.4.6)

A) WITH THERAPEUTIC USE

1) STOMATITIS has been reported as an adverse effect:

a) CASE REPORT: Bullous and erosive stomatitis was reported in a patient taking diclofenac and nimesulide in therapeutic doses for 5 days prior to presentation of symptoms (Valsecchi et al, 1992).

Cardiovascular

3.5.1)

A) Although rare, hypotension, bradycardia and tachycardia have been reported following an NSAID overdose.

3.5.2)

A) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Although rare, hypotension, bradycardia and tachycardia have been reported following an NSAID overdose (Meredith & Vale, 1986).
b) CASE REPORT: A 17-year-old girl presented with coma, hypotension, metabolic acidosis, and respiratory depression within 4 hours of ingesting 24 to 36 grams of fenoprofen (Kolodzik et al, 1990).
c) CASE REPORT: A 41-year-old woman ingested 60 to 72 grams of fenoprofen presented with sinus tachycardia of 150 beats per minute, but the ECG was otherwise normal (along with diffuse abdominal tenderness and a serum creatinine of 2.8 mg/dL). Twelve hours after ingestion, the patient became hypotensive and was semi-comatose. At 24 hours after ingestion, renal function worsened and hypotension was stabilized with dopamine (Appleby, 1981).

B) CONDUCTION DISORDER OF THE HEART

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 53-year-old woman developed paroxysmal coarse muscle fibrillation and muscle spasms 40 hours after ingesting a large (specific amount unknown) amount of benoxaprofen. Oliguria and hyperkalemia developed and the patient was dialyzed. Despite treatment, the patient developed ventricular fibrillation and died (Fancourt et al, 1984).

Respiratory

3.6.1)

A) Although rare, respiratory arrest has been reported. Pulmonary fibrosis has been associated with therapeutic use.

3.6.2)

A) APNEA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 61-year-old woman became disoriented, hallucinated, lost consciousness, and suffered respiratory arrest following the coingestion of diclofenac 375 mg, ibuprofen 400 mg, and indomethacin 75 mg (Bright & McNulty, 1991).
b) CASE REPORT: A 17 year-old girl presented with coma, hypotension, metabolic acidosis, and respiratory depression within 4 hours after of ingestion of 24 to 36 grams of fenoprofen (Kolodzik et al, 1990).

B) FIBROSIS OF LUNG

1) WITH THERAPEUTIC USE

a) Pulmonary infiltration and fibrosis has been described with therapeutic use of nabumetone (Morice et al, 1991).

C) BRONCHOSPASM

1) WITH THERAPEUTIC USE

a) CASE REPORT: A case is reported of an asthmatic patient expiring due to an acute asthmatic attack caused by a single 60-mg dose of loxoprofen sodium 3 hours following a dental procedure (Watanabe et al, 1993).
b) CASE REPORT: Two cases are reported of asthmatic patients presenting with acute asthmatic attacks after receiving a single 60-mg intramuscular dose of ketorolac (Hebert & Scopelitis, 1994) (Zikowski et al, 1993).
c) CASE REPORT: A 48-year-old woman, with a history of mild bronchial asthma, developed an asthma exacerbation each time that she administered diclofenac eye drops, and her symptoms improved following discontinuation of the diclofenac (Sharir, 1997).

Neurologic

3.7.1)

3.7.2)

A) TOXIC ENCEPHALOPATHY

1) WITH THERAPEUTIC USE

a) CASE REPORTS

1) SULINDAC: Acute delirium (irritability, depression and paranoid behavior) was reported in a 53-year-old man following his first dose of sulindac (Thornton, 1980).
2) SULINDAC: Confusion and psychomotor agitation were reported in a 38-year-old man approximately 10 days after beginning sulindac 150 mg three times daily (Neufeld & Korczyn, 1986).

a) In a review of the literature, the authors found that sulindac has been implicated in development of psychosis, especially in elderly patients (Hoppmann et al, 1991).

3) DICLOFENAC/IBUPROFEN/INDOMETHACIN: A 61-year-old woman became disoriented, hallucinated, lost consciousness, and suffered respiratory arrest following the coingestion of diclofenac 375 mg, ibuprofen 400 mg, and indomethacin 75 mg (Bright & McNulty, 1991).
4) SULINDAC/TIARAMIDE/DICLOFENAC: A 20-year-old woman presented with confusion and agitation progressing to unconsciousness within 2 hours after ingesting sulindac 2600 mg, tiaramide hydrochloride 4800 mg and diclofenac sodium 750 mg (Harima et al, 1987).
5) DICLOFENAC: A 19-year-old man who ingested 1500 mg of diclofenac with 4 grams of chlormezanone and alcohol (blood alcohol, 0.13 g/L) presented to the emergency room moderately confused with general hypotonia (reflexes normal) (Netter et al, 1984).
6) FENBUFEN: A case of encephalitis and generalized skin rash is reported after 10 days of therapeutic use of fenbufen. The patient became convulsive and comatose within 24 hours. Within 5 days, the patient made an astonishingly rapid recovery and was discharged. The authors conclude that the patient had an adverse reaction to fenbufen (Crosse & Stanley, 1994).

B) SEIZURE

1) WITH POISONING/EXPOSURE

a) Seizures are most common after mefenamic acid overdose, but have also been reported following overdose of piroxicam, naproxen, and ketoprofen (Macdougall et al, 1984; Martinez et al, 1989; Bond et al, 1989) Kingowell, 1981; (Balali-Mood et al, 1981; Frank et al, 1983; Shipton & Muller, 1985; Frank et al, 1983), and one case in a 4-year-old child following unintentional oral exposure to benzydamine (Ballesteros et al, 2009).
b) CASE REPORT: A 2-year-old child ingested 100 mg piroxicam. Severe multisystem toxicity was described which included a generalized seizure and mental confusion (Macdougall et al, 1984).
c) CASE SERIES: In a prospective study of 54 cases of mefenamic acid overdose (1.5 to 50 grams, 1 to 18 hours prior to admission), 29 cases had serum levels greater than therapeutic levels (above 10 mcg/ml). Of these, 15 reported effects (grand mal convulsions 11/15, muscle twitching 4/15, vomiting 4/15, and diarrhea 1/15) (Balali-Mood et al, 1981).
d) CASE REPORT: An 18-year-old woman was admitted with a generalized convulsion within 1 hours of ingesting about 22.5 grams of mefenamic acid. With supportive treatment for the seizure, the patient made an uneventful recovery by the next day (Shipton & Muller, 1985).
e) CASE REPORT: A 19-year-old teenager was admitted to the hospital for a generalized motor seizure 4 hours after ingesting between 6.25 and 7.5 grams of mefenamic acid. She became apneic, cyanotic, and rigid. There was an absence of pulse and respirations for 30 seconds, after which the patient became limp and her pulse and respirations returned. The patient recovered (Frank et al, 1983).
f) CASE REPORT: A 13-year-old teenager ingested between 5 to 10 grams of mefenamic acid and complained of nausea and fatigue. Approximately, 90 minutes later, she became unconscious with muscle twitching followed by grand mal seizures. Diazepam was administered and the epileptic features subsided. The patient recovered fully within half a day (Gossinger et al, 1982).

C) DROWSY

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 25-year-old man presented with drowsiness and was responsive only to pain 2 hours after ingesting 560 mg piroxicam, 12 grams of griseofulvin and 1 gram fentiazac. Liver function tests were elevated. The level of consciousness improved within 12 hours, but involuntary movements the of lips and jaw and myoclonic twitching of limbs occurred from 14 to 60 hours after admission. However, he completely recovered within 4 days (Lo & Chan, 1983).

D) HEADACHE

1) Headache, often frontal, has been reported during therapeutic use (3% to 9%) and in overdose of most NSAIDs. Indomethacin, an indole structurally similar to serotonin, has an increased propensity to cause headaches (11% with therapeutic doses).

E) COMA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 17-year-old girl presented with coma, hypotension, metabolic acidosis, and respiratory depression within 4 hours of ingesting 24 to 36 grams of fenoprofen (Kolodzik et al, 1990).
b) CASE REPORT: A 13-year-old teenager ingested 5 to 10 grams of mefenamic acid. Within 1.5 hours, the patient became comatose and then experienced grand mal seizures (Gossinger et al, 1982).
c) CASE REPORT: Overdose of 2400 mg sulindac, 4800 mg tiaramide, and 750 mg diclofenac sodium caused excitability followed by unconsciousness within 2 hours of ingestion (Harima et al, 1987).

F) DYSKINESIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A patient presented with confusion and writhing movements of the limbs. Spasm of the tongue, facial grimacing, and torticollis also occurred. The patient had ingested unknown amounts of alcohol, diazepam, and mefenamic acid (Redmond, 1981).

G) MYOCLONUS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 25-year-old man presented with drowsiness and was responsive only to pain 2 hours after ingesting 560 mg piroxicam, 12 g griseofulvin, and 1 g fentiazac. The level of consciousness improved within 12 hours, but involuntary movements of lips and jaw and myoclonic twitching of limbs occurred from 14 to 60 hours after admission. Recovery was complete in 4 days (Lo & Chan, 1983).

H) MENINGITIS

1) WITH THERAPEUTIC USE

a) Aseptic meningitis has been reported in patients taking therapeutic doses of ibuprofen, sulindac, tolementin, and naproxen (Hoppmann et al, 1991).

Gastrointestinal

3.8.1)

3.8.2)

A) GASTROINTESTINAL TRACT FINDING

1) WITH POISONING/EXPOSURE

a) NAUSEA/VOMITING/ABDOMINAL PAIN

1) Vomiting is frequent. Gastrointestinal distress, nausea, epigastric pain, and hematemesis have been reported following an NSAID overdose (Joubert, 1982; Fredell & Strand, 1977; Balali-Mood et al, 1981) Gomez- Lopez et al, 1999).
2) INCIDENCE: In a retrospective series of 724 cases of oral exposure to vaginal preparations containing benzydamine from 1991 to 2003 reported to the Spanish Poison Control Center, gastrointestinal effects (n=110; 48%) were the most common overall events reported. Of these events, nausea (n=75; 32.8%), vomiting (n=64; 27.9%), abdominal pain (n=32; 13.4%), and esophageal irritation (n=24; 10.5%) were the most common. Most exposures (85.9%) were due to inadvertent ingestion of vaginal preparations. In this series, no deaths were reported and most patients improved with drug cessation (Ballesteros et al, 2009).
3) CASE REPORT: Nausea and abdominal pain were reported in a case of an 1800-mg piroxicam ingestion. Endoscopy revealed superficial ulcerations in the pyloric antrum and duodenum. Recovery was uneventful (Mosvold et al, 1984).

B) ESOPHAGITIS

1) WITH THERAPEUTIC USE

a) MECLOFENAMATE/CASE REPORT: Pill esophagitis has been described with meclofenamate therapy. Retrosternal pain and odynophagia started 4 days after initiation of 100 mg every 8 hours. Symptoms resolved in 5 weeks with supportive therapy (Minocha & Greenbaum, 1991).
b) SULINDAC: A 22-year-old man intentionally ingested 15 g of sulindac and developed acute renal failure, pill esophagitis and ischemic skin necrosis. He became anuric on day 4 and his creatinine peaked at 8.23 mg/dL with a BUN of 93 mg/dL requiring hemodialysis. His hemoglobin (11.4 on day 4) was also noted to be trending downward over several days. An esophagogastroduodenoscopy was performed and showed large superficial esophageal ulcers with stigmata of recent bleeding and large exudative duodenal ulcers. Ten days after ingestion, he developed ischemic skin changes with a gangrenous appearance on his hands and feet. He developed severe foot pain. A doppler ultrasound showed normal arterial and venous blood flow. Approximately 15 days after exposure, his skin changes began to improve and the skin on his hands and feet began to peel. By day 25, he was able to urinate with improved creatinine clearance and he was successfully removed from hemodialysis. His acute renal failure and ischemic skin changes were thought to be due to impairment of prostaglandin synthesis following overdose (Vaughn et al, 2015).

C) GASTROINTESTINAL HEMORRHAGE

1) WITH THERAPEUTIC USE

a) CHRONIC TOXICITY

1) INCIDENCE: Gastrointestinal bleeding has been reported during therapeutic use, with an incidence ranging from 0.33% (overall) up to 5.5% (indomethacin) and 19.7% (aspirin) (Rainsford, 1982; Carson et al, 1987; Goodwin, 1987; Semble & Wu, 1987). Blood loss of more than 2 mL/day may occur with daily use (Semble & Wu, 1987). Erosive esophagitis was reported in 20% of arthritis patients taking NSAIDs for 1 month to 3 years; strictures occurred in 2 patients (Semble et al, 1989). Perforating ulcer was not associated with NSAID use in one large case-control study (Jick et al, 1987).
2) DOSE-RELATIONSHIP: In a study of 35 healthy volunteers taking different doses of flurbiprofen, a dose-response relationship was found with respect to gastric injury. Those subjects taking 200 mg/day for 7 days experienced significantly more gastric irritation (Friedman et al, 1989).
3) RISK FACTORS: Risk factors for upper gastrointestinal bleeding and perforation include advanced age, smoking, history of peptic ulcer, and use of oral corticosteroids or anticoagulants, as reported in a retrospective controlled study (Rodriguez & Jick, 1994).

D) COLITIS

1) WITH THERAPEUTIC USE

a) Long-term NSAID therapy has been implicated in development of colitis. Four cases are presented and literature reviewed by author (Gibson et al, 1992).
b) In one study, 38% of patients presenting with colitis had a history of NSAID use. Most common drugs were diclofenac and mefenamic acid (Gleeson et al, 1994).

E) GASTRIC ULCER

1) WITH THERAPEUTIC USE

a) Multiple ileal ulcers with bleeding and multiple strictures were reported in one case of therapeutic piroxicam use (Matsuhashi et al, 1992).
b) There have been several case reports of giant gastric ulcerations, duodenal ulcerations and upper gastrointestinal hemorrhage with acute therapeutic use of oral and injectable ketorolac (Wolfe et al, 1993; (Estes et al, 1993; Quigley & Ruh, 1994; Quigley & Ruh, 1994).
c) Several cases of stercoral perforation of the colon due to NSAID therapeutic use have been reported (Hollingworth & Alexander-Williams, 1991).
d) A study of 217 endoscopy-proven gastric ulcer (GU) patients were studied for presence of H. pylori and NSAID use. Advanced age (greater than 65 years) and NSAID use carried an increased risk of GU bleeding (odds ratio (OR), 3.4 and 6.8, respectively). H. pylori infection alone was not associated with additional GU bleeding risk (OR, 0.8). However, multivariate analysis demonstrated that H. pylori infection in the presence of NSAID use and advanced age increased the OR to 2.4, suggesting an interaction between these factors (Ng et al, 2000).
e) A prospective matched, case-control study was conducted, with 132 patients with a bleeding peptic ulcer (n=124) or hemorrhagic gastritis (n=8) at endoscopy who had taken an NSAID in the previous week and 136 controls who had taken NSAIDs without gastrointestinal complications. An adjusted odds ratio of bleeding from a peptic ulcer owing to H. pylori infection in NSAID users was determined to be 1.81 and was similar in aspirin and non-aspirin NSAID users. About 16% of bleeding ulcers in NSAID users could be attributable to H. pylori infection (Aalykke et al, 1999).

F) PANCREATITIS

1) WITH THERAPEUTIC USE

a) CASE SERIES: In a postmarketing review of therapeutic use of several NSAIDs, pancreatitis was reported in 2 patients taking diclofenac and 1 patient taking piroxicam (Jick et al, 1993).

G) STENOSIS OF INTESTINE

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 53-year-old woman with a history of rheumatoid arthritis who had been taking diclofenac regularly for 5 years developed colonic perforation secondary to a tight stricture of the ascending colon and a stricture of the ileocecal valve (Robinson et al, 1995).
b) Recurrent colonic strictures with inflammatory changes and mucosal ulceration were reported in a patient who had been chronically ingesting etodolac to treat rheumatoid arthritis (Eis et al, 1998).

Hepatic

3.9.1)

A) Hepatotoxicity has been reported following chronic therapeutic use, especially with sulindac and bromfenac, and in one piroxicam overdose.

3.9.2)

A) LIVER DAMAGE

1) WITH POISONING/EXPOSURE

a) ACUTE EXPOSURE

1) CASE REPORT: Moderate hepatotoxicity (peak AST, 570 Units/L; alkaline phosphatase 234 Units/L) developed in a 2-year-old boy who ingested 199 mg piroxicam (Macdougall et al, 1984).

b) CHRONIC EXPOSURE

1) SUMMARY: Hepatotoxicity, including hepatocellular injury, centrilobular necrosis, and/or cholestatic jaundice, with some fatalities, has been reported with all chemical classes of NSAIDs during therapeutic multiple dosing, especially with sulindac and bromfenac (Gallanosa & Spyker, 1985) McIndoe, 1981; (Rodriguez et al, 1994; Prod Info Duract(R), bromfenac capsules, 1998; Moses et al, 1999; Rabkin et al, 1999; Kethu et al, 1999; Greaves et al, 2001).
2) SULINDAC: The incidence of liver injury during sulindac therapy was 27 per 100,000 prescriptions, compared with 1.1 per 100,000 prescriptions for NSAIDs as a group in a large, retrospective, cohort study. Although more frequent with sulindac, none of the cases produced severe effects or required hospitalization (Rodriguez et al, 1994).
3) CASE REPORT: Elevated liver enzymes were reported in a 61-year-old male following therapeutic doses of fenbufen (300 mg twice daily) for 5 days (Krivoy et al, 1997).
4) BROMFENAC

a) There have been several reported cases of severe hepatitis and liver failure occurring in patients following long-term ingestion of bromfenac for greater than one month and without liver enzyme monitoring. Some patients who developed liver failure required transplantation (Prod Info Duract(R), bromfenac capsules, 1998; Rabkin et al, 1999).
b) The manufacturer has voluntarily withdrawn bromfenac from the market as of June 1998 in response to several reports of severe liver failure that have occurred following long-term ingestion (greater than 10 days) ((Anon, 1998)).
c) CASE REPORT: A 40-year-old woman experienced nausea, vomiting, and jaundice approximately 3 weeks after beginning bromfenac therapy, 25 mg three times daily. Despite discontinuing bromfenac, the nausea and vomiting persisted along with progressive jaundice. Laboratory analysis revealed elevated liver enzyme levels, an abdominal CT showed a large edematous-appearing liver and a small amount of ascites; and a liver biopsy showed evidence of multifocal bile ductule proliferation with focal canalicular and intraparenchymal cholestasis, all of which was consistent with a diagnosis of submassive hepatic necrosis. The patient gradually recovered following administration of diuretics (Moses et al, 1999).
d) CASE REPORT: Three months after beginning bromfenac therapy, 50 mg three times daily, a 36-year-old male developed fulminant liver failure requiring transplantation. Examination of the explanted liver showed hepatic necrosis and parenchymal collapse, subacute inflammation, and extensive bile ductular stasis with plugging (Hunter et al, 1999).

5) OXAPROZIN

a) CASE REPORT: A 56-year-old woman developed fulminant hepatic failure six weeks after beginning oxaprozin therapy (600 to 1200 mg/day). A liver biopsy showed massive hepatic necrosis (Purdum et al, 1994).
b) CASE REPORT: A 41-year-old woman developed malaise, anorexia, upper right quadrant pain, and jaundice approximately 6 weeks after beginning oxaprozin therapy 1200 mg daily for shoulder pain. Laboratory analysis showed elevated liver enzyme levels. A liver biopsy revealed acute hepatitis with lobular inflammation. Six days after cessation of oxaprozin therapy the patient gradually recovered, with complete normalization of liver enzyme levels occurring 8 weeks after drug cessation (Kethu et al, 1999).

6) DICLOFENAC

a) CASE REPORT: A 53-year-old woman developed jaundice with elevated serum transaminase levels one month after beginning diclofenac (Voltarol(R)) therapy for treatment of a soft tissue injury of her ankle. The diagnosis was drug-induced hepatitis and the patient was advised to avoid the use of NSAIDs. Ten months later, the patient was prescribed generic diclofenac by a different physician for treatment of the same injury. The patient subsequently developed severe hepatitis with multi-acinar collapse requiring liver transplantation (Greaves et al, 2001).

Genitourinary

3.10.1)

A) Acute renal failure, azotemia, and nephrotic syndrome have occurred with both acute overdose and chronic ingestion of most NSAIDs.

3.10.2)

A) RENAL FAILURE SYNDROME

1) WITH THERAPEUTIC USE

a) SUMMARY

1) Acute renal failure, nephrotic syndrome, flank pain, hematuria, and acute interstitial nephritis have been reported following chronic ingestion of therapeutic doses of most NSAIDs (Lofgren, 1981; Warren & Mosley, 1983; Ratner, 1982; McCarthy, 1982; Rossi et al, 1985; Abraham et al, 1988; Lindsley & Warady, 1990; Shankel et al, 1992).
2) CASE REPORTS

a) DICLOFENAC: Acute renal failure and flank pain were reported following administration of diclofenac and heavy alcohol intake (Enriquez et al, 1997).
b) FENBUFEN: A 61-year-old man developed interstitial nephritis and elevated liver enzymes 5 days after starting fenbufen 300 mg twice daily. Initial creatinine was 1105 mol/L; following drug cessation the level was 106 mol/L by approximately 4 weeks (Krivoy et al, 1997).
c) KETOROLAC: Acute, oliguric renal failure developed rapidly 2 hours following a single 60-mg intramuscular dose of ketorolac. The patient's serum chemistries returned to baseline on day 8 after aggressive supportive therapy (Quan & Kayser, 1994).
d) KETOROLAC: Six cases are reported with renal insufficiency (greater than 30% increase in serum creatinine) after intramuscular administration of ketorolac (mean duration of administration, 3 days; mean dose, 153 mg) (Corelli & Gericke, 1993).
e) KETOROLAC: A case of acute renal failure developed following 3 doses of intramuscular ketorolac (Schoch et al, 1992).
f) KETOROLAC: A 17-year-old teenager developed acute oliguric renal failure after taking ketorolac ten 10-mg doses of ketorolac over 30 hours. Biopsy showed acute tubular necrosis. She recovered following hemodialysis and drug cessation (Buck & Norwood, 1996).
g) SUPROFEN: Reversible renal failure was reported following 3 200-mg doses of suprofen (Henann & Morales, 1986). Acute flank pain, hematuria, and transient renal dysfunction has been reported after 1 or 2 therapeutic doses (Abraham et al, 1988).
h) TOLMETIN: Acute renal failure was reported after a 53-year-old diabetic male was prescribed 200 mg tolmentin sodium 3 times a day (Patmas et al, 1984).

3) CASE SERIES

a) PEDIATRIC

1) Four children (ages ranging from 3.5 to 19 years) developed acute nonoliguric renal failure after therapeutic administration (naproxen and ibuprofen) and overdose (naproxen) of NSAID agents. All four patients recovered with supportive care (Schaller & Kaplan, 1998).
2) A nested case-control study, using Tennessee Medicaid enrollees 65 years of age or greater, was performed in patients who had been hospitalized with community-acquired acute renal failure. Eighteen percent were found to be current users of prescription NSAIDs compared with 11.3% of controls. Use of NSAIDs increased the risk of acute renal failure (odds ratio, (OR), 1.58). Ibuprofen accounted for 35% of NSAID use. Odds ratios associated with ibuprofen were 0.94 for dosages of 1200 mg/day or less, 1.89 for dosages between 1200 and 2400 mg/day, and 2.32 for dosages of 2400 mg or greater. There were similar dose-response relationships demonstrated for fenoprofen and indomethacin. Prescription NSAID use resulted in an estimated 25 excess hospitalizations associated with renal failure per 10,000 years of use in an elderly population (Griffen et al, 2000).

4) RISK FACTORS

a) Renal effects are more common in patients with underlying conditions predisposing dependence on prostaglandins for maintenance of renal blood flow, such as volume depletion, congestive heart failure, and concomitant loop diuretic therapy (Gurwitz et al, 1990), in patients with preexisting renal insufficiency (Whelton et al, 1990), in children receiving high doses for rheumatoid arthritis (Lindsley & Warady, 1990; Szer et al, 1991) and in patients ingesting ethanol (Wen et al, 1992).

2) WITH POISONING/EXPOSURE

a) CASE REPORTS

1) BENOXAPROFEN: Rhabdomyolysis and subsequent renal failure developed 40 hours after overdose in a 53-year-old woman (Fancourt et al, 1984).
2) FENOPROFEN: A case of acute renal failure following fenoprofen overdose was reported (Appleby, 1981).
3) SULINDAC: A 22-year-old man intentionally ingested 15 g of sulindac and developed acute renal failure, pill esophagitis and ischemic skin necrosis. He became anuric on day 4 and his creatinine peaked at 8.23 mg/dL with a BUN of 93 mg/dL requiring hemodialysis. His hemoglobin (11.4 on day 4) was also noted to be trending downward over several days. An esophagogastroduodenoscopy was performed and showed large superficial esophageal ulcers with stigmata of recent bleeding and large exudative duodenal ulcers. Ten days after ingestion, he developed ischemic skin changes with a gangrenous appearance on his hands and feet. He developed severe foot pain. A doppler ultrasound showed normal arterial and venous blood flow. Approximately 15 days after exposure, his skin changes began to improve and the skin on his hands and feet began to peel. By day 25, he was able to urinate with improved creatinine clearance and he was successfully removed from hemodialysis. His acute renal failure and ischemic skin changes were thought to be due to impairment of prostaglandin synthesis following overdose (Vaughn et al, 2015).

B) ABNORMAL RENAL FUNCTION

1) WITH POISONING/EXPOSURE

a) SULINDAC: There were 5 reported cases of sulindac overdose ingestions (4 to 24 g) resulting in vomiting, anorexia, abdominal pain, hematuria, proteinuria, and elevated serum creatinine levels. All patients improved following general supportive care (Kulling et al, 1995).

C) CYSTITIS

1) WITH THERAPEUTIC USE

a) Several reports have reported a causal relationship between tiaprofenic acid and development of nonbacterial cystitis (O'Neill, 1994; Ahmed & Davison, 1991).

Acid-Base

3.11.1)

A) Metabolic acidosis occurs rarely in overdose, usually in conjunction with seizures.

3.11.2)

A) ACIDOSIS

1) Metabolic acidosis may occur, usually in conjunction with seizures or hypotension, following an NSAID overdose (Bond et al, 1989; Martinez et al, 1989; Kolodzik et al, 1990).
2) CASE REPORT: A 17-year-old girl presented with coma, hypotension, metabolic acidosis, and respiratory depression within 4 hours after of ingestion of 24 to 36 grams of fenoprofen (Kolodzik et al, 1990).

Hematologic

3.13.1)

3.13.2)

A) GRANULOCYTOSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Acute, severe granulocytosis occurred following sulindac overdose in a 16-year-old following ingestion of 60 200-mg tablets (Gross, 1982).

B) COAG./BLEEDING TESTS ABNORMAL

1) WITH THERAPEUTIC USE

a) By decreasing platelet adhesion and aggregation, NSAIDs can increase bleeding time approximately by 3 to 4 minutes with therapeutic doses.
b) A randomized, double-blind, placebo-controlled study in 24 healthy adults found significant reductions in platelet aggregation, serum thromboxane levels, and increased bleeding time with 10 days of naproxen 500 mg twice daily, compared with no significant effects on these parameters of supratherapeutic celecoxib (600 mg twice daily) over the same period (Leese et al, 2000).
c) Ketorolac, 0.4 mg/kg IV, inhibited platelet aggregation and decreased thromboxane B2. Platelet dysfunction was still seen after 24 hours. Coagulation was unaffected. There was no correlation between maximal platelet aggregation, thromboxane levels, and plasma concentrations of ketorolac (Niemi et al, 2000).
d) CASE REPORT (THROMBOCYTOPENIA): A 55-year-old male developed thrombocytopenia after ingesting diclofenac 50 mg twice daily for 4 weeks. Complement fixation testing suggested that the thrombocytopenia was drug-induced (George & Rahi, 1995).

2) WITH POISONING/EXPOSURE

a) PT prolongation has been reported following overdose with etodolac, piroxicam and naproxen. Prothrombin time normalized with supportive care (Boldy et al, 1988; Waugh & Keatinge, 1983; Macdougall et al, 1984).
b) CASE REPORT: A multiple NSAID overdose resulted in the partial thromboplastin time 3 times the control at 3 hours after ingestion. Values returned to normal by the next day (Harima et al, 1987).

C) THROMBOCYTOPENIC DISORDER

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Progressive anemia, neutropenia, and thrombocytopenia due to bone marrow aplasia occurred in a 2-year-old after ingesting 100 mg piroxicam (Macdougall et al, 1984).

D) APLASTIC ANEMIA

1) WITH THERAPEUTIC USE

a) Aplastic anemia has occurred with piroxicam (Lee et al, 1982); piroxicam has also been associated with thrombocytopenia and autoimmune hemolytic anemia (Patmas et al, 1984).
b) CASE REPORT: A 12-year-old male developed aplastic anemia after taking an herbal medication over several days that contained phenylbutazone, chlorpheniramine, and diclofenac (Nelson et al, 1995).

E) HEMOLYTIC ANEMIA

1) WITH THERAPEUTIC USE

a) Hemolytic anemia has been reported with diclofenac in therapeutic doses (Jick et al, 1993; Bougie et al, 1997).

F) LEUKOPENIA

1) WITH THERAPEUTIC USE

a) Neutropenia has been associated with NSAID therapeutic use (Strom et al, 1993).

Dermatologic

3.14.1)

A) Photosensitivity, toxic epidermal necrolysis, erythema multiforme, and phototoxicity have been reported with therapeutic use.

3.14.2)

A) PHOTOSENSITIVITY

1) WITH THERAPEUTIC USE

a) Photosensitivity has been reported with therapeutic doses of piroxicam, carprofen, and benoxaprofen (Stern, 1983; Goh & Kwok, 1985; Sneddon, 1986).
b) CASE REPORTS

1) PIROXICAM: In a report of 11 cases of piroxicam-induced photosensitive dermatitis, facial skin was affected in all patients and 6 developed a pronounced vesicular hand dermatitis involving both the dorsal and palmar surfaces (McKerrow & Greig, 1986).
2) CARPROFEN: Three cases of photosensitivity confirmed by patch testing were confirmed, although the patch test procedure was questioned by another author (Roelandts (1986)). One of the patients developed photodermatitis after taking 4 tablets (150 mg) of carprofen; the other two developed dermatitis after taking 150 mg carprofen for 6 days (Goh & Kwok, 1985).
3) BENOXAPROFEN: Painful persistent phototoxicity, without a visible rash has been reported in 30 patients on benoxaprofen (Sneddon, 1986).
4) BENZYDAMINE: A case of contact and photodermatitis was reported in a 74-year-old man who had been using a topical ointment containing 5% benzydamine for 20 years (Vincenzi et al, 1990).

B) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE

1) WITH THERAPEUTIC USE

a) Toxic epidermal necrolysis and erythema multiforme have been reported with piroxicam, isoxicam, and oxaprozin (Penso et al, 1986; Carucci & Cohen, 1999). Fenbufen in therapeutic doses has resulted in toxic epidermal necrolysis in an adult (Krivoy et al, 1997).
b) CASE REPORT (OXAPROZIN): A 65-year-old woman presented to a burn center 3 days after initiating oxaprozin therapy of 600 mg daily, with an extensive epidermal exfoliation. The patient had developed chills, fever, malaise, and sloughing blisters over 60% of her body before presenting to the burn center. Over the next 3 days, the blistering progressed to 95% of her body, including the oral mucous membranes, oropharynx, tracheal bronchial tree, and the conjunctiva.

1) The patient's health continued to deteriorate with development of renal insufficiency, refractory hypotension, and pulmonary failure progressing to acute respiratory distress syndrome. The patient eventually died 14 days after admission (17 days after initiation of oxaprozin therapy) (Paul et al, 1998).

C) DISORDER OF TENDON

1) WITH THERAPEUTIC USE

a) CASE SERIES: Three cases of necrotizing fascitis after Caesarean section have been reported with the acute use of indomethacin suppositories (2 cases) and flurbiprofen suppositories (Van Ammers et al, 1991).

D) STEVENS-JOHNSON SYNDROME

1) WITH THERAPEUTIC USE

a) CASE REPORT: A case of fatal Stevens-Johnson syndrome is reported with therapeutic use of tiaprofenic acid 300 mg 2 times a day for 14 days (Davidson & Speed, 1993) and with niflumic acid therapy in a 10-month-old infant (Menniti-Ippolito et al, 2001).
b) CASE REPORT (OXAPROZIN): A 61-year-old woman developed a pruritic papular erythematous rash on her face and upper trunk 14 days after beginning oxaprozin therapy, 1200 mg once daily. The patient was also taking hydroxychloroquine and prednisone. The patient discontinued the oxaprozin, but subsequently developed ulceration of the oral mucosa and a diffuse, erythematous rash on the face, trunk, and extremities. A diagnosis of oxaprozin-induced Stevens-Johnson syndrome was made with the lesions gradually resolving over a 2-week period (Bell & Bishara, 1998).

E) BULLOUS ERUPTION

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 31-year-old man developed dermatitis herpetiformis after beginning flurbiprofen therapy; the rash resolved after discontinuing flurbiprofen and initiating therapy with dapsone (Tousignant et al, 1994).

F) LICHENOID DERMATITIS

1) WITH THERAPEUTIC USE

a) Lichen planus has been reported following ingestions of naproxen, fenclofenac, diflunisal, and indomethacin. The onset of clinical symptoms ranged from 10 days to 2 years. The symptoms generally improved within 7 days to 3 months after discontinuation of the medications (Thompson & Skaehill, 1994).

G) SKIN NECROSIS

1) WITH POISONING/EXPOSURE

a) SULINDAC: A 22-year-old man intentionally ingested 15 g of sulindac and developed acute renal failure, pill esophagitis and ischemic skin necrosis. He became anuric on day 4 and his creatinine peaked at 8.23 mg/dL with a BUN of 93 mg/dL requiring hemodialysis. His hemoglobin (11.4 on day 4) was also noted to be trending downward over several days. An esophagogastroduodenoscopy was performed and showed large superficial esophageal ulcers with stigmata of recent bleeding and large exudative duodenal ulcers. Ten days after ingestion, he developed ischemic skin changes with a gangrenous appearance on his hands and feet. He developed severe foot pain. A doppler ultrasound showed normal arterial and venous blood flow. Approximately 15 days after exposure, his skin changes began to improve and the skin on his hands and feet began to peel. By day 25, he was able to urinate with improved creatinine clearance and he was successfully removed from hemodialysis. His acute renal failure and ischemic skin changes were thought to be due to impairment of prostaglandin synthesis following overdose (Vaughn et al, 2015).

Immunologic

3.19.1)

3.19.2)

A) ANAPHYLACTOID REACTION

1) WITH THERAPEUTIC USE

a) Anaphylactoid reactions with tolmetin and zomepirac occur more frequently than with other NSAIDs. The chemical structure of zomepirac is almost identical to tolmetin and probably explains the increased frequency of anaphylactoid reactions associated with tolmetin, as previously observed with zomepirac (Rossi & Knapp, 1982; McNeil Pharmaceutical, 1982).
b) CASE REPORT: An anaphylactoid reaction to injectable ketorolac occurred in a patient with no prior history of allergies or risk factors associated with NSAID hypersensitivity reactions (Goetz et al, 1992).
c) Fifty patients with single-blind, challenge-proven hypersensitivity to NSAIDs were studied with prick skin tests to inhalant allergens, and personal and family histories of allergy were obtained. There were significantly higher rates of a history of atopy, a family history of atopy, and positive prick skin tests in patients with challenge-proven hypersensitivity to NSAIDs. Reactions were cutaneous alone (34/50), cutaneous plus respiratory (12/50), respiratory alone (3), and one anaphylactoid reaction. Aspirin, pyrazolone, paracetamol, and ibuprofen were the most frequently implicated drugs. The presence of atopy may represent an important risk factor for developing hypersensitivity to NSAIDs (Sanchez-Borges & Capriles-Hulett, 2000).

B) ANGIOEDEMA

1) WITH THERAPEUTIC USE

a) CASE REPORT: Acute angioedema occurred after 3 days of ketorolac ingestion (Shapiro, 1994).

C) VASCULITIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: Leukocytoclastic vasculitis (LCV), a type III hypersensitivity reaction, occurred in a 68-year-old woman 3 days after beginning oral aceclofenac therapy, 100 mg twice daily. The patient presented to the emergency department with purpuric skin lesions over the entire body, except on the palms of her hands and the soles of her feet, and with hemoptysis as a result of vasculitic pulmonary involvement. Chest X-ray and ECG appeared normal. The LCV and hemoptysis resolved following treatment with dexclorfenhydramine and discontinuation of the aceclofenac (Epelde & Boada, 1995).
b) Several cases of vasculitis, urticaria, and Schonlein-Henoch purpura have been reported following niflumic acid therapy. Other drugs concurrently ingested included paracetamol, various antibiotics, and other NSAID agents (Menniti-Ippolito et al, 2001).

Reproductive

3.20.1)

3.20.2)

A) DICLOFENAC

1) Prenatal ductal closure was reported following ingestion of a single-dose of diclofenac in a 31-year-old pregnant woman during gestation week 37. This was the patient's third pregnancy and she had no medical history of gestational diabetes, congenital heart disease, or preterm labor. Fetal echocardiographic examination revealed mild right ventricular hypertrophy as well as moderate tricuspid valve regurgitation. Doppler examination revealed a turbulent flow through the constricted ductus arteriosus and a significantly increased peak systolic velocity (24.6 m/sec). Due to the possibility of fatal complications and because of the proximity of full term gestation, an uneventful cesarean section was performed (Karadeniz et al, 2013).
2) Premature in utero closure of the fetal ductus arteriosus (DA) and hydrops occurred with maternal diclofenac use. A 28-year-old woman who was unaware she was pregnant until the day of delivery had taken 75 mg of diclofenac daily when she was approximately 5 months pregnant and for 2 weeks when she was 7 months pregnant. Four days before delivery, she took 75 to 150 mg for ongoing back pain. The infant, carried to term, had signs of marked dilation of the right atrium and right ventricle with marked hypertrophy, elevated pulmonary pressures, and no flow through the DA. The infant also had evidence of fetal ascites and small pericardial and pleural effusions. Further testing showed mixed acidosis and massive cardiomegaly via chest x-ray. Treatment included fluid restriction, diuretics, and continuous positive airway pressure support, followed by nasal cannula oxygen for 24 hours with gradual improvement in heart failure. A follow-up echocardiogram at 4 days continued to show right ventricular hypertrophy and mild tricuspid regurgitation. However, pulmonary arterial pressure was improving and heart failure had resolved. The infant was discharged on day 9. At 6 weeks, a repeat echocardiogram showed involution of the right ventricular hypertrophy (Shastri et al, 2013).

B) SULINDAC

1) Use of sulindac during pregnancy showed a significant increased risk of necrotizing enterocolitis (NEC) after adjusting for covariates significantly associated with NEC (adjusted odds ratio 5.33; 95% confidence interval, 1.38 to 20.57) in a retrospective study of 241 infants. After adjusting for infants with an isolated perforation, plus infants with free air on an abdominal film who did not have surgery, and removing cases (n=45) of suspected NEC, use of sulindac during pregnancy showed a significant increased risk of NEC (adjusted odds ratio 10.27; 95% confidence interval, 1.26 to 83.86) compared to the control group (Kamath-Rayne et al, 2015).

C) ANIMAL STUDIES

1) BROMFENAC

a) In animal studies, there was no evidence of teratogenicity when rats and rabbits were given oral bromfenac at doses up to 1,300 times the recommended human ophthalmic dose (RHOD) or 90 times the systemic exposure predicted from the RHOD and up to 11,000 times the RHOD or 150 times the predicted human systemic exposure, respectively. At these doses, there was embryo-fetal lethality, increased neonatal mortality, and decreased postnatal growth in rats and increased postimplantation loss in rabbits (Prod Info Bromday(R) ophthalmic solution, 2012). Also in rats, doses 30 times the predicted human exposure resulted in delayed parturition (Prod Info PROLENSA(TM) ophthalmic solution, 2013).

2) DICLOFENAC

a) Neuronal loss was observed in the offspring of pregnant rats administered 1 mg/kg diclofenac intraperitoneally (Prod Info Zipsor(R) oral liquid filled capsules, 2012).

3) DICLOFENAC EPOLAMINE

a) Embryotoxicity and increased incidences of skeletal abnormalities were reported in rats and embryotoxicity was reported in rabbits when administered oral diclofenac epolamine at a dose of 6 mg/kg/day (3 and 6.5 times the MRHD in rats and rabbits, respectively, based on surface area) during gestation days 6 through 15 in rats and 6 through 18 in rabbits. Embryotoxicity (early resorptions, post-implantation, and a decrease in live fetuses) was also reported when 6 mg/kg (3 times the MRHD, based on body surface area) diclofenac epolamine was administered to male rats throughout mating and female rats 14 days prior to mating through lactation (Prod Info FLECTOR PATCH(R) topical patch, 2011).

4) DICLOFENAC SODIUM

a) In pregnant mice, rats, and rabbits given diclofenac sodium doses up to 10 mg/kg/day (up to 1 time the recommended human dose on a mg/m(2) basis), no sign of teratogenicity was noted despite maternal and fetal toxicity induction. Dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival were associated with maternally toxic doses in rats (Prod Info CAMBIA(TM) oral solution, 2013). Diclofenac crosses the placental barrier in mice, rats, and humans (Prod Info Dyloject(TM) intravenous injection, 2014; Prod Info ZORVOLEX(TM) oral capsules, 2013).

5) KETOROLAC PHENYLEPHRINE

a) RABBITS, RATS: No teratogenicity occurred in the offspring of rabbits and rats following ketorolac exposures during organ formation that were 1150 times and 4960 times, respectively, the recommended human ophthalmic dose. Increased pup mortality occurred in rats exposed to ketorolac doses 740 times the recommended human ophthalmic dose following gestation day 17 (Prod Info OMIDRIA(TM) ophthalmic solution injection, 2014).

6) KETOROLAC TROMETHAMINE

a) RATS, RABBITS: No evidence of teratogenicity or other adverse fetal developmental outcomes were reported in studies of rabbits and rats administered maternally toxic doses of oral ketorolac 0.6 times the human exposure of an intranasal dose of 31.5 mg 4 times daily based on AUC and 1.5 times the human AUC), respectively, during organogenesis. However, animal studies have shown that use of NSAIDs, including ketorolac, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth (Prod Info SPRIX(R) nasal spray, 2016).

7) MELOXICAM

a) In studies of pregnant animals treated with meloxicam, an increase in septal defects of the heart occurred at doses up to 116 times the maximum recommended daily dose (MRDD). Animals treated throughout organogenesis developed embryolethality with meloxicam doses up to 10 times the MRDD. No teratogenic signs were observed with doses up to 3.9 times the MRDD throughout organogenesis (Prod Info VIVLODEX(TM) oral capsules, 2015; Prod Info MOBIC(R) oral tablets, suspension, 2008a). An increase in stillbirths was noted in animals when given an oral dose greater than or equal to 1 mg/kg/day (Prod Info MOBIC(R) oral tablets, suspension, 2008a).

8) PIROXICAM

9) SULINDAC

a) RATS, RABBITS: Reproductive studies in rats and rabbits have not shown evidence of developmental abnormalities. Reproduction studies showed a decrease in average fetal weight and an increase in numbers of dead pups in rats given doses of 20 and 40 mg/kg/day (2.5 and 5 times the usual maximum human exposure). During the remainder of the postpartum period no additional adverse effects on survival and growth were reported. Sulindac prolongs the gestation period in rats, as do other NSAID compounds. Visceral and skeletal malformations were observed in low incidence among rabbits in some teratology studies, however, these malformations did not occur at the same dosage levels or in higher dosage levels in repeat studies. NSAIDs administered to rats during labor and delivery resulted in an increased incidence of decreased pup survival, delayed parturition and dystocia (Prod Info CLINORIL(R) oral tablets, 2010).

10) TOLMETIN

a) Animal data indicate no evidence of impaired fertility or teratogenesis with tolmetin doses comparable to 1.5 times the maximum clinical dose in a 60-kg adult (Prod Info Tolectin(R), 1988).

3.20.3)

A) ASTHMA

1) A prospective cohort study examining NSAID use during pregnancy found no major congenital malformations; however, there were low birthweight and asthma with ibuprofen use, and low birthweight and maternal vaginal bleeding with diclofenac use during second and/or third trimesters. This study involved 90,147 pregnant women, with 6,511 exposed and 83,906 unexposed to the following 4 NSAIDs: diclofenac, ibuprofen, naproxen, or piroxicam. There was no significant difference in infant survival, congenital malformations, or structural heart defects in women taking these NSAIDs during the first-trimester; however, ibuprofen was associated asthma in 18-month-old infants when used in the second and third trimesters (adjusted odds ratio (OR), 1.5; 95% CI, 1.2 to 1.9; adjusted OR, 1.5; 95% CI, 1.1 to 2.1) (Nezvalova-Henriksen et al, 2013).

B) DECREASED BIRTHWEIGHT

1) A prospective cohort study examining NSAID use during pregnancy found no major congenital malformations; however, there were low birthweight and asthma with ibuprofen use, and low birthweight and maternal vaginal bleeding with diclofenac use during second and/or third trimesters. This study involved 90,147 pregnant women, with 6,511 exposed and 83,906 unexposed to the following 4 NSAIDs: diclofenac, ibuprofen, naproxen, or piroxicam. There was no significant difference in infant survival, congenital malformations, or structural heart defects in women taking these NSAIDs during the first-trimester; however, ibuprofen and diclofenac were associated with decreased birthweight when used during the second trimester (adjusted odds ratio (OR) 1.7; 95% CI, 1.3 to 2.3; adjusted OR, 3.1; 95% CI, 1.1 to 9) (Nezvalova-Henriksen et al, 2013).

C) MATERNAL VAGINAL BLEEDING

1) A prospective cohort study examining NSAID use during pregnancy found no major congenital malformations; however, there were low birthweight and asthma with ibuprofen use, and low birthweight and maternal vaginal bleeding with diclofenac use during second and/or third trimesters. This study involved 90,147 pregnant women, with 6,511 exposed and 83,906 unexposed to the following 4 NSAIDs: diclofenac, ibuprofen, naproxen, or piroxicam. There was no significant difference in infant survival, congenital malformations, or structural heart defects in women taking these NSAIDs during the first-trimester; however, diclofenac was associated with maternal vaginal bleeding when used in the third trimester (adjusted OR, 1.8; 95% CI, 1.1 to 3) (Nezvalova-Henriksen et al, 2013).

D) PATENT DUCTUS ARTERIOSUS

1) Use of NSAIDs in pregnancy is not recommended. Inhibition of prostaglandin synthesis may cause closure of the ductus arteriosus (Prod Info VIVLODEX(TM) oral capsules, 2015). NSAIDs may prolong pregnancy if taken before the onset of labor, especially during the third trimester (Briggs et al, 1994). Cardiopulmonary effects of NSAIDs during late pregnancy reportedly include closure of the ductus arteriosus, pulmonary hypertension cardiopathy and tricuspid valve insufficiency. NSAIDs were responsible for 31 neonatal accidents, of which 8 were fatal. Renal effects include acute renal failure, edema, oliguria, hyponatremia, and marked hyperkalemia. NSAIDs were responsible for 23 neonatal accidents, of which 8 were fatal (Bavoux, 1992).
2) SULINDAC

a) There have been no reports of congenital abnormalities caused by maternal use of sulindac. However, sulindac should be avoided in late pregnancy because of the effects of prostaglandin inhibition on the fetal cardiovascular system (closure of ductus arteriosus) (Levin, 1980; Needs & Brooks, 1985).

3) KETOROLAC PHENYLEPHRINE

a) Ocular ketorolac/phenylephrine administration yields detectable ketorolac plasma concentrations. Third-trimester use of oral and injectable NSAIDs has been linked with premature closure of the fetal ductus arteriosus (Prod Info OMIDRIA(TM) ophthalmic solution injection, 2014).

E) MISCARRIAGE

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

F) SPECIFIC AGENT

1) INDOMETHACIN/SULINDAC

a) Indomethacin use has been associated with a wide range of fetal and maternal effects which include: neonatal cyanosis, right to left shunting, fetal death, fetal pulmonary hypertension, reduction of fetal renal function, fetal ileal perforation, neonatal gastrointestinal bleeding, maternal postpartum hemorrhage, maternal gastrointestinal adverse reactions and hypertensive crisis. Sulindac appears to have less adverse reactions as compared to indomethacin (Schoenfeld et al, 1992).
b) The safety of sulindac in comparison with indomethacin in the treatment of preterm labor was studied. Thirty-six women were randomized to receive either oral indomethacin or oral sulindac for 48 hours. Sulindac-treated women had significantly greater hourly fetal urine output, deepest amniotic fluid pocket, and amniotic fluid index. In the indomethacin group, higher ductus arteriosus flow velocities were noted (Carlan et al, 1992).

2) MELOXICAM

a) Meloxicam should not be used during the third trimester (30 weeks of gestation) of pregnancy. Exercise caution with use during the first or second trimesters of pregnancy. Observational studies regarding the potential embryofetal risks of NSAID use in women in the first or second trimester of pregnancy have been inconclusive (Prod Info VIVLODEX(TM) oral capsules, 2015).

3) PIROXICAM

a) There are no adequate or well controlled studies of piroxicam use during human pregnancy. Use of NSAIDs during the third trimester of pregnancy increases the risk of premature closure of the ductus arteriosus. The manufacturer recommends the use of piroxicam during the first or second trimester only if the potential benefit outweighs the potential risk. Use is not recommended during the third trimester. Apprise patient of the potential for fetal harm if used during the third trimester (Prod Info FELDENE(R) oral capsules, 2015). For minor analgesia or fever, acetaminophen, used short-term in normal doses, appears to be safer for the fetus. Salicylates, although best avoided during pregnancy, are preferred to NSAIDs for treatment of rheumatoid arthritis during pregnancy (Gladman & Urowitz, 1995).

4) TIAPROFENIC ACID

a) Of 12 pregnant women with first-trimester exposure to tiaprofenic acid, 3 pregnancies were miscarried and 1 was terminated electively. Of the 8 live births, there were no malformations detected and development was normal (Pastuszak et al, 1993).

5) TOLMETIN

a) Tolmetin should be avoided in late pregnancy because of the effects of prostaglandin inhibition on the fetal cardiovascular system (closure of ductus arteriosus) (Levin, 1980a; Needs & Brooks, 1985a).

G) PREGNANCY CATEGORY

1) The following NSAIDs are classified as FDA pregnancy category C prior to 30 weeks gestation and FDA pregnancy category D starting at 30 weeks gestation:

1) Diclofenac (Prod Info ZORVOLEX(TM) oral capsules, 2013)
2) Diclofenac epolamine (Prod Info FLECTOR PATCH(R) topical patch, 2011).
3) Diclofenac potassium (oral capsule, oral solution) (Prod Info Zipsor(R) oral liquid filled capsules, 2012; Prod Info CAMBIA(TM) oral solution, 2013)
4) Diclofenac sodium (topical solution 1.5% and IV solution) (Prod Info Dyloject(TM) intravenous injection, 2014; Prod Info PENNSAID(R) topical solution, 2013)
5) Ketorolac tromethamine (Prod Info SPRIX(R) nasal spray, 2016)
6) Piroxicam (Prod Info FELDENE(R) oral capsules, 2015)

2) The following NSAIDs are classified as FDA pregnancy category C:

1) Diclofenac potassium (immediate-release tablet) (Prod Info Cataflam(R) oral immediate-release tablets, 2011)
2) Diclofenac sodium (topical gel 1%, ophthalmic solution 0.1%, extended-release oral tablets, delayed-release oral tablets) (Prod Info Voltaren(R) topical gel, 2009; Prod Info VOLTAREN OPHTHALMIC(R) ophthalmic solution, 2012; Prod Info Voltaren(R)-XR oral extended-release tablets, 2011; Prod Info diclofenac sodium delayed-release oral tablets, 2006).
3) Fenoprofen (Prod Info NALFON(R) oral capsules, 2007).
4) Ketorolac and phenylephrine (ophthalmic solution used for ocular irrigation) (Prod Info OMIDRIA(TM) ophthalmic solution injection, 2014).
5) Meloxicam (Prod Info MOBIC(R) oral tablets, suspension, 2008).
6) Sulindac (Prod Info CLINORIL(R) oral tablets, 2010).
7) Tolmetin (Prod Info tolmetin sodium oral capsules, oral tablets, 2006).

3) Diclofenac sodium (topical gel 3%) is classified as FDA pregnancy category B (Prod Info SOLARAZE(R) topical gel, 2011).

H) LACK OF EFFECT

1) DICLOFENAC

a) In a prospective, observational study, diclofenac use during pregnancy was associated with an increased incidence of birth defects when compared with the control group (5.6% and 2.4%, respectively), although the increase was not significant (odds ratio (OR), 2.5; 95% CI, 0.9 to 6.6; p=0.07). Among 145 women exposed to diclofenac between the 5th and the 14th gestational week of pregnancy (median dose: 109 mg daily; mean duration: 3.8 weeks), there was no significant difference reported in preterm births (13.5% vs 15.2%; p=0.6), spontaneous abortions (6.2% vs 5.4%; p=0.7), gestational age at delivery (p=0.8), or average birth weight (p=0.6) when compared with the control group (n=501) (Cassina et al, 2010).

I) ANIMAL STUDIES

1) DICLOFENAC

a) Prolonged gestation and liver toxicity were observed in the offspring of pregnant rats administered 1 mg/kg diclofenac intraperitoneally (Prod Info Zipsor(R) oral liquid filled capsules, 2012).

2) DICLOFENAC EPOLAMINE

a) Maternal toxicity and embryotoxicity were reported in rats and embryotoxicity was reported in rabbits when administered oral diclofenac epolamine at a dose of 6 mg/kg/day (3 and 6.5 times the MRHD in rats and rabbits, respectively, based on surface area) during gestation days 6 through 15 in rats and 6 through 18 in rabbits. Embryotoxicity (early resorptions, post-implantation, and a decrease in live fetuses) was also reported when 6 mg/kg (3 times the MRHD, based on body surface area) diclofenac epolamine was administered to male rats throughout mating and female rats 14 days prior to mating through lactation (Prod Info FLECTOR PATCH(R) topical patch, 2011).

3) MELOXICAM

a) RATS: In studies of pregnant rats treated with meloxicam, an increase in stillbirths was noted when given an oral dose greater than or equal to 1 mg/kg/day (Prod Info MOBIC(R) oral tablets, suspension, 2008a).

4) PIROXICAM

a) During animal studies, administration of piroxicam 2, 5, or 10 mg/kg/day during organogenesis resulted in increased postimplantation loss in pregnant rats. There were no reports of developmental abnormalities. Gastrointestinal tract toxicities occurred more frequently in pregnant rats administered piroxicam during the last trimester of pregnancy compared with non-treated rats or rats administered piroxicam earlier in pregnancy. During pre- and postnatal development studies, pregnant rats administered piroxicam 2, 5, or 10 mg/kg/day from gestation day 15 through delivery and weaning of offspring resulted in reduced maternal weight gain and maternal death at 10 mg/kg/day starting on gestation day 20. Peritonitis, adhesions, gastric bleeding, hemorrhagic enteritis, and dead fetuses found in utero were also reported in treated dams. Parturition was delayed and there was an increased incidence of stillbirths in all piroxicam-treated groups (Prod Info FELDENE(R) oral capsules, 2015).
b) As with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia and delayed parturition has occurred with piroxicam in animals (Prod Info Feldene(R), 1999).

3.20.4)

A) LACK OF INFORMATION

1) BROMFENAC

a) It is unknown whether bromfenac is excreted into human breast milk or affects milk production or the breastfeeding infant; however, systemic exposure from ocular bromfenac administration is low. Bromfenac should be administered to breastfeeding women only after consideration of the developmental and health benefits of breastfeeding against the mother's clinical need for bromfenac and the potential risks to the breastfeeding infant (Prod Info BROMSITE(TM) topical ophthalmic solution , 2016).

2) KETOROLAC AND PHENYLEPHRINE

a) It is unknown whether ketorolac/phenylephrine is excreted into human breast milk, and the potential for adverse effects in the nursing infant from exposure to the drug are unknown. Until more data are available, use caution with use in nursing women (Prod Info OMIDRIA(TM) ophthalmic solution injection, 2014).

B) BREAST MILK

1) Many NSAIDs are excreted in low concentrations in breast milk (Prod Info SPRIX(TM) nasal spray, 2009; Ostensen et al, 1988; Seagraves et al, 1985).
2) A review article lists NSAIDs as generally compatible with breastfeeding (Kauffman et al, 1994).
3) DICLOFENAC

a) Limited data from 2 studies indicate that diclofenac is undetectable in breast milk. However, the presence or absence of diclofenac metabolites in breast milk was not assessed (Davies & Anderson, 1997).
b) One woman who received an oral diclofenac salt at a dose of 150 mg/day had a diclofenac level of 100 mcg/L in breast milk, which is equivalent to an infant dose of approximately 0.03 mg/kg/day. In 12 women using diclofenac (either 100 mg/day orally for 7 days or a single 50-mg IM dose administered immediately postpartum), diclofenac was not detectable in breast milk (Prod Info Dyloject(TM) intravenous injection, 2014; Prod Info ZORVOLEX(TM) oral capsules, 2013).

4) KETOROLAC TROMETHAMINE

a) Ketorolac, like other NSAIDs, is a weak acid and highly protein bound and will dissociate less into milk than plasma. Ten female postpartum patients, not able to breastfeed, were given 10 mg of ketorolac orally 4 times a day for 2 days to determine the extent of excretion into breast milk. In 4 of 10 patients, ketorolac concentrations in breast milk were lower than detectable by assay. Detectable milk levels in 6 patients occurred at 2 hours after dose 1 and dose 3 on both days of administration. Concentrations achieved in milk ranged from 5.2 to 7.3 nanograms (ng)/mL on day 1 and 5.9 to 7.9 ng/mL on day 2. Milk to plasma ratios ranged from 0.015 to 0.037 at those times when ketorolac could be detected. Plasma concentrations were detectable at all collection times and maternal concentrations correlated with other pharmacokinetic studies. It is suggested that maximum doses available to the infant would be 3.16 to 7.9 mg/day, assuming consumption of 400 mL to 1 L and breast milk concentrations of 7.9 ng/mL. This would be equivalent to 0.16% to 0.4% of the maternal dose (Wischnik et al, 1989).

5) MELOXICAM

a) It is not known if meloxicam is excreted in any significant amount into human breast milk (Prod Info VIVLODEX(TM) oral capsules, 2015; Prod Info MOBIC(R) oral tablets, suspension, 2008a). Administer to a lactating woman only if the potential maternal benefit outweighs the potential risk to the infant (Prod Info VIVLODEX(TM) oral capsules, 2015)
b) Meloxicam is excreted in the milk of lactating rats at concentrations higher than those reported in plasma (Prod Info VIVLODEX(TM) oral capsules, 2015).

6) PIROXICAM

a) Piroxicam is known to be present in human milk (approximately 1% to 3% of the maternal concentration). During treatment, no accumulation of piroxicam occurred in milk relative to the maternal plasma concentrations. The manufacturer recommends exercising caution when administering piroxicam to a lactating woman (Prod Info FELDENE(R) oral capsules, 2015).
b) Only small amounts of piroxicam were observed in breast milk during long-term therapy in lactating women. Four women with arthritis were treated with oral piroxicam 20 mg once daily for up to 52 days. The mean milk concentrations at steady-state were 78 mcg/L (maximum 141 mcg/L); the concentrations in breast milk represented 1% to 3% of simultaneous maternal plasma levels. Accumulation of the drug was not observed in breast milk relative to plasma. All infants remained healthy during the study period. In 1 breastfed infant, piroxicam or its metabolites were not detected in urine samples. The estimated daily dose of piroxicam ingested by the breastfeeding infant averaged 3.5% (maximum, 6.3%) of the maternal dose (Ostensen et al, 1988).

7) SULINDAC

a) It is not known if sulindac is excreted in any significant amount into human breast milk (Prod Info CLINORIL(R) oral tablets, 2010; Anon: Committee on Drugs & American Academy of Pediatrics, 1994).

8) TOLMETIN

a) Data on the distribution of tolmetin into human breast milk are limited to 1 report describing assays of plasma and milk from 1 mother following administration of a single 400 mg oral dose. This study involved systematic blood and breast milk sampling at precise times throughout 7 hours after dosing and employed an accurate (detection capability, 0.03 mg/L) high performance liquid chromatographic assay for tolmetin. Peak concentrations of tolmetin in breast milk occurred at 1 hour after administration and were reported as 0.18 mg/L. The simultaneous milk-to-plasma ratio was calculated to be 0.0055 (Seagraves et al, 1985).

C) ANIMAL STUDIES

1) MELOXICAM

a) The manufacturer states that meloxicam is excreted into the milk of lactating rats (Prod Info MOBIC(R) oral tablets, suspension, 2008a).

2) SULINDAC

a) RATS: Sulindac was excreted into the milk of lactating rats (Prod Info CLINORIL(R) oral tablets, 2010).

3.20.5)

A) DELAYED OVULATION

1) MELOXICAM

a) Reversible delay in ovulation has been reported during small human studies with NSAIDs including meloxicam (Prod Info Mobic(R) oral tablets, oral suspension, 2012).

B) ANIMAL STUDIES

1) BROMFENAC

a) RATS: No impairment of fertility was observed when bromfenac was administered orally to male and female rats at doses up to 1,300 times the recommended human ophthalmic dose (RHOD) or 90 times the predicted human exposure and up to 450 times the RHOD or 30 times the predicted human exposure, respectively (Prod Info PROLENSA(TM) ophthalmic solution, 2013; Prod Info Bromday(R) ophthalmic solution, 2012).

2) DICLOFENAC

a) No impairment of fertility was observed when male and female rats were administered diclofenac at doses up to 4 mg/kg/day (approximately 2 times greater than the maximum human topical dose, based on body surface area) (Prod Info Voltaren(R) topical gel, 2009).

3) DICLOFENAC EPOLAMINE

a) No impairment of fertility was observed when diclofenac epolamine was administered orally to male and female rats at doses up to 6 mg/kg/day (3 times the maximum recommended human dose on a mg/m(2) basis) 60 days prior to mating in males and 14 days prior to mating in females (Prod Info FLECTOR PATCH(R) topical patch, 2011).

4) DICLOFENAC SODIUM

a) No impairment of fertility was observed when male and female rats were administered diclofenac sodium at a dose of 4 mg/kg/day (less than the recommended human dose, based on mg/m(2) or 0.3-fold the maximum recommended human dose of 150 mg/day based on body surface area) (Prod Info Dyloject(TM) intravenous injection, 2014; Prod Info CAMBIA(TM) oral solution, 2013).

5) KETOROLAC TROMETHAMINE

a) RATS: Male and female rats given ketorolac at oral doses of 1.3 and 2.4 times, respectively, the human AUC did not show impairment of fertility. Animal studies have shown that use of prostaglandin synthesis inhibitors may disrupt prostaglandin-mediated follicular rupture required for ovulation (Prod Info SPRIX(R) nasal spray, 2016).

6) MELOXICAM

a) Reversible delay in ovulation has been reported during animal studies with NSAIDs including meloxicam (Prod Info Mobic(R) oral tablets, oral suspension, 2012).

Carcinogenicity

3.21.2)

3.21.4)

A) LACK OF EFFECT

1) DICLOFENAC SODIUM: Rats exposed to diclofenac sodium up to 2 mg/kg/day (0.13 times the maximum recommended human dose [MRHD] of 150 mg/day based on body surface area [BSA]) did not exhibit any significant increase in tumor incidence in long-term studies. Mice exposed to doses up to 0.03 mg/kg/day (0.01 times the MRHD based on BSA) for males and 1 mg/kg/day (0.04 times the MRHD) for females also did not show any carcinogenic potential in a 2-year study (Prod Info Dyloject(TM) intravenous injection, 2014).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Measurement of serum concentrations of NSAIDs are not rapidly available in most hospital settings, and are not useful in guiding clinical management.
B) Serum electrolytes, creatinine and BUN concentrations should be measured in patients with an intentional overdose.
C) If significant CNS or respiratory toxicity is present, acid-base status should be assessed.
D) Obtain a serum acetaminophen and salicylate concentration as these agents may be coingested.

4.1.2)

A) ACID/BASE

1) If significant CNS or respiratory toxicity is present, acid-base status should be assessed.

B) BLOOD/SERUM CHEMISTRY

1) ELDERLY PATIENTS: It is recommended that elderly patients who are to be initiated on NSAID therapy have a baseline serum creatinine and electrolyte determination done, which should be repeated 7 days after the start of treatment. These measurements should be repeated after each change in medication or dosage and after addition of other medications. (Poirier, 1989).

C) LABORATORY INTERFERENCE

1) False-positive reactions for urinary protein have been reported with tolmetin when a sulfosalicylic acid method or trichloroacetic acid method was used. No interference is reported with dye impregnated reagent strips, electrophoresis or spectrophotometric methods. Tolmetin is the only NSAID to produce this effect (Knodel et al, 1986).

D) TOXICITY

1) Monitor liver enzyme levels and bilirubin levels for possible hepatotoxicity, after long-term (more than 10 days) use or overdose of bromfenac.

Methods

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

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients who may have ingested a large dose of NSAIDs and who present with CNS or cardiovascular toxicity or metabolic acidosis, or who have a known risk factor for organ system toxicity associated with NSAIDs should be considered at higher risk of complications and warrant admission.

6.3.1.2) HOME CRITERIA/ORAL

A) Inadvertent exploratory ingestions in asymptomatic children can generally be managed with dilution and observation at home.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with a large or deliberate ingestion should be observed for 4 to 6 hours. If they remain asymptomatic with normal laboratory evaluation they may be discharged after appropriate psychiatric evaluation.

Monitoring

Oral Exposure

6.5.1)

A) 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) Acute overdose with these agents rarely produces life threatening toxicity. Activated charcoal alone is sufficient GI decontamination in most patients.

B) ACTIVATED CHARCOAL

1) Fifty grams of charcoal administered 5 minutes after a 20-mg oral dose of piroxicam almost completely prevented absorption. Bioavailability decreased to 2.1% of control (Laufen & Leitold, 1986). Activated charcoal also adsorbs tolfenamic acid (Olkkola & Neuvonen, 1984). Multiple-dose charcoal may be useful for drugs with long half-lives and extensive biliary excretion, such as piroxicam or sulindac (Laufen & Leitold, 1986; Ferry et al, 1990).
2) CHARCOAL ADMINISTRATION

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

3) CHARCOAL DOSE

b) ADVERSE EFFECTS/CONTRAINDICATIONS

6.5.3)

A) SUPPORT

1) Treatment is SYMPTOMATIC and SUPPORTIVE. Management of seizures, hypotension, and gastrointestinal bleeding may be necessary.

B) SEIZURE

1) SUMMARY

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

2) DIAZEPAM

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

3) NO INTRAVENOUS ACCESS

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

4) LORAZEPAM

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

5) PHENOBARBITAL

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

6) OTHER AGENTS

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

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

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).

D) MONITORING OF PATIENT

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

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

Enhanced Elimination

1) Enhanced elimination may occur with multiple dose charcoal or cholestyramine, but no effect on outcome has been demonstrated. NSAIDs are highly protein bound and extensively metabolized; therefore, hemodialysis is unlikely to be effective.

1) Activated charcoal, 70 g per day given in multiple doses from 10 through 58 hours following piroxicam 20 mg orally or rectally, increased the apparent total clearance 63.6% and 87.9% respectively. The half-life was decreased from 40.2 hours to 19.6 hours after the oral dose and from 40.7 hours to 21.6 hours after the rectal dose (Laufen & Leitold, 1986).
2) Activated charcoal, 5 g 4 times a day for 1 day, then 5 g 3 times a day at meal times for 4 days was given starting 24 hours after a single 20-mg piroxicam dose. The mean elimination half-life for piroxicam was 53.1 hr (control) and was reduced to 40 hr by charcoal administration (Ferry et al, 1990).

1) Cholestyramine 4 g three times daily for 10 days, started 3.5 hours after a single oral dose of piroxicam 20 mg, decreased the elimination half-life of piroxicam (from 46.8 hours to 28.1 hours) and increased clearance by 60%. Similar effects were observed for intravenous tenoxicam 20 mg when cholestyramine was begun two hours before injection of tenoxicam. The elimination half-life was decreased from 67.4 hours to 31.9 hours (Guentert et al, 1988).
2) Cholestyramine 4 g four times daily beginning 24 hours after a single 20-mg dose of piroxicam resulted in a reduction of the mean piroxicam elimination half life from 53.1 hours to 29.6 hours in 8 subjects (Ferry et al, 1990).

1) Direct hemoperfusion was reported as probably effective in the treatment of a 20-year-old patient seen 1 hour after ingesting 2600 mg of sulindac, 4800 mg of tiaramide hydrochloride, 750 mg of diclofenac sodium, and 1 mg fludiazepam (Harima et al, 1987). Hemoperfusion clearance data were not provided.

1) Alkalinization of the urine is recommended by several manufacturers based on animal data. There is no evidence of clinical efficacy in humans. Since NSAIDs are highly protein-bound and excreted largely as metabolites, there appears to be no indication for alkalinization.

Abstracts

Case Reports

1) BENOXAPROFEN: A 53-year-old woman developed paroxysmal coarse muscle fibrillation and muscle spasms 40 hours after ingesting a large, but unknown, amount of benoxaprofen. She then became oliguric and hyperkalemic and was dialyzed. Despite dialysis, she developed ventricular fibrillation and died (Fancourt et al, 1984).
2) DICLOFENAC: A 19-year-old man who ingested 1500 mg of diclofenac with 4 grams of chlormezanone and alcohol (blood alcohol, 0.13 g/L) presented to the emergency department moderately confused with general hypotonia (reflexes normal) (Netter et al, 1984).
3) ETODOLAC: A 53-year-old woman who was reported to ingest up to 46 etodolac tablets remained asymptomatic (Boldy et al, 1988).
4) FENOPROFEN

a) CASE REPORT: A 17-year-old teenager developed coma, hypotension, metabolic acidosis, and respiratory depression within four hours of an ingestion of 24 to 36 grams of fenoprofen (Kolodzik et al, 1990).
b) CASE REPORT: A 41-year-old woman who ingested 60 to 72 grams of fenoprofen presented with diffuse abdominal tenderness, sinus tachycardia of 150, fever, and a serum creatinine of 2.8 mg/dL. Twelve hours after ingestion, renal function worsened and hypotension developed and was treated with furosemide and dopamine. The patient was stabilized within 24 hours and tapered over the next 48 hours. Serum creatinine and BUN peaked at day 9 (15.2 mg/dL and 114 mg/dL, respectively), and the patient was discharged on day 25 (Appleby, 1981).

5) PIROXICAM

a) CASE REPORT: A case of piroxicam, griseofulvin, and fentiazac overdose in a 25-year-old Chinese male is reported . From 14 to 60 hours postadmission, the patient developed episodic involuntary movements of the lips and jaw and myoclonic twitching of the limbs. Recovery was uneventful after 4 days (Lo & Chan, 1983).
b) CASE REPORT: Piroxicam overdose (1.8 g) in a 54-year-old woman was associated with only symptoms of nausea and abdominal pain; endoscopy revealed multiple superficial ulcerations in the pyloric antrum and first part of the duodenum, without bleeding. The patient was treated with antacids alone and discharged in 10 days without sequelae (Mosvold et al, 1984).
c) CASE REPORT: Severe gastrointestinal symptoms resulting in fluid and electrolyte imbalances, mental confusion and seizure activity, and hepatic and renal dysfunction developed in a 2-year-old within three days of a 100-mg piroxicam ingestion. The patient developed progressive pancytopenia, bone marrow aplasia, and coagulopathy; hematological and biochemical abnormalities reversed by day 22 (Macdougall et al, 1984).

6) SULINDAC: An anaphylactic reaction was reported in a 16-year-old girl following a single 150-mg dose of sulindac. The patient was treated successfully with epinephrine, Benadryl(R), and steroids (Burrish & Kaatz, 1981).
7) SUPROFEN: Reversible renal failure has been reported in a healthy 31-year-old who was being treated with therapeutic doses of suprofen following 3 doses. Abdominal complaints persisted for several days and the patient was admitted to the hospital because of development of polydipsia, polyuria, and profuse diaphoresis (Henann & Morales, 1986).
8) SULINDAC/TIARAMIDE/DICLOFENAC: Overdose of 2400 mg sulindac, 4800 mg tiaramide, and 750 mg diclofenac sodium caused excitability followed by unconsciousness within 2 hours of ingestion. Direct hemoperfusion was instituted and the patient was discharged in 3 days (Harima et al, 1987).
9) MEFENAMIC ACID

a) CASE REPORT: An 18-year-old teenager was admitted with a generalized convulsion within 1 hours of ingesting about 22.5 grams of mefenamic acid. With supportive treatment for the seizure, she made an uneventful recovery by the next day (Shipton & Muller, 1985).
b) In a prospective study of 54 cases of mefenamic acid overdose (1.5 to 50 grams, 1 to 18 hours prior to admission), 29 cases had serum levels greater than therapeutic levels (above 10 mcg/mL). Of these, 15 reported effects (grand mal convulsions 11/15, muscle twitching 4/15, vomiting 4/15, and diarrhea 1/15) (Balali-Mood et al, 1981).
c) CASE REPORT: A 19-year-old teenager was admitted to the hospital for a generalized motor seizure 4 hours after ingesting between 6.25 and 7.5 grams of mefenamic acid. She became apneic, cyanotic and rigid. No pulse or respirations were noted for 30 seconds, after which the patient became limp and pulse and respiration returned. The patient recovered (Frank et al, 1983).
d) CASE REPORT: A 13-year-old girl who ingested 5 to 10 grams of mefenamic acid complained of nausea and fatigue. One and a half hours later, she became unconscious and muscle twitching followed by grand mal convulsions occurred. Diazepam was administered and the epileptic features subsided. The patient recovered fully within half a day (Gossinger et al, 1982).

10) SUTOPROFEN: An 18-year-old teenager, who was addicted to heroin and was having abnormal liver function tests, had taken 40 sutoprofen capsules (strength not provided) 6 hours before admission. She complained of slight abdominal tenderness and recovery was uncomplicated (Freestone & Critchley, 1984).

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) SPECIFIC SUBSTANCE

1) BROMFENAC SODIUM

a) OPHTHALMIC SOLUTION FOR PATIENTS UNDERGOING CATARACT SURGERY:

1) PROLENSA(TM) AND BROMDAY(R): Apply 1 drop to affected eye(s) once daily beginning 1 day prior to surgery, continuing on day of surgery, and through 14 days postoperatively (Prod Info PROLENSA(TM) ophthalmic solution, 2013; Prod Info Bromday(R) ophthalmic solution, 2012).
2) BROMSITE(TM): Apply 1 drop to affected eye(s) twice daily beginning 1 day prior to surgery, continuing on day of surgery, and through 14 days postoperatively (Prod Info BROMSITE(TM) topical ophthalmic solution , 2016).

2) DICLOFENAC

a) CAPSULES:

1) ACUTE PAIN: The recommended dose is 18 or 35 mg orally 3 times daily (Prod Info ZORVOLEX(R) oral capsules, 2014).
2) OSTEOARTHRITIS PAIN: The recommended dose is 35 mg orally 3 times daily (Prod Info ZORVOLEX(R) oral capsules, 2014).

3) DICLOFENAC EPOLAMINE

a) TOPICAL PATCH:

1) ACUTE PAIN: Apply 1 patch to the most painful area twice daily (Prod Info FLECTOR PATCH(R) topical patch, 2011).

4) DICLOFENAC POTASSIUM

a) IMMEDIATE-RELEASE TABLETS:

1) OSTEOARTHRITIS: Recommended dose is 100 to 150 mg/day in divided doses of 50 mg 2 or 3 times daily (Prod Info Cataflam(R) oral immediate-release tablets, 2011).
2) PAIN OR PRIMARY DYSMENORRHEA: Recommended dose is 50 mg 3 times daily; in some patients, initial dose of 100 mg followed by 50 mg 3 times daily may provide better pain relief (Prod Info Cataflam(R) oral immediate-release tablets, 2011).
3) RHEUMATOID ARTHRITIS: Recommended dose is 150 to 200 mg/day in divided doses of 50 mg 3 or 4 times daily (Prod Info Cataflam(R) oral immediate-release tablets, 2011).

b) LIQUID-FILLED CAPSULES:

1) PAIN: Recommended dose is 25 mg 4 times daily (Prod Info Zipsor(R) oral liquid filled capsules, 2012).

c) POWDER FOR ORAL SOLUTION:

1) MIGRAINE HEADACHE: Recommended dose is 50 mg (one packet) as a single dose for an acute headache. Mix packet contents with 30 to 60 mL of water and drink immediately (Prod Info CAMBIA(TM) oral solution, 2013).

5) DICLOFENAC SODIUM

a) ENTERIC-COATED, IMMEDIATE-RELEASE TABLETS:

1) ANKYLOSING SPONDYLITIS: Recommended dose is 100 to 125 mg/day in divided doses of 25 mg 4 times daily, with an extra dose of 25 mg at bedtime if needed (Prod Info Voltaren(R) enteric-coated oral tablets, 2009).
2) OSTEOARTHRITIS: Recommended dose is 100 to 150 mg/day in divided doses of 50 mg 2 or 3 times daily or 75 mg two times per day (Prod Info Voltaren(R) enteric-coated oral tablets, 2009).
3) RHEUMATOID ARTHRITIS: Recommended dose is 150 to 200 mg/day in divided doses of 50 mg 3 or 4 times daily or 75 mg 2 times daily (Prod Info Voltaren(R) enteric-coated oral tablets, 2009).

b) EXTENDED-RELEASE TABLETS:

1) OSTEOARTHRITIS: Recommended dose is 100 mg once daily (Prod Info Voltaren(R)-XR oral extended-release tablets, 2011).
2) RHEUMATOID ARTHRITIS: Recommended dose is 100 mg once daily; if inadequate response, it may be given twice daily (Prod Info Voltaren(R)-XR oral extended-release tablets, 2011).

c) INTRAVENOUS SOLUTION:

1) PAIN: Recommended dose is 37.5 mg by IV bolus over 15 seconds every 6 hours as needed to a MAXIMUM daily dose of 150 mg (Prod Info Dyloject(TM) intravenous injection, 2014).

d) OPHTHALMIC SOLUTION:

1) CATARACT SURGERY, POSTOPERATIVELY: Apply 1 drop to affected eye 4 times daily 24 hours after surgery and continue through the first 2 weeks after surgery (Prod Info VOLTAREN OPHTHALMIC(R) ophthalmic solution, 2012).
2) CORNEAL REFRACTIVE SURGERY: Apply 1 or 2 drops to operative eye within the hour prior to surgery. Within 15 minutes after surgery, apply 1 or 2 drops to the operative eye and continue 4 times daily for up to 3 days (Prod Info VOLTAREN OPHTHALMIC(R) ophthalmic solution, 2012).

e) TOPICAL GEL:

1) ACTINIC KERATOSES: Recommended dose is normally 0.5 g per 5 cm by 5 cm lesion site applied 2 times daily. Make sure enough gel is applied to cover each lesion. Recommended duration is 60 to 90 days (Prod Info SOLARAZE(R) topical gel, 2011).
2) OSTEOARTHRITIS, LOWER EXTREMITIES: Recommended dose is 4 g to affected joint (eg, foot, ankle, knee) 4 times daily. Do not exceed 16 g/day to any single joint of the lower extremity (Prod Info Voltaren(R) topical gel, 2009).
3) OSTEOARTHRITIS, UPPER EXTREMITIES: Recommended dose is 2 g to affected joint (ie, hand, elbow, wrist) 4 times daily. Do not exceed 8 g/day to any single joint of the upper extremity (Prod Info Voltaren(R) topical gel, 2009).
4) TOTAL DAILY DOSE: Do not exceed 32 g/day over all affected joints (Prod Info Voltaren(R) topical gel, 2009).

f) TOPICAL SOLUTION:

1) OSTEOARTHRITIS, KNEE: Recommended dose of 1.5% solution is 40 drops total per knee 4 times daily; apply 10 drops topically and spread around front, back, and sides of each affected knee; repeat until 40 drops have been applied (Prod Info PENNSAID(R) topical solution, 2013).
2) OSTEOARTHRITIS, KNEE: Recommended dose of 2% solution is 40 mg (2 pump actuations) applied topically to affected knee(s) 2 times daily (Prod Info PENNSAID(R) topical solution, 2014).

6) DICLOFENAC SODIUM/MISOPROSTOL

a) ENTERIC-COATED, IMMEDIATE-RELEASE TABLETS:

1) OSTEOARTHRITIS: Recommended dose is diclofenac sodium 50 mg/misoprostol 200 mcg 2 or 3 times a day or diclofenac sodium 75 mg/misoprostol 200 mcg twice daily. Diclofenac doses that exceed 150 mg/day are not recommended. Misoprostol dose should not exceed 200 mcg/dose or 800 mcg/day (Prod Info ARTHROTEC(R) oral tablets, 2009).
2) RHEUMATOID ARTHRITIS: Recommended dose is diclofenac sodium 50 mg/misoprostol 200 mcg 2 or 3 times a day or diclofenac sodium 75 mg/misoprostol 200 mcg twice daily. Diclofenac doses that exceed 225 mg/day are not recommended. Misoprostol dose should not exceed 200 mcg/dose or 800 mcg/day (Prod Info ARTHROTEC(R) oral tablets, 2009).

7) ETODOLAC

a) EXTENDED-RELEASE TABLETS:

1) OSTEOARTHRITIS/RHEUMATOID ARTHRITIS: Recommended dose is 400 to 1000 mg once daily (Prod Info etodolac extended-release oral tablets, 2006).

b) IMMEDIATE-RELEASE CAPSULES/TABLETS:

1) OSTEOARTHRITIS/RHEUMATOID ARTHRITIS: Recommended initial dose is 300 mg 2 or 3 times per day, 400 mg twice daily, or 500 mg twice daily, with maintenance doses of 600 mg/day. Doses exceeding 1000 mg/day have not been adequately evaluated (Prod Info etodolac oral tablets, oral capsules, 2006).
2) PAIN: Recommended total daily dose is up to 1000 mg/day, given as 200 to 400 mg every 6 to 8 hr. Doses exceeding 1000 mg/day have not been adequately evaluated (Prod Info etodolac oral tablets, oral capsules, 2006).

8) FENOPROFEN

a) IMMEDIATE-RELEASE CAPSULES/TABLETS:

1) OSTEOARTHRITIS/RHEUMATOID ARTHRITIS: Recommended dose is 400 to 600 mg three or four times per day. Total dose should not exceed 3200 mg/day (Prod Info NALFON(R) oral capsules, 2009; Prod Info fenoprofen calcium oral tablets, 2006).
2) PAIN: Recommended dose is 200 mg every 4 to 6 hr as needed (Prod Info NALFON(R) oral capsules, 2009; Prod Info fenoprofen calcium oral tablets, 2006).

9) FLURBIPROFEN

a) IMMEDIATE-RELEASE TABLETS:

1) OSTEOARTHRITIS/RHEUMATOID ARTHRITIS: Recommended dose is 200 to 300 mg/day in divided doses two, three, or four times per day. The largest recommended single dose is 100 mg (Prod Info ANSAID(R) oral tablets, 2009).

b) OPHTHALMIC SOLUTION:

1) INTRAOPERATIVE MIOSIS INHIBITION: Apply one drop in operative eye every 30 min beginning 2 hours prior to surgery for a total of four (4) drops (Prod Info OCUFEN(R) topical ophthalmic solution, 2003).

10) KETOROLAC

a) IMMEDIATE-RELEASE TABLETS:

1) Oral formulation should not be administered as initial dose. The combined duration of use for IV/IM and oral ketorolac should not exceed 5 days (Prod Info ketorolac tromethamine oral tablets, 2008).
2) PAIN, 17 TO 64 YEARS: Recommended dose is 20 mg once, then 10 mg every 4 to 6 hr as needed. The dose should not exceed 40 mg/day and the dosing interval should not be shortened to less than every 4 to 6 hr (Prod Info ketorolac tromethamine oral tablets, 2008).
3) PAIN, 65 YEARS AND OLDER: Recommended dose is 10 mg every 4 to 6 hr as needed. The dose should not exceed 40 mg/day and the dosing interval should not be shortened to less than every 4 to 6 hr (Prod Info ketorolac tromethamine oral tablets, 2008).

b) INTRAMUSCULAR INJECTION:

1) The combined duration of use for IV/IM and oral ketorolac should not exceed 5 days (Prod Info ketorolac tromethamine IV, IM injection, 2009).
2) PAIN, LESS THAN 65 YEARS: Recommended single-use dose is 60 mg. Recommended multiple-use dose is 30 mg every 6 hours. MAXIMUM DOSE should not exceed 120 mg/day (Prod Info ketorolac tromethamine IV, IM injection, 2009).
3) PAIN, 65 YEARS AND OLDER: Recommended single-use dose is 30 mg. Recommended multiple-use dose is 15 mg every 6 hours. MAXIMUM DOSE should not exceed 60 mg/day (Prod Info ketorolac tromethamine IV, IM injection, 2009).

c) INTRAVENOUS INJECTION:

1) The combined duration of use for IV/IM and oral ketorolac should not exceed 5 days (Prod Info ketorolac tromethamine IV, IM injection, 2009).
2) PAIN, LESS THAN 65 YEARS: Recommended single-use dose is 30 mg. Recommended multiple-use dose is 30 mg every 6 hours. MAXIMUM DOSE should not exceed 120 mg/day (Prod Info ketorolac tromethamine IV, IM injection, 2009).
3) PAIN, 65 YEARS AND OLDER: Recommended single-use dose is 15 mg. Recommended multiple-use dose is 15 mg every 6 hours. MAXIMUM DOSE should not exceed 60 mg/day (Prod Info ketorolac tromethamine IV, IM injection, 2009).

d) OPHTHALMIC SOLUTION:

1) CATARACT SURGERY: Apply 1 drop to affected eye twice daily beginning 1 day prior to cataract surgery and continue through the first 2 weeks after surgery (Prod Info ACUVAIL(TM) topical ophthalmic solution, 2009).
2) CORNEAL REFRACTIVE SURGERY: Recommended dose is 1 drop four times per day in the operated eye as needed for up to 4 days following surgery (Prod Info ACULAR LS(R) topical ophthalmic solution, 2008).

11) KETOROLAC AND PHENYLEPHRINE

a) Dilute 4 mL of a single-use vial containing phenylephrine 10.16 mg/mL (1%) and 2.88 mg/mL (0.3%) ketorolac in 500 mL ophthalmic irrigation solution and administer INTRAOCULARLY as needed during cataract surgery or intraocular lens replacement (Prod Info OMIDRIA(TM) ophthalmic solution injection, 2014).

12) MELOXICAM

a) IMMEDIATE-RELEASE TABLETS/SUSPENSION:

1) OSTEOARTHRITIS/RHEUMATOID ARTHRITIS: Recommended dose is 7.5 mg once a day. MAXIMUM DOSE is 15 mg/day (Prod Info MOBIC(R) oral tablets, suspension, 2008a).

b) IMMEDIATE-RELEASE CAPSULES:

1) OSTEOARTHRITIS PAIN: Recommended dose is 5 mg ORALLY once daily. Dose may be increased to 10 mg if additional analgesia is required. MAXIMUM: 10 mg/day (Prod Info VIVLODEX(TM) oral capsules, 2015).

13) NABUMETONE

a) IMMEDIATE-RELEASE TABLETS:

1) OSTEOARTHRITIS/RHEUMATOID ARTHRITIS: Recommended initial dose is 1000 mg as a single dose, with maintenance doses of 1000 to 2000 mg/day as either a single dose or divided twice daily. Doses exceeding 2000 mg/day have not been studied (Prod Info nabumetone oral tablets, 2006).

14) NEPAFENAC

a) OPHTHALMIC SUSPENSION:

1) PAIN/INFLAMMATION ASSOCIATED WITH CATARACT SURGERY: Recommended dose is 1 drop in affected eye once daily starting 1 day prior to surgery, the day of surgery, and continuing through the first 2 weeks postoperatively; apply 1 additional drop 30 to 120 minutes prior to surgery (Prod Info ILEVRO(TM) ophthalmic suspension, 2014).

15) OXAPROZIN

a) IMMEDIATE-RELEASE TABLETS:

1) OSTEOARTHRITIS/RHEUMATOID ARTHRITIS: Recommended dose is 1200 mg once daily. MAXIMUM DOSE: 1800 mg/day or 26 mg/kg/day, whichever is less (Prod Info DAYPRO(R) oral caplets, 2006).

16) PIROXICAM

a) IMMEDIATE-RELEASE CAPSULES:

1) OSTEOARTHRITIS/RHEUMATOID ARTHRITIS: Recommended dose is 20 mg/day as a single dose or divided twice daily (Prod Info FELDENE(R) oral capsules, 2009).

17) SULINDAC

a) IMMEDIATE-RELEASE TABLETS:

1) ANKYLOSING SPONDYLITIS/OSTEOARTHRITIS/RHEUMATOID ARTHRITIS: Recommended dose is 150 mg twice daily (Prod Info CLINORIL(R) oral tablets, 2008).
2) ACUTE GOUTY ARTHRITIS/ACUTE PAINFUL SHOULDER: Recommended dose is 200 mg twice daily (Prod Info CLINORIL(R) oral tablets, 2008).
3) MAXIMUM DOSE: 400 mg/day (Prod Info CLINORIL(R) oral tablets, 2008).

18) TOLMETIN

a) IMMEDIATE-RELEASE CAPSULES/TABLETS:

1) OSTEOARTHRITIS/RHEUMATOID ARTHRITIS: Recommended initial dose is 400 mg three times daily, with maintenance doses of 200 to 600 mg three times daily. Doses exceeding 1800 mg/day have not been studied and are not recommended (Prod Info TOLECTIN(R) DS, TOLECTIN(R) 600 oral capsules, oral tablets, 2006).

7.2.2)

A) SPECIFIC SUBSTANCE

1) BROMFENAC SODIUM

a) OPHTHALMIC SOLUTION: Safety and efficacy have not been established in pediatric patients younger than 18 years of age (Prod Info BROMSITE(TM) topical ophthalmic solution , 2016; Prod Info PROLENSA(TM) ophthalmic solution, 2013; Prod Info Bromday(R) ophthalmic solution, 2012).

2) DICLOFENAC

a) Safety and efficacy have not been established in pediatric patients (Prod Info ZORVOLEX(R) oral capsules, 2014).

3) DICLOFENAC EPOLAMINE

a) TOPICAL PATCH: Safety and efficacy in the pediatric or adolescent population have not been established (Prod Info FLECTOR PATCH(R) topical patch, 2011).

4) DICLOFENAC POTASSIUM

a) IMMEDIATE-RELEASE CAPSULES/SOLUTION/TABLETS: Safety and efficacy in the pediatric or adolescent population have not been established (Prod Info Cataflam(R) oral immediate-release tablets, 2011; Prod Info Zipsor(R) oral liquid filled capsules, 2012; Prod Info CAMBIA(TM) oral solution, 2013).

5) DICLOFENAC SODIUM

a) EXTENDED-RELEASE TABLETS:

1) Safety and efficacy in the pediatric or adolescent population have not been established (Prod Info Voltaren(R)-XR oral extended-release tablets, 2011).

b) IMMEDIATE-RELEASE TABLETS:

1) According to the manufacturer, safety and efficacy have not been established in pediatric patients (Prod Info Voltaren(R) enteric-coated oral tablets, 2009). However, an oral dose of 2 to 3 mg/kg/day in divided doses has been used to treat juvenile rheumatoid arthritis in children (Silver, 1988).

c) INTRAVENOUS SOLUTION:

1) Safety and efficacy in the pediatric or adolescent population have not been established (Prod Info Dyloject(TM) intravenous injection, 2014).

d) OPHTHALMIC SOLUTION:

1) Safety and efficacy in the pediatric or adolescent population have not been established (Prod Info VOLTAREN OPHTHALMIC(R) ophthalmic solution, 2012).

e) TOPICAL:

1) Safety and efficacy in the pediatric or adolescent population have not been established (Prod Info SOLARAZE(R) topical gel, 2011; Prod Info Voltaren(R) topical gel, 2009; Prod Info PENNSAID(R) topical solution, 2013).

6) DICLOFENAC SODIUM/MISOPROSTOL

a) ENTERIC-COATED, IMMEDIATE-RELEASE TABLETS: Safety and efficacy have not been established in pediatric patients (Prod Info ARTHROTEC(R) oral tablets, 2009).

7) ETODOLAC

a) EXTENDED-RELEASE TABLETS:

1) CHILDREN 6 TO 16 YEARS: Recommended dose for juvenile rheumatoid arthritis is 400 to 1000 mg once daily based on body weight (Prod Info etodolac extended-release oral tablets, 2006).
2) CHILDREN LESS THAN 6 YEARS: Safety and efficacy have not been established (Prod Info etodolac extended-release oral tablets, 2006).

b) IMMEDIATE-RELEASE CAPSULES/TABLETS:

1) Safety and efficacy have not been established in pediatric patients (Prod Info etodolac oral tablets, oral capsules, 2006).

8) FENOPROFEN

a) IMMEDIATE-RELEASE CAPSULES/TABLETS: According to the manufacturer, safety and efficacy have not been established in pediatric patients younger than 18 years of age (Prod Info NALFON(R) oral capsules, 2009; Prod Info fenoprofen calcium oral tablets, 2006). However, an oral dose of 900 to 1800 mg/m(2)/day in divided doses has been used to treat juvenile rheumatoid arthritis in children (Silver, 1988).

9) FLURBIPROFEN

a) IMMEDIATE-RELEASE TABLETS:

1) According to the manufacturer, safety and efficacy have not been established in pediatric patients (Prod Info ANSAID(R) oral tablets, 2009). However, an oral dose of 4 mg/kg/day in divided doses has been used to treat juvenile rheumatoid arthritis in children (Silver, 1988).

b) OPHTHALMIC SOLUTION:

1) Safety and efficacy have not been established in pediatric patients (Prod Info OCUFEN(R) topical ophthalmic solution, 2003).

10) KETOROLAC

a) IMMEDIATE-RELEASE TABLETS:

1) Safety and efficacy have not been established in pediatric patients younger than 17 years of age (Prod Info ketorolac tromethamine oral tablets, 2008).

b) INJECTION:

1) Safety and efficacy have not been established in pediatric patients younger than 17 years of age (Prod Info ketorolac tromethamine IV, IM injection, 2009).

c) OPHTHALMIC SOLUTION:

1) CATARACT SURGERY: Safety and effectiveness have not been established in pediatric patients (Prod Info ACUVAIL(TM) topical ophthalmic solution, 2009).
2) CORNEAL REFRACTIVE SURGERY:

a) CHILDREN 3 YEARS AND OLDER: Recommended dose is 1 drop four times per day in the operated eye as needed for up to 4 days following surgery (Prod Info ACULAR LS(R) topical ophthalmic solution, 2008).
b) CHILDREN LESS THAN 3 YEARS: Safety and efficacy have not been established (Prod Info ACULAR LS(R) topical ophthalmic solution, 2008).

11) KETOROLAC AND PHENYLEPHRINE

a) Safety and efficacy have not been established in pediatric patients (Prod Info OMIDRIA(TM) ophthalmic solution injection, 2014).

12) MELOXICAM

a) IMMEDIATE-RELEASE SUSPENSION/TABLETS:

1) CHILDREN 2 TO 17 YEARS: Recommended dose for juvenile rheumatoid arthritis is 0.125 mg/kg once daily. MAXIMUM DOSE: 7.5 mg/day (Prod Info MOBIC(R) oral tablets, suspension, 2008a).
2) CHILDREN LESS THAN 2 YEARS: Safety and efficacy have not been established (Prod Info MOBIC(R) oral tablets, suspension, 2008a).

b) IMMEDIATE-RELEASE CAPSULES:

1) Safety and effectiveness have not been established in pediatric patients (Prod Info VIVLODEX(TM) oral capsules, 2015).

13) NABUMETONE

a) IMMEDIATE-RELEASE TABLETS: Safety and efficacy have not been established in pediatric patients (Prod Info nabumetone oral tablets, 2006).

14) NEPAFENAC

a) OPHTHALMIC SUSPENSION:

1) CHILDREN 10 YEARS OR OLDER: Recommended dose is 1 drop in affected eye once daily starting 1 day prior to surgery, the day of surgery, and continuing through the first 2 weeks postoperatively; apply 1 additional drop 30 to 120 minutes prior to surgery (Prod Info ILEVRO(TM) ophthalmic suspension, 2014).

15) OXAPROZIN

a) IMMEDIATE-RELEASE TABLETS:

1) CHILDREN 6 TO 16 YEARS: Recommended dose for juvenile rheumatoid arthritis is 600 to 1200 once daily based on body weight. Doses exceeding 1200 mg/day have not been studied in pediatric patients (Prod Info DAYPRO(R) oral caplets, 2006).
2) CHILDREN LESS THAN 6 YEARS: Safety and efficacy have not been established (Prod Info DAYPRO(R) oral caplets, 2006).

16) PIROXICAM

a) IMMEDIATE-RELEASE CAPSULES: According to the manufacturer, safety and efficacy have not been established in pediatric patients (Prod Info FELDENE(R) oral capsules, 2009). However, the following oral dose has been used to treat juvenile rheumatoid arthritis in children:

1) CHILDREN WITH BODY WEIGHT GREATER THAN 25 KG: 5 to 20 mg/day (Silver, 1988).
2) CHILDREN WITH BODY WEIGHT LESS THAN 25 KG: 5 to 10 mg/day (Silver, 1988).

17) SULINDAC

a) IMMEDIATE-RELEASE TABLETS: According to the manufacturer, safety and efficacy have not been established in pediatric patients (Prod Info CLINORIL(R) oral tablets, 2008). However, the following oral dose has been used to treat juvenile rheumatoid arthritis in children:

1) CHILDREN WITH BODY WEIGHT GREATER THAN 25 KG: 75 to 150 mg/day (Silver, 1988).
2) CHILDREN WITH BODY WEIGHT LESS THAN 25 KG: 50 mg/day (Silver, 1988).

18) TOLMETIN

a) IMMEDIATE-RELEASE CAPSULES/TABLETS:

1) CHILDREN 2 YEARS AND OLDER: Recommended initial dose for juvenile rheumatoid arthritis is 20 mg/kg/day in divided doses three or four times per day, with maintenance dose range of 15 to 30 mg/kg/day. Doses exceeding 30 mg/kg/day have not been studied and are not recommended (Prod Info TOLECTIN(R) DS, TOLECTIN(R) 600 oral capsules, oral tablets, 2006).
2) CHILDREN LESS THAN 2 YEARS: Safety and efficacy have not been established (Prod Info TOLECTIN(R) DS, TOLECTIN(R) 600 oral capsules, oral tablets, 2006).

Minimum Lethal Exposure

1) BENZYDAMINE

a) Toxic doses of benzydamine have ranged between 14 mg/kg and 50 mg/kg (Ballesteros et al, 2009).

1) CASE REPORT: In a review of the literature, there has only been one report of death following the ingestion of 70 mg/kg of benzydamine in an 18-month-old child. At autopsy, pneumonia, an unexpected finding, was also observed (Ballesteros et al, 2009).

Maximum Tolerated Exposure

1) Insufficient human data in the literature to accurately assess the range of toxicity following acute overdose.

1) BENOXAPROFEN

a) A young adult survived an ingestion of 12 g with minimal clinical signs (Court & Volans, 1984).

2) BENZYDAMINE

a) One adult ingested 3.5 g (50 mg/kg) and developed minor symptoms of nausea and vomiting (Ballesteros et al, 2009).

3) DICLOFENAC

a) A 61-year-old woman became disoriented, hallucinated, lost consciousness, and suffered respiratory arrest following the ingestion of diclofenac 375 mg plus ibuprofen 400 mg plus indomethacin 75 mg (Bright & McNulty, 1991).

4) ETODOLAC

a) A 53-year-old woman who reportedly ingested up to forty-six etodolac tablets remained asymptomatic (Boldy et al, 1988).

5) FENOPROFEN

a) A case of hyperpyrexia, hypotension, tachycardia, and renal failure following ingestion of 60 to 72 g of fenoprofen (Nalfon(R)) was reported in a 41-year-old woman (Appleby, 1981).

6) PIROXICAM

a) Ingestion of 100 mg in a 2-year-old resulted in multisystem toxicity, including confusion, seizure, fluid-electrolyte imbalance, and liver, renal, and bone marrow toxicity (Macdougall et al, 1984).

7) SULINDAC

a) A 22-year-old man intentionally ingested 15 g of sulindac and developed acute renal failure, pill esophagitis and ischemic skin necrosis. He became anuric on day 4 and his creatinine peaked at 8.23 mg/dL with a BUN of 93 mg/dL requiring hemodialysis. His hemoglobin (11.4 on day 4) was also noted to be trending downward over several days. An esophagogastroduodenoscopy was performed and showed large superficial esophageal ulcers with stigmata of recent bleeding and large exudative duodenal ulcers. Ten days after ingestion, he developed ischemic skin changes with a gangrenous appearance on his hands and feet. He developed severe foot pain. A doppler ultrasound showed normal arterial and venous blood flow. Approximately 15 days after exposure, his skin changes began to improve and the skin on his hands and feet began to peel. By day 25, he was able to urinate with improved creatinine clearance and he was successfully removed from hemodialysis. His acute renal failure and ischemic skin changes were thought to be due to impairment of prostaglandin synthesis following overdose (Vaughn et al, 2015).

8) SULINDAC/TIARAMIDE/DICLOFENAC

a) Overdose of 2600 mg sulindac, 4800 mg tiaramide hydrochloride and 750 mg diclofenac sodium caused excitability followed by unconsciousness. Direct hemoperfusion was effective in enhancing elimination and the patient was discharged in 3 days (Harima et al, 1987).

9) SUTOPROFEN

a) Ingestion of forty sutoprofen capsules resulted in only mild abdominal tenderness in an 18-year-old woman (Freestone & Critchley, 1984).

10) ZOMEPIRAC

a) Lethargy, drowsiness, and a transient increase in the serum creatinine (up to 2.3 mg/dL) was reported in one patient after ingesting 3 to 4 g of zomepirac. The patient recovered without apparent sequelae.

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) GENERAL

a) THERAPEUTIC DOSES: Approximate blood concentrations at peak after therapeutic doses are (USPDI, 1995):

DRUG	PEAK BLOOD CONCENTRATIONS (mcg/mL)
Diclofenac	0.28
Etodolac	total 2.6 (free 44 to 84 nanograms/mL)
Flurbiprofen	4.4
Nabumetone	20
Tenoxicam	1.82
Tiaprofenic acid 200-mg tablet 300-mg tablet
Tiaprofenic acid 200-mg tablet 300-mg tablet	5.3 7.7
Tolmetin	5.6

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) SPECIFIC SUBSTANCE

a) FENOPROFEN

1) CASE REPORT: A woman who ingested an unknown amount of fenoprofen survived with a blood level of 711mg/L (Court & Volans, 1984).

b) PIROXICAM

1) CASE REPORT: A patient ingesting 560 mg of piroxicam had a peak serum level of 23.5 mg/L (normal therapeutic level is 1 to 5 mg/L) and a serum half-life of 35 hours. Only altered consciousness and muscle twitching were noted (Lo & Chan, 1983).

c) SULINDAC/TIARAMIDE/DICLOFENAC SODIUM

1) CASE REPORT: A 20-year-old, 52-kg woman was admitted with excitability progressing to coma after ingesting 2600 mg of sulindac, 4800 mg of tiaramide hydrochloride, and 750 mg of diclofenac sodium. Direct hemoperfusion was instituted 4 hours after ingestion, plasma levels are listed below:

2.5 hrs postingestion: tiaramide 33.3 mcg/mL
                       diclofenac 9.6 mcg/mL
                       sulindac 50.8 mcg/mL
                       sulindac sulfide 13.5 mcg/mL
                       sulindac sulfone 4.0 mcg/mL
4 hrs postingestion: tiaramide 9.1 mcg/mL
                       diclofenac 2.5 mcg/mL
                       sulindac 19.6 mcg/mL
                       sulindac sulfide 16.5 mcg/mL
                       sulindac sulfone 5.0 mcg/mL
7.5 hrs postingestion (after hemoperfusion)
                       tiaramide 1.0 mcg/mL
                       diclofenac 0.7 mcg/mL
                       sulindac 3.1 mcg/mL
                       sulindac sulfide 5.0 mcg/mL
                       sulindac sulfone 1.1 mcg/mL
24 hrs postingestion:  sulindac 1.0 mcg/mL
                       sulindac sulfide 1.1 mcg/mL
                       sulindac sulfone 0.9 mcg/mL

d) DICLOFENAC

1) CASE REPORT: A 19-year-old man ingested 1500 mg of diclofenac sodium. He was confused and exhibited general hypotonia. His serum level 7 hours after ingestion was 60.1 mcg/mL and at 15 hours was 190 nanograms/mL (Netter et al, 1984).

e) ETODOLAC

1) CASE REPORT: A 53-year-old ingested up to 46 tablets (strength not listed by author) and was symptom free; a small rise of the prothrombin time was noted. A serum level 5 hours after ingestion was 22 mg/L. The authors concluded that the quantity ingested must have been minor or that gastric lavage was effective (Boldy et al, 1988).

f) SUTOPROFEN

1) CASE REPORT: Ingestion of 40 sutoprofen (dose not indicated) in an 18-year-old resulted in a serum level of 66.2 mg/dL 6 hours after ingestion and 4.6 mg/dL 18 hours after ingestion (Freestone & Critchley, 1984).

g) KETOROLAC

1) Estimated concentration above which side effects are frequent is estimated as 5 mcg/mL (Prod Info, 1995) .

Toxicity Information

7.7.1)

A) BENZYDAMINE
B) SUPROFEN

1) LD50- (ORAL)MOUSE:

a) 590 mg/kg (Prod Info, 1986)

2) LD50- (ORAL)RAT:

a) 353 mg/kg (Prod Info, 1986)

Pharmacology Toxicology

Pharmacologic Mechanism

Toxicologic Mechanism

1) In addition, all NSAIDs are local gastric irritants.

Physicochemical

Physical Characteristics

Ph

Molecular Weight

Animal Toxicology

Clinical Effects

11.1.3)

A) SIGNS: Nausea, vomiting, and abdominal pain are most common. Lethargy, drowsiness, ataxia, and stupor may follow. Metabolic acidosis may occur. Either seizures or coma may rarely occur. Acute renal failure has been reported, especially with ibuprofen. Phenylbutazone may more commonly cause hepatic and renal failure (Beasley et al, 1990).

1) FLUNIXIN MEGLUMINE

a) A 9.5-year-old Doberman Pinscher developed a perforated duodenal ulcer complicated by peritonitis following administration of flunixin 1 milligram/kilogram orally every 12 hours for 6 days (Vonderhaar & Salisbury, 1993).
b) A 5-year-old Lhasa Apso was given flunixin 2.2 milligrams/kilogram intravenously for back pain. This dose was repeated two days later, followed by daily subcutaneous injections of 1.1 milligrams/kilogram for 3 days, then every other day for 3 more days. After referral for continued vomiting and melena, the dog was discovered to have a perforated ulcer in the pyloric antrum (Vonderhaar & Salisbury, 1993).
c) A 3-year-old Miniature Schnauzer was treated with flunixin 2.3 milligrams/kilogram intravenously every 24 hours for 2 days nine days prior to admission for evaluation of vomiting and melena. Gastroscopy revealed a perforated pyloric antrum ulcer (Vonderhaar & Salisbury, 1993).

11.1.6)

A) FLURBIPROFEN

1) SUMMARY: Pets exposed to topical pain medications containing flurbiprofen may be at risk of developing significant illness and death (U.S. Food and Drug Administration (FDA), 2015).

a) CATS: The FDA has received reports of severe illness in several households where pet owners applied the topical medication to themselves (ie, neck and feet). In these cases, it was unclear how the cats became exposed. However, 2 cats in one household developed renal failure and recovered with supportive care and 2 cats in another household developed lethargy, vomiting, melena, and anemia and died despite care. A third cat died after the pet owner had stopped using the topical product. Upon necropsy, the cats showed evidence of renal and gastrointestinal injury that are consistent with NSAID toxicity (U.S. Food and Drug Administration (FDA), 2015).
b) TOPICAL MEDICATION: The medication was found to contain flurbiprofen and cyclobenzaprine; additional ingredients included baclofen, gabapentin, lidocaine or prilocaine (U.S. Food and Drug Administration (FDA), 2015).
c) RECOMMENDATIONS: The FDA recommends that patients using this product should take extra measures to prevent exposure of pets to this medication (U.S. Food and Drug Administration (FDA), 2015).

Treatment

11.2.1)

A) SUPPORT

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

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

11.2.2)

A) SUPPORT

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 orally.

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 orally. Dogs may also be given apomorphine intravenously at 40 mcg/kg. Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage. Pass large bore stomach tube and instill 5 to 10 mL/kg water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).

b) ACTIVATED CHARCOAL: Administer activated charcoal. Dose: 2 g/kg orally 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). If access to these agents is limited, give 5 to 15 mL magnesium oxide (Milk of Magnesia) orally for dilution.

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.

a) Neonates: Administer 250 g (one-half pound) activated charcoal in up to 2 quarts water.

2) Adult cattle: Administer 2 to 9 g/kg of activated charcoal in a slurry of 1 g charcoal per 3 to 5 mL warm water via stomach tube.
3) Sheep may be given 0.5 kilogram charcoal in slurry.

c) CATHARTIC: Administer an oral cathartic:

1) Mineral oil (small ruminants and swine, 60 to 200 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) Or 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 orally). 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 milligram/kilogram intravenous bolus; may repeat dose every 10 minutes for 4 total doses. Give slowly over 1 to 2 minutes.
b) PHENOBARBITAL: Phenobarbital may be used as adjunct treatment at 5 to 30 milligrams/kilogram over 5 to 10 minutes intravenously.
c) REFRACTORY SEIZURES: Consider anaesthesia or heavy sedation. Administer pentobarbital to DOGS & CATS at a dose of 3 to 15 mg/kg IV slowly to effect. May need to repeat in 4 to 8 hours. Be sure to protect the airway.

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

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

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

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

a) SUCRALFATE: For relief of gastric irritation or ulceration, administer sucralfate as follows: DOGS (body weight less than 20 kg): 500 mg 3 to 4 times daily; (weight greater than 20 kg) one gram 3 to 4 times daily.

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

b) CIMETIDINE: To decrease gastric acid, administer cimetidine: DOGS: 5 to 10 mg/kg orally, intravenously, or intramuscularly every 6 to 8 hours; CATS: 2.5 to 5 mg/kg orally, intravenously, or intramuscularly every 8 to 12 hours.

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

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

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

B) RUMINANTS/HORSES/SWINE

1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.
2) SEIZURES: Seizures may be controlled with diazepam. Doses of diazepam, given slowly intravenously:

a) HORSES: 1 milligram/kilogram
b) CATTLE, SHEEP AND SWINE: 0.5 to 1.5 milligrams/kilogram

3) FLUIDS: Administer electrolyte and fluid therapy as needed.

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

Range Of Toxicity

11.3.1)

A) SUPPORT

1) IBUPROFEN is not recommended for use in animals.
2) DIPYRONE is dosed in dogs at 25 mg/kg three times daily (IV, IM, or SubQ). In horses: 22 mg/kg IM or IV BID or TID. In cattle and swine: 5 mL/50 kg body weight IV, IM, or SubQ (Plumb, 1989).
3) MECLOFENAMIC ACID is dosed in dogs at 1.1 mg/kg after a full meal once daily (Plumb, 1989).
4) FLUNIXIN MEGLUMINE is dosed in horses at 1.1 mg/kg orally, IM, IV, or SubQ every 6 to 24 hours. In cattle: 1.1 mg/kg IM or SubQ once daily. In dogs: 1.1 mg/kg IV or IM once daily, not to exceed 3 days of therapy (Plumb, 1989).

11.3.2)

A) SPECIFIC TOXIN

1) Cats are more sensitive to the effects of NSAIDs than dogs. These drugs should NOT BE USED in cats.
2) INDOMETHACIN: Gastric ulcers with possible perforation is likely to occur at doses greater than or equal to 2 milligrams/kilogram in dogs (Roudebush & Morse, 1981).
3) PHENYLBUTAZONE: Animals who have received multiple doses of phenylbutazone or who are dehydrated are more likely to become toxic (Beasley et al, 1990).

a) Animals receiving phenylbutazone at repeated typical doses (ie, 8.8 mg/kg) have suffered renal papillary necrosis (Beasley et al, 1990).

4) DMSO: Dimethylsulfoxide LD50 in dogs is 2.5 grams/kg (Plumb, 1989).

Continuing Care

11.4.1)

11.4.1.2) DECONTAMINATION/TREATMENT

A) SUPPORT

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 orally.

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.

a) Neonates: Administer 250 g (one-half pound) activated charcoal in up to 2 quarts water.

2) Adult cattle: Administer 2 to 9 g/kg of activated charcoal in a slurry of 1 g charcoal per 3 to 5 mL warm water via stomach tube.
3) Sheep may be given 0.5 kilogram charcoal in slurry.

c) CATHARTIC: Administer an oral cathartic:

11.4.3)

11.4.3.5) SUPPORTIVE CARE

A) SUPPORT

1) Ongoing treatment is symptomatic and supportive.

11.4.3.6) OTHER

A) OTHER

1) SUPPORT

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: 99% protein-bound in humans (Beasley et al, 1990).
2) PIROXICAM: Volume of distribution in Beagle dogs: 0.29 +/- 0.02 L/kg (Galbraith & McKellar, 1991).

11.5.4)

A) SPECIFIC TOXIN

1) FLUNIXIN MEGLUMINE: Elimination half-life in cats is approximately 0.7 to 1.5 hours (Taylor et al, 1991).
2) PIROXICAM: Elimination half-life in Beagle dogs: 40.2 hours (Galbraith & McKeller, 1991).

Pharmacology Toxicology

1) IBUPROFEN

a) Ibuprofen interferes with prostaglandin synthesis via inhibition of the cyclooxygenase pathway. It is irritating to the mucosa of the gastrointestinal tract.
b) Dogs appear to be very sensitive to the proprionic acid group of NSAIDs (ibuprofen) and easily develop gastric ulcers and renal failure.

References

General Bibliography

10)

11)

12)

13)

14)

15)

16)

17)

18)

19)

20)

21)

22)

23)

24)

25)

26)

27)

28)

29)

30)

31)

32)

33)

34)

35)

36)

37)

38)

39)

40)

41)

42)

43)

44)

45)

46)

47)

48)

49)

50)

51)

52)

53)

54)

55)

56)

57)

58)

59)

60)

61)

62)

63)

64)

65)

66)

67)

68)

69)

70)

71)

72)

73)

74)

75)

76)

77)

78)

79)

80)

81)

82)

83)

84)

85)

86)

87)

88)

89)

90)

91)

92)

93)

94)

95)

96)

97)

98)

99)

100)

101)

102)

103)

104)

105)

106)

107)

108)

109)

110)

111)

112)

113)

114)

115)

116)

117)

118)

119)

120)

121)

122)

123)

124)

125)

126)

127)

128)

129)

130)

131)

132)

133)

134)

135)

136)

137)

138)

139)

140)

141)

142)

143)

144)

145)

146)

147)

148)

149)

150)

151)

152)

153)

154)

155)

156)

157)

158)

159)

160)

161)

162)

163)

164)

165)

166)

167)

168)

169)

170)

171)

172)

173)

174)

175)

176)

177)

178)

179)

180)

181)

182)

183)

184)

185)

186)

187)

188)

189)

190)

191)

192)

193)

194)

195)

196)

197)

198)

199)

200)

201)

202)

203)

204)

205)

206)

207)

208)

209)

210)

211)

212)

213)

214)

215)

216)

217)

218)

219)

220)

221)

222)

223)

224)

225)

226)

227)

228)

229)

230)

231)

232)

233)

234)

235)

236)

237)

238)

239)

240)

241)

242)

243)

244)

245)

246)

247)

248)

249)

250)

251)

252)

253)

254)

255)

256)

257)

258)

259)

260)

261)

262)

263)

264)

265)

266)

267)

268)

FeedBack

NONSTEROIDAL ANTIINFLAMMATORY DRUGS

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Acid-Base

Hematologic

Dermatologic

Immunologic

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Toxicity Information

Pharmacologic Mechanism

Toxicologic Mechanism

Physical Characteristics

Ph

Molecular Weight

Clinical Effects

Treatment

Range Of Toxicity

Continuing Care

Kinetics

Pharmacology Toxicology

General Bibliography