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INDOMETHACIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Indomethacin is a nonsteroidal anti-inflammatory agent.
    B) Acemetacin is a glycolic acid ester of indomethacin and is also a nonsteroidal anti-inflammatory agent.

Specific Substances

    A) INDOMETHACIN
    1) (1-(4-Chlorobenzoyl)-5-methoxy-2-methylindol-3-yl) acetic acid
    2) Molecular Formula: C19-H16-Cl-N-O4
    3) Indometacin
    4) Indometacina (Mexican)
    5) Indometacinum
    6) Indomethine
    7) Indorectolmin
    8) CAS 53-86-1
    ACEMETACIN
    1) Acemetacina
    2) Bay-f-4975
    3) TVX-1322
    4) O-[(1-p-Chlorobenzoyl-5-methoxy-2-methylindol-3-yl)acetyl]glycolic acid
    5) CAS 53164-05-9

    1.2.1) MOLECULAR FORMULA
    1) INDOMETHACIN: C19H16ClNO4
    2) INDOMETHACIN SODIUM: C19H15ClNNaO4 3H2O

Available Forms Sources

    A) FORMS
    1) Indomethacin is available as 25 mg and 50 mg oral capsules, 75 mg extended-release capsules, 25 mg/5 mL oral suspension, and 50 mg rectal suppositories (Prod Info TIVORBEX(TM) oral capsules, 2014; Prod Info INDOCIN(R) oral capsules, oral suspension, suppositories, 2007; Prod Info indomethacin extended-release oral capsules, 2006). Intravenous powder for injection is available in single dose vials of 1 mg (as sodium trihydrate) (Prod Info indomethacin intravenous injection lyophilized powder for solution, 2014).
    2) ACEMETACIN: Acemetacin is available in Germany as: 30 and 60 mg capsules, and 90 mg delayed-release capsules.
    B) USES
    1) Indomethacin (Indocin(R)) is indicated for treating acute gouty arthritis, moderate-to-severe ankylosing spondylitis, moderate-to-severe osteoarthritis, moderate-to-severe rheumatoid arthritis, and bursitis and tendinitis of the shoulder (Prod Info INDOCIN(R) oral capsules, oral suspension, suppositories, 2007).
    2) Indomethacin (Tivorbex(TM)) is indicated for treatment of mild to moderate acute pain in adults (Prod Info TIVORBEX(TM) oral capsules, 2014).
    3) Indomethacin sodium injection is indicated for closure of patent ductus arteriosus in premature infants weighing between 500 and 1750 g (Prod Info indomethacin intravenous injection lyophilized powder for solution, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Used as an analgesic, antipyretic, and antiinflammatory drug to treat a wide range of pain and inflammatory conditions such as gout, pericarditis, several arthritis conditions, and dysmenorrhea. It is used in neonates for treatment of patent ductus arteriosus.
    B) PHARMACOLOGY: Inhibits cyclooxygenases, COX1 and COX2. This results in the decreased synthesis of prostaglandins, thromboxane A2, and decreased pain and inflammation.
    C) TOXICOLOGY: GI: Indomethacin is a direct GI irritant, and the inhibition of prostaglandin synthesis interferes with the maintenance of the GI barrier. Inhibition of thromboxane A2 in platelets prolongs bleeding time and predisposes to GI bleeding. RENAL: Decreases in prostaglandins I2 and E2, which have vasodilatory and natriuretic effects in the kidney that can lead to salt and water retention, and renal failure.
    D) WITH THERAPEUTIC USE
    1) COMMON: Nausea, vomiting, gastritis, GI ulceration with perforation and hemorrhage, frontal headache, LESS COMMON: Dizziness, vertigo, stupor, hypersensitivity reactions, renal insufficiency, neutropenia, thrombocytopenia, and aplastic anemia.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, vomiting, and mild abdominal pain may develop.
    2) SEVERE TOXICITY: CNS disorientation, mental confusion, and lethargy have been reported. Upper GI bleeding and acute renal failure are also possible.
    0.2.20) REPRODUCTIVE
    A) Indomethacin is classified as FDA pregnancy category C before 30 weeks' gestation and category D at 30 weeks' gestation and later. Although there have been no well-controlled studies conducted in pregnant women, exposure to indomethacin or other NSAIDs during the third trimester of pregnancy has been linked with fetal cardiovascular abnormalities, renal dysgenesis and dysfunction, oligohydramnios, and other serious effects.

Laboratory Monitoring

    A) Plasma indomethacin concentrations are not clinically useful or widely available
    B) Patients should be monitored for evidence of gastrointestinal hemorrhage. Monitor serum electrolytes, renal function and CBC after significant overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treat GI distress and administer IV fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Administer IV fluids, treat GI distress and monitor for GI bleeding. Patients with severe altered mental status may require intubation.
    C) DECONTAMINATION
    1) PREHOSPITAL: No pre-hospital decontamination is recommended.
    2) HOSPITAL: Administer activated charcoal after large, recent overdose if the patient is alert and can protect the airway. Gastric lavage has no role in the management of indomethacin overdose or toxicity as overdose is not life threatening.
    D) AIRWAY MANAGEMENT
    1) Very rarely patients with severe altered mental status may require intubation.
    E) ANTIDOTE
    1) None.
    F) IRRITATION SYMPTOM
    1) Antacids, histamine-2 antagonists, sucralfate may be useful with severe irritation.
    G) ENHANCED ELIMINATION
    1) Hemodialysis is UNLIKELY to be of benefit due to the large volume of distribution and high degree of protein binding.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients with no symptoms or only mild GI distress after inadvertent overdose can be monitored at home.
    2) OBSERVATION CRITERIA: Patients with deliberate overdose or more than mild symptoms should be referred to a healthcare facility for evaluation and treatment. If symptoms resolve over 4 to 6 hours, there is no evidence of GI bleeding and laboratory evaluation is normal, the patient discharged home.
    3) ADMISSION CRITERIA: Patients with significant systemic signs and symptoms (hematologic disorders such as pancytopenia, metabolic acidosis, altered mental status, renal failure, and significant electrolyte disturbances, or GI hemorrhage) should be admitted and receive appropriate supportive care.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe signs and symptoms or in whom the diagnosis is unclear.
    I) PITFALLS
    1) When managing an overdose with indomethacin, the possibility of coingestion of other agents should be considered.
    J) PHARMACOKINETICS
    1) Indomethacin is rapidly absorbed and achieves peak serum concentration within 1-2 hours. It has a half-life of 2.5-3 hours. The drug undergoes demethylation in the liver, is more than 90% protein bound and has a small volume of distribution (0.1-0.2L/kg).
    K) DIFFERENTIAL DIAGNOSIS
    1) Flu-like illness, ingestion of other NSAIDs, ethanol intoxication, or aspirin ingestion.

Range Of Toxicity

    A) There are insufficient data in the literature to accurately assess the minimal toxic or lethal dose. Severity of intoxication should be based on clinical findings.
    B) Doses of 0.2 to 3.75 mg/kg have resulted in toxic GI symptoms in pre-term infants. Doses up to 175 mg in children and 1500 mg in adults have been tolerated with minor symptoms.
    C) Transient renal failure with oliguria, hyponatremia, and hyperkalemia developed in a preterm infant who received 20 mg/kg of indomethacin intramuscularly.
    D) The EPA Chemical Profile lists the probable acute lethal dose as 50 to 150 mg/kg.
    E) THERAPEUTIC DOSE: The usual therapeutic dose is 25 to 50 mg 3 to 4 times a day. The maximum recommended adult oral dose is 200 mg daily.

Clinical Effects

Summary Of Exposure

    A) USES: Used as an analgesic, antipyretic, and antiinflammatory drug to treat a wide range of pain and inflammatory conditions such as gout, pericarditis, several arthritis conditions, and dysmenorrhea. It is used in neonates for treatment of patent ductus arteriosus.
    B) PHARMACOLOGY: Inhibits cyclooxygenases, COX1 and COX2. This results in the decreased synthesis of prostaglandins, thromboxane A2, and decreased pain and inflammation.
    C) TOXICOLOGY: GI: Indomethacin is a direct GI irritant, and the inhibition of prostaglandin synthesis interferes with the maintenance of the GI barrier. Inhibition of thromboxane A2 in platelets prolongs bleeding time and predisposes to GI bleeding. RENAL: Decreases in prostaglandins I2 and E2, which have vasodilatory and natriuretic effects in the kidney that can lead to salt and water retention, and renal failure.
    D) WITH THERAPEUTIC USE
    1) COMMON: Nausea, vomiting, gastritis, GI ulceration with perforation and hemorrhage, frontal headache, LESS COMMON: Dizziness, vertigo, stupor, hypersensitivity reactions, renal insufficiency, neutropenia, thrombocytopenia, and aplastic anemia.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, vomiting, and mild abdominal pain may develop.
    2) SEVERE TOXICITY: CNS disorientation, mental confusion, and lethargy have been reported. Upper GI bleeding and acute renal failure are also possible.

Heent

    3.4.4) EARS
    A) WITH POISONING/EXPOSURE
    1) TINNITUS has been reported following indomethacin poisoning (Sheehan et al, 1986).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIAC ARREST
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Cardiac arrest was reported as a secondary reaction to renal failure in a 59-year-old diabetic (Kharasch et al, 1990).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) WITH POISONING/EXPOSURE
    a) Lethargy and arousable stupor have been reported following overdoses (Prod Info INDOCIN(R) oral capsules, oral suspension, suppositories, 2007).
    B) CLOUDED CONSCIOUSNESS
    1) WITH POISONING/EXPOSURE
    a) Disorientation and mental confusion have been reported following overdoses (Prod Info INDOCIN(R) oral capsules, oral suspension, suppositories, 2007).
    C) PSYCHOMOTOR AGITATION
    1) WITH POISONING/EXPOSURE
    a) Queneau et al (1978) reported the effects of indomethacin overdose in 18 patients, 14 adults taking 175 to 1500 mg and 4 children taking 75 to 175 mg. Five patients had GI upset and 7 had agitation or vigil coma. There were no serious symptoms (Queneau et al, 1978).
    D) PSYCHOTIC DISORDER
    1) WITH THERAPEUTIC USE
    a) In a review of the literature, the authors found a relationship between indomethacin and development of psychosis and cognitive dysfunction. This was especially evident in elderly patients (Hoppmann et al, 1991).
    E) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Therapeutic doses are associated with a wide variety of neurologic adverse effects (Kaarela et al, 1989). The most common are headache, lightheadedness, vertigo, dizziness, mental confusion, and occasionally somnolence, stupor, or hallucinations.

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Gastritis, epigastric distress, and pain have been reported with therapeutic use of indomethacin (Prod Info INDOCIN(R) oral capsules, oral suspension, suppositories, 2007).
    B) VOMITING
    1) WITH THERAPEUTIC USE
    a) Vomiting may occur with therapeutic use of indomethacin (Prod Info INDOCIN(R) oral capsules, oral suspension, suppositories, 2007).
    C) GASTROINTESTINAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) Occult bleeding and GI hemorrhage have been reported with therapeutic use of indomethacin (Prod Info INDOCIN(R) oral capsules, oral suspension, suppositories, 2007).
    b) CASE REPORT: Gastrointestinal bleeding did not develop in a preterm infant who received 20 mg/kg of indomethacin (Schuster et al, 1990).
    D) PEPTIC ULCER
    1) WITH THERAPEUTIC USE
    a) Peptic ulcerations have been reported with therapeutic use of indomethacin (Prod Info INDOCIN(R) oral capsules, oral suspension, suppositories, 2007).
    b) SLOW RELEASE CAPSULE: Osmotic slow release capsules may produce similar effects in the colon (Day, 1983).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Transient renal failure with oliguria developed in an 1850 gram male preterm infant of 30 gestational weeks following inadvertent administration of 20 mg/kg of indomethacin intramuscularly for symptomatic patent ductus arteriosus (Schuster et al, 1990).
    2) WITH THERAPEUTIC USE
    a) INDOMETHACIN ALONE has been reported to result in renal failure:
    1) CASE REPORT: Chan (1987) reported a case of fatal renal failure following daily doses of 25 mg in a 52-year-old man; Kharasch et al (1990) reported acute renal failure in a 59-year-old diabetic.
    b) INDOMETHACIN/TRIAMTERENE: Renal failure has been reported after therapeutic administration of triamterene with indomethacin (Mathews & Baillie, 1986; Weinberg et al, 1985; McCarthy et al, 1982).
    1) It is postulated that triamterene promotes increased renin activity normally reflex controlled by increased prostaglandin production. In the presence of indomethacin, inhibiting prostaglandin, renin-induced renal vasoconstriction may result in anuric renal failure.

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) Leukopenia, thrombocytopenia, and agranulocytosis have been reported infrequently (Prod Info INDOCIN(R) oral capsules, oral suspension, suppositories, 2007). Prolongation of prothrombin time was also reported by Sheehan et al (1986). It was transient in nature and resolved without treatment (Sheehan et al, 1986).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Generalized skin eruptions may occur with therapeutic use (Prod Info INDOCIN(R) oral capsules, oral suspension, suppositories, 2007).
    B) URTICARIA
    1) WITH THERAPEUTIC USE
    a) Urticaria may occur with therapeutic use of indomethacin (Prod Info INDOCIN(R) oral capsules, oral suspension, suppositories, 2007).
    C) PURPURA
    1) WITH THERAPEUTIC USE
    a) Purpura has been reported with therapeutic use (Prod Info INDOCIN(R) oral capsules, oral suspension, suppositories, 2007).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) Allergic reactions manifested by the precipitation of bronchial asthma may occur in patients with asthma and/or aspirin allergies (Prod Info INDOCIN(R) oral capsules, oral suspension, suppositories, 2007).
    B) DISORDER OF IMMUNE FUNCTION
    1) WITH THERAPEUTIC USE
    a) IMMUNOSUPPRESSION: In isolated cases involving pediatric patients receiving chronic, high doses (100 to 200 mg/day), indomethacin was suggested to mask signs of infections or activate latent infections resulting in impaired host defenses, which rapidly led to death. Sudden onset of high fever may be the only indication of these fatal infections (Block, 1972; Jacobs, 1967; Solomon, 1966) .

Reproductive

    3.20.1) SUMMARY
    A) Indomethacin is classified as FDA pregnancy category C before 30 weeks' gestation and category D at 30 weeks' gestation and later. Although there have been no well-controlled studies conducted in pregnant women, exposure to indomethacin or other NSAIDs during the third trimester of pregnancy has been linked with fetal cardiovascular abnormalities, renal dysgenesis and dysfunction, oligohydramnios, and other serious effects.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) MICE: Increased fetal resorptions and malformations were observed in mice administered 5 mg/kg/day and higher doses (Prod Info INDOCIN(R) rectal suppositories, 2008; Prod Info INDOCIN(R) oral suspension, 2010).
    2) MICE, RATS: Retarded fetal ossification occurred in the offspring of mice and rats administered 4 mg/kg/day doses (0.16 and 0.32 times the maximum recommended human dose, based on mg/m(2), respectively). Neuronal necrosis in diencephalon was observed in the fetuses of rats and mice administered 4 mg/kg/day during the last 3 days of gestation; no neuronal necrosis was observed at the 2 mg/kg/day dose (Prod Info TIVORBEX(TM) oral capsules, 2014; Prod Info INDOCIN(R) rectal suppositories, 2008; Prod Info INDOCIN(R) oral suspension, 2010).
    3) RABBITS, RATS: No evidence of developmental abnormalities have been observed in rats or rabbits (Prod Info indomethacin oral extended release capsules, 2013).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Indomethacin oral capsules are classified as FDA pregnancy category C prior to 30 weeks' gestation and category D starting at 30 weeks' gestation (Prod Info TIVORBEX(TM) oral capsules, 2014).
    2) Indomethacin oral extended-release capsules, oral suspension, and rectal suppositories are classified as FDA pregnancy category C (Prod Info INDOCIN(R) rectal suppositories, 2008; Prod Info indomethacin oral extended release capsules, 2013; Prod Info INDOCIN(R) oral suspension, 2010).
    3) Avoid use during pregnancy, especially late pregnancy, due to the risk of premature ductus arteriosus (Prod Info TIVORBEX(TM) oral capsules, 2014; Prod Info INDOCIN(R) rectal suppositories, 2008; Prod Info indomethacin oral extended release capsules, 2013; Prod Info INDOCIN(R) oral suspension, 2010), and use only if the potential maternal benefit outweighs the fetal risk (Prod Info TIVORBEX(TM) oral capsules, 2014; Prod Info INDOCIN(R) rectal suppositories, 2008; Prod Info INDOCIN(R) oral suspension, 2010).
    4) Apprise patients to the potential fetal hazard if indomethacin oral capsules are used during pregnancy (Prod Info TIVORBEX(TM) oral capsules, 2014).
    B) BLEEDING EVENTS
    1) Bleeding events (ie, intracranial bleeding, gastrointestinal bleeding or perforation) have occurred with platelet dysfunction (Prod Info INDOCIN(R) rectal suppositories, 2008; Prod Info INDOCIN(R) oral suspension, 2010; Prod Info TIVORBEX(TM) oral capsules, 2014).
    C) CARDIOVASCULAR ABNORMALITIES
    1) Indomethacin can cause fetal harm when administered at 30 weeks' gestation or later. Prenatal constriction or postnatal non-closure of the ductus arteriosus (which many be resistant to medical management), tricuspid incompetence, pulmonary hypertension, and myocardial degenerative changes have been reported (Prod Info INDOCIN(R) rectal suppositories, 2008; Prod Info INDOCIN(R) oral suspension, 2010; Prod Info TIVORBEX(TM) oral capsules, 2014).
    2) Maternal indomethacin 25 to 75 mg daily as rectal suppository from gestation week 26 through 34 apparently caused in utero closure of the ductus arteriosus, leading to right ventricular pressure overload, subsequent right ventricular hypertrophy and left ventricular dilatation. The infant was born at 35 weeks (3846 g birthweight; Apgar 5 at 1 minute). Cyanosis, despite 40% oxygen, led to intubation. Cardiomegaly was present on chest x-ray; congenital cardiac malformation was not apparent. Despite aggressive supportive therapy, death followed at 34 hours. Autopsy findings showed evidence of chronic ductal wall occlusion. Fetal monitoring with echocardiography and amniotic fluid assessment for evidence of early closure is strongly recommended if COX inhibition is used during late-stage pregnancy (Mushiake et al, 2002). There have been other case reports of constriction of the ductus arteriosus (Kramer et al, 1994; Bivins et al, 1993; Carmona et al, 1993; Moise et al, 1990) complicated by hydrops fetalis (Ben-David et al, 1996), renal dysfunction (Carlan et al, 1991), and bleeding disorders (Carmona et al, 1993; Carlan et al, 1991).
    3) Transient constriction of the ductus arteriosus appears to occur in some fetuses whose mothers are treated with indomethacin for preterm labor even after short-term use (Moise et al, 1990). One source suggested that prostaglandin inhibitors can reduce amniotic fluid volume, possibly via a reduction in fetal urinary production. The same report also suggested that indomethacin-induced effects on amniotic fluid volume may occur as early as 21 weeks of gestation. Amniotic fluid volume should be monitored closely during indomethacin therapy for preterm labor (Goldenberg et al, 1989).
    D) OLIGOHYDRAMNIOS
    1) Oligohydramnios, edema, transient renal dysfunction, bleeding disorders and focal ileal perforation have been observed in preterm infants following antenatal exposure to indomethacin for chronic tocolysis beginning at 28 weeks of gestation or later (Vanhaesebrouck et al, 1988).
    2) Three cases of neonatal oligohydramnios, meconium staining and perinatal death following several days of maternal indomethacin therapy for premature labor have been reported. Gastric hemorrhage and intraperitoneal hemorrhage were also observed in two infants (Itskovitz et al, 1980).
    E) RENAL DYSFUNCTION
    1) Indomethacin can cause fetal harm when administered at 30 weeks' gestation or later. Renal dysgenesis leading to renal dysfunction and renal failure has been reported (Prod Info INDOCIN(R) rectal suppositories, 2008; Prod Info INDOCIN(R) oral suspension, 2010; Prod Info TIVORBEX(TM) oral capsules, 2014).
    2) Fetal anuria, neonatal edema, and gastrointestinal bleeding were reported in a neonate exposed to indomethacin and cocaine in utero (Carlan et al, 1991). The authors suggest that indomethacin and cocaine may act synergistically to adversely affect renal, cardiovascular, and platelet function of the fetus; therefore, it may be prudent to obtain a cocaine urine screen in at risk patients before the administration of indomethacin for preterm labor or polyhydramnios.
    3) Oligohydramnios, edema, transient renal dysfunction, bleeding disorders and focal ileal perforation have been observed in preterm infants following antenatal exposure to indomethacin for chronic tocolysis beginning at 28 weeks of gestation or later (Vanhaesebrouck et al, 1988).
    F) ANIMAL STUDIES
    1) MICE: Maternal toxicity and death were observed in mice administered 5 mg/kg/day (0.2 times the maximum recommended human dose, based on mg/m(2)) and higher doses (Prod Info TIVORBEX(TM) oral capsules, 2014; Prod Info INDOCIN(R) rectal suppositories, 2008; Prod Info INDOCIN(R) oral suspension, 2010). Fetal resorptions and fetal malformations were also observed (Prod Info TIVORBEX(TM) oral capsules, 2014).
    2) MICE, RATS: A decrease in maternal weight gain and some maternal and fetal deaths were observed in mice and rats at 4 mg/kg/day doses (Prod Info INDOCIN(R) rectal suppositories, 2008; Prod Info INDOCIN(R) oral suspension, 2010).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Indomethacin is not recommended in a woman who is breastfeeding (Prod Info INDOCIN(R) rectal suppositories, 2008; Prod Info INDOCIN(R) oral suspension, 2010). If a woman is taking this drug while nursing, either indomethacin or breastfeeding should be discontinued, taking into account the importance of the drug to the mother (Prod Info indomethacin oral extended release capsules, 2013).
    2) Exercise caution when administering indomethacin oral capsules to a nursing woman, and weigh the developmental and health benefits of breastfeeding with the mother's clinical need for this drug and any potential fetal adverse effects (Prod Info TIVORBEX(TM) oral capsules, 2014).
    3) The mean indomethacin concentration in the breast milk of 15 postpartum women treated with indomethacin 75 mg orally to 300 mg/day rectally (0.94 to 4.29 mg/kg daily) was estimated to be 0.27% of the maternal weight-adjusted dose in one clinical study. In another study, the estimated infant dose of indomethacin from breast milk was less than 30 mcg/day or 4.5 mcg/kg/day, assuming breast milk intake of 150 mL/kg/day by an infant. The breast milk concentrations were estimated at 0.5% of the maternal weight-adjusted dosage (about 3% of the neonatal dose for treatment of patent ductus arteriosus) in 8 postpartum women treated with indomethacin 75 mg/day (Prod Info TIVORBEX(TM) oral capsules, 2014).
    4) No adverse effects were reported in 16 breastfeeding infants whose mothers were receiving daily doses of indomethacin 75 mg orally or 300 mg rectally. Furthermore, infant indomethacin plasma concentrations were below detection in 6 to 7 infants sampled; one infant had an indomethacin plasma concentration of 47 mcg/L. The authors calculated that the maximum possible dose to which a breastfeeding infant could be exposed would be 1% of the maternal dose (Lebedevs et al, 1991).
    5) One case of convulsions in a breastfed infant whose mother received indomethacin for analgesia 3 mg per kg per day orally for approximately one week has been reported. The infant suffered two episodes of generalized seizures. The maternal plasma concentration of indomethacin was reported to be 1 to 4 mcg/mL. The drug was discontinued and the child completely recovered. A direct causal relationship could not be established, however, and no additional cases of seizures have been reported in this setting (Eeg-Olofsson et al, 1978).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) MICE, RATS: No effect on the fertility of mice and rats was noted with 0.5 mg/kg/day doses in a 2-generation study in mice and in a 2-litter study in rats (Prod Info TIVORBEX(TM) oral capsules, 2014; Prod Info INDOCIN(R) rectal suppositories, 2008; Prod Info INDOCIN(R) oral suspension, 2010; Prod Info TIVORBEX(TM) oral capsules, 2014).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS53-86-1 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma indomethacin concentrations are not clinically useful or widely available
    B) Patients should be monitored for evidence of gastrointestinal hemorrhage. Monitor serum electrolytes, renal function and CBC after significant overdose.

Methods

    A) OTHER
    1) Methods to assay blood or serum concentrations of indomethacin are available, but not on a widespread basis.
    B) TOXICITY
    1) Although it appears that common side effects of indomethacin are dose related, there are no data demonstrating a correlation between toxic effects and drug concentration.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with significant systemic signs and symptoms (hematologic disorders such as pancytopenia, metabolic acidosis, altered mental status, renal failure, and significant electrolyte disturbances, or GI hemorrhage) should be admitted and receive appropriate supportive care.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients with no symptoms or only mild GI distress after inadvertent overdose can be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe signs and symptoms or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate overdose or more than mild symptoms should be referred to a healthcare facility for evaluation and treatment. If symptoms resolve over 4 to 6 hours, there is no evidence of GI bleeding and laboratory evaluation is normal, the patient discharged home.

Monitoring

    A) Plasma indomethacin concentrations are not clinically useful or widely available
    B) Patients should be monitored for evidence of gastrointestinal hemorrhage. Monitor serum electrolytes, renal function and CBC after significant overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) No prehospital gastrointestinal decontamination is recommended.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor for evidence of GI bleeding (eg, guaiac positive stools, decreased hematocrit). Monitor CBC, serum electrolytes and renal function after significant overdose Plasma indomethacin concentrations are not clinically useful or widely available.
    B) ANTACID
    1) Antacids may be of some value for relief of symptoms in patients with gastrointestinal symptoms.
    2) "Full dose" antacids, histamine-2 antagonists (e.g., ranitidine, cimetidine, famotidine), or protective agents (e.g., sucralfate) may be of benefit in treatment of patients with NSAID-induced peptic ulcer disease.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is UNLIKELY to be of benefit due to the high degree of protein binding.

Abstracts

Case Reports

    A) OVERDOSE
    1) Queneau et al (1978) reported the effects of indomethacin overdose in 18 patients, 14 adults taking 175 to 1500 mg and 4 children taking 75 to 175 mg. Five patients had GI upset and 7 had agitation or vigil coma. There were no serious symptoms (Queneau et al, 1978).
    2) ASYMPTOMATIC: Court & Volans (1984) reviewed 31 cases, with 19 (61%) asymptomatic after acute ingestion (Court & Volans, 1984).
    3) Sheehan et al (1986) reported 2 cases of overdose in an 18-year-old woman receiving 0.9 g and a 29-year-old woman after ingestion of 0.5 g. No serious symptoms were reported (Sheehan et al, 1986).

Range Of Toxicity

Summary

    A) There are insufficient data in the literature to accurately assess the minimal toxic or lethal dose. Severity of intoxication should be based on clinical findings.
    B) Doses of 0.2 to 3.75 mg/kg have resulted in toxic GI symptoms in pre-term infants. Doses up to 175 mg in children and 1500 mg in adults have been tolerated with minor symptoms.
    C) Transient renal failure with oliguria, hyponatremia, and hyperkalemia developed in a preterm infant who received 20 mg/kg of indomethacin intramuscularly.
    D) The EPA Chemical Profile lists the probable acute lethal dose as 50 to 150 mg/kg.
    E) THERAPEUTIC DOSE: The usual therapeutic dose is 25 to 50 mg 3 to 4 times a day. The maximum recommended adult oral dose is 200 mg daily.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) INDOMETHACIN
    a) CAPSULES
    1) 20 mg orally 3 times daily or 40 mg orally 2 to 3 times daily (Prod Info TIVORBEX(TM) oral capsules, 2014).
    b) EXTENDED-RELEASE CAPSULES
    1) 75 mg orally once or twice a day (Prod Info indomethacin oral extended release capsules, 2013).
    c) ORAL SUSPENSION
    1) ACUTE GOUTY ARTHRITIS: 50 mg (10 mL) orally 3 times daily (Prod Info INDOCIN(R) oral suspension, 2010).
    2) ACUTE BURSITIS OR TENDONITIS: 75 to 150 mg/day (15 to 30 mL) orally in 3 or 4 divided doses for 7 to 14 days (Prod Info INDOCIN(R) oral suspension, 2010).
    3) ALKYLOSING SPONDYLITIS: 25 to 50 mg (5 to 10 mL) orally 2 to 3 times a day; maximum dose 200 mg/day, 100 mg/dose ((Prod Info INDOCIN(R) oral suspension, 2010).
    4) MODERATE TO SEVERE RHEUMATOID ARTHRITIS: 25 to 50 mg (5 to 10 mL) orally 2 to 3 times a day; maximum dose 200 mg/day, 100 mg/dose (Prod Info INDOCIN(R) oral suspension, 2010).
    d) RECTAL SUPPOSITORIES
    1) ACUTE BURSITIS OR TENDONITIS: Initial dose, 75 to 150 mg/day rectally in 3 or 4 divided doses for 7 to 14 days (Prod Info INDOCIN(R) rectal suppositories, 2008).
    2) ACUTE GOUTY ARTHRITIS: 50 mg rectally 3 times daily (Prod Info INDOCIN(R) rectal suppositories, 2008)
    3) ANKYLOSING SPONDYLITIS: Initial dose, 25 mg rectally 2 to 3 times/day; titrate by 25 or 50 mg at weekly intervals to a maximum daily dose of 200 mg/day. A maximum 100 mg dose given at bedtime may be used for persistent night pain or morning stiffness (Prod Info INDOCIN(R) rectal suppositories, 2008).
    4) MODERATE TO SEVERE OSTEOARTHRITIS: Initial dose, 25 mg rectally 2 to 3 times/day; titrate by 25 or 50 mg at weekly intervals to a maximum daily dose of 200 mg/day. A maximum 100 mg dose given at bedtime may be used for persistent night pain or morning stiffness (Prod Info INDOCIN(R) rectal suppositories, 2008).
    5) MODERATE TO SEVERE RHEUMATOID ARTHRITIS: 25 to 50 mg rectally 2 to 3 times/day; maximum daily dose 200 mg/day, 100 mg dose (Prod Info INDOCIN(R) rectal suppositories, 2008).
    2) ACEMETACIN
    a) The usual oral daily dose is 60 mg 2 to 3 times daily (Moore et al, 2009).
    7.2.2) PEDIATRIC
    A) INDOMETHACIN
    1) CAPSULES
    a) Safety and effectiveness have not been established in patients up to 17 years of age (Prod Info TIVORBEX(TM) oral capsules, 2014).
    2) EXTENDED-RELEASE CAPSULES
    a) Safety and effectiveness has not been established in patients up to 14 years of age (Prod Info indomethacin oral extended release capsules, 2013).
    3) INJECTION
    a) AGED LESS THAN 48 HOURS: Initial, 0.2 mg/kg IV, followed by 0.1 mg/kg IV at 12 to 24 hour intervals for the second and third doses (Prod Info indomethacin intravenous injection lyophilized powder for solution, 2014)
    b) AGED BETWEEN 2 AND 7 DAYS: Initial, 0.2 mg/kg IV, followed by 0.2 mg/kg IV at 12 to 24 hour intervals for the second and third doses (Prod Info indomethacin intravenous injection lyophilized powder for solution, 2014)
    c) AGED GREATER THAN 7 DAYS: Initial, 0.2 mg/kg IV, followed by 0.25 mg/kg IV at 12 to 24 hour intervals for the second and third doses (Prod Info indomethacin intravenous injection lyophilized powder for solution, 2014)
    4) ORAL SUSPENSION
    a) Safety and effectiveness have not been established in patients up to 14 years of age (Prod Info INDOCIN(R) oral suspension, 2010).
    5) RECTAL SUPPOSITORIES
    a) Safety and effectiveness has not been established in pediatric patients up to 14 years of age (Prod Info INDOCIN(R) rectal suppositories, 2008).
    6) 2 YEARS OF AGE AND OLDER: The therapeutic dose can range from 1 to 4 mg/kg/day orally in 2 or 3 divided doses. The highest reported maximum dose for therapeutic use is 5 mg/kg/day or 150 mg to 200 mg/day, whichever is less (Jen et al, 2006; Job-Deslandre et al, 2001; Hollingworth, 1993; Rose & Doughty, 1992; Brewer & Arroyo, 1986; Blankenburg et al, 2009).

Minimum Lethal Exposure

    A) ACUTE
    1) According to EPA Chemical Profile (CAS No. 53-86-1, October 31, 1985), the probable oral lethal dose in humans is 50 to 150 milligrams/kilogram.

Maximum Tolerated Exposure

    A) ADULT
    1) 1500 milligrams have been tolerated (Queneau et al, 1978).
    B) PEDIATRIC
    1) Toxic doses of up to 175 milligrams have been tolerated with minor symptoms (Queneau et al, 1978).
    2) Transient renal failure with oliguria, mild hyponatremia, and hyperkalemia developed in an 1850-gram, male preterm infant of 30 gestational weeks following accidental administration of 20 milligrams/kilogram of indomethacin intramuscularly (Schuster et al, 1990).
    3) In 4 infants who accidentally received 1 mg/kg (10 times the therapeutic dose), none developed necrotizing enterocolitis, intracranial hemorrhage, or chronic lung disease. Two of four infants developed transient increases in serum creatinine or BUN, and 3 of 4 had decreased urine output. All infants recovered without apparent sequelae (Narayanan et al, 1999).
    4) Doses of 0.2 to 3.75 mg/kg have produced toxic GI symptoms in pre-term infants.

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) The proposed therapeutic concentration of serum indomethacin is 1000 nanograms/mL (Schuster et al, 1990).
    b) The serum indomethacin concentration 36 hours after an 1850 gram preterm infant was inadvertently administered 20 mg/kg of indomethacin was 9915 nanograms/mL (Schuster et al, 1990).

Workplace Standards

    A) ACGIH TLV Values for CAS53-86-1 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS53-86-1 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS53-86-1 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS53-86-1 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Indomethacin is an NSAID drug that has an unknown mechanism of action. However, the drug exerts anti-inflammatory, analgesic and antipyretic effects by inhibiting the synthesis of prostaglandin (Prod Info TIVORBEX(TM) oral capsules, 2014; Prod Info INDOCIN(R) oral capsules, oral suspension, suppositories, 2007).

Physicochemical

Physical Characteristics

    A) INDOMETHACIN is practically insoluble in water and sparingly soluble in alcohol; has a pKa of 4.5; is stable in neutral or slightly acidic media; and decomposes in strong alkali (Prod Info INDOCIN(R) oral suspension, 2008).

Ph

    A) INDOMETHACIN: 4 to 5 (oral suspension) (Prod Info INDOCIN(R) oral suspension, 2008)
    B) INDOMETHACIN SODIUM: 6 to 7.5 (injection) (Prod Info indomethacin intravenous injection lyophilized powder for solution, 2014)

Molecular Weight

    A) INDOMETHACIN: 357.8 (Prod Info TIVORBEX(TM) oral capsules, 2014)
    B) INDOMETHACIN SODIUM: 433.82 (Prod Info Indocin(R) intravenous injection, 2009)

Animal Toxicology

Clinical Effects

    11.1.5) EQUINE/HORSE
    A) EQUILIBRIUM DISORDERS were noted in 3 ponies given intravenous indomethacin. Dyspnea and perspiration were also seen.
    1) The effects were seen within 1 minute of administration of 0.3 to 1 milligram/kilogram, and resolved within 3 to 5 minutes (Roberts, 1982) Vandenbossche et al, 1990).

Treatment

    11.2.1) SUMMARY
    A) GENERAL TREATMENT
    1) Begin treatment immediately.
    2) Keep animal warm and do not handle unnecessarily.
    3) Sample vomitus, blood, urine, and feces for analysis.
    4) Remove the patient and other animals from the source of contamination.
    5) Treatment should always be done on the advice and with the consultation of a veterinarian.
    6) Additional information regarding treatment of poisoned animals may be obtained from a Board Certified (ABVT) Veterinary Toxicologist (check with nearest veterinary school or veterinary diagnostic laboratory) or the National Animal Poison Control Center.
    7) ANIMAL POISON CONTROL CENTERS
    a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
    b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
    c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.
    11.2.2) LIFE SUPPORT
    A) GENERAL
    1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.
    11.2.4) DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) GENERAL TREATMENT
    a) EMESIS AND LAVAGE - If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os.
    1) Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.
    2) Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram. Do not use an emetic if the animal is hypoxic.
    3) In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
    4) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).
    b) ACTIVATED CHARCOAL - Administer activated charcoal. Dose: 2 grams/kilogram per os or via stomach tube. Avoid aspiration by proper restraint, careful technique, and if necessary tracheal intubation.
    c) CATHARTIC - Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution.
    11.2.5) TREATMENT
    A) GENERAL TREATMENT
    1) MAINTAIN VITAL FUNCTIONS - as necessary.
    2) ANEMIA - Prior to running large amounts of fluids, check hematocrit. Blood transfusions may be necessary and clinical condition may be worsened by giving large amounts of fluids.
    a) TRANSFUSION - Transfuse with whole blood or plasma, 25 milliliters/kilogram.
    b) FLUID THERAPY - If necessary, begin fluid therapy at maintenance doses (66 milliliters solution/kilogram body weight/day intravenously) or, in hypotensive patients, at high doses (up to shock dose 60 milliliters/kilogram/hour).
    1) Monitor for urine production and pulmonary edema.
    3) GASTRIC PROTECTANTS - Administer antacids, protectants such as sucralfate, and cimetadine as needed for gastric irritation and damage.
    4) ALKALINE DIURESIS - 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.
    5) MONITOR - For CBC changes and renal and hepatic damage. Provide good supportive care; treatment may need to be continued for several days.

Range Of Toxicity

    11.3.2) MINIMAL TOXIC DOSE
    A) CAT
    1) Cats are more sensitive to the effects of NSAIDs than dogs. These drugs should NOT BE USED in cats.
    B) DOG
    1) INDOMETHACIN - Gastric ulcers with possible perforation are likely to occur at doses greater than or equal to 2 milligrams/kilogram in dogs (Roudebush & Morse, 1981).

Continuing Care

    11.4.1) SUMMARY
    11.4.1.2) DECONTAMINATION/TREATMENT
    A) GENERAL TREATMENT
    1) Begin treatment immediately.
    2) Keep animal warm and do not handle unnecessarily.
    3) Sample vomitus, blood, urine, and feces for analysis.
    4) Remove the patient and other animals from the source of contamination.
    5) Treatment should always be done on the advice and with the consultation of a veterinarian.
    6) Additional information regarding treatment of poisoned animals may be obtained from a Board Certified (ABVT) Veterinary Toxicologist (check with nearest veterinary school or veterinary diagnostic laboratory) or the National Animal Poison Control Center.
    7) ANIMAL POISON CONTROL CENTERS
    a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
    b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
    c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.
    11.4.2) DECONTAMINATION
    11.4.2.2) GASTRIC DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) GENERAL TREATMENT
    a) EMESIS AND LAVAGE - If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os.
    1) Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.
    2) Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram. Do not use an emetic if the animal is hypoxic.
    3) In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
    4) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).
    b) ACTIVATED CHARCOAL - Administer activated charcoal. Dose: 2 grams/kilogram per os or via stomach tube. Avoid aspiration by proper restraint, careful technique, and if necessary tracheal intubation.
    c) CATHARTIC - Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution.

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