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BEDAQUILINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Bedaquiline, a diarylquinoline antimycobacterial agent, is used in combination with other therapies to treat pulmonary multidrug resistant tuberculosis.

Specific Substances

    1) Bedaquiline fumarate

Available Forms Sources

    A) FORMS
    1) Bedaquiline is available as an uncoated, white, round biconvex 100 mg tablet. Each bottle contains 188 tablets (Prod Info SIRTURO(TM) oral tablets, 2012).
    B) USES
    1) Bedaquiline is a diarylquinoline antimycobacterial drug used as part of combination therapy in adults with pulmonary multi-drug resistant tuberculosis. It is not indicated for the treatment of latent, extra-pulmonary or drug-sensitive tuberculosis (Prod Info SIRTURO(TM) oral tablets, 2012).

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: Bedaquiline is used in combination with other therapies to treat multidrug resistant pulmonary tuberculosis. It is not indicated for the treatment of latent, extra-pulmonary or drug-sensitive tuberculosis.
    B) PHARMACOLOGY: Bedaquiline is a diarylquinoline antimycobacterial agent. It inhibits mycobacterial ATP synthase which is an enzyme required for the generation of energy in Mycobacterium tuberculosis.
    C) EPIDEMIOLOGY: Exposure is uncommon.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: Nausea, arthralgia and headache were the most common adverse events occurring in 10% or more of patients treated with bedaquiline therapy. Bedaquiline can prolong the QT interval. Other events include elevated liver enzymes, hemoptysis and chest pain.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: There are no reports of overdose with bedaquiline.
    2) MILD TO MODERATE TOXICITY: Clinical events are likely an extension of therapeutic adverse events and may include nausea, arthralgia and headache. Elevated liver enzymes may develop.
    3) SEVERE TOXICITY: Prolongation of QT interval may occur following overdose. Although there are no reports of torsades de pointes, it may develop following a significant exposure or in combination with other QT prolonging drugs.
    0.2.20) REPRODUCTIVE
    A) Bedaquiline is classified as FDA pregnancy category B. There are no adequate and well-controlled studies of bedaquiline use in pregnant women. In animal studies, no fetal harm occurred in rats administered bedaquiline.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of bedaquiline in humans.

Laboratory Monitoring

    A) Monitor vital signs. Institute continuous cardiac monitoring and obtain serial ECGs to evaluate for evidence of QT prolongation.
    B) If QT prolongation develops, monitor serum electrolytes including potassium, calcium and magnesium. Correct any abnormalities.
    C) Monitor liver enzymes (ie, ALT, AST, alkaline phosphatase and bilirubin) following a significant exposure.
    D) Serum bedaquiline concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. QT prolongation has been reported with therapeutic doses and may occur following overdose. Obtain serial ECGs and institute continuous cardiac monitoring following a significant exposure. In patients with QT prolongation, monitor serum electrolytes including potassium, calcium and magnesium in patients with significant overdose; correct any abnormalities. At the time of this review, torsades de pointes has not been reported with therapy.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not likely to be necessary following a minor exposure, but can be considered in a recent, large exposure if the patient is alert.
    2) HOSPITAL: Consider activated charcoal for a large overdose if the ingestion is recent and the patient is not vomiting and the airway can be maintained.
    D) AIRWAY MANAGEMENT
    1) Airway management is very unlikely to be necessary unless other toxic agents have been administered concurrently.
    E) ENHANCED ELIMINATION
    1) It is unlikely that hemodialysis would be useful after overdose because of significant protein binding (99.9%).
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: A minor (a single dose) inadvertent dose in an asymptomatic patient currently being treated with bedaquiline can likely be managed at home. An asymptomatic child with an inadvertent exposure (a single dose) can likely be monitored at home, if a responsible adult is present.
    2) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions or with symptoms should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility.
    3) ADMISSION CRITERIA: Patients with persistent dysrhythmias should be admitted with ongoing ECG and electrolyte monitoring; correct any electrolyte abnormalities.
    4) CONSULT CRITERIA: Consult a Poison Center or medical toxicologist for assistance in managing patients with severe toxicity or for whom the diagnosis is unclear.
    G) PITFALLS
    1) When managing a suspected bedaquiline overdose, multi-drug involvement is likely to occur based on its therapeutic use. Toxic effects may be prolonged due to long mean terminal elimination half-life of bedaquiline.
    H) PHARMACOKINETICS
    1) Following oral administration, maximum plasma concentration is typically achieved at approximately 5 hours post dose. Plasma protein binding is greater than 99.9% and the volume of distribution in the central compartment is approximately 164 L. Bedaquiline is mainly eliminated in the feces. Renal clearance of unchanged drug is insignificant. The mean terminal elimination half-life of bedaquiline and the N-monodesmethyl metabolite (M2) is approximately 5.5 months. This long terminal elimination phase likely reflects slow release of bedaquiline and M2 from peripheral tissues.
    I) DIFFERENTIAL DIAGNOSIS
    1) Underlying disease process, other agents that may produce QT prolonging effects.

Range Of Toxicity

    A) TOXIC DOSE: A specific toxic dose has not been established.
    B) THERAPEUTIC DOSE: ADULT: The usual therapeutic dose is 400 mg for the first 2 weeks followed by 200 mg 3 times per week (a total of 600 mg/week) for a total duration of 24 weeks. PEDIATRIC: The safety and effectiveness of bedaquiline have not been established for pediatric patients.

Clinical Effects

Summary Of Exposure

    A) USES: Bedaquiline is used in combination with other therapies to treat multidrug resistant pulmonary tuberculosis. It is not indicated for the treatment of latent, extra-pulmonary or drug-sensitive tuberculosis.
    B) PHARMACOLOGY: Bedaquiline is a diarylquinoline antimycobacterial agent. It inhibits mycobacterial ATP synthase which is an enzyme required for the generation of energy in Mycobacterium tuberculosis.
    C) EPIDEMIOLOGY: Exposure is uncommon.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: Nausea, arthralgia and headache were the most common adverse events occurring in 10% or more of patients treated with bedaquiline therapy. Bedaquiline can prolong the QT interval. Other events include elevated liver enzymes, hemoptysis and chest pain.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: There are no reports of overdose with bedaquiline.
    2) MILD TO MODERATE TOXICITY: Clinical events are likely an extension of therapeutic adverse events and may include nausea, arthralgia and headache. Elevated liver enzymes may develop.
    3) SEVERE TOXICITY: Prolongation of QT interval may occur following overdose. Although there are no reports of torsades de pointes, it may develop following a significant exposure or in combination with other QT prolonging drugs.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) In a double-blind, randomized trial in newly diagnosed patients with multidrug-resistant pulmonary Mycobacterium tuberculosis (MDR-TB), the mean increase in QT interval (corrected for heart rate) was greater in patients who received bedaquiline 400 mg once daily for 2 weeks followed by 200 mg 3 times/week for 22 weeks, compared with patients who received placebo. The largest mean increase in QTc was 15.7 milliseconds at treatment-week 24 for patients who received bedaquiline, compared with 6.2 milliseconds at week 18 for patients who received placebo. The increase in QTc from baseline persisted in patients who received bedaquiline after treatment was stopped (Prod Info SIRTURO(TM) oral tablets, 2012).
    b) There have been no documented cases of torsades de pointes with therapeutic use of bedaquiline (Prod Info SIRTURO(TM) oral tablets, 2012).
    B) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) Chest pain has been reported in patients receiving therapeutic doses of bedaquiline (Prod Info SIRTURO(TM) oral tablets, 2012).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) HEMOPTYSIS
    1) WITH THERAPEUTIC USE
    a) In a double-blind, randomized trial in newly diagnosed patients with multidrug-resistant pulmonary Mycobacterium tuberculosis (MDR-TB), hemoptysis was reported in 17.7% (14 of 79) of patients treated with bedaquiline 400 mg once daily for 2 weeks followed by 200 mg 3 times/week for 22 weeks, compared with 11.1% (9 of 81) of patients who received placebo (Prod Info SIRTURO(TM) oral tablets, 2012).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache was one of the most common adverse events occurring in 10% or more of patients treated with bedaquiline (Prod Info SIRTURO(TM) oral tablets, 2012).
    b) In a double-blind, randomized trial in newly diagnosed patients with multidrug-resistant pulmonary Mycobacterium tuberculosis (MDR-TB), headache was reported in 27.8% (22 of 79) of patients treated with bedaquiline 400 mg once daily for 2 weeks followed by 200 mg 3 times/week for 22 weeks, compared with 12.3% (10 of 81) of patients who received placebo (Prod Info SIRTURO(TM) oral tablets, 2012).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) Nausea was one of the most common adverse events occurring in 10% or more of patients treated with bedaquiline (Prod Info SIRTURO(TM) oral tablets, 2012).
    b) In a double-blind, randomized trial in newly diagnosed patients with multidrug-resistant pulmonary, Mycobacterium tuberculosis (MDR-TB), nausea was reported in 38% (30 of 79) of patients treated with bedaquiline 400 mg once daily for 2 weeks followed by 200 mg 3 times/week for 22 weeks, compared with 32.1% (26 of 81) of patients who received placebo (Prod Info SIRTURO(TM) oral tablets, 2012).
    B) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) Anorexia has been reported in patients receiving therapeutic doses of bedaquiline (Prod Info SIRTURO(TM) oral tablets, 2012).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INCREASED LIVER ENZYMES
    1) WITH THERAPEUTIC USE
    a) In a double-blind, randomized trial in newly diagnosed patients with multidrug-resistant pulmonary Mycobacterium tuberculosis (MDR-TB), increased transaminases (eg, increased AST, increased ALT, increased hepatic enzyme, and abnormal hepatic function) was reported in 8.9% (7 of 79) of patients treated with bedaquiline 400 mg once daily for 2 weeks followed by 200 mg 3 times/week for 22 weeks, compared with 1.2% (1 of 81) of patients who received placebo (Prod Info SIRTURO(TM) oral tablets, 2012).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) In a double-blind, randomized trial in newly diagnosed patients with multidrug-resistant pulmonary Mycobacterium tuberculosis (MDR-TB), rash was reported in 7.6% (6 of 79) of patients treated with bedaquiline 400 mg once daily for 2 weeks followed by 200 mg 3 times/week for 22 weeks, compared with 3.7% (3 of 81) of patients who received placebo (Prod Info SIRTURO(TM) oral tablets, 2012).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Arthralgia was one of the most common adverse events occurring in 10% or more of patients treated with bedaquiline (Prod Info SIRTURO(TM) oral tablets, 2012).
    b) In a double-blind, randomized trial in newly diagnosed patients with multidrug-resistant pulmonary Mycobacterium tuberculosis (MDR-TB), arthralgia was reported in 32.9% (26 of 79) of patients treated with bedaquiline 400 mg once daily for 2 weeks followed by 200 mg 3 times/week for 22 weeks, compared with 22.2% (18 of 81) of patients who received placebo (Prod Info SIRTURO(TM) oral tablets, 2012).

Reproductive

    3.20.1) SUMMARY
    A) Bedaquiline is classified as FDA pregnancy category B. There are no adequate and well-controlled studies of bedaquiline use in pregnant women. In animal studies, no fetal harm occurred in rats administered bedaquiline.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Bedaquiline is classified as FDA pregnancy category B. There are no adequate and well-controlled studies of bedaquiline in pregnant women. In animal studies, no fetal harm resulted from bedaquiline administration to rats (at a dose with a corresponding plasma AUC 2-fold higher than that in humans) and rabbits. Due to the lack of human safety information, bedaquiline be used in pregnant women only if clearly needed (Prod Info SIRTURO(TM) oral tablets, 2014).
    B) ANIMAL STUDIES
    1) RATS, RABBITS: In animal studies, no fetal harm resulted from bedaquiline administration to rats (at a dose with a corresponding plasma AUC 2-fold higher than that in humans) and rabbits (Prod Info SIRTURO(TM) oral tablets, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) As it is unknown whether bedaquiline is excreted in human milk and because of the potential for adverse reactions in the nursing infant exists, it is recommended to discontinue either nursing or bedaquiline, considering the importance of the drug to the mother (Prod Info SIRTURO(TM) oral tablets, 2014).
    B) ANIMAL STUDIES
    1) Animal studies have shown that bedaquiline is concentrated in the milk of lactating rats. The concentrations in milk were 6- to 12-fold higher than the maximum concentration in maternal plasma of rats that received bedaquiline at doses 1 to 2 times the human clinical dose based on AUC comparisons. Compared to control animals, pups from these rat dams had reduced body weights throughout the lactation period (Prod Info SIRTURO(TM) oral tablets, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS: Bedaquiline had no effects on the fertility of male or female rats with plasma exposures 2-fold higher than in humans (Prod Info SIRTURO(TM) oral tablets, 2014).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of bedaquiline in humans.
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) RATS: Bedaquiline was not carcinogenic in rats administered bedaquiline up to 10 mg/kg/day (the maximum tolerated dose). Exposures at this dose were within 1- to 2- fold of those observed in humans during phase 2 clinical trials (Prod Info SIRTURO(TM) oral tablets, 2014).

Genotoxicity

    A) Bedaquiline was not mutagenic or clastogenic in the in vitro non-mammalian reverse mutation (Ames) test, in vitro mammalian (mouse lymphoma) forward mutation assay and an in vivo mouse bone marrow micronucleus assay (Prod Info SIRTURO(TM) oral tablets, 2014).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs. Institute continuous cardiac monitoring and obtain serial ECGs to evaluate for evidence of QT prolongation.
    B) If QT prolongation develops, monitor serum electrolytes including potassium, calcium and magnesium. Correct any abnormalities.
    C) Monitor liver enzymes (ie, ALT, AST, alkaline phosphatase and bilirubin) following a significant exposure.
    D) Serum bedaquiline concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.

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 persistent dysrhythmias should be admitted with ongoing ECG and electrolyte monitoring; correct any electrolyte abnormalities.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A minor (a single dose) inadvertent dose in an asymptomatic patient currently being treated with bedaquiline can likely be managed at home. An asymptomatic child with an inadvertent exposure (a single dose) can likely be monitored at home, if a responsible adult is present.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a Poison Center or medical toxicologist for assistance in managing patients with severe toxicity or for whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions or with symptoms should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility.

Monitoring

    A) Monitor vital signs. Institute continuous cardiac monitoring and obtain serial ECGs to evaluate for evidence of QT prolongation.
    B) If QT prolongation develops, monitor serum electrolytes including potassium, calcium and magnesium. Correct any abnormalities.
    C) Monitor liver enzymes (ie, ALT, AST, alkaline phosphatase and bilirubin) following a significant exposure.
    D) Serum bedaquiline concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is not likely to be necessary following a minor exposure, but should be considered after a large ingestion if the patient is alert.
    6.5.2) PREVENTION OF ABSORPTION
    A) Consider activated charcoal for a large overdose if the ingestion is recent and the patient is not vomiting and the airway can be maintained.
    B) 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) SUPPORT
    1) Treatment is symptomatic and supportive. Monitor vital signs and institute continuous cardiac monitoring following a significant exposure.
    B) MONITORING OF PATIENT
    1) Monitor vital signs.
    2) Institute continuous cardiac monitoring and obtain serial ECGs to evaluate for evidence of QT prolongation.
    3) If QT prolongation develops, monitor serum electrolytes including potassium, calcium and magnesium. Correct any abnormalities.
    4) Monitor liver enzymes (ie, ALT, AST, alkaline phosphatase and bilirubin) in patients following a significant exposure.
    5) Serum bedaquiline concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.

Enhanced Elimination

    A) SUMMARY
    1) It is unlikely that hemodialysis would be useful after overdose because of significant protein binding (99.9%).

Range Of Toxicity

Summary

    A) TOXIC DOSE: A specific toxic dose has not been established.
    B) THERAPEUTIC DOSE: ADULT: The usual therapeutic dose is 400 mg for the first 2 weeks followed by 200 mg 3 times per week (a total of 600 mg/week) for a total duration of 24 weeks. PEDIATRIC: The safety and effectiveness of bedaquiline have not been established for pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) SUMMARY: Bedaquiline is used for the treatment of multidrug-resistant pulmonary tuberculosis in combination with at least 3 other agents to which the patients TB has been shown to be susceptible in vitro (Prod Info SIRTURO(TM) oral tablets, 2012).
    B) INITIAL DOSE: 400 mg (4 100 mg tablets) orally once daily for 2 weeks; then 200 mg (2 100 mg tablets) 3 times per week for a total of 600 mg per week. The total duration of treatment is 24 weeks (Prod Info SIRTURO(TM) oral tablets, 2012).
    7.2.2) PEDIATRIC
    A) The safety and effectiveness of bedaquiline have not been established in children less than 18 years of age (Prod Info SIRTURO(TM) oral tablets, 2012).

Minimum Lethal Exposure

    A) A minimum lethal dose has not been established (Prod Info SIRTURO(TM) oral tablets, 2012).

Maximum Tolerated Exposure

    A) A maximum tolerated dose has not been established (Prod Info SIRTURO(TM) oral tablets, 2012).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Bedaquiline, a diarylquinoline, inhibits mycobacterial ATP synthase, which is an enzyme required for the generation of energy in Mycobacterium tuberculosis (Prod Info SIRTURO(TM) oral tablets, 2012).

References

General Bibliography

    1) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    2) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    3) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    4) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    5) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    6) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    7) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    8) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    9) Product Information: SIRTURO(TM) oral tablets, bedaquiline oral tablets . Janssen Therapeutics (per FDA), Titusville, NJ, 2014.
    10) Product Information: SIRTURO(TM) oral tablets, bedaquiline oral tablets. Janssen Therapeutics (per manufacturer), Titusville, NJ, 2012.
    11) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.