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PIRFENIDONE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Pirfenidone is a pyridone, used for the treatment of idiopathic pulmonary fibrosis.

Specific Substances

    1) AMR-69
    2) F-647
    3) Pirfenidona
    4) Pirfenidonum
    5) 5-Methyl-1-phenyl-2(1H)-pyridone
    6) CAS 53179-13-8
    1.2.1) MOLECULAR FORMULA
    1) C12-H11-NO (Prod Info ESBRIET(R) oral capsules, 2014)

Available Forms Sources

    A) FORMS
    1) Pirfenidone is available as 267 mg capsules (Prod Info ESBRIET(R) oral capsules, 2014).
    B) USES
    1) Pirfenidone is indicated in adults for the treatment of idiopathic pulmonary fibrosis (Prod Info ESBRIET(R) oral capsules, 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: Pirfenidone is indicated in adults for the treatment of idiopathic pulmonary fibrosis.
    B) PHARMACOLOGY: The precise mechanism of action of pirfenidone, a pyridone, has not been established. However, pirfenidone's ability to interfere with TNF-alpha in human astrocytes may prove useful in the treatment of multiple sclerosis.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) MOST COMMON (10% OR GREATER): Nausea, rash, abdominal pain, upper respiratory tract infection, diarrhea, fatigue, headache, dyspepsia, dizziness, vomiting, anorexia, gastroesophageal reflux disease, sinusitis, insomnia, decreased weight, and arthralgia. OTHER EFFECTS: Angioedema, photosensitivity reactions, agranulocytosis, elevated ALT and AST concentrations, and elevated bilirubin concentration.
    2) DRUG INTERACTION: Coadministration of pirfenidone (a CYP1A2 substrate) with moderate (eg, ciprofloxacin) and strong inhibitors (eg, fluvoxamine, enoxacin) of CYP1A2 may increase pirfenidone plasma concentration, resulting in toxicity.
    E) WITH POISONING/EXPOSURE
    1) Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. No adverse effects were reported after patients received up to 4005 mg/day of pirfenidone.
    0.2.20) REPRODUCTIVE
    A) Pirfenidone is classified as FDA pregnancy category C. There are no adequate or well controlled studies of pirfenidone use in human pregnancy. Teratogenic and embryofetal effects were not observed during animal studies. It is unknown whether pirfenidone is excreted into human milk, and the effects on the nursing infant from exposure to the drug in milk have not been determined.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs, CBC with differential, and liver enzymes following significant overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

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. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Airway management is very unlikely to be necessary unless other toxic agents have been administered concurrently.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION PROCEDURE
    1) It is unknown if hemodialysis would be effective in overdose.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) If significant toxicity develops, other causes should be sought. When managing a suspected pirfenidone overdose, the possibility of multidrug involvement should be considered.
    I) PHARMACOKINETICS
    1) Median Tmax: 0.5 hours (range, 30 minutes to 4 hours). Protein binding: 58%. Vd: Approximately 59 to 71 L. Metabolism: Pirfenidone is primarily metabolized in the liver by CYP1A2 (accounts for 70% to 80% of metabolism) and multiple other CYP enzymes including CYP2C9, CYP2C19, CYP2D6, and CYP2E1. Excretion: Approximately 80% of a dose of pirfenidone is excreted as 5-carboxy-pirfenidone in the urine. Elimination half-life: Approximately 3 hours in healthy subjects.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that can cause gastrointestinal symptoms (eg, nausea, vomiting), elevated liver enzymes, or agranulocytosis.

Range Of Toxicity

    A) TOXICITY: The maximum tolerated dose of pirfenidone was 4005 mg/day when healthy adult volunteers received 5 pirfenidone 267 mg capsules 3 times daily over a 12-day dose escalation.
    B) THERAPEUTIC DOSE: ADULT: Initially, 267 mg (1 capsule) orally 3 times daily for 7 days, then 534 mg (2 capsules) orally 3 times daily on days 8 through 14, then 801 mg (3 capsules) orally 3 times daily thereafter; maximum dose: 2403 mg/day (9 capsules/day). CHILD: The safety and efficacy of pirfenidone have not established in pediatric patients.

Clinical Effects

Summary Of Exposure

    A) USES: Pirfenidone is indicated in adults for the treatment of idiopathic pulmonary fibrosis.
    B) PHARMACOLOGY: The precise mechanism of action of pirfenidone, a pyridone, has not been established. However, pirfenidone's ability to interfere with TNF-alpha in human astrocytes may prove useful in the treatment of multiple sclerosis.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) MOST COMMON (10% OR GREATER): Nausea, rash, abdominal pain, upper respiratory tract infection, diarrhea, fatigue, headache, dyspepsia, dizziness, vomiting, anorexia, gastroesophageal reflux disease, sinusitis, insomnia, decreased weight, and arthralgia. OTHER EFFECTS: Angioedema, photosensitivity reactions, agranulocytosis, elevated ALT and AST concentrations, and elevated bilirubin concentration.
    2) DRUG INTERACTION: Coadministration of pirfenidone (a CYP1A2 substrate) with moderate (eg, ciprofloxacin) and strong inhibitors (eg, fluvoxamine, enoxacin) of CYP1A2 may increase pirfenidone plasma concentration, resulting in toxicity.
    E) WITH POISONING/EXPOSURE
    1) Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. No adverse effects were reported after patients received up to 4005 mg/day of pirfenidone.

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) UPPER RESPIRATORY INFECTION
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, placebo-controlled trials of 1247 patients, upper respiratory tract infection developed in 27% of the 623 patients receiving pirfenidone 2403 mg/day (mean duration of exposure: 62 weeks; range 2 to 118 weeks) as compared with 25% of the 624 patients in the placebo group (Prod Info ESBRIET(R) oral capsules, 2014).
    B) SINUSITIS
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, placebo-controlled trials of 1247 patients, sinusitis developed in 11% of the 623 patients receiving pirfenidone 2403 mg/day (mean duration of exposure: 62 weeks; range 2 to 118 weeks) as compared with 10% of the 624 patients in the placebo group (Prod Info ESBRIET(R) oral capsules, 2014).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, placebo-controlled trials of 1247 patients, dizziness developed in 18% of the 623 patients receiving pirfenidone 2403 mg/day (mean duration of exposure: 62 weeks; range 2 to 118 weeks) as compared with 11% of the 624 patients in the placebo group (Prod Info ESBRIET(R) oral capsules, 2014).
    B) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, placebo-controlled trials of 1247 patients, insomnia developed in 10% of the 623 patients receiving pirfenidone 2403 mg/day (mean duration of exposure: 62 weeks; range 2 to 118 weeks) as compared with 7% of the 624 patients in the placebo group (Prod Info ESBRIET(R) oral capsules, 2014).
    C) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, placebo-controlled trials of 1247 patients, headache developed in 22% of the 623 patients receiving pirfenidone 2403 mg/day (mean duration of exposure: 62 weeks; range 2 to 118 weeks) as compared with 19% of the 624 patients in the placebo group (Prod Info ESBRIET(R) oral capsules, 2014).
    D) FATIGUE
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, placebo-controlled trials of 1247 patients, fatigue developed in 26% of the 623 patients receiving pirfenidone 2403 mg/day (mean duration of exposure: 62 weeks; range 2 to 118 weeks) as compared with 19% of the 624 patients in the placebo group (Prod Info ESBRIET(R) oral capsules, 2014).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, placebo-controlled trials of 1247 patients, a dosage reduction or interruption for gastrointestinal disorders was required in 18.5% of the 623 patients receiving pirfenidone 2403 mg/day (mean duration of exposure: 62 weeks; range 2 to 118 weeks) as compared with 5.8% of 624 patients in the placebo group (Prod Info ESBRIET(R) oral capsules, 2014).
    b) In 3 randomized, double-blind, placebo-controlled trials of 1247 patients, discontinuation of treatment for gastrointestinal disorders was required in 2.2% of the 623 patients receiving pirfenidone 2403 mg/day (mean duration of exposure: 62 weeks; range 2 to 118 weeks) as compared with 1% of 624 patients in the placebo group (Prod Info ESBRIET(R) oral capsules, 2014).
    B) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, placebo-controlled trials of 1247 patients, anorexia developed in 13% of the 623 patients receiving pirfenidone 2403 mg/day (mean duration of exposure: 62 weeks; range 2 to 118 weeks) as compared with 5% of the 624 patients in the placebo group (Prod Info ESBRIET(R) oral capsules, 2014).
    C) GASTROESOPHAGEAL REFLUX DISEASE
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, placebo-controlled trials of 1247 patients, gastroesophageal reflux disease developed in 11% of the 623 patients receiving pirfenidone 2403 mg/day (mean duration of exposure: 62 weeks; range 2 to 118 weeks) as compared with 7% of the 624 patients in the placebo group (Prod Info ESBRIET(R) oral capsules, 2014).
    D) WEIGHT DECREASED
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, placebo-controlled trials of 1247 patients, decreased weight occurred in 10% of the 623 patients receiving pirfenidone 2403 mg/day (mean duration of exposure: 62 weeks; range 2 to 118 weeks) as compared with 5% of the 624 patients in the placebo group (Prod Info ESBRIET(R) oral capsules, 2014).
    E) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, placebo-controlled trials of 1247 patients, abdominal pain, including upper abdominal pain, abdominal distension, and stomach discomfort, developed in 24% of the 623 patients receiving pirfenidone 2403 mg/day (mean duration of exposure: 62 weeks; range 2 to 118 weeks) as compared with 15% of the 624 patients in the placebo group (Prod Info ESBRIET(R) oral capsules, 2014).
    F) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, placebo-controlled trials of 1247 patients, diarrhea developed in 26% of the 623 patients receiving pirfenidone 2403 mg/day (mean duration of exposure: 62 weeks; range 2 to 118 weeks) as compared with 20% of the 624 patients in the placebo group (Prod Info ESBRIET(R) oral capsules, 2014).
    G) NAUSEA
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, placebo-controlled trials of 1247 patients, nausea developed in 36% of the 623 patients receiving pirfenidone 2403 mg/day (mean duration of exposure: 62 weeks; range 2 to 118 weeks) as compared with 16% of the 624 patients in the placebo group (Prod Info ESBRIET(R) oral capsules, 2014).
    H) VOMITING
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, placebo-controlled trials of 1247 patients, vomiting developed in 13% of the 623 patients receiving pirfenidone 2403 mg/day (mean duration of exposure: 62 weeks; range 2 to 118 weeks) as compared with 6% of the 624 patients in the placebo group (Prod Info ESBRIET(R) oral capsules, 2014).
    I) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, placebo-controlled trials of 1247 patients, dyspepsia developed in 19% of the 623 patients receiving pirfenidone 2403 mg/day (mean duration of exposure: 62 weeks; range 2 to 118 weeks) as compared with 7% of the 624 patients in the placebo group (Prod Info ESBRIET(R) oral capsules, 2014).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INCREASED LIVER ENZYMES
    1) WITH THERAPEUTIC USE
    a) Increases in ALT and AST levels have been reported with postmarketing use of pirfenidone (Prod Info ESBRIET(R) oral capsules, 2014).
    b) In 3 randomized, double-blind, placebo-controlled trials of 1247 patients, increases in ALT and AST concentrations 3 times or greater than the ULN developed in 3.7% of the 623 patients receiving pirfenidone 2403 mg/day (mean duration of exposure: 62 weeks; range 2 to 118 weeks) as compared with 0.8% of the 624 patients in the placebo group (Prod Info ESBRIET(R) oral capsules, 2014).
    c) In 3 randomized, double-blind, placebo-controlled trials of 1247 patients, increases in ALT and AST concentrations 10 times or greater than the ULN developed in 0.3% of the 623 patients receiving pirfenidone 2403 mg/day (mean duration of exposure: 62 weeks; range 2 to 118 weeks) as compared with 0.2% of the 624 patients in the placebo group (Prod Info ESBRIET(R) oral capsules, 2014).
    B) INCREASED BILIRUBIN LEVEL
    1) WITH THERAPEUTIC USE
    a) Increased bilirubin concentration has been reported with postmarketing use of pirfenidone (Prod Info ESBRIET(R) oral capsules, 2014).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) AGRANULOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) Agranulocytosis has been reported with postmarketing use of pirfenidone (Prod Info ESBRIET(R) oral capsules, 2014).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) PHOTOSENSITIVITY
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, placebo-controlled trials of 1247 patients, photosensitivity reactions developed in 9% of the 623 patients receiving pirfenidone 2403 mg/day (mean duration of exposure: 62 weeks; range 2 to 118 weeks) as compared with 1% of the 624 patients in the placebo group (Prod Info ESBRIET(R) oral capsules, 2014).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, placebo-controlled trials of 1247 patients, rash developed in 30% of the 623 patients receiving pirfenidone 2403 mg/day (mean duration of exposure: 62 weeks; range 2 to 118 weeks) as compared with 10% of the 624 patients in the placebo group (Prod Info ESBRIET(R) oral capsules, 2014).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, placebo-controlled trials of 1247 patients, arthralgia developed in 10% of the 623 patients receiving pirfenidone 2403 mg/day (mean duration of exposure: 62 weeks; range 2 to 118 weeks) as compared with 7% of the 624 patients in the placebo group (Prod Info ESBRIET(R) oral capsules, 2014).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANGIOEDEMA
    1) WITH THERAPEUTIC USE
    a) Angioedema has been reported with postmarketing use of pirfenidone (Prod Info ESBRIET(R) oral capsules, 2014).

Reproductive

    3.20.1) SUMMARY
    A) Pirfenidone is classified as FDA pregnancy category C. There are no adequate or well controlled studies of pirfenidone use in human pregnancy. Teratogenic and embryofetal effects were not observed during animal studies. It is unknown whether pirfenidone is excreted into human milk, and the effects on the nursing infant from exposure to the drug in milk have not been determined.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) During an embryofetal development study in rats and rabbits, administration of oral pirfenidone up to 3 and 2 times the maximum recommended daily dose (MRDD) in adults, respectively, showed no evidence of fetal harm (Prod Info ESBRIET(R) oral capsules, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Pirfenidone is classified as FDA pregnancy category C (Prod Info ESBRIET(R) oral capsules, 2014).
    2) There are no adequate or well controlled studies of pirfenidone use in human pregnancy. Teratogenic and embryofetal effects were not observed during animal studies. Due to the lack of human safety data and because animal studies are not always indicative of human response, pirfenidone should be used during pregnancy only if the potential maternal benefit outweighs the potential fetal risk (Prod Info ESBRIET(R) oral capsules, 2014).
    B) ANIMAL STUDIES
    1) Prolongation of the gestation period, decreases in the number of live newborns, and decreased pup viability and body weights were observed in rats following doses of pirfenidone approximately 3 times the MRDD in adults (Prod Info ESBRIET(R) oral capsules, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Lactation studies with pirfenidone have not been conducted. It is unknown whether pirfenidone is excreted into human milk, and the effects on the nursing infant from exposure to the drug in milk have not been determined. However, radio-labeled pirfenidone and/or its metabolites were excreted into the milk of lactating rats. It is recommended to either discontinue nursing or pirfenidone, because excretion of pirfenidone and/or its metabolites in human milk are possible and the potential for serious adverse reactions from pirfenidone exists in nursing infants (Prod Info ESBRIET(R) oral capsules, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) During a fertility study in rats and rabbits, administration of oral pirfenidone up to 3 and 2 times the maximum recommended daily dose (MRDD) in adults, respectively, showed no evidence of impaired fertility. Acyclic/irregular cycles (eg, prolonged estrous cycle) were observed in rats following doses equal to and higher than the MRDD in adults (Prod Info ESBRIET(R) oral capsules, 2014).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) In animal carcinogenicity studies, the administration of pirfenidone 800 mg/kg or higher (AUC exposure approximately 0.4 times adult exposure at the MRDD) to B6C3F1 mice and pirfenidone 750 mg/kg and higher (AUC exposure approximately 1.9 times adult exposure at the MRDD) to Fischer rats resulted in statistically significant dose-related increases in the incidence of hepatocellular adenoma and carcinoma and hepatoblastoma in male mice and hepatocellular adenoma and carcinoma in male rats (Prod Info ESBRIET(R) oral capsules, 2014).
    2) In female mice, pirfenidone doses of 2000 mg/kg and higher (AUC exposure approximately 0.7 times adult exposure are the MRDD), resulted in statistically significant dose-related increases of the combination of hepatocellular adenoma and carcinoma. In rats, pirfenidone doses of 1500 mg/kg/day (AUC exposure approximately 2 times adult exposure at the MRDD) resulted in statistically significant increases in hepatocellular adenoma and carcinoma, as well as uterine adenocarcinoma and adenoma (Prod Info ESBRIET(R) oral capsules, 2014).

Genotoxicity

    A) Based on the results of mutagenicity tests in bacteria, a chromosomal aberration test in Chinese hamster lung cells, and a micronucleus test in mice, pirfenidone was not mutagenic or clastogenic (Prod Info ESBRIET(R) oral capsules, 2014).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs, CBC with differential, and liver enzymes following significant overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

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 severe symptoms despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs, CBC with differential, and liver enzymes following significant overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    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) 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) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs, CBC with differential, and liver enzymes following significant overdose.
    3) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Enhanced Elimination

    A) HEMODIALYSIS
    1) It is unknown if hemodialysis would be effective in overdose.

Range Of Toxicity

Summary

    A) TOXICITY: The maximum tolerated dose of pirfenidone was 4005 mg/day when healthy adult volunteers received 5 pirfenidone 267 mg capsules 3 times daily over a 12-day dose escalation.
    B) THERAPEUTIC DOSE: ADULT: Initially, 267 mg (1 capsule) orally 3 times daily for 7 days, then 534 mg (2 capsules) orally 3 times daily on days 8 through 14, then 801 mg (3 capsules) orally 3 times daily thereafter; maximum dose: 2403 mg/day (9 capsules/day). CHILD: The safety and efficacy of pirfenidone have not established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) Initially, 267 mg (1 capsule) orally 3 times daily for 7 days, then 534 mg (2 capsules) orally 3 times daily on days 8 through 14, then 801 mg (3 capsules) orally 3 times daily thereafter; maximum dose: 2403 mg/day (9 capsules/day) (Prod Info ESBRIET(R) oral capsules, 2014).
    7.2.2) PEDIATRIC
    A) The safety and efficacy of pirfenidone have not established in pediatric patients (Prod Info ESBRIET(R) oral capsules, 2014).

Minimum Lethal Exposure

    A) A minimum lethal dose has not been established.

Maximum Tolerated Exposure

    A) The maximum tolerated dose of pirfenidone was 4005 mg/day when healthy adult volunteers received 5 pirfenidone 267 mg capsules 3 times daily over a 12-day dose escalation (Prod Info ESBRIET(R) oral capsules, 2014).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The precise mechanism of action of pirfenidone has not been established (Prod Info ESBRIET(R) oral capsules, 2014). However, pirfenidone's ability to interfere with TNF-alpha in human astrocytes may prove useful in the treatment of multiple sclerosis (Walker & Cox, 1998), and data demonstrating pirfenidone's ability to inhibit lung fibroblast proliferation supports it's role in treating obliterative bronchiolitis (Dosanjh et al, 1998).

Physicochemical

Physical Characteristics

    A) A white to pale yellow, non-hygroscopic powder, more soluble in methanol, ethanol, acetone and chloroform than in water (Prod Info ESBRIET(R) oral capsules, 2014).

Molecular Weight

    A) 185.23 (Prod Info ESBRIET(R) oral capsules, 2014)

References

General Bibliography

    1) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    2) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    3) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    4) Dosanjh AK, Wan B, Throndset W, et al: Pirfenidone: a novel antifibrotic agent with implication for the treatment of obliterative bronchiolitis. Transplant Proc 1998; 30:1910-1911.
    5) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    6) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    7) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    8) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    9) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    10) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    11) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    12) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    13) Product Information: ESBRIET(R) oral capsules, pirfenidone oral capsules. InterMune, Inc. (per Manufacturer), Brisbane, CA, 2014.
    14) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    15) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    16) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    17) Walker JE & Cox N: Oral pirfenidone (Deskar) in severe chronic progressive multiple sclerosis. Mult Scler 1998; 4(6):521.