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METYROSINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Metyrosine is a tyrosine hydroxylase inhibitor, blocking the conversion of tyrosine to dihydroxyphenylalanine, resulting in decreased levels of endogenous catecholamines.

Specific Substances

    1) 4-Hydroxy-alpha-methylphenylalanine
    2) (-)-alpha-methyl-L-tyrosine
    3) alpha-MPT
    4) AMPT
    5) Metirosine
    6) L-588357-0
    7) MK-781
    8) Molecular Formula: C10-H13-N-O3
    9) CAS 672-87-7 (metyrosine)
    10) CAS 620-30-4 (racemetyrosine)
    1.2.1) MOLECULAR FORMULA
    1) C10-H13-N-O3 (Sweetman, 2005)

Available Forms Sources

    A) FORMS
    1) Metyrosine is available as 250 mg capsules (Prod Info DEMSER(R) oral capsules, 2010).
    B) USES
    1) Metyrosine is indicated for the treatment of pheochromocytoma as preoperative preparation for surgery. It is also indicated for the management of pheochromocytoma in patients when surgery is contraindicated and for the chronic treatment of malignant pheochromocytoma (Prod Info DEMSER(R) oral capsules, 2010).

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: Metyrosine is indicated for the treatment of pheochromocytoma as preoperative preparation for surgery. It is also indicated for the management of pheochromocytoma in patients when surgery is contraindicated and for the chronic treatment of malignant pheochromocytoma.
    B) PHARMACOLOGY: Metyrosine blocks the rate-limiting step in the biosynthetic pathway of catecholamines. It is a tyrosine hydroxylase inhibitor, blocking the conversion of tyrosine to dihydroxyphenylalanine. This inhibition results in decreased levels of endogenous catecholamines.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Moderate to severe sedation is the most common adverse effect with metyrosine therapy. Other adverse effects that appear to be dose-dependent include extrapyramidal signs (eg, drooling, tremor, and speech difficulty), anxiety, agitation, hallucinations, confusion, diarrhea, and dry mouth. Nausea, vomiting, and abdominal pain may infrequently occur with metyrosine therapy. Peripheral edema, crystalluria, transient dysuria and hematuria, eosinophilia, anemia, thrombocytopenia, and thrombocytosis, and hypersensitivity reactions have been reported rarely.
    E) WITH POISONING/EXPOSURE
    1) Overdose information is limited. It is anticipated that overdose effects would be an extension of adverse effects occurring during therapeutic use. Persistent fatigue or sedation, anxiety, agitation, diarrhea, dry mouth, decreased salivation, and extrapyramidal signs, including tremors of the hands and trunk and tightening of the jaw with trismus, may occur following an overdose.
    0.2.20) REPRODUCTIVE
    A) FDA pregnancy category C

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status in symptomatic patients.
    C) Monitor serum electrolytes in patients with severe diarrhea and/or vomiting.
    D) Examine urine following overdose for evidence of crystalluria, and monitor urine output. Monitor renal function in patients with crystalluria.

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. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression and subsequent aspiration.
    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) Ensure adequate ventilation and perform endotracheal intubation early in patients with significant CNS depression or severe allergic reactions.
    E) ANTIDOTE
    1) None.
    F) INTRAVENOUS FLUID
    1) Administer oral or intravenous fluid to maintain a urine output of at least 2000 mL/day.
    G) DRUG-INDUCED DYSTONIA
    1) Treat dystonia with either benztropine or diphenhydramine.
    H) ENHANCED ELIMINATION
    1) It is unknown if hemodialysis would be effective in overdose.
    I) 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.
    J) PITFALLS
    1) When managing a suspected metyrosine overdose, the possibility of multidrug involvement should be considered.
    K) PHARMACOKINETICS
    1) Well absorbed from the GI tract following ingestion. Less than 1% of a metyrosine dose is recovered as catechol metabolites, insufficient to contribute to the biochemical effects of metyrosine. Following oral maintenance doses of 600 to 4000 mg/24 hours, 53% to 88% of metyrosine (mean 69%) was recovered in the urine as unchanged drug. Elimination half-life: 3 to 3.7 hours.
    L) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause dystonia or dyskinesia (eg, antipsychotics, neuroleptics).

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. Persistent fatigue or sedation may occur following metyrosine doses greater than 2000 mg/day. Anxiety, agitation, diarrhea, dry mouth with decreased salivation, and extrapyramidal signs, including tremors of the hands and trunk and tightening of the jaw with trismus, may occur following metyrosine doses 2000 to 4000 mg/day.
    B) THERAPEUTIC DOSE: ADULTS AND CHILDREN 12 YEARS AND OLDER: The initial recommended dose is 250 mg orally 4 times daily. The dosage may be increased by 250 to 500 mg daily to a maximum dose of 4 grams daily in divided doses.

Clinical Effects

Summary Of Exposure

    A) USES: Metyrosine is indicated for the treatment of pheochromocytoma as preoperative preparation for surgery. It is also indicated for the management of pheochromocytoma in patients when surgery is contraindicated and for the chronic treatment of malignant pheochromocytoma.
    B) PHARMACOLOGY: Metyrosine blocks the rate-limiting step in the biosynthetic pathway of catecholamines. It is a tyrosine hydroxylase inhibitor, blocking the conversion of tyrosine to dihydroxyphenylalanine. This inhibition results in decreased levels of endogenous catecholamines.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Moderate to severe sedation is the most common adverse effect with metyrosine therapy. Other adverse effects that appear to be dose-dependent include extrapyramidal signs (eg, drooling, tremor, and speech difficulty), anxiety, agitation, hallucinations, confusion, diarrhea, and dry mouth. Nausea, vomiting, and abdominal pain may infrequently occur with metyrosine therapy. Peripheral edema, crystalluria, transient dysuria and hematuria, eosinophilia, anemia, thrombocytopenia, and thrombocytosis, and hypersensitivity reactions have been reported rarely.
    E) WITH POISONING/EXPOSURE
    1) Overdose information is limited. It is anticipated that overdose effects would be an extension of adverse effects occurring during therapeutic use. Persistent fatigue or sedation, anxiety, agitation, diarrhea, dry mouth, decreased salivation, and extrapyramidal signs, including tremors of the hands and trunk and tightening of the jaw with trismus, may occur following an overdose.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) OCULOGYRIC CRISIS: One case of oculogyric crisis has been reported in a patient who was treated with metyrosine 1750 to 3000 mg daily (Sweet, 1974).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) Peripheral edema has been rarely reported in patients receiving metyrosine (Prod Info DEMSER(R) oral capsules, 2010).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEDATION
    1) WITH THERAPEUTIC USE
    a) Moderate to severe sedation is very common with metyrosine therapy, occurring in the majority of patients. Sedation onset begins within 24 hours of initiating therapy with maximal effects occurring 2 to 3 days later. The effect usually disappears after 1 week of therapy; however, sedation or fatigue may persist with metyrosine doses that exceed 2000 mg/day (Prod Info DEMSER(R) oral capsules, 2010).
    b) Every patient in one study (n=10) experienced transient mild-to-moderate sedation after receiving metyrosine 3 g/day for a period of 3 weeks (Nasrallah et al, 1977).
    c) In one study, 5 out of 6 patients experienced lethargy or fatigue after 1750 to 3000 mg/day (Sweet, 1974).
    2) WITH POISONING/EXPOSURE
    a) Persistent fatigue or sedation may occur with overdose (Prod Info DEMSER(R) oral capsules, 2010).
    B) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Anxiety, agitation, depression, hallucinations, confusion, and disorientation may occur with metyrosine therapy and appear to be dose-related (Prod Info DEMSER(R) oral capsules, 2010; Engelman, 1988).
    b) Three of 11 healthy volunteers, who were given alpha-methyl-para tyrosine (AMPT) therapy during a clinical trial and who were sleep-deprived, experienced repeated panic attacks. At the time of the panic attacks, the three patients had been awake for 15 to 30 hours. The total dose of AMPT given ranged from 3 to 4.5 grams and the number of hours since the last dose ranged from 1 to 6 hours. Following cessation of therapy, mild anxiety persisted for approximately 18 hours, with complete resolution noted at follow-up visits 9 months later (McCann et al, 1991).
    2) WITH POISONING/EXPOSURE
    a) Anxiety and agitation may occur with overdose (Prod Info DEMSER(R) oral capsules, 2010).
    C) EXTRAPYRAMIDAL SIGN
    1) WITH THERAPEUTIC USE
    a) Extrapyramidal signs including drooling, tremors of the hands and trunk, speech difficulty, and tightening of the jaw with trismus have been reported in approximately 10% of patients who received metyrosine therapy during clinical trials. These signs appeared to be dose-related, frequently occurring at metyrosine doses of 2000 to 4000 mg/day (Prod Info DEMSER(R) oral capsules, 2010).
    2) WITH POISONING/EXPOSURE
    a) Extrapyramidal signs, including tremors of the hands and trunk and tightening of the jaw with trismus may occur with overdose (Prod Info DEMSER(R) oral capsules, 2010).
    D) DYSTONIA
    1) WITH THERAPEUTIC USE
    a) Acute dystonic reactions were reported in 5 of 24 healthy volunteers (21%) who received alpha--methyl-para-tyrosine (AMPT), 750 mg four times daily, during a clinical trial to investigate the role of catecholamines in sleep and alertness. The dystonias occurred between 3.5 and 12 hours after the last AMPT dose had been given, and the total dose of AMPT that had been given, when the reactions occurred, ranged from 5.25 to 6.75 grams. The dystonias involved the neck and upper back and consisted of torticollis and retrocollis. Three of the 5 patients received diphenhydramine as treatment and did not experience a recurrence of the dystonia after receiving repeated doses of AMPT. Two of the 5 patients received neck massages with a change in posture (from sitting to a supine position). Both patients experienced a recurrence of their dystonia when they would move from a supine to a sitting position (McCann et al, 1990).
    E) NEUROLEPTIC MALIGNANT SYNDROME
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 27-year-old man with Huntington's disease developed hyperthermia and dystonia while taking tetrabenazine and alpha-methyltyrosine for the 7 months for treatment of chorea. After discontinuing tetrabenazine and alpha-methyltyrosine therapy, the patient's dystonia and hyperthermia gradually resolved. Tetrabenazine therapy was restarted without a recurrence of the dystonia or fever (Burke et al, 1981).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea, possibly severe, has been reported in approximately 10% of patients, and may occur more frequently with metyrosine doses of 2000 to 4000 mg/day (Prod Info DEMSER(R) oral capsules, 2010).
    b) Patients maintained on 1250 to 2000 mg/day of metyrosine experienced diarrhea (Tscherdakoff, 1972)
    2) WITH POISONING/EXPOSURE
    a) Diarrhea may occur with overdose (Prod Info DEMSER(R) oral capsules, 2010).
    B) APTYALISM
    1) WITH THERAPEUTIC USE
    a) A dry mouth with decreased salivation may occur with metyrosine doses of 2000 to 4000 mg/day (Prod Info DEMSER(R) oral capsules, 2010).
    2) WITH POISONING/EXPOSURE
    a) Dry mouth with decreased salivation may occur with overdose (Prod Info DEMSER(R) oral capsules, 2010).
    C) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea, vomiting, and abdominal pain may infrequently occur with metyrosine therapy (Prod Info DEMSER(R) oral capsules, 2010).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) CRYSTALLURIA
    1) WITH THERAPEUTIC USE
    a) Crystalluria has been reported infrequently with metyrosine therapy. It is suggested that patients who ingest 2 g of metyrosine or more per day maintain sufficient water intake to achieve a daily urine volume of at least 2000 mL (Prod Info DEMSER(R) oral capsules, 2010).
    b) Crystalluria was reported in patients who received metyrosine in doses of 1750 to 3000 mg each day (Sweet, 1974).
    B) DYSURIA
    1) WITH THERAPEUTIC USE
    a) Transient dysuria and hematuria have been reported during metyrosine therapy (Prod Info DEMSER(R) oral capsules, 2010).
    C) IMPOTENCE
    1) WITH THERAPEUTIC USE
    a) Impotence or a failure to ejaculate may infrequently occur with metyrosine therapy (Prod Info DEMSER(R) oral capsules, 2010).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) Hematologic disorders including eosinophilia, anemia, thrombocytopenia, and thrombocytosis have been rarely reported with metyrosine therapy (Prod Info DEMSER(R) oral capsules, 2010).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) GALACTORRHEA NOT ASSOCIATED WITH CHILDBIRTH
    1) WITH THERAPEUTIC USE
    a) Galactorrhea may infrequently occur with metyrosine therapy (Prod Info DEMSER(R) oral capsules, 2010; Engelman, 1988).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Hypersensitivity reactions including urticaria and pharyngeal edema have been reported rarely in patients who received metyrosine therapy during clinical trials (Prod Info DEMSER(R) oral capsules, 2010).

Reproductive

    3.20.1) SUMMARY
    A) FDA pregnancy category C
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) Animal reproduction studies have not been conducted with metyrosine (Prod Info Demser(R), 2002).
    B) GROWTH RETARDATION
    1) In one case report, a woman with pheochromocytoma who was treated with metyrosine from 30 to 33 weeks gestation delivered a growth-retarded infant, who subsequently did well. She was also taking prazosin and timolol (Devoe et al, 1986).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified metyrosine as FDA pregnancy category C (Prod Info Demser(R), 2002).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is unknown whether metyrosine is excreted in human breast milk (Prod Info Demser(R), 2002).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS672-87-7 (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
    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) Long-term carcinogenicity studies have not been conducted in animals (Prod Info Demser(R), 2002).

Genotoxicity

    A) Mutagenicity studies on metyrosine have not been performed (Prod Info Demser(R), 2002).

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 and mental status in symptomatic patients.
    C) Monitor serum electrolytes in patients with severe diarrhea and/or vomiting.
    D) Examine urine following overdose for evidence of crystalluria, and monitor urine output. Monitor renal function in patients with crystalluria.
    4.1.2) SERUM/BLOOD
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor serum electrolytes in patients with severe diarrhea and/or vomiting.
    4.1.3) URINE
    A) Examine urine for evidence of crystalluria, particularly in patients on high-dose metyrosine therapy (greater than 2 g/day). Monitor urine output it patients with crystalluria. In order to minimize the risk of crystalluria, it is suggested that patients, who ingest 2 g of metyrosine or more per day, maintain sufficient water intake to achieve a daily urine volume of at least 2000 mL (Prod Info DEMSER(R) oral capsules, 2010).
    B) LABORATORY TEST INTERFERENCE: Less than 1% of a metyrosine dose is recovered as catechol metabolites. The catechol metabolites may interfere with accurate determination of urinary catecholamines (Prod Info DEMSER(R) oral capsules, 2010).

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 and mental status in symptomatic patients.
    C) Monitor serum electrolytes in patients with severe diarrhea and/or vomiting.
    D) Examine urine following overdose for evidence of crystalluria, and monitor urine output. Monitor renal function in patients with crystalluria.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression and subsequent aspiration.
    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. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. 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 and mental status in symptomatic patients.
    3) Monitor serum electrolytes in patients with severe diarrhea and/or vomiting.
    4) Examine urine following overdose for evidence of crystalluria, and monitor urine output. Monitor renal function in patients with crystalluria.
    C) ACUTE ALLERGIC REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).
    D) DYSTONIA
    1) ADULT
    a) BENZTROPINE: 1 to 4 mg once or twice daily intravenously or intramuscularly; maximum dose: 6 mg/day; 1 to 2 mg of the injection will usually provide quick relief in emergency situations (Prod Info benztropine mesylate IV, IM injection, 2009).
    b) DIPHENHYDRAMINE: 10 to 50 mg intravenously at a rate not exceeding 25 mg/minute or deep intramuscularly; maximum dose: 100 mg/dose; 400 mg/day (Prod Info diphenhydramine hcl injection, 2006).
    2) CHILDREN
    a) DIPHENHYDRAMINE: 5 mg/kg/day or 150 mg/m(2)/day intravenously divided into 4 doses at a rate not to exceed 25 mg/min, or deep intramuscularly; maximum dose: 300 mg/day. Not recommended in premature infants and neonates (Prod Info diphenhydramine hcl injection, 2006).
    3) Five of 21 patients developed acute dystonic reactions, involving the head and upper back, after receiving alpha-methyl-para-tyrosine (AMPT), 750 mg 4 times daily (total dose ranged from 5.25 to 6.75 grams). Three patients were treated with diphenhydramine (50 mg IV or 25 mg orally) and 2 patients received neck massages with a change in posture (from a sitting to a supine position). The patients who received diphenhydramine as treatment did not experience a recurrence of the dystonia after receiving repeat doses of AMPT. The patients who received the neck massage with a change in posture experienced a recurrence of the dystonia when they were placed in a sitting position (McCann et al, 1990).

Enhanced Elimination

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

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. Persistent fatigue or sedation may occur following metyrosine doses greater than 2000 mg/day. Anxiety, agitation, diarrhea, dry mouth with decreased salivation, and extrapyramidal signs, including tremors of the hands and trunk and tightening of the jaw with trismus, may occur following metyrosine doses 2000 to 4000 mg/day.
    B) THERAPEUTIC DOSE: ADULTS AND CHILDREN 12 YEARS AND OLDER: The initial recommended dose is 250 mg orally 4 times daily. The dosage may be increased by 250 to 500 mg daily to a maximum dose of 4 grams daily in divided doses.

Therapeutic Dose

    7.2.1) ADULT
    A) The initial recommended dose is 250 milligrams orally 4 times daily. The dosage may be increased by 250 to 500 milligrams daily to a maximum dose of 4 grams daily in divided doses. The optimally effective dose is typically between 2 to 3 grams daily (Prod Info Demser(R), 2002). In order to minimize the risk of crystalluria, it is suggested that patients, who ingest 2 g of metyrosine or more per day, maintain sufficient water intake to achieve a daily urine volume of at least 2000 mL.
    7.2.2) PEDIATRIC
    A) Children 12 years of age and older - The initial recommended dose is 250 milligrams orally 4 times daily. The dosage may be increased by 250 to 500 milligrams daily to a maximum dose of 4 grams daily in divided doses. The optimally effective dose is typically between 2 to 3 grams daily (Prod Info Demser(R), 2002).
    B) Children less than 12 years of age - Safety and efficacy have not been established (Prod Info Demser(R), 2002).

Maximum Tolerated Exposure

    A) Persistent fatigue or sedation may occur following metyrosine doses greater than 2000 mg/day. Anxiety, agitation, diarrhea, dry mouth with decreased salivation, and extrapyramidal signs, including tremors of the hands and trunk and tightening of the jaw with trismus, may occur following metyrosine doses 2000 to 4000 mg/day (Prod Info DEMSER(R) oral capsules, 2010).

Workplace Standards

    A) ACGIH TLV Values for CAS672-87-7 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS672-87-7 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS672-87-7 :
    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 CAS672-87-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Metyrosine blocks the rate-limiting step in the biosynthetic pathway of catecholamines. It is a tyrosine hydroxylase inhibitor, blocking the conversion of tyrosine to dihydroxyphenylalanine. This inhibition results in decreased levels of endogenous catecholamines (Prod Info Demser(R), 2002).
    B) Catecholamine biosynthesis is reduced by 35% to 80% in patients treated with 1 to 4 grams of metyrosine daily (Prod Info Demser(R), 2002).

Physicochemical

Physical Characteristics

    A) Metyrosine is a white crystalline compound that is soluble in acidic aqueous solutions, very slightly soluble in water, acetone, and methanol, and insoluble in chloroform and benzene (Prod Info Demser(R), 2002).

Molecular Weight

    A) 195.2 (Sweetman, 2005)

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