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  • CLASSES

    All Other Cardiac Preparations

    DEA CLASS

    Rx

    DESCRIPTION

    Oral drug that decreases production of catecholamines by blocking tyrosine hydroxylase; useful for pheochromocytoma; more useful agents preclude use for HTN.

    COMMON BRAND NAMES

    Demser

    HOW SUPPLIED

    Demser Oral Cap: 250mg

    DOSAGE & INDICATIONS

    For the short-term management of patients with pheochromocytoma who are awaiting surgery, or for long-term management of malignant pheochromocytoma when surgery is contraindicated.
    Oral dosage
    Adults and Adolescents

    Initially, 250 mg PO four times daily. Dosage may be increased by 250—500 mg/day. The usual dosage is 2—3 g/day given in 4 divided doses, up to a maximum of 4 g/day. When used preoperatively the patient should receive the drug for at least 5—7 days. In hypertensive patients, the dosage should be adjusted to control blood pressure and clinical symptoms. In normotensive patients, the dosage should be adjusted such that urinary metanephrines and/or vanillylmandelic acid is decreased by 50% or more. If adequate control can not be achieved with metyrosine, an alpha-blocker such as phenoxybenzamine should be added.

    MAXIMUM DOSAGE

    Adults

    4 g/day PO

    Elderly

    4 g/day PO.

    Adolescents

    4 g/day PO.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    Administer orally without regard to meals.

    STORAGE

    Demser:
    - Storage information not listed

    CONTRAINDICATIONS / PRECAUTIONS

    Parkinson's disease

    Metyrosine causes extrapyramidal effects and should be used with caution in patients with Parkinson's disease.

    Driving or operating machinery

    Central nervous system effects can increase depression and confusion, and impair mental alertness. Moderate to severe sedation is possible and has been reported in most patients taking metyrosine. Patients should be advised to exercise caution when driving or operating machinery until the effects of metyrosine is known.

    Hepatic disease, renal disease

    Metyrosine has been administered for prolonged periods of time in only a few patients, so the safety of long-term administration has not been established. Patients with hepatic disease or renal disease should be treated with cautiously with prolonged therapy.

    Dehydration

    Dehydration contraindicates use of metyrosine. An adequate fluid balance (daily urinary volume of 2 L or more) should be maintained to minimize the risk of developing metyrosine-induced crystalluria. Fluid intake should be increased if crystalluria occurs. If crystalluria persists, the dosage of metyrosine may need to be reduced or the drug discontinued.

    Surgery

    Preoperative administration of metyrosine can decrease the incidence of paroxysmal hypertensive crisis during surgery for pheochromocytoma, but hypertensive crisis and/or arrhythmias can still occur due to anesthesia or movement of the tumor. Patients should be carefully monitored for arrhythmias and hypertension (blood pressure and ECGs) during surgery. Intravenous phentolamine may be required as well as beta-adrenergic-blocker administration.

    Pregnancy

    Metyrosine is classified as FDA pregnancy risk category C. No adequate human or animal studies have been undertaken to assess adverse fetal effects. It is also not known whether metyrosine can cause fetal harm when administered to a pregnant woman or if the drug can affect reproduction capacity. Metyrosine should be given during pregnancy only if clearly needed. The definitive treatment for pheochromocytoma is surgery, but in patients past 24 weeks gestation, problems with tumor accessibility may delay surgery. In these patients, alpha- blockade is indicated in the treatment of hypertension secondary to pheochromocytoma in order to reduce maternal and fetal mortality; phenoxybenzamine is the drug of choice (see phenoxybenzamine monograph).

    Breast-feeding

    It is not known whether metyrosine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when metyrosine is administered to a breast-feeding woman. The molecular weight of the drug is low enough that passage to breast milk might be expected, and the pharmacology of the drug might have adverse effect on the nursing infant.

    ADVERSE REACTIONS

    Moderate

    dysarthria / Delayed / 10.0-10.0
    hematuria / Delayed / Incidence not known
    crystalluria / Delayed / Incidence not known
    dysuria / Early / Incidence not known
    trismus / Delayed / Incidence not known
    confusion / Early / Incidence not known
    depression / Delayed / Incidence not known
    hallucinations / Early / Incidence not known
    galactorrhea / Delayed / Incidence not known
    peripheral edema / Delayed / Incidence not known
    thrombocytosis / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known

    Mild

    tremor / Early / 10.0-10.0
    hypersalivation / Early / 10.0-10.0
    diarrhea / Early / 10.0-10.0
    fatigue / Early / 10.0
    drowsiness / Early / 10.0
    headache / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    abdominal pain / Early / Incidence not known
    vomiting / Early / Incidence not known
    xerostomia / Early / Incidence not known
    nausea / Early / Incidence not known
    nasal congestion / Early / Incidence not known
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: (Moderate) The concomitant administration of metyrosine with barbiturates can result in additive sedative effects.
    Acetaminophen; Butalbital; Caffeine: (Moderate) The concomitant administration of metyrosine with barbiturates can result in additive sedative effects.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) The concomitant administration of metyrosine with barbiturates can result in additive sedative effects.
    Amobarbital: (Moderate) The concomitant administration of metyrosine with barbiturates can result in additive sedative effects.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) The concomitant administration of metyrosine with barbiturates can result in additive sedative effects.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) The concomitant administration of metyrosine with barbiturates can result in additive sedative effects.
    Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with metyrosine can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Diphenoxylate: (Moderate) Concurrent administration of diphenoxylate/difenoxin with metyrosine can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) The concomitant administration of metyrosine with barbiturates can result in additive sedative effects.
    Barbiturates: (Moderate) The concomitant administration of metyrosine with barbiturates can result in additive sedative effects.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) The concomitant administration of metyrosine with barbiturates can result in additive sedative effects.
    Benzodiazepines: (Moderate) The concomitant administration of metyrosine with benzodiazepines can result in additive sedative effects.
    Butabarbital: (Moderate) The concomitant administration of metyrosine with barbiturates can result in additive sedative effects.
    Carbidopa; Levodopa: (Major) The extrapyramidal effects of metyrosine can antagonize the effects of levodopa. Dosage adjustments of either of these medications may be required.
    Carbidopa; Levodopa; Entacapone: (Major) The extrapyramidal effects of metyrosine can antagonize the effects of levodopa. Dosage adjustments of either of these medications may be required.
    Chlorpromazine: (Moderate) Because it also blocks central dopamine receptors, metyrosine should be avoided or used cautiously in patients receiving a phenothiazine to minimize the risk of additive adverse CNS effects. A dose reduction may be required if combination therapy is necessary.
    Codeine; Phenylephrine; Promethazine: (Moderate) The concomitant administration of metyrosine with promethazine can result in additive sedative effects.
    Codeine; Promethazine: (Moderate) The concomitant administration of metyrosine with promethazine can result in additive sedative effects.
    Dextromethorphan; Promethazine: (Moderate) The concomitant administration of metyrosine with promethazine can result in additive sedative effects.
    Ethanol: (Moderate) The concomitant administration of metyrosine with ethanol can result in additive sedative effects.
    Fluphenazine: (Moderate) Because it also blocks central dopamine receptors, metyrosine should be avoided or used cautiously in patients receiving a phenothiazine to minimize the risk of additive adverse CNS effects. A dose reduction may be required if combination therapy is necessary.
    Haloperidol: (Moderate) The extrapyramidal effects of haloperidol can be increased by concomitant administration of metyrosine.
    Levodopa: (Major) The extrapyramidal effects of metyrosine can antagonize the effects of levodopa. Dosage adjustments of either of these medications may be required.
    Meperidine; Promethazine: (Moderate) The concomitant administration of metyrosine with promethazine can result in additive sedative effects.
    Mephobarbital: (Moderate) The concomitant administration of metyrosine with barbiturates can result in additive sedative effects.
    Mesoridazine: (Moderate) Because it also blocks central dopamine receptors, metyrosine should be avoided or used cautiously in patients receiving a phenothiazine to minimize the risk of additive adverse CNS effects. A dose reduction may be required if combination therapy is necessary.
    Methohexital: (Moderate) The concomitant administration of metyrosine with barbiturates can result in additive sedative effects.
    Metoclopramide: (Major) Metoclopramide is a central dopamine antagonist and may cause extrapyramidal reactions such as acute dystonic reactions, pseudo-parkinsonism, akathisia, or tardive dyskinesia. Metyrosine decreases the endogenous production of catecholamines. Metyrosine precipitates extrapyramidal symptoms in approximately 10% of patients receiving the drug. The manufacturer of metoclopramide does not specifically contraindicate the use of metoclopramide and metyrosine; however, coadministration should be avoided if possible.
    Molindone: (Moderate) The extrapyramidal effects of molindone can be increased by concomitant administration of metyrosine.
    Opiate Agonists: (Moderate) The concomitant administration of metyrosine with opiate agonists can result in additive sedative effects.
    Pentobarbital: (Moderate) The concomitant administration of metyrosine with barbiturates can result in additive sedative effects.
    Perphenazine: (Moderate) Because it also blocks central dopamine receptors, metyrosine should be avoided or used cautiously in patients receiving a phenothiazine to minimize the risk of additive adverse CNS effects. A dose reduction may be required if combination therapy is necessary.
    Perphenazine; Amitriptyline: (Moderate) Because it also blocks central dopamine receptors, metyrosine should be avoided or used cautiously in patients receiving a phenothiazine to minimize the risk of additive adverse CNS effects. A dose reduction may be required if combination therapy is necessary.
    Phenobarbital: (Moderate) The concomitant administration of metyrosine with barbiturates can result in additive sedative effects.
    Phenothiazines: (Moderate) Because it also blocks central dopamine receptors, metyrosine should be avoided or used cautiously in patients receiving a phenothiazine to minimize the risk of additive adverse CNS effects. A dose reduction may be required if combination therapy is necessary.
    Phenylephrine; Promethazine: (Moderate) The concomitant administration of metyrosine with promethazine can result in additive sedative effects.
    Primidone: (Moderate) The concomitant administration of metyrosine with barbiturates can result in additive sedative effects.
    Prochlorperazine: (Moderate) Because it also blocks central dopamine receptors, metyrosine should be avoided or used cautiously in patients receiving a phenothiazine to minimize the risk of additive adverse CNS effects. A dose reduction may be required if combination therapy is necessary.
    Promethazine: (Moderate) The concomitant administration of metyrosine with promethazine can result in additive sedative effects.
    Secobarbital: (Moderate) The concomitant administration of metyrosine with barbiturates can result in additive sedative effects.
    Sedating H1-blockers: (Moderate) The concomitant administration of metyrosine with sedating H1-blockers can result in additive sedative effects.
    Thiethylperazine: (Moderate) Because it also blocks central dopamine receptors, metyrosine should be avoided or used cautiously in patients receiving a phenothiazine to minimize the risk of additive adverse CNS effects. A dose reduction may be required if combination therapy is necessary.
    Thiopental: (Moderate) The concomitant administration of metyrosine with barbiturates can result in additive sedative effects.
    Thioridazine: (Moderate) Because it also blocks central dopamine receptors, metyrosine should be avoided or used cautiously in patients receiving a phenothiazine to minimize the risk of additive adverse CNS effects. A dose reduction may be required if combination therapy is necessary.
    Thiothixene: (Moderate) Because it also blocks central dopamine receptors, metyrosine, should be avoided or used cautiously in patients receiving thiothixene to minimize the risk of additive adverse CNS effects.
    Tricyclic antidepressants: (Moderate) The concomitant administration of metyrosine with sedating H1-blockers can result in additive sedative effects.
    Trifluoperazine: (Moderate) Because it also blocks central dopamine receptors, metyrosine should be avoided or used cautiously in patients receiving a phenothiazine to minimize the risk of additive adverse CNS effects. A dose reduction may be required if combination therapy is necessary.

    PREGNANCY AND LACTATION

    Pregnancy

    Metyrosine is classified as FDA pregnancy risk category C. No adequate human or animal studies have been undertaken to assess adverse fetal effects. It is also not known whether metyrosine can cause fetal harm when administered to a pregnant woman or if the drug can affect reproduction capacity. Metyrosine should be given during pregnancy only if clearly needed. The definitive treatment for pheochromocytoma is surgery, but in patients past 24 weeks gestation, problems with tumor accessibility may delay surgery. In these patients, alpha- blockade is indicated in the treatment of hypertension secondary to pheochromocytoma in order to reduce maternal and fetal mortality; phenoxybenzamine is the drug of choice (see phenoxybenzamine monograph).

    It is not known whether metyrosine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when metyrosine is administered to a breast-feeding woman. The molecular weight of the drug is low enough that passage to breast milk might be expected, and the pharmacology of the drug might have adverse effect on the nursing infant.

    MECHANISM OF ACTION

    Mechanism of Action: Metyrosine acts to decrease the excess production of catecholamines by blocking tyrosine hydroxylase, the rate-limiting enzyme of catecholamine synthesis. Inhibition of this enzyme decreases the endogenous production of catecholamines, thereby reducing epinephrine and norepinephrine concentrations in patients with normal or excessive catecholamine production. In patients with pheochromocytoma, this activity alleviates attacks of hypertension and subsequently reduces headaches, nausea, sweating, and tachycardia. Catecholamine plasma-concentration decreases of between 35—80% can be obtained by administering 1—4 grams of metyrosine daily.

    PHARMACOKINETICS

    Metyrosine is administered orally. The distribution patterns of the drug have not been clearly elucidated, and it is not known whether the drug distributes into breast milk. Metyrosine appears to cross the blood-brain barrier. The drug is not metabolized to any significant extent; less than 1% is recovered as metabolites. Plasma half-life has been determined over an 8-hour period as 3.4—3.7 hours. Excretion is via the kidney; 53—88% of a 600 mg to 4 g daily dose is excreted unchanged in the urine within 24 hours.

    Oral Route

    Metyrosine is well absorbed across the GI tract following oral administration. Administration of a 1 gm dose of the drug results in peak plasma concentrations of 12—14 mcg/ml, attained within 1—3 hours.