PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Other Cardiovascular Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Oral agent that decreases the production of catecholamines by blocking tyrosine hydroxylase
    Used to treat patients with pheochromocytoma
    Should not be used for the control of essential hypertension

    COMMON BRAND NAMES

    Demser

    HOW SUPPLIED

    Demser Oral Cap: 250mg

    DOSAGE & INDICATIONS

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

    Initially, 250 mg PO 4 times daily. May titrate by 250 to 500 mg/day. The usual dosage is 2 to 3 grams/day given in 4 divided doses, up to a maximum of 4 grams/day. When used preoperatively the patient should receive the drug for at least 5 to 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 are decreased by 50% or more. If adequate control can not be achieved with metyrosine, an alpha-blocker such as phenoxybenzamine should be added.

    Children and Adolescents 12 years and older

    Initially, 250 mg PO 4 times daily. May titrate by 250 to 500 mg/day. The usual dosage is 2 to 3 grams/day given in 4 divided doses, up to a maximum of 4 grams/day. When used preoperatively the patient should receive the drug for at least 5 to 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 are decreased by 50% or more. If adequate control can not be achieved with metyrosine, an alpha-blocker such as phenoxybenzamine should be added.

    Children less than 12 years

    Safety and efficacy have not been established. Use of metyrosine in children less than 12 years of age has been limited and a dosage schedule for this age group cannot be given.

    MAXIMUM DOSAGE

    Adults

    4 grams/day PO

    Geriatric

    4 grams/day PO.

    Adolescents

    4 grams/day PO.

    Children

    12 years: 4 grams/day PO.
    1 to 11 years: Safety and efficacy have not been established. Clinical use has been limited; a maximum dosage for this age group cannot be given.

    Infants

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    It appears that no dosage adjustments are needed since metyrosine is not extensively metabolized; the manufacturer recommends caution.

    Renal Impairment

    Specific data in renal impairment are not available; use caution since metyrosine is extensively excreted by the kidney.

    ADMINISTRATION

    Oral Administration

    Administer orally without regard to meals.
    Advise patients to maintain a liberal fluid intake.

    STORAGE

    Demser:
    - Storage information not listed

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Metyrosine is contraindicated for use in patients who have a known metyrosine hypersensitivity.

    Dehydration, hypovolemia, surgery

    Patients should be advised to maintain liberal fluid intake and avoid dehydration while taking metyrosine. Patients who receive metyrosine preoperatively should be carefully monitored (blood pressure and ECGs) during surgery. When metyrosine is used preoperatively, alone or especially in combination with alpha-adrenergic blocking drugs, avoid hypovolemia; adequate intravascular volume must be maintained intraoperatively (especially after tumor removal) and postoperatively to avoid hypotension and decreased perfusion of vital organs resulting from vasodilatation and expanded volume capacity. Following tumor removal, large volumes of plasma may be needed to maintain blood pressure and central venous pressure within the normal range. While the preoperative use of metyrosine in patients with pheochromocytoma is thought to decrease intraoperative problems with blood pressure control, metyrosine use does not eliminate the danger of hypertensive crises or arrhythmias during manipulation of the tumor, and the alpha-adrenergic blocking drug, phentolamine, may be needed. Life-threatening arrhythmias may occur during anesthesia and surgery, and may require treatment with a beta-blocker or lidocaine.

    Nephrolithiasis

    Crystalluria and nephrolithiasis (urolithiasis) have been found in dogs treated with metyrosine at doses similar to those used in humans, and crystalluria has also been observed in a few patients. To minimize the risk of crystalluria, urge patients to maintain water/fluid intake sufficient to achieve a daily urine volume of 2,000 mL or more, particularly when doses greater than 2 grams/day are given. A routine examination of the urine should be carried out. Metyrosine will crystallize as needles or rods. If metyrosine crystalluria occurs, fluid intake should be increased further. If crystalluria persists, the dosage should be reduced or the drug discontinued.

    Driving or operating machinery

    The most common adverse reaction to metyrosine is moderate to severe sedation, which has been observed in almost all patients, and at all dosages. Patients should be advised to exercise caution when driving or operating machinery or performing other hazardous tasks until the effects of the drug are known. Inform patients that metyrosine may have additive sedative effects with alcohol and other CNS depressants (e.g., hypnotics, sedatives, and tranquilizers).

    Hepatic disease, renal impairment

    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. Suitable laboratory tests should be carried out periodically in patients requiring prolonged use of the drug. Patients with hepatic disease or renal impairment should be treated with cautiously with prolonged therapy; metyrosine is not appreciably metabolized but is significantly excreted unchanged by the kidney.

    Pregnancy

    It is not known whether metyrosine can cause fetal harm when administered to a pregnant woman or if the drug can affect reproduction capacity. No adequate human or animal studies have been undertaken to assess adverse fetal effects. Metyrosine should be given during pregnancy only if clearly needed. The definitive treatment for pheochromocytoma is surgery, but in patients who are past 24 weeks gestation, problems with tumor accessibility may delay surgery. Pretreatment with an alpha-blocker, such as phenoxybenzamine or doxazosin, is recommended prior to surgical removal of the tumor to reduce maternal and fetal mortality; metyrosine is not recommended for use in pregnant women.

    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
    fatigue / Early / 10.0
    drowsiness / Early / 10.0
    hematuria / Delayed / Incidence not known
    nephrolithiasis / Delayed / Incidence not known
    crystalluria / Delayed / Incidence not known
    dysuria / Early / Incidence not known
    pseudoparkinsonism / Delayed / Incidence not known
    trismus / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    confusion / Early / Incidence not known
    hallucinations / Early / Incidence not known
    thrombocytosis / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    galactorrhea / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    peripheral edema / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known

    Mild

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

    DRUG INTERACTIONS

    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.
    Butalbital; Acetaminophen: (Moderate) The concomitant administration of metyrosine with barbiturates can result in additive sedative effects.
    Butalbital; Acetaminophen; Caffeine: (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) 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; Promethazine: (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.
    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) 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.
    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.
    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) 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; Dextromethorphan: (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; Phenylephrine: (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.
    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

    It is not known whether metyrosine can cause fetal harm when administered to a pregnant woman or if the drug can affect reproduction capacity. No adequate human or animal studies have been undertaken to assess adverse fetal effects. Metyrosine should be given during pregnancy only if clearly needed. The definitive treatment for pheochromocytoma is surgery, but in patients who are past 24 weeks gestation, problems with tumor accessibility may delay surgery. Pretreatment with an alpha-blocker, such as phenoxybenzamine or doxazosin, is recommended prior to surgical removal of the tumor to reduce maternal and fetal mortality; metyrosine is not recommended for use in pregnant women.

    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

    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% to 80% can be obtained by administering 1 to 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 to 3.7 hours. Excretion is via the kidney; 53% to 88% of a 600 mg to 4 grams/day dose is excreted unchanged in the urine within 24 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters: None

    Oral Route

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