Demser

Other Cardiovascular Agents

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

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

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

Demser

Rx

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

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.

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.

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.

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

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

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.
Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with metyrosine can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
Barbiturates: (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.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) The concomitant administration of metyrosine with barbiturates can result in additive sedative effects.
Butalbital; Aspirin; Caffeine; Codeine: (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.
Diphenoxylate; Atropine: (Moderate) Concurrent administration of diphenoxylate/difenoxin with metyrosine can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression. (Moderate) The concomitant administration of metyrosine with alcohol 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.
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.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (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.
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.

Demser/Metyrosine Oral Cap: 250mg

4 grams/day PO

4 grams/day PO.

4 grams/day PO.

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.

Safety and efficacy have not been established.

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.

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

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.

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.