Vademecum

Metyrosine Demser�

 

Description: Metyrosine is an orally administered agent used to inhibit catecholamine synthesis in patients with pheochromocytoma, a chromaffin cell tumor that produces excessive amounts of epinephrine and norepinephrine. Metyrosine can be useful in patients who are refractory to phenoxybenzamine therapy, or it can be administered as an adjunct to phenoxybenzamine therapy. Metyrosine also has been used to treat essential hypertension, but other more useful agents preclude its use. Metyrosine was approved by the FDA in 1979. 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 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 �g/mL, attained within 1�3 hours. 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�4 g daily dose is excreted unchanged in the urine within 24 hours.

Indications...Dosage 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 PO 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. Children: Safe and effective use has not been established. Patients with renal impairment: Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Administration Oral Administration �Metyrosine is administered as 250 mg capsules

Contraindications Metyrosine causes extrapyramidal effects and should be used with caution in patients with Parkinson's disease. Central nervous system effects can increase depression and confusion, and impair mental alertness. 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 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. Metyrosine is classified as pregnancy category C. No adequate human or animal studies have been undertaken to assess adverse fetal effects. If used during pregnancy, the potential risks to the fetus must be weighed against the potential benefits to the mother. 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.

Interactions The concomitant administration metyrosine with ethanol, tricyclic antidepressants, opiate agonists, barbiturates, benzodiazepines, H1-blockers, or other CNS agents can result in additive sedative effects. The extrapyramidal effects of haloperidol, metoclopramide, molindone, or phenothiazines can be increased by concomitant administration of metyrosine. The extrapyramidal effects of metyrosine can antagonize the effects of levodopa, and dosage adjustments of either of these medications may be required.

Adverse Reactions Metyrosine causes sedation, which can be moderate to severe, and usually affects all patients within 24 hours. Metyrosine can hamper the patient's ability to operate machinery or drive a motor vehicle, and patients should be advised of the drug's potential to impair mental alertness. These effects may decrease with continued therapy, but they persist in a few cases. Cessation of metyrosine therapy in patients who were sedated by the drug can result in feelings of increased alertness and mild anxiety, and changes in sleeping patterns. Patients who did not experience sedation can experience psychic stimulation upon discontinuance of the drug. Patients should be instructed to maintain an adequate fluid balance (daily urinary volume of 2 L or more) 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 diminished. Administration of metyrosine precipitates extrapyramidal symptoms in approximately 10% of patients receiving the drug. Such effects include increased hypersalivation, tremor, and speech difficulty. Other more infrequent effects include trismus and pseudoparkinsonism. Dosage reduction or discontinuance of the drug can alleviate these symptoms. These symptoms may be partially relieved by administering diphenhydramine. Metyrosine use can precipitate or worsen mental depression, resulting in such effects as anxiety, tremulousness, confusion, and psychic disturbances. Dosage reductions can alleviate these symptoms. Diarrhea is a common adverse effect associated with metyrosine administration, and it can be severe, necessitating the use of antidiarrheal agents if metyrosine therapy must be continued. Other uncommon adverse effects associated with metyrosine administration include dry mouth, impotence or ejaculation dysfunction (failure to ejaculate), hematologic toxicity, galactorrhea, swelling of the breasts, peripheral edema, and urticaria.