metyroSINE (Monograph)

Drug class: Pheochromocytoma
ATC class: C02KB01
VA class: CV490
CAS number: 672-87-7

Medically reviewed by Drugs.com on Mar 10, 2024. Written by ASHP.

Introduction

Metyrosine is an inhibitor of catecholamine synthesis.

Uses for metyroSINE

Pheochromocytoma

Metyrosine is used for the short-term management of patients with pheochromocytoma until surgery is performed and for prolonged management when surgery is contraindicated. The drug is also used for long-term management of patients with malignant pheochromocytoma. In most patients with pheochromocytoma, metyrosine decreases the frequency and severity of hypertensive attacks and the resultant headache, nausea, sweating, and tachycardia. In patients who are not adequately controlled by metyrosine, phenoxybenzamine should be administered concurrently. Metyrosine has been used in only a very limited number of patients; in most, the duration of metyrosine therapy has been 2–8 weeks, but some have received the drug for 1–10 years.

Phenoxybenzamine generally has been considered the drug of choice for the medical management of patients with pheochromocytoma until surgery is performed and for prolonged management of hypertension caused by pheochromocytoma that is not amenable to surgery. Propranolol may be used as an adjunct to phenoxybenzamine to control symptoms resulting from excessive β-adrenergic receptor stimulation in patients with inoperable or metastatic pheochromocytoma, or to control tachycardia prior to or during pheochromocytomectomy. Metyrosine has been effective in some patients refractory to phenoxybenzamine, and addition of metyrosine to phenoxybenzamine therapy has achieved better control of the symptoms of pheochromocytoma than phenoxybenzamine alone. Although some clinicians prefer metyrosine to adrenergic blockers, more widespread use of metyrosine is required to determine whether the drug is more useful than phenoxybenzamine alone or with propranolol in the management of pheochromocytoma.

Hypertension

Although metyrosine effectively decreases blood pressure in patients with pheochromocytoma, in most patients with hypertension (i.e., unknown etiology), metyrosine does not decrease blood pressure. Metyrosine should not be used for the treatment of hypertension of unknown etiology.

Mental Disorders

In a limited number of patients with chronic schizophrenic disorder^{† [off-label]}, metyrosine has potentiated the antipsychotic effects of thioridazine and chlorpromazine, thereby allowing a decrease in the dosage of these phenothiazines. In other studies, however, metyrosine did not potentiate the antipsychotic effects of phenothiazines (chlorpromazine, fluphenazine, thioridazine), and further studies are required to establish the usefulness of this combined therapy. In addition, since metyrosine might potentiate extrapyramidal symptoms in patients receiving phenothiazines or haloperidol, there may be no advantage to using metyrosine in combination with these antipsychotic drugs. (See Drug Interactions: Antipsychotic Agents.) Some studies in patients with acute and chronic schizophrenic disorder indicate that metyrosine alone does not have antipsychotic effects. In one limited study, some patients with bipolar disorder^{† [off-label]} (manic) became less manic during metyrosine therapy (2–4 g daily).

Other Uses

Because of its inhibitory effect on the synthesis of catecholamines, metyrosine has been used to elucidate the mechanism of action of some drugs^{† [off-label]} and to investigate the role of catecholamines in various disease states^{† [off-label]}.

Related/similar drugs

propranolol, labetalol, Inderal, Trandate, phentolamine, phenoxybenzamine

metyroSINE Dosage and Administration

Administration

Metyrosine is administered orally.

Dosage

Pheochromocytoma

Dosage of metyrosine must be adjusted to achieve normalization of blood pressure and control of symptoms in patients with pheochromocytoma who have associated hypertension. In patients with pheochromocytoma who are usually normotensive, dosage of the drug must be adjusted to decrease urinary concentrations of metanephrines and/or VMA by 50% or more. If the effects of pheochromocytoma are not adequately controlled by metyrosine alone, an α-Adrenergic blocking agent (e.g., phenoxybenzamine) should be added to the therapeutic regimen.

For the short-term management of pheochromocytoma until surgery is performed or for the long-term management of pheochromocytoma when surgery is contraindicated or when malignant, the usual initial oral dosage of metyrosine in adults and children 12 years of age and older is 250 mg 4 times daily. Dosage may be increased by 250–500 mg every day up to a maximum total daily dosage of 4 g in divided doses. The optimum effective dosage of metyrosine is usually 2–3 g daily. When metyrosine is used prior to pheochromocytomectomy, the optimum effective dosage should be given for at least 5–7 days. Dosage in children younger than 12 years of age has not been established.

Mental Disorders

In patients with chronic schizophrenic disorder^{† [off-label]}, 1.5–3 g of metyrosine has been given daily in divided doses in conjunction with a phenothiazine. When combined therapy is used, the risk of metyrosine potentiating the extrapyramidal effects of the phenothiazine should be considered.

Cautions for metyroSINE

Sedation

The most common adverse effect during metyrosine therapy is moderate to severe sedation which occurs in almost all patients regardless of dosage. Sedation usually begins within the first 24 hours of therapy and is maximal after 2–3 days. Although sedation usually decreases after a few days, sedation or fatigue may persist, especially in patients receiving dosages greater than 2 g daily. In most patients who experience sedation, temporary changes in sleep pattern (i.e., insomnia for 2–3 days), feelings of increased alertness and ambition, and mild anxiety occur following discontinuance of metyrosine. When metyrosine is discontinued in patients who were not sedated, symptoms of psychic stimulation may occur.

Extrapyramidal Effects

Extrapyramidal symptoms such as drooling, speech difficulty, and tremor occur in about 10% of patients receiving metyrosine. Less frequently, trismus and frank parkinsonian syndrome have been reported. Extrapyramidal symptoms disappear following a reduction in metyrosine dosage or discontinuance of the drug. Diphenhydramine will partially relieve metyrosine-induced extrapyramidal symptoms.

Other Nervous System Effects

Mental depression may develop or worsen in patients receiving metyrosine. Anxiety, tremulousness, excitability, and psychic disturbances such as hallucinations, disorientation, emotional instability, and confusion have occurred in some patients; these adverse nervous system effects may disappear following a reduction in dosage.

Diarrhea

Diarrhea occurs in about 10% of patients receiving metyrosine. Occasionally, metyrosine-induced diarrhea is severe. Antidiarrhea agents may be required if it is necessary to continue metyrosine therapy.

Other Adverse Effects

Crystalluria and transient dysuria and hematuria have occurred in a few patients receiving metyrosine, and the urine should be examined regularly for metyrosine crystals (needles or rods). Urolithiasis has occurred in dogs who received metyrosine dosages similar to those used in humans.

Slight swelling of the breasts, galactorrhea, nasal stuffiness, decreased salivation, dry mouth, headache, enuresis, nausea, vomiting, abdominal pain, and impotence or failure to ejaculate may occur infrequently. Adverse hematologic effects (including eosinophilia, anemia, thrombocytopenia, and thrombocytosis), increased serum AST (SGOT) concentrations, peripheral edema, and hypersensitivity reactions (including urticaria and pharyngeal edema) have occurred rarely.

Precautions and Contraindications

Patients should be warned that metyrosine may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle).

To minimize the risk of crystalluria during metyrosine therapy, patients should be instructed to maintain fluid intake sufficient to achieve a urine volume of 2 L or more daily, especially when they are receiving more than 2 g of metyrosine daily. If metyrosine crystalluria occurs, fluid intake should be increased further; if crystalluria persists, dosage of metyrosine should be decreased or the drug discontinued.

The patient’s blood pressure and ECG should be monitored continuously during surgery for pheochromocytoma. Although preoperative use of metyrosine in patients with pheochromocytoma may prevent or control paroxysmal hypertension caused by anesthesia or operative manipulation of the tumor, the danger of hypertensive crises and arrhythmias is not eliminated, and IV administration of phentolamine may be required. In addition, administration of a β-adrenergic blocker (e.g., propranolol) or lidocaine may be required to treat serious arrhythmias during anesthesia and surgery. When metyrosine is used preoperatively (alone and especially with an α-adrenergic blocking drug), adequate intravascular volume must be maintained during surgery (especially after removal of the pheochromocytoma) and postoperatively. The hypotension and decreased blood volume that commonly follow removal of a pheochromocytoma are prevented by administration of large volumes of blood, plasma, 5% albumin in 0.9% sodium chloride injection, and/or IV fluids.

Since metyrosine has been used in only a limited number of patients and because few patients have used the drug for prolonged periods, appropriate laboratory tests should be performed periodically during long-term administration. Animal studies to determine the long-term safety of metyrosine have not been performed.

Metyrosine should be used with caution in patients with impaired hepatic or renal function.

Metyrosine is contraindicated in patients with a known hypersensitivity to the drug.

Pediatric Precautions

Clinical experience with metyrosine in children younger than 12 years of age is limited, and safety and efficacy of the drug in this age group have not been established. Specific dosage recommendations for children younger than 12 years of age have not been established.

Mutagenicity and Carcinogenicity

Studies to determine the mutagenic and carcinogenic potentials of metyrosine have not been performed.

Pregnancy, Fertility, and Lactation

Pregnancy

Animal reproduction studies using metyrosine have not been performed to date. It is not known whether metyrosine can cause fetal harm when administered to pregnant women. There are no adequate and controlled studies to date using metyrosine in pregnant women. Metyrosine should be used during pregnancy only when clearly needed.

Fertility

It is not known whether metyrosine affects fertility. Impotence and failure to ejaculate have occurred infrequently during metyrosine therapy.

Lactation

Since it is not known whether metyrosine is distributed into milk, the drug should be used with caution in nursing women.

Drug Interactions

CNS Depressants

Metyrosine may be additive with, or may potentiate the action of, alcohol and other CNS depressants such as hypnotics, sedatives, tranquilizers, and anxiolytic agents.

Antipsychotic Agents

Metyrosine should be used with caution in patients receiving phenothiazines or butyrophenones (e.g., haloperidol) because the extrapyramidal effects of these drugs may be potentiated by metyrosine-induced inhibition of catecholamine synthesis.

Laboratory Test Interferences

Falsely elevated concentrations of urinary catecholamines resulting from the presence of catechol metabolites of metyrosine may be reported for patients without pheochromocytoma receiving the drug.

Pharmacology

By competitively inhibiting tyrosine 3-monoxygenase (tyrosine hydroxylase), metyrosine inhibits the conversion of tyrosine to dihydroxyphenylalanine (dopa) in the brain, sympathetic neurons, and the chromaffin cells of the adrenal medulla and pheochromocytomas. Because tyrosine 3-monoxygenase catalyzes the first and rate-limiting step in catecholamine synthesis, inhibition of this enzyme by metyrosine decreases endogenous catecholamine concentrations in patients with normal or increased catecholamine production. In patients with pheochromocytoma who produce excessive amounts of norepinephrine and epinephrine, administration of 1–4 g of metyrosine daily decreases catecholamine synthesis by 35–80% as measured by the total excretion of catecholamines and their metabolites [metanephrines and vanillylmandelic acid (VMA)]; in some of these patients, total excretion of catecholamines and their metabolites may be decreased to approximately normal levels (less than 10 mg/24 hours). In patients without pheochromocytoma receiving metyrosine, urinary VMA concentrations are used as an index of decreased catecholamine production.

metyroSINE Pharmacokinetics

Absorption

Metyrosine is well absorbed from the GI tract following oral administration. Following oral administration of a single 1-g dose of metyrosine in one study in healthy fasting adults, peak plasma metyrosine concentrations of 12–14 mcg/mL were attained within 1–3 hours. In patients with pheochromocytoma, blood pressure decreases gradually during the first 2 days of therapy with metyrosine, and urinary concentrations of catecholamines and their metabolites usually decrease maximally within 2–3 days. When metyrosine is discontinued in patients with pheochromocytoma, blood pressure gradually increases to pretreatment levels within 2–3 days, and urinary concentrations of catecholamines and their metabolites return to pretreatment levels within 3–4 days.

Distribution

Limited information is available on the distribution of metyrosine into human body tissues and fluids; however, the drug crosses the blood-brain barrier. It is not known if metyrosine is distributed into milk.

Elimination

In healthy individuals, the plasma half-life of metyrosine is about 3.4–7.2 hours.

Metyrosine undergoes minimal biotransformation in the body. Following oral metyrosine maintenance dosages of 600 mg to 4 g daily in patients with pheochromocytoma or hypertension, 53–88% of the dose is excreted in urine as unchanged drug within 24 hours. Less than 1% of the drug is excreted in urine as catechol metabolites (i.e., methyldopa, methyldopamine, and methylnorepinephrine) and α-methyltyramine; these metabolites probably do not contribute to the pharmacologic effects of metyrosine.

Chemistry and Stability

Chemistry

Metyrosine is an inhibitor of catecholamine synthesis. The drug occurs as a white, crystalline compound and is very slightly soluble in water and practically insoluble in alcohol. Metyrosine occurs as the L- and D-isomers; only the L-isomer, the form contained in metyrosine capsules, is pharmacologically active. Solubility is increased in acidic or alkaline aqueous solutions. (See Chemistry and Stability: Stability.) Metyrosine has pK_a values of 2.7 and 10.1.

Stability

Metyrosine capsules should be stored in well-closed containers at a temperature less than 40°C, preferably between 15–30°C. Although solubility of the drug is increased in alkaline aqueous solutions, metyrosine undergoes oxidative degradation in these solutions.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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