DEMSER ® (metyrosine) Capsules

DEMSER (metyrosine) is (–)-α-methyl-L-tyrosine or (α-MPT). It has the following structural formula:

Metyrosine is a white to off-white, crystalline compound of molecular weight 195.22. It is very slightly soluble in water, acetone, and methanol, and insoluble in chloroform and benzene. It is soluble in acidic aqueous solutions. It is also soluble in alkaline aqueous solutions, but is subject to oxidative degradation under these conditions.

DEMSER is supplied as capsules for oral administration. Each capsule contains 250 mg metyrosine.

Inactive ingredients are colloidal silicon dioxide, gelatin, hydroxypropyl cellulose, magnesium stearate, titanium dioxide, FD&C Blue 2 and edible black ink.

DEMSER inhibits tyrosine hydroxylase, which catalyzes the first transformation in catecholamine biosynthesis, i.e., the conversion of tyrosine to dihydroxyphenylalanine (DOPA). Because the first step is also the rate-limiting step, blockade of tyrosine hydroxylase activity results in decreased endogenous levels of catecholamines, usually measured as decreased urinary excretion of catecholamines and their metabolites.

In patients with pheochromocytoma, who produce excessive amounts of norepinephrine and epinephrine, administration of 1 to 4 grams of DEMSER per day has reduced catecholamine biosynthesis from about 35% to 80% as measured by the total excretion of catecholamines and their metabolites (metanephrine and vanillylmandelic acid). The maximum biochemical effect usually occurs within two to three days, and the urinary concentration of catecholamines and their metabolites usually returns to pretreatment levels within three to four days after DEMSER is discontinued. In some patients the total excretion of catecholamines and catecholamine metabolites may be lowered to normal or near normal levels (less than 10 mg/24 hours). In most patients, the duration of treatment has been two to eight weeks, but several patients have received DEMSER for periods of 1 to 10 years.

Most patients with pheochromocytoma treated with DEMSER experience decreased frequency and severity of hypertensive attacks with their associated headache, nausea, sweating, and tachycardia. In patients who respond, blood pressure decreases progressively during the first two days of therapy with DEMSER; after withdrawal, blood pressure usually increases gradually to pretreatment values within two to three days.

Metyrosine is well absorbed from the gastrointestinal tract. From 53% to 88% (mean 69%) was recovered in the urine as unchanged drug following maintenance oral doses of 600 to 4000 mg/24 hours in patients with pheochromocytoma or essential hypertension. Less than 1% of the dose was recovered as catechol metabolites. These metabolites are probably not present in sufficient amounts to contribute to the biochemical effects of metyrosine. The quantities excreted, however, are sufficient to interfere with accurate determination of urinary catecholamines determined by routine techniques.

Plasma half-life of metyrosine determined over an 8-hour period after single oral doses was 3-3.7 hours in three patients.

For further information, refer to: Sjoerdsma A, Engelman K, Waldman TA, Cooperman LH, Hammond WG. Pheochromocytoma: Current Concepts of Diagnosis and Treatment: Combined Clinical Staff Conference at the National Institutes of Health. Ann Intern Med. 1966;65:1302-1326.

DEMSER is indicated in the treatment of patients with pheochromocytoma for:

1. Preoperative preparation of patients for surgery

2. Management of patients when surgery is contraindicated

3. Chronic treatment of patients with malignant pheochromocytoma

DEMSER is not recommended for the control of essential hypertension.

DEMSER is contraindicated in persons known to be hypersensitive to this compound.

Maintain Fluid Volume During and After Surgery
When DEMSER is used preoperatively, alone or especially in combination with alpha-adrenergic blocking drugs, 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.

In addition, life-threatening arrhythmias may occur during anesthesia and surgery, and may require treatment with a beta-blocker or lidocaine. During surgery, patients should have continuous monitoring of blood pressure and electrocardiogram.

Intraoperative Effects
While the preoperative use of DEMSER in patients with pheochromocytoma is thought to decrease intraoperative problems with blood pressure control, DEMSER 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.

Interaction with Alcohol
DEMSER may add to the sedative effects of alcohol and other CNS depressants, e.g., hypnotics, sedatives, and tranquilizers. (See PRECAUTIONS, Information for Patients and Drug Interactions .)

General

Signs of metyrosine overdosage include those central nervous system effects observed in some patients even at low dosages.

At doses exceeding 2000 mg/day, some degree of sedation or feeling of fatigue may persist. Doses of 2000-4000 mg/day can result in anxiety or agitated depression, neuromuscular effects (including fine tremor of the hands, gross tremor of the trunk, tightening of the jaw with trismus), diarrhea, and decreased salivation with dry mouth.

Reduction of drug dose or cessation of treatment results in the disappearance of these symptoms.

The acute toxicity of metyrosine was 442 mg/kg and 752 mg/kg in the female mouse and rat, respectively.

The recommended initial dosage of DEMSER for adults and children 12 years of age and older is 250 mg orally four times daily. This may be increased by 250 mg to 500 mg every day to a maximum of 4 g/day in divided doses. When used for preoperative preparation, the optimally effective dosage of DEMSER should be given for at least five to seven days.

Optimally effective dosages of DEMSER usually are between 2 and 3 g/day, and the dose should be titrated by monitoring clinical symptoms and catecholamine excretion. In patients who are hypertensive, dosage should be titrated to achieve normalization of blood pressure and control of clinical symptoms. In patients who are usually normotensive, dosage should be titrated to the amount that will reduce urinary metanephrines and/or vanillylmandelic acid by 50% or more.

If patients are not adequately controlled by the use of DEMSER, an alpha-adrenergic blocking agent (phenoxybenzamine) should be added.

Use of DEMSER in children under 12 years of age has been limited and a dosage schedule for this age group cannot be given.

DEMSER Capsules 250 mg are blue opaque capsules imprinted with “ATON/305” on body, and “DEMSER” on cap, filled with white to off-white granular free-flowing powder. They are supplied as follows:

     NDC 25010-305-15 bottles of 100

Storage: Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Dispense in a well-closed container.

Distributed by:

Bausch Health US, LLC

Bridgewater, NJ 08807 USA

Manufactured by:

Bausch Health Companies Inc.

Steinbach, MB R5G 1Z7, Canada

DEMSER is a trademark of Bausch Health Companies Inc. or its affiliates.

© 2021 Bausch Health Companies Inc. or its affiliates

Rev. 07/2021                                                                                                          9620202 20003159

NDC 25010-305-15

Rx only

Demser^®
(metyrosine)
Capsules

250 mg

100 Capsules

Each capsule contains
250 mg metyrosine

BAUSCH Health