DEMSER1 (Metyrosine) is (-)-α-methyl-L-tyrosine or (α-MPT). It has
the following structural formula:
Metyrosine is a white, crystalline compound
of molecular weight 195. 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, and FD&C Blue 2.
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 one to four grams of DEMSER per day has reduced catecholamine biosynthesis
from about 35 to 80 percent 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 one to 10
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 percent (mean 69 percent)
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
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, T.A.; Cooperman, L.H.;
Hammond, W.G.: Pheochromocytoma: Current concepts of diagnosis and
treatment, Ann. Intern. Med. 65: 1302-1326, Dec. 1966.
INDICATIONS AND USAGE
DEMSER is indicated in the treatment of patients
with pheochromocytoma for:
Preoperative preparation of patients for surgery
Management of patients when surgery is contraindicated
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.
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.
Metyrosine Crystalluria: Crystalluria and urolithiasis have been found in
dogs treated with DEMSER (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, patients should be urged to
maintain water intake sufficient to achieve a daily urine volume of
2000 mL or more, particularly when doses greater than 2 g
per day are given. 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.
Data Regarding Long-term Use: The total human experience
with the drug is quite limited and few patients have been studied
long-term. Chronic animal studies have not been carried out. Therefore,
suitable laboratory tests should be carried out periodically in patients
requiring prolonged use of DEMSER and caution should be observed in
patients with impaired hepatic or renal function.
Information for Patients
When receiving DEMSER, patients should be warned about engaging in
activities requiring mental alertness and motor coordination, such
as driving a motor vehicle or operating machinery. DEMSER may have
additive sedative effects with alcohol and other CNS depressants,
e.g., hypnotics, sedatives, and tranquilizers.
should be observed in administering DEMSER to patients receiving phenothiazines
or haloperidol because the extrapyramidal effects of these drugs can
be expected to be potentiated by inhibition of catecholamine synthesis.
Spurious increases in urinary catecholamines may
be observed in patients receiving DEMSER due to the presence of metabolites
of the drug.
Impairment of Fertility
Long-term carcinogenic studies in animals and studies
on mutagenesis and impairment of fertility have not been performed
Pregnancy Category C
Animal reproduction studies have not been conducted with
DEMSER. It is also not known whether DEMSER can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity.
DEMSER should be given to a pregnant woman only if clearly needed.
It is not known whether DEMSER is excreted in human
milk. Because many drugs are excreted in human milk, caution should
be exercised when DEMSER is administered to a nursing woman.
Safety and effectiveness in pediatric patients below
the age of 12 years have not been established.
Clinical studies of DEMSER did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects. Other reported clinical experience
has not identified differences in responses between the elderly and
younger patients. In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing
range, reflecting the greater frequency of decreased hepatic, renal,
or cardiac function, and of concomitant disease or other drug therapy.
Central Nervous System
The most common adverse reaction to DEMSER is moderate
to severe sedation, which has been observed in almost all patients.
It occurs at both low and high dosages. Sedative effects begin within
the first 24 hours of therapy, are maximal after two to three days,
and tend to wane during the next few days. Sedation usually is not
obvious after one week unless the dosage is increased, but at dosages
greater than 2000 mg/day some degree of sedation or fatigue may
In most patients who experience sedation,
temporary changes in sleep pattern occur following withdrawal of the
drug. Changes consist of insomnia that may last for two or three days
and feelings of increased alertness and ambition. Even patients who
do not experience sedation while on DEMSER may report symptoms of
psychic stimulation when the drug is discontinued.
Extrapyramidal signs such as drooling, speech difficulty,
and tremor have been reported in approximately 10 percent of patients.
These occasionally have been accompanied by trismus and frank parkinsonism.
Anxiety and Psychic Disturbances
Anxiety and psychic disturbances such as depression,
hallucinations, disorientation, and confusion may occur. These effects
seem to be dose-dependent and may disappear with reduction of dosage.
Diarrhea occurs in about 10 percent of patients and
may be severe. Anti-diarrheal agents may be required if continuation
of DEMSER is necessary.
Infrequently, slight swelling of the breast, galactorrhea,
nasal stuffiness, decreased salivation, dry mouth, headache, nausea,
vomiting, abdominal pain, and impotence or failure of ejaculation
may occur. Crystalluria (see PRECAUTIONS) and transient dysuria and hematuria have been observed in a few
patients. Hematologic disorders (including eosinophilia, anemia, thrombocytopenia,
and thrombocytosis), increased SGOT levels, peripheral edema, and
hypersensitivity reactions such as urticaria and pharyngeal edema
have been reported rarely.
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
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.
DOSAGE AND ADMINISTRATION
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 4.0 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 2.0 and
3.0 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 percent 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.
No. 3355 — Capsules DEMSER, 250 mg,
are opaque, two-toned blue capsules coded MSD 690 on one side
and DEMSER on the other. They are supplied as follows:
NDC 0006-0690-68 bottles
Merck & Co.,
Inc., Whitehouse Station, NJ 08889, USA