DEMSER^* (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.

Last updated on RxList: 11/20/2008

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.

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 of 100.

MERCK AND CO., INC., Whitehouse Station, NJ 08889,USA. Issued April 2002. FDA Rev date:

Last updated on RxList: 11/20/2008

Central Nervous System

Sedation: 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 persist.

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: 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

Diarrhea occurs in about 10 percent of patients and may be severe. Anti-diarrheal agents may be required if continuation of DEMSER is necessary.

Miscellaneous

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.

Caution 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.

Concurrent use of DEMSER with alcohol or other CNS depressants can increase their sedative effects. (See WARNINGS and PRECAUTIONS: Information for Patients.)

Laboratory Test Interference

Spurious increases in urinary catecholamines may be observed in patients receiving DEMSER due to the presence of metabolites of the drug.

Last updated on RxList: 11/20/2008

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

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.

Relatively Little 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenic studies in animals and studies on mutagenesis and impairment of fertility have not been performed with metyrosine.

Pregnancy

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.

Nursing Mothers

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.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 12 years have not been established.

Geriatric Use

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.

Last updated on RxList: 11/20/2008

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.

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

Last updated on RxList: 11/20/2008

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 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 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 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, T.A.; Cooperman, L.H.; Hammond, W.G.: Pheochromocytoma: Current concepts of diagnosis and treatment, Ann. Intern. Med. 65: 1302-1326, Dec. 1966.

Last updated on RxList: 11/20/2008

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.

Patients should be advised to maintain a liberal fluid intake. (See PRECAUTIONS, General.)

Last updated on RxList: 11/20/2008

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

METYROSINE - ORAL

(me-TYE-roe-seen)

COMMON BRAND NAME(S): Demser

USES: This medication is used to treat high blood pressure in people with a certain adrenal gland tumor (pheochromocytoma). Metyrosine is used to prevent high blood pressure before and immediately after surgery to remove the tumor. It is also used long-term in people who cannot have the surgery. It is not used for other kinds of high blood pressure.

Metyrosine prevents the tumor from making certain natural substances (catecholamines) that raise the blood pressure and make the heart beat faster. Lowering the amount of catecholamines lessens the risk of a very serious attack of high blood pressure (hypertensive crisis).

HOW TO USE: Take this medication by mouth with or without food, usually 4 times a day or as directed by your doctor. The dosage is based on your medical condition and response to treatment. Do not take more than a total of 4 grams each day.

Your doctor may direct you to start taking this drug at a low dose and slowly increase your dose until you are taking the best dose for you. Your doctor will check your blood pressure and order lab tests (e.g., urine tests for catecholamines) to find the best dose.

During treatment with this medication, it is important that you get plenty of fluids and pass urine frequently to help avoid kidney and bladder side effects. Ask your doctor how much fluid you should drink and how often you should urinate each day, and follow these instructions carefully.

Use this medication regularly to get the most benefit from it. To help you remember, take it at the same times each day. Do not stop taking this medication without consulting your doctor. It is important to continue taking this medication even if you feel well. Most people with high blood pressure do not feel sick. You may have trouble sleeping (insomnia) for 2 to 3 days after you stop taking this medication. Tell your doctor if these symptoms persist or worsen or if you have other symptoms of very high blood pressure (e.g., headache, nausea, sweating, fast heartbeat).

This medication is usually taken for at least 5 to 7 days before surgery.

Tell your doctor if your condition does not improve or if it worsens (e.g., headache, nausea, sweating, fast heartbeat, high blood pressure readings).

SIDE EFFECTS: Drowsiness, tiredness, dizziness, lightheadedness, dry mouth, and diarrhea may occur as your body adjusts to the medication. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

To lower your risk of dizziness and lightheadedness, get up slowly when rising from a sitting or lying position.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: difficulty speaking, drooling, unwanted/uncontrolled movements, muscle stiffness, shaking (tremor), decrease in sexual ability, tenderness/swelling of the breast.

Tell your doctor immediately if any of these rare but very serious side effects occur: mental/mood changes (e.g., confusion, depression, severe anxiety), painful urination, pink/bloody urine, change in the amount of urine.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking metyrosine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney disease, liver disease, severe loss of body water (dehydration), small amount of urine.

Before having surgery, tell your doctor or dentist that you are taking this medication.

This drug may make you drowsy or dizzy. Use caution while driving, using machinery, or doing any other activity that requires alertness. Avoid alcoholic beverages because alcohol may increase drowsiness/dizziness and may also cause you to lose too much body water (become dehydrated).

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: anti-psychotic medication (e.g., haloperidol, thiothixene), certain drugs (phenothiazines) used to treat mental/mood conditions or nausea (e.g., chlorpromazine, prochlorperazine).

Tell your doctor or pharmacist if you also take drugs that cause drowsiness such as: certain antihistamines (e.g., diphenhydramine), anti-seizure drugs (e.g., carbamazepine), medicine for sleep or anxiety (e.g., alprazolam, diazepam, zolpidem), muscle relaxants, narcotic pain relievers (e.g., codeine), psychiatric medicines (e.g., risperidone, amitriptyline, trazodone).

Check the labels on all your medicines (e.g., cough-and-cold products, diet aids, nonsteroidal anti-inflammatory drugs-NSAIDs such as ibuprofen for pain/fever reduction) because they may contain ingredients that cause drowsiness or could increase your blood pressure. Ask your pharmacist about using those products safely.

Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., blood pressure, EKG, urine catecholamine tests) should be performed regularly to monitor your progress or check for side effects. Consult your doctor for more details.

Have your blood pressure checked regularly while taking this medication. Learn how to monitor your own blood pressure at home, and share the results with your doctor.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.