Sansert^® (methysergide maleate) is a partially synthetic compound structurally related to lysergic acid butanolamide, well-known as methylergonovine in obstetrical practice as an oxytocic agent. Chemically, methysergide maleate is designated as ergoline-8-carboxamide, 9,10-didehydro-N-[1-(hydroxymethyl)propyl]-1,6-dimethyl-, (8ß)-, (Z)-2-butenedioate (1:1) (salt). The chemical structure is:

Methylation in the number 1 position of the ring structure enormously enhances the antagonism to serotonin which is present to a much lesser degree in the partially methylated compound (methylergonovine maleate) as well as profoundly altering other pharmacologic properties.

Active Ingredient: methysergide maleate, USP.

Inactive Ingredients: acacia, carnauba wax, colloidal silicon dioxide, FD&C Blue #1, FD&C Yellow #5, gelatin, lactose, malic acid, povidone, sodium benzoate, starch (corn), stearic acid, sucrose, synthetic black iron oxide, talc, and titanium dioxide.

For the prevention or reduction of intensity and frequency of vascular headaches in the following kinds of patients:

1. Patients suffering from one or more severe vascular headaches per week.

2. Patients suffering from vascular headaches that are uncontrollable or so severe that preventive therapy is indicated regardless of the frequency of the attack.

Usual adult dose 4-8 mg daily. Tablets to be given with meals.

Note: There must be a medication-free interval of 3-4 weeks after every 6-month course of treatment. (See WARNINGS) No pediatric dosage has been established.

If, after a 3-week trial period, efficacy has not been demonstrated, longer administration of Sansert^® (methysergide maleate) is unlikely to be of benefit.

Bright yellow, coated tablets with "SANDOZ" imprinted on one side, "78-58" imprinted on the other side, in black.

Bottle of 100.....................................................NDC 0078-0058-05

Below 86°F (30°C); tight container.

Considering structure/effect relationships, it has been demonstrated that methylation of the indole nitrogen in the lysergic acid ring of the alkanolamides fundamentally alters their pharmacologic behavior and is associated with inhibition or blockade of a great variety of serotonin-induced effects:

1. Methysergide maleate is 6 times more active than methylergonovine maleate in antagonizing the effect of serotonin on the rat uterus in vitro.

2. Greater inhibition of the serotonin-induced edema in the rats paw is revealed by the ^ED50 of 12.9 µg/kg for methysergide maleate as against 37.4 µg/kg for methylergonovine maleate

3. The more complex effects of serotonin on the cardiovascular system are equally subject to inhibition by methysergide maleate as is evident from the subsequent record of various circulatory parameters in the dog before and after administration of 10 µg/kg.

Oral administration of 1, 2, and 5 mg/kg/day of methysergide maleate failed to produce any major signs of toxicity over a period of 6 months.

*Trademark of Medical Economics Company, Inc.

Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936,

REV: NOVEMBER 2000, PRINTED IN USA, T2000-69 89011201

Within the recommended dose levels, the following side effects have been reported:

1) Fibrotic Complications

Fibrotic changes have been observed in the retroperitoneal, pleuropulmonary, cardiac, and other tissues, either singly or, very rarely, in combination.

This nonspecific fibrotic process is usually confined to the retroperitoneal connective tissue above the pelvic brim and may present clinically with one or more symptoms such as general malaise, fatigue, weight loss, backache, low grade fever (elevated sedimentation rate), urinary obstruction (girdle or flank pain, dysuria, polyuria, oliguria, elevated BUN), vascular insufficiency of the lower limbs (leg pain, Leriche syndrome, edema of legs, thrombophlebitis). The single most useful diagnostic procedure in suspected cases of retroperitoneal fibrosis is intravenous pyelography. Typical deviation and obstruction of one or both ureters may be observed.

A similar nonspecific fibrotic process, limited to the pleural and immediately subjacent pulmonary tissues, usually presents clinically with dyspnea, tightness and pain in the chest, pleural friction rubs, and pleural effusion. These findings may be confirmed by chest X-ray.

Nonrheumatic fibrotic thickenings of the aortic root and of the aortic and mitral valves usually present clinically with cardiac murmurs and dyspnea.

Several cases of fibrotic plaques, simulating Peyronies Disease have been described.

2) Cardiovascular Complications

Encroachment of retroperitoneal fibrosis on the aorta, inferior vena cava and their common iliac branches may result in vascular insufficiency of the lower limbs, the presenting features of which are mentioned under Retroperitoneal Fibrosis.

Intrinsic vasoconstriction of large and small arteries, involving one or more vessels or merely a segment of a vessel, may occur at any stage of therapy. Depending on the vessel involved, this complication may present with chest pain, abdominal pain, or cold, numb, painful extremities with or without paresthesias and diminished or absent pulses. Progression to ischemic tissue damage has rarely been reported. Prompt withdrawal of the drug at the first signs of impaired circulation is recommended (see WARNINGS) to obviate such effects.

Postural hypotension and tachycardia have also been observed.

3) Gastrointestinal Symptoms

Nausea, vomiting, diarrhea, heartburn, abdominal pain. These effects tend to appear early and can frequently be obviated by gradual introduction of the medication and by administration of the drug with meals. Constipation and elevation of gastric HCl have also been reported.

4) CNS Symptoms

Seizure, insomnia, drowsiness, mild euphoria, dizziness, ataxia, lightheadedness, hyperesthesia, unworldly feelings (described variously as "dissociation", "hallucinatory experiences", etc.). Some of these symptoms may be associated with vascular headaches, per se, and may, therefore, be unrelated to the drug.

5) Dermatological Manifestations

Facial flush, telangiectasia, and nonspecific rashes have rarely been reported. Increased hair loss may occur, but in many instances the tendency has abated despite continued therapy.

6) Edema

Peripheral edema, and, more rarely, localized brawny edema may occur. Dependent edema has responded to lowered doses, salt restriction, or diuretics.

7) Weight Gain

Weight gain may be a reason to caution patients regarding their caloric intake.

8) Hematological Manifestations

Neutropenia, eosinophilia, and thrombocytopenia.

9) Miscellaneous

Weakness, arthralgia, myalgia, fever, and mydriasis.

Methysergide may reverse the analgesic activity of narcotic analgesics. Concurrent use with vasoconstrictor agents including ergot alkaloids, sumatriptan, and nicotine (e.g. smoking) may result in enhanced vasoconstriction.

With long-term, uninterrupted administration, retroperitoneal fibrosis or related conditions pleuropulmonary fibrosis and cardiovascular disorders with murmurs or vascular bruits have been reported. Patients must be warned to report immediately the following symptoms and to discontinue the drug: cold, numb, and painful hands and feet; leg cramps on walking; any type of girdle, flank, or chest pain, shortness of breath, or any associated symptomatology. Should any of these symptoms develop, methysergide should be discontinued. Continuous administration should not exceed 6 months. There must be a drug-free interval of 3-4 weeks after each 6-month course of treatment. The dosage should be reduced gradually during the last 2-3 weeks of each treatment course to avoid "headache rebound." The drug is not recommended for use in children.

All patients receiving Sansert^® (methysergide maleate) should remain under constant supervision of the physician and be examined regularly for the development of fibrotic or vascular complications. (See ADVERSE REACTIONS) The manifestations of retroperitoneal fibrosis, pleuropulmonary fibrosis, and vascular shutdown have shown a high incidence of regression once Sansert^® (methysergide maleate) is withdrawn. These facts should be borne in mind to avoid unnecessary surgical intervention. Cardiac murmurs, which may indicate endocardial fibrosis, have shown varying degrees of regression, with complete disappearance in some and persistence in others.

Sansert^® (methysergide maleate) has been specifically designed for the prophylaxis of vascular headache and has no place in the management of the acute attack.

Sansert^® (methysergide maleate) tablets contain FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

INFORMATION FOR PATIENTS

Sansert^® (methysergide maleate) is intended for use as a preventive agent in the treatment of vascular headaches. It should not be used for acute migraine attacks. If, after a 3-week trial period, Sansert^® (methysergide maleate) has not been effective in decreasing the frequency or intensity of headaches, it is unlikely that longer administration of Sansert^® (methysergide maleate) will be beneficial.

Patients should be advised to report the following symptoms immediately and to discontinue the drug: cold, numb, and painful hands and feet; leg cramps on walking; any type of girdle, flank, or chest pain; shortness of breath; or any associated symptomatology. There must be a drug-free interval of 3-4 weeks after each 6-month course of treatment.

Sansert^® (methysergide maleate) should be taken with meals. Weight gain may necessitate modification of diet.

Pregnancy Category X

Sansert^® (methysergide maleate) is contraindicated in pregnancy due to its oxytocic actions.

Nursing Mothers

There are no specific studies on the use of Sansert^® (methysergide maleate) in nursing mothers. Ergot alkaloids, in general, appear in mothers milk.

Sansert^® (methysergide maleate) is a semi-synthetic compound structurally related to ergotamine, and thus it may appear in breast milk. Ergot alkaloids have been reported to cause nausea, vomiting, diarrhea and weakness in the nursing infant and suppression of prolactin secretion and lactation in the mother.

Because of the potential for serious adverse reactions in nursing infants from Sansert^® (methysergide maleate), a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Few cases of acute Sansert^® (methysergide maleate) intoxication have been reported. The possible symptom complex is therefore not fully known. The following symptoms are based on these few case reports. Euphoria, hyperactivity, tachycardia, dilated pupils, and dizziness have been reported in a child with a dose of 20-24 mg of Sansert^® (methysergide maleate). In adults, peripheral vasospasm, with diminished or absent pulses, coldness, mottling and cyanosis, has been observed at a dose of 200 mg. Ischemic tissue damage has not been reported in acute overdosage with Sansert^® (methysergide maleate).

Treatment consists of removal of the offending drug by induction of emesis, or gastric lavage in the case of very recent intake, repeat dose administration of activated charcoal and catharsis. There is no evidence that forced diuresis accelerates the elimination of Sansert^® (methysergide maleate). However, I.V. fluids may be given as a general supportive measure. Treatment of peripheral vasospasm should consist of warmth, but not heat, and protection of the ischemic limbs. In reported cases of Sansert^® (methysergide maleate) overdosage, the use of vasodilators has not been necessary. However, if vasospasm is persistent, severe, or if there is evidence of impending ischemic tissue damage, these agents may be beneficial. Careful nursing care is recommended in order to prevent tissue damage.

Up-to-date information about the treatment of overdose can often be obtained from a certified Regional Poison Control Center. Telephone numbers of certified Regional Poison Control Centers are listed in the Physicians Desk Reference^®.*

Hypersensitivity to the drug or to tartrazine (FD&C Yellow #5) or any other components of the formulation, pregnancy, lactation, peripheral vascular disease, severe arteriosclerosis, severe hypertension, coronary artery disease, phlebitis or cellulitis of the lower limbs, pulmonary disease, collagen diseases or fibrotic processes, impaired liver or renal function, valvular heart disease, debilitated states and serious infections.

Sansert^® (methysergide maleate) has been shown, in vitro and in vivo, to inhibit or block the effects of serotonin, a substance which may be involved in the mechanism of vascular headaches. Serotonin has been variously described as a central neurohumoral agent or chemical mediator, as a "headache substance" acting directly or indirectly to lower pain threshold (others in this category include tyramine; polypeptides, such as bradykinin; histamine; and acetylcholine), as an intrinsic "motor hormone" of the gastrointestinal tract, and as a "hormone" involved in connective tissue reparative processes. Suggestions have been made by investigators as to the mechanism whereby methysergide produces its clinical effects, but this has not been finally established.

Sansert^® (methysergide maleate) is intended for use as a preventive agent in the treatment of vascular headaches. It should not be used for acute migraine attacks. If, after a 3-week trial period, Sansert^® (methysergide maleate) has not been effective in decreasing the frequency or intensity of headaches, it is unlikely that longer administration of Sansert^® (methysergide maleate) will be beneficial.

Patients should be advised to report the following symptoms immediately and to discontinue the drug: cold, numb, and painful hands and feet; leg cramps on walking; any type of girdle, flank, or chest pain; shortness of breath; or any associated symptomatology. There must be a drug-free interval of 3-4 weeks after each 6-month course of treatment.

Sansert^® (methysergide maleate) should be taken with meals. Weight gain may necessitate modification of diet.

Please also refer to the WARNINGS and PRECAUTIONS sections.

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.

METHYSERGIDE - ORAL

(meth-eh-SER-jide)

WARNING: When used for an extended time, methysergide has infrequently caused abnormal thickening of heart valves and of the lining of the lungs/abdomen. Therefore, methysergide should be used only when the headaches are frequent and severe. Patients must be under close medical supervision.

Tell your doctor immediately if you develop chest pain, difficulty breathing, backache, trouble urinating, unusual tiredness, numbness or tingling of the hands or feet, or fast heartbeat.

USES: This medication is used to prevent or decrease the pain/frequency of certain severe recurring headaches (vascular headaches such as migraine headaches and cluster headaches). Because of possible serious side effects, it is used after other treatments (e.g., beta blockers) have not worked.

Methysergide is an ergot alkaloid. It is thought to work by narrowing blood vessels in the head, thereby reducing the throbbing effects of vascular headaches. Methysergide is not used to treat migraine attacks when they occur.

HOW TO USE: When starting this medication, take it at night with food or milk to prevent stomach upset. As your doctor increases your dose, this medication is usually taken 2 to 3 times a day with meals. Your dosage depends on your condition and response to treatment.

Your doctor may direct you to take a low dose at first, gradually increasing the dose to lower the chance of side effects such as nausea. Your doctor will adjust your dose to find the best dose for you. Follow your doctor's directions carefully. The usual maximum dose for adults is 12 milligrams of methysergide each day.

Take this medication regularly in order to get the most benefit from it. To help you remember, take it at the same times each day. If you are using this medication for headaches that occur in groups for periods of time (cluster headaches), it is usually taken only during the cluster and stopped after the cluster is over. Follow your doctor's directions carefully.

Very serious side effects may occur when methysergide is taken continuously for a long time. Do not take methysergide for more than 6 months in a row. (See also Warning section.) This medication is for prevention. Do not use this medication to treat a current headache.

Do not stop taking this medication without consulting your doctor. Your headaches may become worse ("rebound headache") when the drug is suddenly stopped. Your doctor will direct you to stop taking the medication by gradually lowering your dose over 2 to 3 weeks. After properly stopping the medication, do not take it again for 3 to 4 weeks as directed by your doctor.

Methysergide usually starts to work in 1 to 2 days. Tell your doctor if your condition persists or worsens after 3 weeks.

SIDE EFFECTS: Nausea, vomiting, diarrhea, dizziness, drowsiness, stomach upset, heartburn, trouble sleeping, and flushing may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

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 very serious side effects occur: dizziness (especially upon standing), tingling/pain/coldness in the fingers/toes, whitish fingers/toes/nails, loss of feeling in the fingers/toes, bluish hands/feet, muscle pain/weakness, unusual weight gain.

Seek immediate medical attention if any of these rare but very serious side effects occur: vision changes, confusion, slurred speech.

A very serious scarring/thickening of the lining in the lungs, around the heart, and in the abdomen/pelvis may occur. Stop taking methysergide and tell your doctor immediately if any of these effects occur: shortness of breath, tightness/pain in the chest, slow/fast/irregular heartbeat, lower back pain, leg cramps, pain/redness/swelling of the legs/feet, severe stomach/abdominal pain, change in the amount/color of urine, difficult/painful urination, unusual weakness/tiredness.

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, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, tell 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 this medication, tell your doctor or pharmacist if you are allergic to methysergide; or to other ergot alkaloids (e.g., methylergonovine); or to a certain yellow dye (tartrazine) found in some brands; or to aspirin (because some aspirin-allergic people are also allergic to tartrazine); or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: autoimmune disease (e.g., rheumatoid arthritis), blood vessel disease (e.g., peripheral vascular disease, hardening/inflammation of the arteries, blood clots, Raynaud's disease, stroke), uncontrolled high blood pressure, heart disease (e.g., coronary artery disease, heart attack, heart valve problems), scarring caused by a drug (e.g., retroperitoneal fibrosis), severe infection (e.g., cellulitis of the legs/feet, sepsis), severe liver disease, certain lung disease (pulmonary fibrosis), severe kidney disease, certain types of migraine (hemiplegic or basilar migraine), nutrient deficiency (malnutrition), urinary blockage.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: smoking, diabetes, high blood pressure (controlled), stomach/intestinal ulcers.

This drug may make you dizzy or drowsy. Use caution while driving, using machinery, or doing any other activity that requires alertness. Limit alcoholic beverages. Remember that alcohol may cause headaches.

Smoking can make headaches worse. Do not smoke.

This medication is not recommended for use in children because of the risk of scarring (fibrosis).

This medication may harm an unborn baby. Therefore, it must not be used during pregnancy. It is recommended that women use 2 effective forms of birth control (e.g., condoms, birth control pills) while taking this medication. If you become pregnant or think you may be pregnant, tell your doctor immediately. Consult your doctor for more details and to discuss reliable forms of birth control.

This drug may pass into breast milk and could have undesirable effects on a nursing infant. Therefore, breast-feeding is not recommended while using this drug. 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.

This drug should not be used with the following medications because very serious interactions may occur: drugs affecting liver enzymes that remove methysergide from your body (e.g., azole antifungals such as ketoconazole, itraconazole, voriconazole, macrolide antibiotics such as erythromycin, clarithromycin, HIV drugs such as delavirdine, efavirenz, indinavir, nelfinavir, ritonavir), other ergot alkaloids (e.g., ergonovine), smoking/nicotine products (e.g., patches, gum), sibutramine.

If you also take "triptan" migraine drugs (e.g., sumatriptan, rizatriptan), you will need to separate your "triptan" dose from your dose of this medication to reduce the risk of serious side effects. Ask your doctor how long you should wait between your doses of these drugs.

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting this medication.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially: drugs for diabetes (e.g., insulin, tolbutamide), nitrates (e.g., isosorbide, nitroglycerin), SSRI antidepressants (e.g., fluoxetine, fluvoxamine).

Check the labels on all your medicines (e.g., cough-and-cold products, diet aids, other migraine medications) because they may contain ingredients that could increase your heart rate or blood pressure. Ask your pharmacist about the safe use of those products.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. 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. Symptoms of overdose may include: mental/mood changes, hyperactivity, sweating, rapid heartbeat, blue/cold arms, hands, legs, and feet.

NOTES: Do not share this medication with others.

Certain foods/beverages or food additives (e.g., red wine, cheese, chocolate, monosodium glutamate, alcohol) as well as some lifestyle patterns (e.g., irregular eating/sleeping habits, stress) may cause a migraine headache. Avoiding these "triggers" may help decrease the frequency of migraine headaches. Consult your doctor for more details.

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 away from sunlight 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.

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