Santarus Announces Launch of Type 2 Diabetes Drug CYCLOSET®

CYCLOSET is the first in-class and only centrally acting dopamine agonist oral antidiabetic. CYCLOSET is a prescription drug approved by the U.S. Food and Drug Administration (FDA) as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus both as monotherapy and in combination with other oral antidiabetic agents.   CYCLOSET is now available through retail pharmacies. 

CYCLOSET lowered HbA1c by 0.6% to 0.9% relative to placebo.

Ralph A. DeFronzo, M.D., Professor of Medicine, Chief of the Diabetes Division, University of Texas Health Sciences Center, San Antonio, said, "CYCLOSET represents a new treatment for adults with type 2 diabetes. Although the mechanism by which CYCLOSET improves glycemic control is unknown, it contains bromocriptine mesylate, which increases dopaminergic activity in the hypothalamus. In a clinical trial, CYCLOSET lowered HbA1c by 0.6% to 0.9% relative to placebo, when added to other oral antidiabetic agents. CYCLOSET can be prescribed for adults who are inadequately controlled with diet/exercise, metformin, sulfonylureas or thiazolidinediones."

A 24-week, placebo-controlled, monotherapy study of the impact of CYCLOSET on glycemic control in 159 overweight adults (BMI greater-than or equal to 26.0 kg/m(2) for males and greater-than or equal to 28.0 kg/m(2) for females) with type 2 diabetes and baseline HbA1c of 7.5% – 11% indicated that once-daily morning dosing of CYCLOSET provided significant postprandial plasma glucose reductions throughout the day without increasing plasma insulin concentrations and significantly improved HbA1c.

Additional data from a prospective 24-week assessment of the efficacy of CYCLOSET in improving glycemic control in type 2 diabetes, patients poorly controlled on one or two oral anti-diabetes agents indicated that 35% – 40% of patients reached an HbA1c goal of less-than or equal to 7.0% with CYCLOSET versus approximately 10% of placebo treated patients. When added to other oral antidiabetic agents, once-daily morning administration of CYCLOSET improved glycemic control after 24 weeks of treatment, as demonstrated by a significant reduction in mean HbA1c (0.6% — 0.9% versus placebo, data on file). These findings were from a prospective 24-week assessment for treatment differences in the change from baseline to Week 24 in HbA1c among patients with a baseline HbA1c greater-than or equal to 7.5%, taking one or two oral antidiabetic medications, and completing 24 weeks of therapy within a 52-week, randomized controlled study to evaluate the safety and efficacy of CYCLOSET. In this 52-week study, CYCLOSET was not associated with an increased risk for adverse cardiovascular events relative to placebo.

CYCLOSET is a dopamine receptor agonist that acts on the central nervous system and is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. CYCLOSET should not be used to treat type 1 diabetes or diabetic ketoacidosis. Efficacy data in combination with thiazolidinediones are limited. Efficacy has not been confirmed in combination with insulin. Although the precise mechanism of action by which CYCLOSET improves glycemic control in type 2 diabetes patients is unknown, results from preclinical studies suggest that appropriately timed daily administration of bromocriptine normalizes aberrant hypothalamic neurotransmitter activities that induce, potentiate, and maintain the insulin-resistant, glucose-intolerant state. Timed bromocriptine effects on insulin resistance and glucose intolerance have been demonstrated when administered directly to the central nervous system and bypassing the periphery. It has been established that morning administration of CYCLOSET improves glycemic control, particularly postprandial glycemic control, in patients with type 2 diabetes without increasing plasma insulin concentrations. In a 52-week, randomized clinical trial of 3,070 patients, CYCLOSET was not associated with an increased risk for adverse cardiovascular events.

CYCLOSET is contraindicated in patients with hypersensitivity to ergot-related drugs, bromocriptine, or any of the excipients in CYCLOSET. Do not use in patients with syncopal migraines. It may precipitate hypotension. Do not use in nursing women. It may inhibit lactation. There are postmarketing reports of stroke in this patient population.

CYCLOSET can cause orthostatic hypotension and syncope, particularly upon initiation or dose escalation. Use with caution in patients taking antihypertensive medications. CYCLOSET may exacerbate psychotic disorders or reduce the effectiveness of drugs that treat psychosis. Use in patients with severe psychotic disorders is not recommended. CYCLOSET may cause somnolence. Advise patients not to operate heavy machinery if symptoms of somnolence occur. Concomitant use with dopamine antagonists such as neuroleptic agents is not recommended.

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with CYCLOSET or any other antidiabetic drug. CYCLOSET does not increase the risk of macrovascular events. In controlled clinical trials, adverse reactions reported in greater-than or equal to 5% of patients treated with CYCLOSET, and reported more commonly than in patients treated with placebo, included nausea, fatigue, dizziness, vomiting, and headache.

Safety and effectiveness have not been established in pediatric patients.

• tell your doctor and pharmacist if you are allergic to bromocriptine; ergot alkaloids such as cabergoline (Dostinex), dihydroergotamine (D.H.E. 45, Migranal), ergoloid mesylates (Germinal, Hydergine), ergonovine (Ergotrate), ergotamine (Bellergal-S, Cafergot, Ergomar, Wigraine), methylergonovine (Methergine), methysergide (Sansert), and pergolide (Permax); any other medications; or any of the ingredients in bromocriptine tablets or capsules. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: amitriptyline (Elavil); antifungals such as itraconazole (Sporanox) and ketoconazole (Nizoral); antihistamines; chloramphenicol; dexamethasone (Decadron, Dexpak); other dopamine agonists such as cabergoline (Dostinex), levodopa (Dopar, Larodopa), pergolide (Permax), and ropinirole (Requip); ergot-type medications such as dihydroergotamine (D.H.E. 45, Migranal), ergoloid mesylates (Germinal, Hydergine), ergonovine (Ergotrate), ergotamine (Bellergal-S, Cafergot, Ergomar, Wigraine), methylergonovine (Methergine), and methysergide (Sansert); haloperidol (Haldol); imipramine (Tofranil); insulin; macrolide antibiotics such as clarithromycin (Biaxin, in PrevPac) and erythromycin (E.E.S., E-Mycin, Erythrocin); certain medications for human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) such as indinavir (Crixivan), nelfinavir (Viracept), and ritonavir (Norvir, in Kaletra); oral medications for diabetes; medications for asthma, colds, high blood pressure, migraines, and nausea; medications for mental illness such as clozapine (Clozaril, FazaClo), olanzapine (Zyprexa, in Symbyax), thiothixene (Navane), and ziprasidone (Geodon); methyldopa (in Aldoril); metoclopramide (Reglan); nefazodone; octreotide (Sandostatin); pimozide (Orap); probenecid (in Col-Probenecid, Probalan); reserpine; rifampin (Rifadin, in Rifamate, in Rifater, Rimactane); and sumatriptan (Imitrex). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with bromocriptine, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
• tell your doctor if you have high blood pressure or migraine headaches that cause fainting. Your doctor may tell you not to take bromocriptine.
• tell your doctor if you have recently given birth, if you have ever fainted, and if you have or have ever had a heart attack; a slow, fast, or irregular heartbeat; mental illness; low blood pressure;ulcers; bleeding in the stomach or intestines; Raynaud’s syndrome (condition in which the hands and feet become numb and cool when exposed to cold temperatures); heart, kidney, or liver disease; or any condition that prevents you from digesting foods containing sugar, starch, or dairy products normally.
• tell your doctor if you are pregnant or plan to become pregnant. If you are taking bromocriptine (Parlodel) to treat lack of menstrual periods and infertility caused by hyperprolactinemia, use a method of birth control other than hormonal contraceptives (birth control pills, patches, rings, or injections) until you have regular menstrual periods; then stop using birth control. You should be tested for pregnancy once every 4 weeks as long as you do not menstruate. Once your menstrual period returns, you should be tested for pregnancy any time your menstrual period is 3 days late. If you do not wish to become pregnant, use a method of birth control other than hormonal contraceptives while you are taking bromocriptine. If you become pregnant during your treatment with bromocriptine, stop taking the medication and call your doctor.
• do not breast-feed while you are taking bromocriptine.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking bromocriptine (Cycloset).
• you should know that bromocriptine may make you drowsy and cause you to suddenly fall asleep. Do not drive a car or operate machinery until you know how this medication affects you.
• ask your doctor about the safe use of alcoholic beverages while you are taking bromocriptine. Alcohol can make the side effects from bromocriptine worse.
• you should know that bromocriptine may cause dizziness, nausea, sweating, and fainting when you get up too quickly from a lying position. This is more common when you first start taking bromocriptine or when your dose is increased. To avoid this problem, get out of bed slowly, resting your feet on the floor for a few minutes before standing up.
• ask your doctor what to do if you get sick, develop an infection or fever, experience unusual stress, or are injured. These conditions can affect your blood sugar and the amount of bromocriptine (Cycloset) you may need.

Talk to your doctor about eating grapefruit and drinking grapefruit juice while taking this medicine.

Be sure to follow all exercise and dietary recommendations made by your doctor or dietitian.

If you take bromocriptine (Parlodel), take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

If you take bromocriptine (Cycloset) once a day and miss your morning dose, wait until the next morning to take your medication. Do not take a double dose to make up for a missed one.

This medication may cause changes in your blood sugar. You should know the symptoms of low and high blood sugar and what to do if you have these symptoms.

Bromocriptine may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• nausea
• vomiting
• diarrhea
• constipation
• stomach cramps
• heartburn
• loss of appetite
• headache
• weakness
• tiredness
• dizziness or lightheadedness
• drowsiness
• difficulty falling asleep or staying asleep
• depression

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately:

• fainting
• watery discharge from the nose
• numbness, tingling, or pain in your fingers especially in cold weather
• black and tarry stools
• bloody vomit
• vomiting material that looks like coffee grounds
• swelling of the feet, ankles, or lower legs
• seizures
• severe headache
• blurred or impaired vision
• slow or difficult speech
• weakness or numbness of an arm or leg
• chest pain
• pain in the arms, back, neck or jaw
• shortness of breath
• confusion
• hallucinations (seeing things or hearing voices that do not exist)

Bromocriptine may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration’s (FDA) MedWatch Adverse Event Reporting program online [at https://www.fda.gov/Safety/MedWatch] or by phone [1-800-332-1088].

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from light, excess heat, and moisture (not in the bathroom). Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication.

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

• nausea
• vomiting
• constipation
• sweating
• pale skin
• general feeling of discomfort or uneasiness
• lack of energy
• fainting
• dizziness
• drowsiness
• confusion
• hallucinations (seeing things or hearing voices that do not exist)
• believing things that are not true
• yawning repeatedly

Keep all appointments with your doctor, eye doctor, and the laboratory. Your blood pressure should be checked periodically. Your doctor may order regular eye examinations and certain lab tests to check your body’s response to bromocriptine. Your blood sugar and glycosylated hemoglobin (HbA1c) should be checked regularly to determine your response to bromocriptine (Cycloset). Your doctor will also tell you how to check your response to bromocriptine (Cycloset) by measuring your blood or urine sugar levels at home. Follow these directions carefully.

Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

• Bromocryptine
• Brom-ergocryptine
• 2-Bromoergocryptine
• 2-Br-α-ergocryptine