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CYCLOSET®: First-in-class therapy for type 2 diabetes in adults

Centrally acting glycemic control* with a demonstrated CV safety profile†

*CYCLOSET is a dopamine receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Preclinical studies suggest that appropriately timed daily administration of bromocriptine, the active ingredient of CYCLOSET, may positively affect hypothalamic activities associated with insulin resistance and glucose intolerance.1-3 In clinical studies, morning administration of CYCLOSET improved glycemic control in adults with type 2 diabetes without increasing plasma insulin concentrations.4,5 The precise mechanism of action of CYCLOSET is unknown. † In a 52-week, randomized clinical trial of 3,070 patients, CYCLOSET was not associated with an increased risk for adverse cardiovascular events.4

Safety and effectiveness have not been established in pediatric patients. Please see page 6 for Important Safety Information. Please see accompanying Full Prescribing Information.


CYCLOSET® and the role of hypothalamic dopamine in type 2 diabetes

Hypothalamus

Early morning hypothalamic dopamine levels in type 2 diabetes

– Glucose intolerance – Insulin resistance – Dyslipidemia Adapted from DeFronzo. CV disease

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CYCLOSET increases insulin sensitivity in patients with type 2 diabetes2,5 Increases insulin sensitivity2,5,7-13*† Improves postprandial hepatic glucose metabolism2,12‡

Increases glucose uptake5

Demonstrated CV safety profile4

Decreases A1C5

*The precise mechanism of action of CYCLOSET is unknown. • CYCLOSET, a quick-relase formulation of bromocriptine, increases CNS dopamine receptor activity6 CYCLOSET is a dopamine receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. 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. In a 24-week monotherapy clinical trial, CYCLOSET improved postprandial glucose (PPG) without increasing plasma insulin concentrations.4 ‡ In preclinical studies, bromocriptine improved insulin-mediated suppression of hepatic glucose production.14

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Please see page 6 for Important Safety Information. Please see accompanying Full Prescribing Information.


CYCLOSET adds consistent glycemic control Once-daily dosing of CYCLOSET significantly reduced PPG

No increase in plasma insulin concentrations

CYCLOSET improved A1C when added to other oral antidiabetics7,15,16†

0.6% to 0.9% A1C reductions when added to one or more other OADs7,15,16† Average baseline A1C 8.3%6

*Findings from a 24-week, placebo-controlled, monotherapy trial that evaluated the efficacy and safety of CYCLOSET as an adjunct to diet and exercise in 159 overweight adults (BMI ≥26.0 kg/m2 for males and ≥28.0 kg/m2 for females) with type 2 diabetes and inadequate glycemic control (A1C 7.5%-11%). † Findings from a 52-week, randomized controlled trial to evaluate the safety and efficacy of CYCLOSET. Data shown are from a prospective 24-week assessment for treatment differences in the change from baseline to week 24 in A1C among subjects with a baseline A1C ≥7.5%, taking 1 or 2 oral antidiabetes medications (OADs), and completing 24 weeks of therapy. In the intent-to-treat, last-observation-carried-forward (LOCF) population, A1C reductions in the CYCLOSET arm vs placebo were 0.5% for patients failing any OAD, 0.5% for patients failing metformin ± OAD, 0.5% for patients failing metformin + sulfonylurea (SU), and 0.6% for patients failing Improved glycemic control; Demonstrated CV safety profile thiazolidinedione (TZD) ± OAD.

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CYCLOSET: Demonstrated cardiovascular safety profile Patients with type 2 diabetes are at increased risk for CV disease • Stroke, all manifestations of coronary heart disease, myocardial infarction (MI), sudden death, and angina are at least 2 times more frequent in patients with type 2 diabetes vs nondiabetic individuals17 • More than 70% of patients with type 2 diabetes will die due to CV causes17

CYCLOSET: CV safety evaluated in 3,070-patient, 52-week study in adults with type 2 diabetes18* Patients with CV risk factors at baseline CYCLOSET (n=2,054)

Placebo (n=1,016)

Hypertension

75%

75.5%

Hypercholesterolemia

77%

75.5%

Hypertriglyceridemia

41.5%

41.5%

MI

9.1%

10%

Revascularization surgery

10%

13%

• CV safety endpoint (composite): time to first MI, stroke, coronary revascularization, hospitalization for angina, or hospitalization for congestive heart failure (CHF) – All patients taking cardioprotective medications were allowed to continue medications throughout the trial – All patients were allowed up to 2 OADs or insulin + 1 OAD, which they continued to take after randomization to either CYCLOSET or placebo – Mean duration of diabetes at baseline was 8 years – Mean baseline A1C was 7% *Findings from a 52-week, 74-center, randomized placebo-controlled trial to evaluate the safety of CYCLOSET. 3,070 patients were randomized 2:1 to add either CYCLOSET or placebo, respectively, to their current antidiabetic regimen, which could consist of diet alone or no more than 2 agents (2 OADs or insulin + 1 OAD). Inclusion criteria: age 30-80, BMI <43 kg/m2, diagnosis of type 2 diabetes of >6 months with an A1C ≤10.0% with no lower A1C boundary.

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Please see page 6 for Important Safety Information. Please see accompanying Full Prescribing Information.


CYCLOSET: Demonstrated cardiovascular safety profile In a 3,070-patient, 52-week safety study, CYCLOSET use was not associated with an increased risk for adverse CV events4,15,18,19* 42% relative risk reduction for composite CVD endpoint† vs placebo. Hazard ratio=0.58 (95% CI, 0.35-0.96); P<.054,15 • 1.5% of patients (31/2,054) on CYCLOSET vs 3% (30/1,016) on placebo experienced the primary CVD endpoint4

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. *Findings from a 52-week, 74-center, randomized placebo-controlled trial to evaluate the safety of CYCLOSET. 3,070 patients were randomized

2:1 to add either CYCLOSET or placebo, respectively, to their current antidiabetic regimen, which could consist of diet alone or no more than 2 agents (2 OADs or insulin + 1 OAD). Inclusion criteria: age 30-80, BMI <43 kg/m2, diagnosis of type 2 diabetes of >6 months with an A1C ≤10.0% with no lower A1C boundary. Patients with a history of cardiovascular disease (CVD) and CHF were included in the trial. † Prespecified composite CVD endpoint of time to first MI, stroke, coronary revascularization, hospitalization for angina, or hospitalization for CHF.

Improved glycemic control; Demonstrated CV safety profile

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CYCLOSET: Demonstrated overall safety profile Weight neutral—no significant weight gain vs placebo4 No severe hypoglycemia compared with placebo4 Safety profile comparable to placebo • Serious adverse events (SAEs)—8.5% with CYCLOSET vs 9.6% with placebo4

Nausea is the most common adverse event • Generally transient and experienced during initial titration period, lasting less than 2 weeks18

Important Safety Information 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 ≥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. References: 1. Luo S, Meier AH, Cincotta AH. Bromocriptine reduces obesity, glucose intolerance and extracellular monoamine metabolite levels in the ventromedial hypothalamus of Syrian hamsters. Neuroendocrinology. 1998;68:1-10. 2. Luo S, Luo J, Cincotta AH. Chronic ventromedial hypothalamic infusion of norepinephrine and serotonin promotes insulin resistance and glucose intolerance. Neuroendocrinology. 1999;70:460-465. 3. Luo S, Luo J, Meier AH, Cincotta AH. Dopaminergic neurotoxin administration to the area of the suprachiasmatic nuclei induces insulin resistance. Neuroreport. 1997;8:3495-3499. 4. Cycloset [package insert]. Tiverton, RI: VeroScience, LLC; 2010. 5. Pijl H, Ohashi S, Matsuda M, et al. Bromocriptine: a novel approach to the treatment of type 2 diabetes. Diabetes Care. 2000;23:1154-1161. 6. Defronzo RA. Bromocriptine: a sympatholytic, d2dopamine agonist for the treatment of type 2 diabetes. Diabetes Care. 2011;34:789-794. 7. Scranton RE, Farwell W, Ezrokhi M, Gaziano JM, Cincotta AH. Quick release bromocriptine (Cycloset™) improves glycaemic control in patients with diabetes failing metformin/sulfonylurea combination therapy. Presented at: 44th Annual Meeting of the European Association for the Study of Diabetes (EASD); September 7-11, 2008; Rome, Italy. 8. Cincotta AH, Meier AH, Cincotta Jr M. Bromocriptine improves glycaemic control and serum lipid profile in obese type 2 diabetic subjects: a new approach in the treatment of diabetes. Expert Opin Investig Drugs. 1999;8:1683-1707. 9. Scranton R, Cincotta A. Bromocriptine—unique formulation of a dopamine agonist for the treatment of type 2 diabetes. Expert Opin Pharmacother. 2010;11:269-279. 10. Kamath V, Jones CN, Yip JC, et al. Effects of a quick-release form of bromocriptine (Ergoset) on fasting and postprandial plasma glucose, insulin, lipid, and lipoprotein concentrations in obese nondiabetic hyperinsulinemic women. Diabetes Care. 1997;20:1697-1701. 11. Cincotta AH, Meier AH. Bromocriptine (Ergoset) reduces body weight and improves glucose tolerance in obese subjects. Diabetes Care. 1996;19:667-670. 12. Cincotta AH, Meier AH. Bromocriptine inhibits in vivo free fatty acid oxidation and hepatic glucose output in seasonally obese hamsters (Mesocricetus auratus). Metabolism. 1995;44:1349-1355. 13. Luo S, Ezrokhi M, Trubitsyna Y, Cincotta AH. Intrahypothalamic circuitry regulating hypothalamic fuel sensing to induce insulin sensitivity or insulin resistance. Diabetologia. 2008;51(suppl 1):S59. 14. Luo S, Liang Y, Cincotta AH. Intracerebroventricular administration of bromocriptine ameliorates the insulin-resistant/glucose-intolerant state in hamsters. Neuroendocrinology. 1999;69:160-166. 15. Data on file, Santarus, Inc. 16. Cincotta AH, Gaziano JM, Ezrokhi M, Scranton R. Cycloset (quick-release bromocriptine mesylate), a novel centrally acting treatment for type 2 diabetes. Presented at: 44th Annual Meeting of the European Association for the Study of Diabetes (EASD); September 7-11, 2008; Rome, Italy. 17. Laakso M. Cardiovascular disease in type 2 diabetes from population to man to mechanisms. Diabetes Care. 2010; 33:442-449. 18. Gaziano JM, Cincotta AH, O’Connor CM, et al. Randomized clinical trial of quick-release bromocriptine among patients with type 2 diabetes on overall safety and cardiovascular outcomes. Diabetes Care. 2010; 33:1503-1508. 19. Scranton RE, Cincotta A, Gaziano JM. The effect of timed Cycloset (a quick-release formulation of bromocriptine mesylate) on cardiovascular events in patients with type 2 diabetes. Presented at: 68th Scientific Sessions of the American Diabetes Association; June 6-10, 2008; San Francisco, CA.

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Please see accompanying Full Prescribing Information.


CYCLOSET: A novel approach to type 2 diabetes in adults Consistent glycemic control • Decreases PPG levels without increasing plasma insulin concentrations4 • 0.6% to 0.9% A1C reductions seen when added to other oral agents7,15,16*

Demonstrated cardiovascular safety profile • 1.5% of patients on CYCLOSET vs 3% on placebo experienced the composite CVD endpoint4†

Demonstrated overall safety profile • No significant weight gain or severe hypoglycemia compared with placebo observed in clinical trials4 • Rate of SAEs vs placebo 8.5% vs 9.6%, respectively4

Now—most patients with commercial insurance will pay only $10 for CYCLOSET!‡ Option 1: eVoucherRxTM Program—no cards or coupons needed. Patients receive an automatic co-pay reduction at the pharmacy counter when they pick up their prescription. Option 2: CYCLOSET Instant Savings Card Patients show their Instant Savings Card to the pharmacist when they present their CYCLOSET prescription. The patient’s co-pay is reduced at the pharmacy counter.

*Findings from a 52-week, randomized controlled trial to evaluate the safety and efficacy of CYCLOSET. Data shown are from a prospective 24-week assessment for treatment differences in the change from baseline to week 24 in A1C among subjects with a baseline A1C ≥7.5% (average baseline A1C of 8.3%), taking 1 or 2 OADs, and completing 24 weeks of therapy. In the intent-to-treat, LOCF population, A1C reductions in the CYCLOSET arm vs placebo were 0.5% for patients failing any OAD, 0.5% for patients failing metformin ± OAD, 0.5% for patients failing metformin + SU, and 0.6% for patients failing TZD ± OAD. † In a 52-week, randomized clinical trial of 3,070 patients, CYCLOSET was not associated with an increased risk for adverse CV events.4 ‡ Some restrictions apply. Santarus reserves the right to modify or cancel these offerings at any time.

Improved glycemic control; Demonstrated CV safety profile

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CYCLOSET: Convenient once-daily dosing • CYCLOSET is taken once daily within 2 hours of waking in the morning • The initial dose is one 0.8 mg tablet daily, titrated weekly by 1 tablet until therapeutic dose (1.6 mg to 4.8 mg, or between 2 to 6 tablets per day) is achieved • In clinical trials, most patients reached a dose between 3.2 mg and 4.8 mg (4 to 6 tablets) per day15

Recommended Titration Schedule Actual Tablet Size

Week 1

1 tablet daily

Week 2

2 tablets daily

Week 3

3 tablets daily

Week 4

4 tablets daily

Week 5

5 tablets daily

Week 6

6 tablets daily

(starting dose)

Patients should take tablet(s) with food within 2 hours of waking in the morning

(maximum dose—do not take more than 6 tablets daily)

CYCLOSET should be taken with food to potentially reduce gastrointestinal side effects such as nausea.

Now—most patients with commercial insurance will pay only $10 for CYCLOSET! Please see page 6 for Important Safety Information. Please see accompanying Full Prescribing Information. CYCLOSET is a registered trademark of VeroScience, LLC, Tiverton, RI 02878. Manufactured for: VeroScience, LLC, Tiverton, RI. Distributed and Marketed by: Santarus, Inc., San Diego, CA. Please visit www.cycloset.com for more information. © 2012 Santarus, Inc.

1-CYCXXXXX

Janurary 2012

Printed in the USA

Improved glycemic control; Demonstrated CV safety profile


Cycloset