Daiichi Sankyo Release: SAVAYSA (edoxaban) Now Available In U.S. Pharmacies

TOKYO and PARSIPPANY, N.J., Feb. 9, 2015 /PRNewswire/ -- Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) announced today that SAVAYSA (edoxaban), an oral, once-daily selective factor Xa-inhibitor, is now commercially available in U.S. pharmacies.

SAVAYSA was approved by the U.S. Food and Drug Administration (FDA) on January 8, 2015 for the reduction in risk of stroke and systemic embolism (SE) in patients with non-valvular atrial fibrillation (NVAF), as well as for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5-10 days of initial therapy with a parenteral anticoagulant. According to the U.S. label, SAVAYSA should not be used in NVAF patients with creatinine clearance (CrCL) levels greater than 95 mL/min because in that population there is an increased risk of ischemic stroke compared to warfarin.¹

"The availability of SAVAYSA provides appropriate patients and their physicians with a new anticoagulant that has been shown to reduce the risk of stroke and SE with significantly less major bleeding compared to warfarin in patients with NVAF and that treats venous thromboembolism with significantly less clinically relevant bleeding compared to warfarin," said Howard Rutman, M.D., Vice President, Medical Affairs, Daiichi Sankyo, Inc. "It is important to have additional treatment options for these complex conditions with diverse patient populations, and it is good to know that new treatments like SAVAYSA are available to patients with NVAF or venous thromboembolism."

"The availability of SAVAYSA now expands our cardiovascular-metabolic U.S. product portfolio to seven FDA-approved treatments, reinforcing our longstanding commitment towards helping to address the needs of patients with cardiovascular diseases, including those with NVAF and venous thromboembolism," said Ken Keller, President, U.S. Commercial, Daiichi Sankyo, Inc. "We are proud to be able to provide these patients a new treatment option with a compelling safety and efficacy profile that offers the convenience of once-daily dosing, no need for routine blood monitoring and the flexibility to be taken with or without a meal."

With the launch of SAVAYSA, Daiichi Sankyo has developed resources for physicians and patients to help ensure patients can begin and/or remain on SAVAYSA per physician instructions. The SAVAYSA Savings Plus program will include a reimbursement hotline to assist patients and prescribers who request help understanding the patient's available coverage. Eligible patients who are prescribed SAVAYSA can enroll in a copay savings program and pay $4 per month through the SAVAYSA SAVINGS CARD. Vouchers will also be available to provide patients and doctors a way to try SAVAYSA at no cost to see if it is right for the patient. In addition, the SAVAYSA Patient Assistance Program will offer assistance to qualified individuals, providing free product to eligible patients who are prescribed SAVAYSA, are uninsured and are unable to identify alternative payment sources.

The approval of SAVAYSA in the U.S. is based on data from the ENGAGE AF-TIMI 48 and Hokusai-VTE trials, the largest and longest single comparative global trials of a novel oral anticoagulant with NVAF or VTE, involving 21,105 and 8,292 patients, respectively.

In ENGAGE AF-TIMI 48, SAVAYSA demonstrated significantly less major bleeding in patients with NVAF in the overall study population (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.70 to 0.91, p<0.001) and was non-inferior to warfarin for the primary efficacy endpoint of stroke or SE. In the indicated NVAF patient population in the U.S. (patients with CrCL 95 mL/min), the rate of stroke and SE was 1.2% per year for SAVAYSA versus 1.8% per year for warfarin (HR, 0.68; 95% CI, 0.55 to 0.84). Consistent with the overall results, SAVAYSA also demonstrated fewer major bleeding events compared to warfarin in the indicated NVAF population, as well as lower rates of intracranial hemorrhage (0.5% per year for SAVAYSA and 1.0% per year for warfarin) and fatal bleeding (0.2% per year for SAVAYSA and 0.4% per year for warfarin), but higher rates of major GI bleeding (1.8% per year for SAVAYSA and 1.3% per year for warfarin).^1,2

In Hokusai-VTE, SAVAYSA was shown to be non-inferior to warfarin for the primary endpoint of symptomatic recurrent VTE, with a significant 19% reduction in clinically relevant bleeding compared to warfarin (8.5% vs. 10.3%; HR, 0.81; 95% CI, 0.71 to 0.94, p=0.004) in patients with DVT or PE, following 5 to 10 days of initial therapy with a parenteral anticoagulant.³

The most common side effects observed in ENGAGE AF-TIMI 48 and Hokusai-VTE clinical trial participants were bleeding and anemia.^2,3 SAVAYSA increases the risk of bleeding and can cause serious and potentially fatal bleeding.

Important Safety Information About SAVAYSA (edoxaban) Tablets 
BOXED WARNINGS:

• REDUCED EFFICACY IN NONVALVULAR ATRIAL FIBRILLATION PATIENTS WITH CRCL > 95 ML/MIN
  SAVAYSA should not be used in patients with CrCL > 95 mL/min.  In the ENGAGE AF- TIMI 48 study, nonvalvular atrial fibrillation patients with CrCL > 95 mL/min had an increased rate of ischemic stroke with SAVAYSA 60 mg once-daily compared to patients treated with warfarin.  In these patients another anticoagulant should be used.
  
  
• PREMATURE DISCONTINUATION OF SAVAYSA INCREASES THE RISK OF ISCHEMIC EVENTS
  Premature discontinuation of any oral anticoagulant in the absence of adequate alternative anticoagulation increases the risk of ischemic events. If SAVAYSA is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant as described in the transition guidance in the Prescribing Information.
  
  
• SPINAL/EPIDURAL HEMATOMA
  • Epidural or spinal hematomas may occur in patients treated with SAVAYSA who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures.
  • Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: use of indwelling epidural catheters; concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants; a history of traumatic or repeated epidural or spinal punctures; a history of spinal deformity or spinal surgery.
  • Optimal timing between the administration of SAVAYSA and neuraxial procedures is not known.

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.  Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated.

CONTRAINDICATIONS 
SAVAYSA is contraindicated in patients with active pathological bleeding.

WARNINGS AND PRECAUTIONS 
Bleeding Risk 
SAVAYSA increases the risk of bleeding and can cause serious and potentially fatal bleeding. Promptly evaluate any signs or symptoms of blood loss. Discontinue SAVAYSA in patients with active pathological bleeding. There is no established way to reverse the anticoagulant effects of SAVAYSA, which can be expected to persist for approximately 24 hours after the last dose. The anticoagulant effect of SAVAYSA cannot be reliably monitored with standard laboratory testing. A specific reversal agent for edoxaban is not available. Hemodialysis does not significantly contribute to edoxaban clearance. Protamine sulfate, vitamin K and tranexamic acid are not expected to reverse its anticoagulant activity.

Mechanical Heart Valves or Moderate to Severe Mitral Stenosis 
The safety and efficacy of SAVAYSA has not been studied in patients with mechanical heart valves or moderate to severe mitral stenosis. SAVAYSA is not recommended in these patients.

ADVERSE REACTIONS

• NVAF: The most common adverse reactions ( 5%) are bleeding and anemia.
• DVT/PE: The most common adverse reactions ( 1%) are bleeding, rash, abnormal liver function tests and anemia.

DISCONTINUATION FOR SURGERY AND OTHER INTERVENTIONS 
Discontinue SAVAYSA at least 24 hours before invasive or surgical procedures because of the risk of bleeding. SAVAYSA can be restarted after the surgical or other procedure as soon as adequate hemostasis has been established.

DRUG INTERACTIONS

• Anticoagulants, Antiplatelets and Thrombolytics: Coadministration of anticoagulants, antiplatelet drugs and thrombolytics may increase the risk of bleeding. 
• P-gp Inducers: Avoid concomitant use of SAVAYSA with rifampin.

SPECIAL POPULATIONS

• Nursing mothers: Discontinue drug or discontinue nursing.
• Impaired renal function (CrCL 15 to 50 mL/min): Reduce SAVAYSA dose to 30 mg once-daily.
• Moderate or severe hepatic impairment: Not recommended.
• Pregnancy Category C.

Please see full Prescribing Information, including boxed WARNINGS and Medication Guide.

INDICATIONS 
SAVAYSA (edoxaban) is indicated to reduce the risk of stroke and systemic embolism (SE) in patients with non-valvular atrial fibrillation (NVAF).  SAVAYSA should not be used in patients with creatinine clearance (CrCL) > 95 mL/min because of increased risk of ischemic stroke compared to warfarin.

SAVAYSA is indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5-10 days of initial therapy with a parenteral anticoagulant.

Dosing and Administration for SAVAYSA (edoxaban) Tablets 
Reduction of Stroke and SE in NVAF: The recommended dose of SAVAYSA is 60 mg taken orally once-daily. Creatinine clearance should be assessed before initiating therapy with SAVAYSA.  SAVAYSA should not be used in patients with CrCL > 95 mL/min. The dose of SAVAYSA should be reduced to 30 mg once daily in patients with CrCL 15 to 50 mL/min.

Treatment of DVT and PE: The recommended dose of SAVAYSA is 60 mg taken orally once-daily following 5-10 days of initial therapy with a parenteral anticoagulant. The recommended dose of SAVAYSA is 30 mg taken once-daily following initial use of 5-10 days of a parenteral anticoagulant for patients who have CrCL between 15 mL/min and 50 mL/min, patients who weigh less than or equal to 60 kg and patients who are on concomitant p-glycoprotein inhibitors based on clinical data in this indication.

Global Clinical Trial Program for Edoxaban 
Edoxaban is an oral, once-daily anticoagulant that selectively inhibits factor Xa, which is an important factor in the coagulation system that leads to blood clotting.⁴ The global clinical trial program includes two phase 3 clinical studies, Hokusai-VTE and ENGAGE AF-TIMI 48 (Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation), which included nearly 30,000 patients combined. The results from these trials form the basis of regulatory filings for edoxaban for symptomatic VTE in patients with DVT and/or PE, and for the reduction in the risk of stroke in NVAF, respectively.^2,3 Edoxaban is currently under regulatory review around the world for these indications, including in the EU.

On September 26, 2014, Daiichi Sankyo announced that it received approval from the Ministry of Health, Labour and Welfare in Japan for LIXIANA^® (JAN: Edoxaban Tosilate Hydrate, INN: edoxaban) for the prevention of ischemic stroke and SE in patients with NVAF and for the treatment and recurrence prevention of VTE [DVT and pulmonary thromboembolism].⁵

Edoxaban was approved in Japan in April 2011 for the prevention of VTE after major orthopedic surgery and was launched in July 2011.⁶

About the ENGAGE AF-TIMI 48 Trial 
ENGAGE AF-TIMI 48 (Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation) was a three-arm, randomized, double-blind, double-dummy, global phase 3 clinical trial comparing once-daily edoxaban with warfarin in 21,105 patients with NVAF at moderate-to-high risk of thromboembolic events at 1,393 centers in 46 countries. ENGAGE AF-TIMI 48 compared two edoxaban treatment strategies, a higher dose arm (60 mg or 30 mg dose reduced) once-daily and a lower dose arm (30 mg or 15 mg dose reduced) once-daily, with warfarin in patients with NVAF for a median of 2.8 years. Patients were dose reduced for creatinine clearance 30 to 50 mL/min, body weight less than 60 kg or certain p-glycoprotein inhibitor use. The lower dose arm (30 mg or 15 dose reduced) is not an approved treatment regimen in the U.S. ENGAGE AF-TIMI 48 represents the largest and longest single comparative global trial of a novel anticoagulant in patients with NVAF performed to date.² The full results were presented at the AHA Scientific Sessions 2013 in Dallas and published in the New England Journal of Medicine.

About the Hokusai-VTE Trial 
Hokusai-VTE was a global, event-driven, randomized, double-blind, parallel-group phase 3 clinical study involving 8,292 patients in 439 clinical sites across 37 countries to evaluate once-daily edoxaban in patients with either acute symptomatic DVT, PE or both. The Hokusai-VTE study was designed to reflect clinical practice using a flexible treatment duration of 3-12 months, including initial use of parenteral anticoagulant (heparin) for 5-10 days, the proven global standard of care, in both arms, in a broad spectrum of VTE patients. Following treatment with open-label enoxaparin or unfractionated heparin for at least five days, and either warfarin or placebo (administered to edoxaban group), patients were randomized to receive either edoxaban 60 mg (patients were dose reduced to 30 mg for CrCL 30 to 50 mL/min, body weight less than 60 kg or certain p-glycoprotein inhibitor use) or warfarin for at least three months and up to a maximum of one year (duration of study treatment was determined by the investigator based on the patient's clinical features).³ The full results were presented at the ESC Congress 2013 in Amsterdam and published in the New England Journal of Medicine.

About Atrial Fibrillation 
AF is a condition in which the heartbeat is irregular, and can potentially lead to a stroke.⁷ AF is a common condition, affecting approximately 2.3-3.4% of people in developed nations.⁸ AF affects approximately 6.1 million people in the U.S.⁹ The incidence of AF increases with age, with a prevalence of 2.3% and 5.9% in people older than 40 and 65 years, respectively.^10,11 Approximately 70% of individuals with AF are between 65 and 85 years of age.¹² Stroke due to all causes is the fourth most common cause of death in the U.S., responsible for approximately 200,000 deaths each year.⁹ Compared to those without AF, people with the arrhythmia have a 3-5 times higher risk of stroke.⁸ Strokes due to AF are nearly twice as likely to be fatal than strokes in patients without AF at 30 days and have poorer prognosis than non-AF related strokes, with a 50% increased risk of remaining disabled at three months.^13,14

About Venous Thromboembolism 
VTE is an umbrella term for two conditions, DVT and PE. DVT is a disease caused by a blood clot found in deep veins, usually within the lower leg, thigh or pelvis, although they can occur in other parts of the body as well.¹⁵ PE occurs when part of a clot detaches and lodges in the pulmonary arteries, causing a potentially fatal condition.¹⁶ In the U.S., it is currently estimated that more than 950,000 VTE events and approximately 300,000 VTE related deaths occur each year.^17,18 Approximately 30% of people with VTE die within one month of diagnosis and about 20% of those with PE experience sudden death.¹⁹

About Daiichi Sankyo  
Daiichi Sankyo Group is dedicated to the creation and supply of innovative pharmaceutical products to address the diversified, unmet medical needs of patients in both mature and emerging markets. While maintaining its portfolio of marketed pharmaceuticals for hypertension, dyslipidemia and bacterial infections used by patients around the world, the Group has also launched treatments for thrombotic disorders and is building new product franchises. Furthermore, Daiichi Sankyo research and development is focused on bringing forth novel therapies in oncology and cardiovascular-metabolic diseases, including biologics. The Daiichi Sankyo Group has created a "Hybrid Business Model," to respond to market and customer diversity and optimize growth opportunities across the value chain. For more information, please visit: www.daiichisankyo.com.

Contact

Alyssa Dargento (US Media) 
Daiichi Sankyo, Inc.  
adargento@dsi.com   
+1 973 944 2913 (office) 
+1 973 727 1604 (mobile)

Michaela Paudler-Debus, PhD 
Daiichi Sankyo
michaela.paudler-debus@daiichi-sankyo.eu   
+49 89 7808 685 (office) 
+49 176 11780966 (mobile)

Forward-looking statements
This press release contains forward-looking statements and information about future developments in the sector, and the legal and business conditions of DAIICHI SANKYO Co., Ltd. Such forward-looking statements are uncertain and are subject at all times to the risks of change, particularly to the usual risks faced by a global pharmaceutical company, including the impact of the prices for products and raw materials, medication safety, changes in exchange rates, government regulations, employee relations, taxes, political instability and terrorism as well as the results of independent demands and governmental inquiries that affect the affairs of the company. All forward-looking statements contained in this release hold true as of the date of publication. They do not represent any guarantee of future performance. Actual events and developments could differ materially from the forward-looking statements that are explicitly expressed or implied in these statements. DAIICHI SANKYO Co., Ltd. assume no responsibility for the updating of such forward-looking statements about future developments of the sector, legal and business conditions and the company.

References
[1].  SAVAYSA (edoxaban) Tablets Prescribing Information. Parsippany, New Jersey, USA: Daiichi Sankyo, Inc.; January 2015. Available at: http://dsi.com/prescribing-information-portlet/getPIContent?productName=Savaysa&inline=true. [Last accessed: February 2015]. 
[2].  Giugliano R, et al. Edoxaban versus Warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093-2104. 
[3].  Buller H, et al. Edoxaban versus Warfarin for the treatment of Symptomatic Venous Thromboembolism. N Engl J Med. 2013. 
[4].  Ogata K, Mendell-Harary J, Tachibana M, et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol. 2010;50:743-753. 
[5].  Daiichi Sankyo press release - Daiichi Sankyo Receives Approval for Additional Indications of LIXIANA® (edoxaban) in Japan. 26 September 2014. Available at: http://www.daiichisankyo.com/media_investors/media_relations/press_releases/detail/006189.html. [Last accessed: February 2015]. 
[6].  Daiichi Sankyo press release - Daiichi Sankyo launches LIXIANA® (edoxaban), a direct oral factor Xa inhibitor, in Japan for the prevention of venous thromboembolism after major orthopaedic surgery. 19 July 2011. Available at: http://www.daiichisankyo.com/media_investors/media_relations/press_releases/detail/005784.html. [Last accessed: February 2015]. 
[7].  Patient.co.uk. Atrial fibrillation. Available at: http://www.patient.co.uk/pdf/4198.pdf. Updated 2012. [Last accessed: February 2015]. 
[8].  Ball J, et al. Atrial fibrillation: Profile and burden of an evolving epidemic in the 21st century. Int J Card. 2013; 167:1807-1824. 
[9].  Go AS, et al. Heart Disease and Stroke Statistics -- 2013 Update: A Report From the American Heart Association. Circulation. 2013; 127:6-245. 
[10]. Marinigh R, Lip GYH, Fiotti N, Giansante C, Lane DA. Age as a Risk Factor for Stroke in Atrial Fibrillation Patients. J Am Coll Cardiol. 2010;56(11):827-837. 
[11].  Laish-Farkash A, Khalameizer V, Katz A. Atrial Fibrillation in the ElderlyTo Ablate or Not to Ablate. J Cardiovasc Electrophysiol. 2013;24(7):739-741.
[12].  Kannel WB, Benjamin EJ. Epidemiology of Atrial Fibrillation. Med Clin North Am. 2008;92(1):17-40. 
[13].  Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation. Stroke. 1996;27:1760-1764.
[14].  Lamassa M, Di Carlo A, Pracucci G, et al. Characteristics, Outcome, and Care of Stroke Associated With Atrial Fibrillation in Europe. Stroke. 2001;32:392-398. 
[15].  Centers for Disease Control and Prevention. Deep Vein Thrombosis (DVT) / Pulmonary Embolism (PE) Blood Clot Forming in a Vein. Available at: http://www.cdc.gov/ncbddd/dvt/facts.html. [Last accessed: February 2015]. 
[16].  Van Beek E, et al. Deep Vein Thrombosis and Pulmonary Embolism. New York: John Wiley & Sons, 2009. Print. 
[17].  Deitelzweig S, Lin J, Johnson BH, Schulman KL. Prevalence of venous thromboembolism in the USA: now and future. Thromb Haemost. 2009;7(Suppl. 2):207-8(abstract OC-WE-018).
[18].  Heit JA, Cohen AT, Anderson FAJ, on behalf of the VTE Impact Assessment Group. Estimated annual number of incident and recurrent, non-fatal and fatal venous thromboembolism (VTE) events in the US. ASH Annual Meeting Abstracts. 106:910. 2005.
[19].  Heit JA. Venous thromboembolism epidemiology: implications for prevention and management. Semin Thromb Hemost. 2002;(s2):003014.

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SOURCE Daiichi Sankyo