New Study Data Published Assessing the Effect of LIVALO® vs. Crestor® on International Normalized Ratio on Steady-State Warfarin

MONTGOMERY, Ala., Feb. 13, 2012 /PRNewswire/ -- Kowa Pharmaceuticals America, Inc. today announced data assessing the effect of LIVALO® (pitavastatin) compared with Crestor® (rosuvastatin) on steady-state pharmacodynamics (PD) of warfarin by measuring international normalized ratio (INR) in healthy adult subjects.(1)  The study, published in Current Medical Research & Opinion, showed INR during stable warfarin treatment did not change significantly when LIVALO was added to the regimen, while a significant increase was observed when Crestor was added to warfarin.(1) INR is a laboratory test that measures the time it takes for blood to clot and compares it to an average.(2) Warfarin is a widely used anticoagulant that inhibits vitamin K-dependent clotting factors to prevent blood clot formation.(3)

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It is not uncommon for patients on chronic warfarin therapy to have high cholesterol that requires lipid modifying agents, particularly statins.(4) The concomitant use of statins and warfarin has been studied, and a large database outcomes study reported that the initiation of certain statins was associated with an increased risk of hospitalization for gastrointestinal bleeding.(5) LIVALO and Crestor have not been studied in this context. Given there may be potential differences among statins and their effect on warfarin, the purpose of the study was to assess the effect of LIVALO compared with Crestor on steady-state INR when coadministered with warfarin.(1)

Results showed that, in healthy subjects taking LIVALO 4 mg, mean INR changed from 1.73+/-0.18 (n=42) on day 14 before starting statin dosing, to 1.78+/-0.29 (n=42) on day 22 at treatment end; the difference in INR was not significant.(1)  For Crestor 40 mg, mean INR increased significantly from 1.74+/-0.20 (n=43) at baseline to 1.90+/-0.30 (n=43) at treatment end (p<0.001).(1) There were no severe adverse events, serious adverse events, or deaths.(1) Patients receiving warfarin should have their prothrombin time (PT) and INR monitored when LIVALO is added to their therapy. 

"These data are important as this is the first study to investigate differences in steady-state pharmacodynamic response and effect on anticoagulation between two statins when each are independently added to warfarin," said Craig Sponseller, MD, Vice President of Medical Affairs, Kowa Pharmaceuticals America, Inc.  "Physicians now have additional information to reference with this pharmacodynamic data when considering statin options for patients with high cholesterol who are on chronic warfarin treatment."

Study Design

Kowa Pharmaceuticals America, Inc. was a sponsor of this open-label, crossover, drug-drug interaction study. Subjects received oral doses of warfarin 5 mg once daily on days 1 through 3.(1) The dose was titrated on days 4 through 9 to reach a steady-state INR of 1.5 to 2.2.(1) Warfarin was continued on days 10 through 21, and LIVALO 4 mg or Crestor 40 mg was administered once daily on days 14 through 22.(1) After a 14-day washout period, the process was repeated with the alternate statin.(1) The highest FDA-approved daily dose of each statin was chosen in order to optimize any potential differences between these statin agents on effect of steady-state INR and potential drug interactions with warfarin.(1)

About LIVALO

LIVALO is a HMG-CoA reductase inhibitor indicated for patients with primary hyperlipidemia and mixed dyslipidemia as an adjunctive therapy to diet to reduce elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C).  Pitavastatin is only minimally metabolized through cytochrome P450 (CYP); marginally by CYP2C9 and to a lesser extent by CYP2C8. The principle route of metabolism is glucuronidation which leads to the formation of  the major metabolite, pitavastatin lactone.

In addition to being launched in the U.S. June 2010, LIVALO is also approved in Japan (2003), South Korea (2005), Thailand (2007), China (2008), European Union (2010), Taiwan (2011), Mexico (2009) and Australia (2010).

About Primary Hyperlipidemia and Mixed Dyslipidemia

Primary Hyperlipidemia is defined as an elevation of cholesterol, particularly "bad" cholesterol (LDL-C), triglycerides (TG), or both. Mixed dyslipidemia is usually characterized by an elevation of LDL-C, TG, and a decrease in the "good" cholesterol (HDL-C) in the blood.

Despite the availability of treatments in the U.S. there is still a need for more options to help treat elevated cholesterol. According to the American Heart Association, approximately one out of every three American adults has an LDL-C level of 130 mg/dL or higher, which is a major health risk. In addition, less than half of patients who qualify for any kind of lipid-modifying treatment are receiving it, and only about one-third of patients who are on treatment are achieving their LDL-C goals.

Important Safety Information for LIVALO® (pitavastatin) Tablets

Who should NOT take LIVALO?

LIVALO is not right for everyone, including:

• Those who have had an allergic reaction to LIVALO
• Anyone with active liver disease
• Women who are nursing, pregnant, or who may become pregnant
• Anyone currently taking cyclosporine

What should I talk to my doctor about?

• If you take LIVALO, tell your doctor right away if you experience any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by fever or a general feeling of discomfort. This could be a sign of a rare but serious side effect.
• Your doctor should do blood tests to monitor your liver function before starting LIVALO, and then at 12 weeks following the start of LIVALO, after any increase in dose, and periodically (e.g., every 6 months) thereafter.
• Please talk to your doctor about your alcohol use.
• Tell your doctor about all the medications you take including nonprescription medicines, vitamins, or herbal supplements.

What are the most common side effects of LIVALO?

The most common side effects of LIVALO in clinical studies were:

• Back pain
• Constipation
• Diarrhea 
• Muscle pain 
• Pain in the legs or arms 

This is not a complete list of side effects. 

Other Important Information about LIVALO

• LIVALO has not been studied to evaluate its effect on reducing heart-related disease or death.
• LIVALO is available by prescription only.

Please see the Full Prescribing Information available at www.LivaloRx.com.  
LIV-RA-0032 PS73370 8/2011

About Kowa Company, Ltd. and Kowa Pharmaceuticals America, Inc.

Kowa Company, Ltd. (KCL) is a privately held multinational company headquartered in Nagoya, Japan. Established in 1894, KCL is actively engaged in various manufacturing and commercial activities in the fields of pharmaceutical, life science, information technology, textiles, machinery and various consumer products. KCL's pharmaceutical division is focused on cardiovascular therapeutics, with sales of the company's flagship product LIVALO, totaling $530 million (14.6% market share) in Japan in the 2010 fiscal year, and was launched in the United States in June 2010.

Kowa Pharmaceuticals America, Inc. (KPA) is a pharmaceutical company specializing primarily in the area of cardiometabolic diseases. The company, started in 2001 as ProEthic Pharmaceuticals, Inc., was acquired by KCL in September of 2008. A privately held company, KPA directs its efforts towards the acquisition, licensing and marketing of pharmaceutical products.

exchange rate used $1=85JPY

LIVALO is a registered trademark of the Kowa group of companies.
CRESTOR is a registered trademark of the AstraZeneca group of companies.

Media Contacts

Lisa Garman
Kowa Pharmaceuticals America, Inc.
Office: (334) 288-1288
Mobile: (404) 291-4772
[email protected]

Eliza Merves
Makovsky + Company Inc. for Kowa Pharmaceuticals America, Inc.
Office: (212) 508-9631
Mobile: (908) 256-1243
[email protected]  

(1) Yu C, Campbell S, Zhu B, et al.   Effect of pitavastatin vs. rosuvastatin on international normalized ratio in healthy volunteers on steady-state warfarin. Current Medical Research & Opinion.  2012;28:187-194.
(2) Heart Rhythm Foundation. "International Normalized Ratio (INR)." Available at http://www.hrsonline.org/uploaddocs/inr_final.pdf.  Accessed January 30, 2012.
(3) AHA Website. "American Heart Association/American College of Cardiology Foundation Guide to Warfarin Therapy." Available at http://circ.ahajournals.org/content/107/12/1692.full. Accessed January 31, 2012.
(4) Paciaroni M, Agnelli G. "Risk Factors for Cerebral Ischemic Events in Patients with Atrial Fibrillation on Warfarin for Stroke Prevention." Atherosclerosis. Accessed January 25, 2012.
(5) Schelleman H, Bilker WB, Brensinger CM, et al. Fibrate/Statin initiation in warfarin users and gastrointestinal bleeding risk. Am J Med 2010;123:151-7.

SOURCE Kowa Pharmaceuticals America, Inc.