Presented by Valeria Antonella AguirreFellow at Academy of Applied Pharmaceutical Sciences, AAPS, 2015

SibutramineOral appetite suppressant

• Discovery Regulatory History: • Pre- approval trials• Approval and conditions• Pharmacovigilance• Safety concerns • SCOUT clinical trial• Discussion• Conclusion

• The active ingredient is a racemic mixture of the (+) and (-) enantiomers of cyclobutanemethanamine• empirical formula: C17H29Cl2NO• molecular weight: 334.33• Structural formula:

History:

 

• First discovered as a potential drug in 1987 by Buckett et al

• Investigated for its potential antidepressant properties for 6 years

• Its properties in this field were never fully evaluated or clinical trials were never published. This may be due to poor results

•   Kiyoharu Ukai : Treatment of cerebral function disorders such as Parkinson's disease

• Jerussi, et al: Sibutramine and more potent derivatives such as demethylsibutramine (DMS) : treating sexual dysfunction

• Mendel et al: Treating addictive disorders, pulmonary hypertension, cardiovascular disease, Chronic Fatigue Syndrome, hyperactivity disorders, menstrual dysfunction and orthostatic hypotension

• Kelly et al. discovered a noticeable decrease in weight amongst obese patients, leading to use it as an anorexiant to help clinically obese patients lose weight

Meridia (sibutramine) inhibits the reuptake of certain neurotransmitters:

Norepinephrine: 73%Serotonin: 54%Dopamine: 16%

Sibutramine primarily works by increasing feelings of satiety and reducing appetite

Only effective as part of a full treatment program, including a reduced calorie diet

It is recommended for people with a BMI of 30kg m-2 or 27kg m-2 if there are other risk factors

Active weight normally loss occurs for 6 months, and weight loss can be maintained for a period of up to 2 years with sustained therapy.

Treatment for further periods of time have not been evaluated yet

Regulatory History

sibutramine vs placebo:• caused 1-3 mmHg mean increase in blood pressure • 5-beat-per-minute average increase in pulse rate• Inhibition of reuptake of norepinephrine stimulate the sympathetic nervous system (autonomic)• Tachycardia, premature atrial contractions, premature ventricular contractions, palpitations• No evidence of clinically significant outcomes

Pre- approval trials:

•Knoll Pharmaceuticals submitted NDA to FDA seeking approval of 5, 10, 15, 20 and 30 mg once daily doses• Primary Medical Reviewer: concern about blood pressure

Single risk outweigh the documented benefits:improvements in HDL and TG

August 1995

• Division of Cardio- Renal Drug Products: Long-term benefits of weight reduction could outweigh short- term risks of blood pressure elevation• Dr John Flack , blood pressure expert, Bowman Gray School of Medicine:

  Increase pressure 1 to 3 mmHg Risks /benefits unfavorable in obese patients with HP, Coronary artery disease , congestive heart failure, stroke or cardiac arrhythmias

September 1996

• Endocrinologic and Metabolic Drug’s advisory committee:

8 of 9 agreed that the drug’s effect on blood pressure was clinically important

FDA conclude that Sibutramine was an effective obesity agent using Guidance for the Clinical Evaluation of Weight Control

FDA request that Knoll conduct additional analysis of clinical trials blood pressure data:

• Risk increased with 20 and 30 mg• Risk for increase in blood pressure in small

percent of patients

November 22, 1997• After 26 month of regulatory review

• FDA approve Knoll Pharmaceuticals’s NDA for Sibutramine 5, 10, 15 mg once daily dose

• Approve in 72 Countries and marketed in 65 Countries worldwide

Reductil, Meridia, Siredia, and Sibutrex

It was sold under a variety of brand names including:

Conditions:• Management of obesity including loss and

maintenance of weight loss• Obese patients body mass index > o =30

kg/m2 or > o = 27 kg/m2 • Risks factors: hypertension, diabetes ,

dyslipemia• Regular monitoring of blood pressure is

required

Warnings: Blood Pressure and Pulse 

MERIDIA SUBSTANTIALLY INCREASES BLOOD PRESSURE AND/OR PULSE RATE IN SOME PATIENTS. REGULAR MONITORING OF BLOOD PRESSURE AND PULSE RATE IS REQUIRED WHEN PRESCRIBING MERIDIA

March 2, 2001:

Abbott Laboratories acquired Knoll Pharmaceuticals and holds the NDA for Meridia

Pharmacovigilance

AERS

Passive post-approval drug safety surveillance system useful for detecting signal of serious , previously unrecognized , rare adverse events

March 2002:• Minister of Health in Italy suspend the

Marketing license• Reports of SAR and 2 death• Revision of safety and efficacy datas by

committee for proprietary medicinal products (CPMP)• Reinstated marketing license in August

2002

From November 22 to August 2003 54 domestic reports of death were submitted to AERS• 30 due to a cardiovascular cause• 24 due to suicide, motor vehicle accident,

respiratory failure, serotonin syndrome, etc

224 reports of serious nonfatal Cardiovascular and stroke events

FDA argument

Myocardial infarction, stroke, heart failure and arrythmias are very common in patients with obesity

AERS reports limited value

SAFETY CONCERNS:• Studies were ongoing into reports of

sudden death, heart failure, renal failure and gastrointestinal problems

• Despite a 2002 petition by Ralph Nader-founded NGO Public Citizen, the FDA made no attempts to withdraw the drug, but was part of a Senate hearing in 2005

SAFETY CONCERNS:

• Dr. David Graham, FDA "whistleblower", testified before a Senate Finance Committee hearing that sibutramine may be more dangerous than the conditions it is used for

Assessment of Cardiovascular safety profile

December 2002

SCOUT clinical trial

not include Asia where different criteria apply for overweight and obesity

300 centres in 16 countries

• First study to evaluate the potential benefits of weight management on cardiovascular outcomes in overweight and obese patients at high risk for cardiovascular events

• Weight management includes weight loss and weight maintenance induced by a novel lifestyle intervention programme

• Patient enrolment began in late December 2002 with the first patient randomized in February 2003

• it was expected that randomization were completed in mid-2005

• All patients were followed for 3 years till 2008

• multi-centre, double-blind, placebo-controlled trial

• 9000 patients were randomized to receive either sibutramine (10–15 mg daily) or placebo

• 600 kcal per day diet and at least 150 min per week of moderate physical activity (e.g. walking/cycling)

• An independent Data Safety Monitoring Board was monitoring all data collected

Inclusion criteria• Includes patients aged 55 years and older • BMI of ≥27 and ≤45 kg/m2 or ≥25 and <27 

kg/m2 

• waist circumference of ≥102 cm (men) or ≥88 cm (women)

• cardiovascular event or have diagnosed Type 2 diabetes and another cardiovascular risk factor

 

Inclusion criteria• history of coronary artery disease,

peripheral arterial occlusive disease, cerebrovascular disease (stroke or transient ischaemic attack), controlled hypertension, or New York Heart Association classes I and II heart failure

The SCOUT study design

Results:• The study  was published by the New

England Journal of Medicine, in mid-2010. In it, participants who took Meridia suffered 28% more heart attacks and 36% more strokes than those taking placebo

• The authors of the study, all employed by Abbott, concluded that patients with heart problems should not take Meridia

• The editors of New England Journal of Medicine wrote that the results indicated that Meridia should be recalled

• Upon seeing the preliminary results of the trial in January, the European Medicines Agency recalled Meridia from European markets

• The FDA, members split on whether to ask for a recall or only update labeling, only asked Abbott to include a warning on the label of the drug, even though the FDA had linked 17 deaths to Meridia up to that point

• October, 2010, with the FDA having gone over the study’s results again, the FDA requested a recall

 FDA wrote, "On October 8, 2010, the U.S. Food and Drug Administration (FDA) asked Abbott Laboratories to voluntarily withdraw from the U.S. market, its weight loss drug Meridia (sibutramine) because of clinical trial data indicating an increased risk of cardiovascular adverse events, including heart attack and stroke, in the studied population."

References:http://www.ch.ic.ac.uk/local/projects/rowlands/http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4210b_04_06_MeridiaCitizenPetitionFDALtr.pdf http://eurheartjsupp.oxfordjournals.org/content/7/suppl_L/L44.fullhttp://www.drugsdb.com/blog/fda-approved-drugs-pulled-from-market.htmlhttp://www.rxlist.com/meridia-drug.htm

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