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QSYMIA™
LisaLuna Medical Primary Care
www.qsymia.com
What is Qsymia?
Qsymia= Phentermine + Topiramate extended-release
Phentermine, Sympathomimetic amine anorectic Topiramate extended-release, Antiepileptic drug
Phentermine
• An appetite suppressant to help reduce weight in obese patients – used short-term and combined with exercise
• A psycho-stimulant drug of the phenethylamine class, with pharmacology similar to Amphetamine
Topiramate extended-release• An anticonvulsant (antiepilepsy) drug
– Topiramate was first approved by the FDA in 1996– The last patent for topiramate in the U.S. was for
pediatric use; this patent expired on February 28, 2009
• Extended-release: – allowing a twofold or greater reduction in frequency of
administration of a drug in comparison with the frequency required by a conventional dosage form.
Mechanism
Phentermine
• Target organ: Hypothalamus portion of the brain• Effect: Stimulate the adrenal glands to release
norepinephrine
• Peripheral Effect: Release epinephrine or adrenaline, causing fat cells to break down stored fat
– Epinephrine(adrenaline)& Norepinephrine: fight-or-flight response
Topiramate
• blockage of voltage-dependent sodium channels
• an augmentation of gamma-aminobutyrate (GABA) acid activity at some subtypes of the GABA- α receptors
• antagonism of AMPA/kainate subtype of the glutamate receptor
• inhibition of the carbonic anhydrase enzyme, particularly isozymes II and IV
Topiramate (continued)
• The exact mechanism of action is unknown
• Weight loss was initially seen as a side effect– effect on taste
Clinical Trials
Phase 0 study Phase I Study
Phase II Study Phase III studyPhase IV study
Phase 0 Study
• Exploratory study involving very limited human exposure to the drug, with no therapeutic or diagnostic goals
• Pharmacodynamics and Pharmacokinetics
– Pharmacodynamics: what dose Drug do to Person?– Pharmacokinetics: what dose person do to Drugs?
Pharmacodynamics of Qysmia
Central Nervous System stimulation and elevation of blood pressure
Pharmacokinetics for Phentermine
– Approximately dose-proportional– 6 hours to reach the peak blood concentration– A high fat meal does not affect phentermine
pharmacokinetics, 17.5% plasma protein bound
Maximum concentration (Cmax) 49.1 ng/mL
time to Cmax (Tmax) 6 hr
area under the concentration curve from time zero to the last time with measureable concentration (AUC0-t)
1990 ng hr/mL⋅
Fig.1.1 Pharmacokinetics descriptive values for Phentermine
Pharmacokinetics for Topiramate
– approximately dose-proportional– 9 hours to reach the peak blood concentration– 15-41% plasma protein bound
Maximum concentration (Cmax) 1020.0 ng/mL
time to Cmax (Tmax) 9 hr
area under the concentration curve from time zero to the last time with measureable concentration (AUC0-t)
61600 ng hr/mL⋅
Fig.1.2 Pharmacokinetics descriptive values for Topiramte
Phase I Study---- Screening for safety
Studies that are usually conducted with healthy volunteers and that emphasize safety. The goal is to find out what the drug's most frequent and serious adverse events are and, often, how the drug is metabolized and excreted
• A Phase I, Open-Label, Parallel-Group, Single Dose, Non-Randomized Study To Compare The Pharmacokinetics Of Each Individual Component ( Topiramate And Phentermine) Of The Combination Product VI-0521 In Subjects With Mild, Moderate And Severe Renal Impairment To Subjects With Normal Renal Function
Reporting Groups Description
Placebo No text entered
Top Dose PHEN/TPM 15mg/92mg
Fig.1.3 Upper Level for Phen/Tpm dosage
Adverse reactions
NO serious adverse reaction found
Other adverse reaction includes paraesthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth
Phase II Study
Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition). For example, participants receiving the drug may be compared with similar participants receiving a different treatment, usually an inactive substance (called a placebo) or a different drug. Safety continues to be evaluated, and short-term adverse events are studied
Phase II Study provided by VIVUS:
*Phentermine 3.75 mg and topiramate 23 mg daily for the 1st week; Phentermine 7.5 mg and topiramate 46 mg daily for the 2nd week; Phentermine 11.25 mg and topiramate 69 mg daily for the 3rd week; Phentermine 15 mg and topiramate 92 mg daily for the 4th week**Placebo daily for 4 weeks
Values
Enrollment number 80
Ages Eligible for Study 21 Years to 45 Years
Genders Eligible for Study Both
Condition ICMJE OverweightObesity
Intervention ICMJE Drug: VI-0521*Drug: Placebo**Other: Alcohol or fruit juice
Fig.2.1 Phase II Study of Drug VI-0521 and Placebo descriptive values
Effectiveness
For the Treatment of Obstructive Sleep Apnea Hypopnea Syndrome in Obese Adults
Study Type: Interventional
Study Design:
Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Investigator); Primary Purpose: Treatment
Condition: Sleep Apnea
Interventions: Drug: VI-0521Drug: placebo
Fig.2.2 Results for the effectiveness of VI-0521 in Phase II Study
Effectiveness(continued)
Placebo Top Dose
Number of Participants Analyzed 23 22
Change in the Apnea/Hypopnea Index Between Baseline and Week 28/Early Term**
-16.6 ± 4.15 -31.46 ± 4.25
Placebo Top Dose
Number of Participants Analyzed 23 22
Percent Change in Weight From Baseline to Week 28*
-10.26 ± 1.17 -4.21 ± 1.15
*[units: percent change] Least Squares Mean ± Standard Error**[units: events/hour] Least Squares Mean ± Standard Error
Fig.2.3 Results for the effectiveness of VI-0521 on weight change in Phase II Study
Fig.2.4 Results for the effectiveness of VI-0521 on Apnea/hypopnea Change in Phase II Study
Adverse Reaction
NO serious adverse reaction found
Other adverse reaction includes paraesthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth
Phase III Study
Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.
#1 A Safety and Efficacy Study of VI-0521 to Evaluate the Long Term Treatment of Obesity in Adults With Obesity-Related Co-Morbid Conditions.
Description
Placebo Placebo
VI-0521 Mid VI-0521 7.5 mg PHEN/46 mg TPM
VI-0521 Top VI-0521 15 mg PHEN/92 mg TPM
Fig.3.1 Phase III Study of Drug VI-0521 and Placebo descriptive dosage in Experiment 1
*[units: percent weight loss] Least Squares Mean ± Standard Error**[units: percent participants]
Measured Values Placebo VI-0521 Mid VI-0521 Top
Number of Participants Analyzed 227 153 295
Percent Weight Change at End of Treatment, Week 108. -1.8 ± 0.55 -9.32 ± 0.67 -10.5 ± 0.5
Placebo VI-0521 Mid VI-0521 Top
Number of Participants Analyzed 227 153 295
Percentage of Subjects With at Least 5% Weight Loss at End of Treatment, Week 108.
30 75.2 79.3
Effectiveness
Fig.3.3 Results for the effectiveness of VI-0521 on Percentage of Subjects With at Least 5% Weight Loss in Experiment 1 of Phase III Study
Fig.3.2 Results for the effectiveness of VI-0521 on weight change in Experiment 1 of Phase III Study
Adverse Reaction
Total, serious adverse events Placebo VI-0521 Mid VI-0521 Top
# participants affected / at risk 9/227 (3.96%) 4/153 (2.61%) 13/295 (4.41%)
Serious Adverse Events
Fig.3.4 Results for the adverse reaction of VI-0521 in Experiment 1 of Phase III Study
#2 A Study Comparing Multiple Doses of VI-0521 With Placebo and Their Single-agent Constituents for Treatment of Obesity in Adults
Description
Placebo PlaceboPHEN 7.5 mg 7.5 mg phentermineTPM 46 mg 46 mg topiramateVI-0521 Mid 7.5 mg/46 mg phentermine/topiramatePHEN 15 mg 15 mg phentermineTPM 92 mg 92 mg topiramateVI-0521 Top 15 mg/92 mg phentermine/topiramate
Fig.3.5 Phase III Study of Drug VI-0521 and Placebo descriptive dosage in Experiment 2
*[units: participants] [units: percent weight loss]**Least Squares Mean ± Standard Error
Placebo PHEN 7.5 mg TPM 46 mg VI-0521
Mid PHEN 15 mg
TPM 92 mg VI-0521 Top
# of Participants 103 104 102 103 106 105 103
Percent Weight Loss From Baseline to Week 28
1.7 ± 0.61
5.5 ± 0.61
5.1 ± 0.61
8.5 ± 0.62
6.1 ± 0.61
6.4 ± 0.62
9.2 ± 0.61
Placebo PHEN 7.5 mg TPM 46 mg VI-0521 Mid
PHEN 15 mg TPM 92 mg VI-0521 Top
# of Participants 103 104 102 103 106 105 103
Percentage of Subjects With at Least 5% Weight Loss at Week 28
15.5 43.3 39.2 62.1 46.2 48.6 66.0
Effectiveness
Fig.3.6 Results for the effectiveness of VI-0521 on weight change in Experiment 2 of Phase III Study
Fig.3.7 Results for the effectiveness of VI-0521 on Percentage of Subjects With at Least 5% Weight Loss in Experiment 1 of Phase III Study
Adverse Reaction
Placebo PHEN 7.5 mg TPM 46 mg VI-0521 Mid
PHEN 15 mg
TPM 92 mg VI-0521 Top
# participants affected / at risk
0/109 (0.00%)
2/109 (1.83%)
0/106 (0.00%)
1/106(0.94%)
1/108 (0.93%)
1/107 (0.93%)
2/108 (1.85%)
Fig.3.8 Results for the adverse reaction of VI-0521 in Experiment 1 of Phase III Study
Phase IV Study
Studies occurring after FDA has approved a drug for marketing. These including postmarket requirement and commitment studies that are required of or agreed to by the sponsor. These studies gather additional information about a drug's safety, efficacy, or optimal use.
Phase IV Study Status: Active, not Recruiting
http://www.clinicaltrials.gov
Potential Side Effect
• Fetal Toxicity• Increase in Heart Rate• Suicidal Behavior and Ideation• Acute Myopia and Secondary Angle Closure Glaucoma• Mood and Sleep Disorders• Cognitive Impairment• Metabolic Acidosis• Elevation in Creatinine
Sources
• Phase I, II, III, IV Study http://www.clinicaltrials.gov
• Adverse Studyhttp://www.vivus.com
QSYMIA™ This Medication Guide has been approved by the U.S. Food and Drug Administration©2012, VIVUS, Inc. All rights reserved.VIVUS, Inc1172 Castro StreetMountain View, CA 94040 USAUS Patent Numbers: 7,056,890 and 7,553,818Qsymia is a trademark of VIVUS, Inc.©2012, VIVUS, Inc.Issued: July/2012
Thank you
We Appreciate Your Patience!
http://www.youtube.com/watch?v=B2SP3yaK9Nw