1. QSYMIA™
Lisa
Luna Medical Primary Care

2. www.qsymia.com

3. What is Qsymia?
Qsymia= Phentermine + Topiramate extended-release
Phentermine, Sympathomimetic amine anorectic
Topiramate extended-release, Antiepileptic drug

4. 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

5. 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.

6. Mechanism

7. 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

8. 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

9. Topiramate (continued)
• The exact mechanism of action is unknown
• Weight loss was initially seen as a side effect
– effect on taste

10. Clinical Trials
Phase 0 study
Phase I Study
Phase II Study
Phase III study
Phase IV study

11. 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?

12. Pharmacodynamics of Qysmia
Central Nervous System stimulation and
elevation of blood pressure

13. Pharmacokinetics for Phentermine
Maximum concentration (Cmax) 49.1 ng/mL
6 hr
time to Cmax (Tmax)
area under the concentration
curve from time zero to the last
1990 ng⋅hr/mL
time with measureable
concentration (AUC0-t)
Fig.1.1 Pharmacokinetics descriptive values 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

14. Pharmacokinetics for Topiramate
Maximum concentration (Cmax) 1020.0 ng/mL
9 hr
time to Cmax (Tmax)
area under the concentration
curve from time zero to the last
61600 ng⋅hr/mL
time with measureable
concentration (AUC0-t)
Fig.1.2 Pharmacokinetics descriptive values for Topiramte
– approximately dose-proportional
– 9 hours to reach the peak blood concentration
– 15-41% plasma protein bound

15. 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

16. • 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

17. Adverse reactions
NO serious adverse reaction found
Other adverse reaction includes paraesthesia,
dizziness, dysgeusia, insomnia, constipation, and
dry mouth

18. 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

19. Phase II Study provided by VIVUS:
Values
Enrollment number 80
Ages Eligible for Study 21 Years to 45 Years
Genders Eligible for Study Both
Condition ICMJE Overweight
Obesity
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
*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

20. Effectiveness
For the Treatment of Obstructive Sleep Apnea Hypopnea
Syndrome in Obese Adults
Study Type: Interventional
Allocation: Randomized; Endpoint Classif
ication: Safety/Efficacy Study; Interventi
Study Design: on Model: Parallel Assignment; Masking:
Double Blind (Subject, Investigator); Pri
mary Purpose: Treatment
Condition: Sleep Apnea
Drug: VI-0521
Interventions:
Drug: placebo
Fig.2.2 Results for the effectiveness of VI-0521 in Phase II Study

21. Effectiveness(continued)
Placebo Top Dose
Number of Participants
23 22
Analyzed
Percent Change in Weight
From Baseline to Week -10.26 ± 1.17 -4.21 ± 1.15
28*
Fig.2.3 Results for the effectiveness of VI-0521 on weight change in Phase II Study
Placebo Top Dose
Number of Participants
23 22
Analyzed
Change in the
Apnea/Hypopnea Index
-16.6 ± 4.15 -31.46 ± 4.25
Between Baseline and
Week 28/Early Term**
Fig.2.4 Results for the effectiveness of VI-0521 on Apnea/hypopnea Change in Phase II Study
*[units: percent change] Least Squares Mean ± Standard Error
**[units: events/hour] Least Squares Mean ± Standard Error

22. Adverse Reaction
NO serious adverse reaction found
Other adverse reaction includes paraesthesia,
dizziness, dysgeusia, insomnia, constipation, and
dry mouth

23. 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.

24. #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

25. Effectiveness
Measured Values Placebo VI-0521 Mid VI-0521 Top
Number of Participants Analyzed 227 153 295
Percent Weight Change at End of
-1.8 ± 0.55 -9.32 ± 0.67 -10.5 ± 0.5
Treatment, Week 108.
Fig.3.2 Results for the effectiveness of VI-0521 on weight change in Experiment 1 of Phase III Study
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 30 75.2 79.3
Treatment, Week 108.
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
*[units: percent weight loss] Least Squares Mean ± Standard Error
**[units: percent participants]

26. Adverse Reaction
Serious Adverse Events
Total, serious
Placebo VI-0521 Mid VI-0521 Top
adverse events
# participants
9/227 (3.96%) 4/153 (2.61%) 13/295 (4.41%)
affected / at risk
Fig.3.4 Results for the adverse reaction of VI-0521 in Experiment 1 of Phase III Study

27. #2 A Study Comparing Multiple Doses of VI-0521 With
Placebo and Their Single-agent Constituents for Treatment of
Obesity in Adults
Description
Placebo Placebo
PHEN 7.5 mg 7.5 mg phentermine
TPM 46 mg 46 mg topiramate
VI-0521 Mid 7.5 mg/46 mg phentermine/topiramate
PHEN 15 mg 15 mg phentermine
TPM 92 mg 92 mg topiramate
VI-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

28. Effectiveness
PHEN 7.5 VI-0521 PHEN 15
Placebo TPM 46 mg TPM 92 mg VI-0521 Top
mg Mid mg
# of
103 104 102 103 106 105 103
Participants
Percent
Weight Loss
1.7 5.5 5.1 8.5 6.1 6.4 9.2
From
± 0.61 ± 0.61 ± 0.61 ± 0.62 ± 0.61 ± 0.62 ± 0.61
Baseline to
Week 28
Fig.3.6 Results for the effectiveness of VI-0521 on weight change in Experiment 2 of Phase III Study
PHEN 7.5 VI-0521 TPM 92
Placebo TPM 46 mg PHEN 15 mg VI-0521 Top
mg Mid mg
# of
103 104 102 103 106 105 103
Participants
Percentage of
Subjects With
at Least 5% 15.5 43.3 39.2 62.1 46.2 48.6 66.0
Weight Loss at
Week 28
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
*[units: participants] [units: percent weight loss]
**Least Squares Mean ± Standard Error

29. Adverse Reaction
PHEN 7.5 VI-0521 PHEN 15
Placebo TPM 46 mg TPM 92 mg VI-0521 Top
mg Mid mg
#
participan 0/109 2/109 0/106 1/106 1/108 1/107 2/108
ts affected (0.00%) (1.83%) (0.00%) (0.94%) (0.93%) (0.93%) (1.85%)
/ at risk
Fig.3.8 Results for the adverse reaction of VI-0521 in Experiment 1 of Phase III Study

30. 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.

31. Phase IV Study Status: Active, not Recruiting
http://www.clinicaltrials.gov

32. 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

33. Sources
• Phase I, II, III, IV Study
http://www.clinicaltrials.gov
• Adverse Study
http://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, Inc
1172 Castro Street
Mountain View, CA 94040 USA
US Patent Numbers: 7,056,890 and 7,553,818
Qsymia is a trademark of VIVUS, Inc.
©2012, VIVUS, Inc.
Issued: July/2012

34. Thank you
We Appreciate Your Patience!
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