Transcript (phentermine/topiramate CR) For Chronic Weight Management

The Use of
phentermine/topiramate CR
(Qsymia®) For Chronic Weight
Management
Stefanie L. Drahuschak
PharmD Candidate 2014
October 14, 2013
Learning Objectives
• Explain the severity of the impact of obesity on
society today
• List the non-pharmacologic and pharmacologic
options for short- and long-term weight
management
• Identify the important results of a phase 3
clinical trial with phentermine/topiramate CR
• Determine the place of phentermine/topiramate
CR in the treatment of overweight and obese
patients
Patient Case
• LP is a 45 year old male who presents with concerns
regarding his weight
▫ BMI = 38 kg/m2
• PMH: obesity, hypertension, hyperlipidemia, sleep
apnea, and depression/anxiety
• Patient previously used phentermine 37.5 mg QD
intermittently
▫ Quickly regained the weight he lost upon d/c
• LP is experiencing an extremely decreased QoL and
requests another weight loss option
• Is the study drug an appropriate option for LP?
Obesity
A Growing Epidemic
Epidemiology
• Estimated that more than 140 million (or about
2/3) adults are overweight or obese in the
United States
• Epidemic is projected to affect ~80% of US
adults by 2020
• Increasing health care costs
▫ Overweight/obesity accounts for 5-7% of health
care costs in US
▫ Direct and indirect costs approaches $150 billion
annually
Pharmacotherapy. 2011; 2567-84.
Epidemiology
• Highest prevalence is among non-Hispanic black
women
▫ 52.9% obese, 13.7% extremely obese; compared
with values of 37.2% and 5.9% of non-Hispanic
black men, respectively
• Obesity increases with ages, reaching a
maximum by the eighth decade
• Educational achievement and socioeconomic
status are correlated with obesity
Pharmacotherapy. 2011; 2567-84.
Etiology
• Energy Intake >> Energy Expenditure
▫ Leads to increased energy storage
• This imbalance can be multifactorial
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Genetic influences
Environmental influences
Medical conditions
Medications
Body Mass Index (BMI)
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BMI < 18.5: underweight
BMI 18.5 – 24.9: normal
BMI 25 - 29.9: overweight
BMI ≥ 30: obese
• At the same BMI, women tend to have more
body fat than men
• At the same BMI, older people tend to have
more body fat than younger people
Centers for Disease Control and
Prevention. Overweight and Obesity
Associated Co-morbidities
• Substantial reductions in life expectancy/quality
have been seen in adults with BMI > 35 kg/m2
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Hypertension
Hyperlipidemia
Insulin resistance
Glucose intolerance
Stroke
-Sleep apnea
-Osteoarthritis
-Cardiac events
-Depression
Pharmacotherapy. 2011; 2567-84.
Non-Pharmacologic Options
• Reduce caloric intake through adherence to a
low-calorie diet
▫ 800-1200 kcal/day
• Increased physical activity
▫ At least 30 minutes of moderate activity per day
• Behavioral modification
▫ Increase motivation, promote adherence
• Bariatric Surgery
▫ Reserved for BMI ≥ 40 kg/m2 (or ≥35 if significant
co-morbidities)
Pharmacotherapy. 2011; 2567-84.
Pharmacologic Options
• Short-term weight loss
▫ Nonadrenergic agents
 Phentermine: enhances NE and dopamine
neurotransmission decreasing appetite
 Scheduled medication, insomnia, increased HR
 Many experience weight regain upon discontinuation
 Diethylpropion: activates hypothalamic centers
decreasing appetite
 Insomnia, HTN/Cardiovascular disease concerns
 Amphetamines-decreases appetite
 Insomnia, Schedule II medication
Pharmacotherapy. 2011; 2567-84.
Pharmacologic Options
• Long-term weight loss
▫ Lipase inhibitor
 Orlistat (Alli®)-OTC
 Orlistat (Xenical®)-Rx
 Decreases absorption of fat
▫ Selective serotonin agonist
 Locaserin (Belviq®)
 Reduces food intake by decreasing appetite
 Schedule IV
Pharmacotherapy. 2011; 2567-84.
Phentermine/
topiramate CR
Qsymia®
http://www.cbsnews.com/8301-504763_162-57474619-10391704/obesity-pill-qsymia-gains-fda-approval/
Indications
• PHEN/TPM CR is indicated as an adjunct to a
reduced-calorie diet and increased physical
activity for chronic weight management in adult
patients with an initial body mass index (BMI)
of:
▫ 30 kg/m2 or greater (obese), or
▫ 27 kg/m2 or greater (overweight) in the presence
of at least one weight related comorbidity, such as
HTN, T2DM, or dyslipidemia
Qsymia® [package insert]. Mountain View, CA: Vivus Inc; 2012
Mechanism of Action
• Phentermine is a sympathomimetic amine
anoretic
▫ The effect of phentermine is likely mediated by
release of catecholamines in the hypothalamus,
resulting in reduced appetite and decreased food
consumption
▫ The exact MOA is unknown
• Schedule IV
Qsymia® [package insert]. Mountain View, CA: Vivus Inc; 2012
Mechanism of Action
• Topiramate is an antiepiletpic
• Exact MOA unknown
• The effect on weight management may be due to
its appetite suppression and satiety
enhancement due to a combination of:
▫ Augmenting activity of gamma-aminobutyrate
▫ Modulation of voltage-gated ion channels
▫ Inhibition of AMPA/kainite excitatory glutamate
receptors
▫ Inhibition of carbonic anhydrase
Qsymia® [package insert]. Mountain View, CA: Vivus Inc; 2012
Dosing
• Take 1 capsule once daily in the morning
▫ Avoid evening dose to prevent insomnia
• Recommended dose: 3.75/23 mg daily for 14
days, then increase to 7.5/46 mg daily
• Discontinue or increase dose if 3% weight loss
not achieved after 12 weeks on 7.5/46 mg daily
• Discontinue if 5% weight loss not achieved after
12 weeks on maximum daily dose of 15/92 mg
Qsymia® [package insert]. Mountain View, CA: Vivus Inc; 2012
Pharmacokinetics
• Phentermine
Parameter
Value
Vd
348 L
Protein Binding
17.5% bound
Metabolism
Two pathways: phydroxylation on aromatic
ring and N-oxidation on
alipthatic side chain
CYP3A4 substrate
Half life
~20 hours
Elimination
70-80% unchanged in urine
Qsymia® [package insert]. Mountain View, CA: Vivus Inc; 2012
Pharmacokinetics
• Topiramate CR
Parameter
Value
Protein binding
15-41% bound; fraction
bound decreases as blood
TPM increases
Metabolism
Does not show extensive
metabolism
5 metabolites that make up
<5% of dose
Half-life
~65 hours
Elimination
70% unchanged in urine
Qsymia® [package insert]. Mountain View, CA: Vivus Inc; 2012
Contraindications
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Pregnancy (Category X)
Glaucoma
Hyperthyroidism
During or within 14 days following
administration of monoamine oxidase inhibitors
• Hypersensitivity to sympathomimetic amines
Qsymia® [package insert]. Mountain View, CA: Vivus Inc; 2012
Warnings and Precautions
• Fetal toxicity
▫ Topiramate exposure in first trimester increases risk of
oral clefts
▫ Qsymia REMS-only certified pharmacies
• Increase in resting HR-regular measurement
recommended
• Suicidal behavior and idealation
▫ Antiepileptic drugs increase risk of suicidal thoughts
or behavior
• Secondary angle closure glaucoma
▫ Has been reported with topiramate; present with
decreased ocular acuity and/or ocular pain
Qsymia® [package insert]. Mountain View, CA: Vivus Inc; 2012
Warnings and Precautions
• Mood and sleep disorders
▫ Depression, anxiety, insomnia
• Cognitive impairment
▫ Speech/language problems, memory changes
• Metabolic acidosis
▫ Caution with drug or disease state interactions
that could increase incidence
• Elevation in creatinine
▫ Peak increases observed 4-8 weeks of treatment;
gradually decline but remain above baseline
Qsymia® [package insert]. Mountain View, CA: Vivus Inc; 2012
Drug Interactions
• MAOIs-contraindicated
• Oral contraceptives
▫ Increase exposure of ethinyl estradiol
• CNS depressants + alcohol
▫ May potentiate dizziness
• Non-potassium sparing diuretics
▫ Increase potassium-wasting of diuretics
• Carbonic anhydrase inhibitors
▫ Increase risk of metabolic acidosis
Qsymia® [package insert]. Mountain View, CA: Vivus Inc; 2012
Use in Special Populations
• Moderate-severe renal dysfunction (CrCl < 30
mL/min)
▫ Do not exceed 7.5/46 mg daily
• Has not been studied in ESRD or dialysis
patients-avoid use
• Moderate-severe (Child-Pugh 5-9)
▫ Do not exceed 7.5/46 mg daily
• Has not been studied in patients with severe
hepatic impairment-avoid use
Qsymia® [package insert]. Mountain View, CA: Vivus Inc; 2012
Summary
• Obesity
▫ A growing epidemic that is decreasing life
expectancy/quality of life and increasing medical
costs and comorbidities
▫ Treatment options include diet/exercise, behavior
modification, short-term options (phentermine),
and long-term options (orlistat)
• Phentermine/topiramate CR
▫ A sympathomimetic amine used for long-term
weight management
Two-year sustained weight loss and
metabolic benefits with controlledrelease phentermine/topiramate in
obese and overweight adults (SEQUEL): a
randomized, placebo-controlled, phase 3
extension study
Garvey WT, Ryan DH, Look M et al.
Am J Clin Nutr
2012; 95(2):297-308
Study Design
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Placebo-controlled
Randomized
Double-blind
52-week extension study of CONQUER (weeks
56-108 of treatment)
• 36-site study
• 676 subjects
• All subjects provided written informed consent
for participation
Study Objectives
• Co-primary endpoints
▫ 1) Mean percentage weight loss
▫ 2) Percentage of subjects achieving ≥5% weight
loss from baseline to week 108
Study Objectives
• Secondary endpoints
▫ Weight loss in kilograms (kg)
▫ Percentage of subjects achieving ≥10%, ≥15%, or
≥20% weight loss
▫ Change in waist circumference from baseline to
week 108
• Other efficacy endpoints
▫ BP, serum lipid variables, glycemic measures, and
rate of progression to DM
Inclusion Criteria
• Subjects that completed the CONQUER study on
treatment and complied with protocol requirements
• Subjects with a BMI (in kg/m2) of ≥27 and ≤45 as
well as ≥ 2 weight-related co-morbidities
▫ SBP 140-160 mmHg (130-160 mmHg in DM patients)
DBP 90-100 mmHg (85-100 in DM pts)
▫ Taking at least two hypertensive drugs
▫ Use of lipid-lowering agents
▫ Diagnosed type 2 diabetes managed with lifestyle
modifications or metformin as monotherapy
▫ Weight circumference of at least 102 for men or at
least 88 for women
Exclusion Criteria
• Having a BMI of ≤22 at the completion of CONQUER study
• Continuously not taking the study drug for > 4 weeks at
completion of CONQUER study
• Developing a condition during CONQUER study that would
interfere with compliance or attainment of study measures
• Participation in another weight-loss program
• BP greater than 160/100 mmHg
• Type 1 Diabetes; use DM drugs other than metformin
• History of nephrolithiasis
• Recurrent major depression, presence/hx of suicidal
behavior/idealation with intent to act
• Use of tricyclic antidepressants or monoamine oxidase
inhibitors
Randomization and Masking
• The coordinating center used a computer-generated
algorithm that was implemented through an
interactive voice response system to assign subjects
according to the random allocation sequence, with a
block size of 8.
• Subjects were stratified according to their sex and
diabetic status
• Study drugs were administered as capsules that
were all identical in size and appearance
• Investigators, subjects, and study sponsors were
marked to treatment assignment
Subject Assessment
• Study visits were at screening, baseline, weeks 2
and 4 during titration, and every 4 weeks
thereafter
• Assessment included body weight, blood
pressure, heart rate, waist circumference,
clinical and laboratory values, concomitant
drugs, adverse events, and compliance
• PHQ-9 and Columbia Suicide Severity Rating
Scale (C-SSRS) completed at each visit to assess
depressive symptoms
Treatment Protocol
• Subjects randomized to three different treatment
arms (determined in CONQUER and continued
in SEQUEL)
▫ 1) Lifestyle modification + placebo
▫ 2) Lifestyle modification + 7.5mg
phentermine/46mg topiramate CR
▫ 3) Lifestyle modification + 15mg phentermine/
92mg topiramate CR
Statistical Analysis
• Analyses were made using a modified intent-totreat sample
▫ Defined as all subjects who received at least one
study drug dose with at least one post-baseline
measurement of body weight
• Analysis of covariance (ANCOVA) was used to
evaluate percent weight loss, with treatment,
sex, and diabetic status as fixed effects and
baseline weight as a covariate
Statistical Analysis
• Multiple imputation was used as a sensitivity
analysis to supplement the intent-to-treat lost
observation carried forward (LOCF) approach
▫ An analysis of subjects who completed study while
actively taking study drug was also performed to
understand the effect of treatment after 108 weeks
of exposure
Statistical Analysis
• Treatment emergent adverse events (TEAEs)
were defined as AEs occurring between week 0
of CONQUER and ≤ 28 days after last dose of
study drug in SEQUEL
• Safety analyses were based on incidence of AEs,
changes in laboratory values, vital signs, EKG,
PE, and results from PHQ-9 and C-SSRS
Results: Demographics
• Of the 676 enrolled subjects, 84.0% (568/676) of
subjects completed the extension study
▫ 86.3% assigned to placebo
▫ 82.5% of subjects in the 7.5/46 mg group
▫ 83.1% of subjects in the 15/92 mg group
• No significant differences between study arms
▫ Age, gender, co-morbidities, clinical
characteristics
Results: Weight loss
Study Arm
Percent
Change in
Baseline Body
Weight
Reductions in
Waist
Circumference
(in cm)
P-value
(compared to
placebo)
Placebo
-1.8%
-3.6
7.5/46 mg
-9.3%
-9.8
<0.0001
15/92 mg
-10.5%
-10.6
<0.0001
-7.5/46 and 15/92 groups showed similar effectiveness
in lowering baseline BMI
-15/92 was significantly more effective (p=0.0061)
than 7.5/46 for severely obese subjects (baseline BMI ≥
40 and < 45)
Results: Blood pressure
• BP decreases were similar in all treatment arms
(~3-5 mmHg decrease)
• Medication groups experienced a greater
decrease in hypertensive medications used
▫ 7.5% (n=17) in placebo group; 13.1% (n=20) in
7.5/46 group; 15.6% (n=46) in 15/92 group
• Placebo group experienced an increase in
hypertensive medications used compared to tx
▫ 11.0% (n=25) in placebo group; 9.2% (n=14) in
7.5/46 group; 5.8% (n=17) in 15/92 group
Results: Lipids
• More subjects receiving PHEN/TPM CR had a
decrease in lipid-lowering medications than
placebo
▫ 3.1% (n=7) for placebo group; 5.9% (n=9) for
7.5/46 group; 5.8% (n=17) for 15/92 group
• 20.3% (n=46) of placebo-treated subjects
increased lipid-lowering medications compared
with 11.1% (n=17) in the 7.5/46 group and 10.5%
(n=31) in the 15/92 group
Results: Glycemic variables
Placebo
(n = 227)
7.5/46
(n = 153)
15/92
(n = 295)
Fasting Glucose
(mg/dL)
109.3 ± 24.4
110.7 ± 25.3
108.2 ± 24.1
Glycated
hemoglobin (%)
6.0 ± 0.9
6.0 ± 0.9
6.0 ± 0.8
-In subjects without DM at baseline, effects of weight loss were
associated with decreased progression to T2DM during the study
course
-Based on the annualized incidence rates for progression to
T2DM among subjects without DM at baseline:
-54% reduction in progression to T2DM in the 7.5/46 group
and a 76% reduction in the 15/92 group compared to
placebo
Results: Adverse Events
Placebo
(n=227)
7.5/46 mg
(n=153)
15/92 mg
(n=295)
Constipation
7 (3.1%)
11 (7.2%)
12 (4.1%)
Upper
Respiratory tract
infection
42 (18.5%)
26 (17.0%)
45 (15.3%)
Nasopharyngitis
26 (11.5%)
13 (8.5%)
26 (8.8%)
Sinusitis
18 (7.9%)
12 (7.8%)
28 (9.5%)
Arthralgia
14 (6.2%)
7 (4.6%)
16 (5.4%)
Urinary tract
infection
13 (5.7%)
14 (9.2%)
18 (6.1%)
Bronchitis
7 (3.1%)
8 (5.2%)
10 (3.4%)
Influenza
8 (3.5%)
10 (6.5%)
19 (6.4%)
Back pain
7 (3.1%)
9 (5.9%)
15 (5.1%)
Authors’ Conclusions
• Significant, dose-related weight loss that was
maintained during a 108-week period
• Sustained improvements in clinical
manifestations of weight-related morbidities
• Reduction in the rate of progression to T2DM
Authors’ Conclusions
• “The unmet clinical need for effective weightloss medications, together with the favorable
risk-benefit profile in the current study, suggests
that PHEN/TPM CR in conjunction with a
lifestyle-intervention program could be a
valuable therapeutic approach to counteract
increasing rates of obesity and its related
complications.”
Critique: Strengths
• Remained double-blinded through extension
study
• Extension study provided insight on long-term
benefits of PHEN/TPM CR
• Similarity between baseline characteristics of
study population
Critique: Weaknesses
• Not all CONQUER subjects were able to enroll in
SEQUEL, because only high-enrolling centers
were used
• Second year of study was optional
▫ May have caused bias toward subjects with
positive treatment outcomes
• Higher rate of subjects to discontinue study in
15/92 group for unknown reasons
▫ Possibly due to other adverse effects not reported
• Comorbidity treatment was not universal for all
subjects
• Power was not assessed
Cost Comparison
Drug
30-day Supply Cost
Availability
Qsymia 7.5/46 mg QD
$171.52
Rx-brand only
Qsymia 15/92 mg QD
$220.71
Rx-brand only
Belviq 10 mg QD
$141.87
Rx-brand only
Phentermine 37.5 mg
QD
$19.33
Rx-generic available
Orlistat 120 mg TID
$469.62
Rx-brand only
Orlistat 60 mg TID
$44.97
OTC-brand only
NB Drug Price Search; http://www.rxpricequotes.com/
Therapeutic Recommendation
• PHEN/TPM CR could be an appropriate option
for overweight/obese patients who have failed
other weight loss option, such as:
▫ Diet
▫ Exercise
▫ Short-term, generic option like phentermine
• Patients could be started on 7.5/46 mg option,
unless their BMI is ≥ 40 kg/m2, to reduce cost
and evaluate effectiveness
Recommendation for LP
• Patient should aim for weight loss of
approximately 10%
• Remain adherent to low calorie diet and exercise
• Could start PHEN/TPM CR 7.5/46 mg PO QD
▫ High cost could be a barrier to treatment
▫ Higher side effects associated with lower dose of
PHEN/TMP CR