HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
QSYMIA® safely and effectively. See full prescribing information for
QSYMIA.
QSYMIA (phentermine and topiramate extended-release capsules), fororal use, CIV
Initial U.S. Approval: 2012---------------------------INDICATIONS AND USAGE--------------------------QSYMIA is a combination of phentermine, a sympathomimetic amine
anorectic, and topiramate, indicated as an adjunct to a reduced-calorie diet andincreased physical activity for chronic weight management in:• Adults with an initial body mass index (BMI) of:o 30 kg/m2 or greater (obese) (1) oro 27 kg/m2 or greater (overweight) in the presence of at least one weightrelated comorbidity such as hypertension, type 2 diabetes mellitus, ordyslipidemia (1)• Pediatric patients aged 12 years and older with BMI in the 95th percentile orgreater standardized for age and sex.
Limitations of Use:
• The effect of QSYMIA on cardiovascular morbidity and mortality has notbeen established (1).
• The safety and effectiveness of QSYMIA in combination with otherproducts intended for weight loss, including prescription and over-thecounter drugs, and herbal preparations, have not been established (1).
-----------------------DOSAGE AND ADMINISTRATION----------------------• Take orally once daily in morning. Avoid administration in evening toprevent insomnia (2.3).
• Recommended starting dosage is 3.75 mg/23 mg (phentermine
mg/topiramate mg) daily for 14 days; then increase to 7.5 mg/46 mg daily(2.3).
• Escalate dosage based on weight loss in adults or BMI reduction inpediatric patients. See the Full Prescribing Information for details
regarding discontinuation or dosage escalation (2.3).
• Gradually discontinue 15 mg/92 mg dosage to prevent possible seizure(2.4).
• Do not exceed 7.5 mg/46 mg dosage for patients with moderate or severe
renal impairment or patients with moderate hepatic impairment (2.5, 2.6).
---------------------DOSAGE FORMS AND STRENGTHS--------------------Extended-release capsules: (phentermine mg/topiramate mg)• 3.75 mg/23 mg (3)• 7.5 mg/46 mg (3)• 11.25 mg/69 mg (3)• 15 mg/92 mg (3)
•
•
•
•
•

------------------------CONTRAINDICATIONS-------------------------Pregnancy (4)Glaucoma (4)Hyperthyroidism (4)Taking or within 14 days of stopping monoamine oxidase inhibitors (4)Known hypersensitivity to any component of QSYMIA or idiosyncrasy to
sympathomimetic amines (4)-----------------------WARNINGS AND PRECAUTIONS-----------------------• Embryo-Fetal Toxicity: Can cause fetal harm . In patients who can become
pregnant, a negative pregnancy test is recommended before initiating
QSYMIA and monthly during therapy; advise use of effective
contraception. QSYMIA is available through a limited program under a
Risk Evaluation and Mitigation Strategy (REMS) (5.1).
• Increase in Heart Rate: Monitor heart rate, especially in those with cardiac
or cerebrovascular disease (5.2).
• Suicidal Behavior and Ideation: Monitor for depression or suicidal
thoughts. Discontinue QSYMIA if symptoms develop (5.3).
• Risk of Ophthalmologic Adverse Reactions: Acute myopia and secondary
angle closure glaucoma have been reported. Immediately discontinue
QSYMIA if symptoms develop. Consider QSYMIA discontinuation if
visual field defects occur (5.4).
• Mood and Sleep Disorders: Consider dosage reduction or discontinuation
for clinically significant or persistent mood or sleep disorder symptoms(5.5).
• Cognitive Impairment: May cause disturbances in attention or memory, or
speech/language problems. Caution patients about operating automobiles or
hazardous machinery when starting treatment (5.6).
• Slowing of Linear Growth: Consider dosage reduction or discontinuation if
pediatric patients are not growing or gaining height as expected (5.7).
• Metabolic Acidosis: Measure electrolytes before and during treatment. If
persistent metabolic acidosis develops, reduce dosage or discontinue
QSYMIA (5.8).
• Decrease in Renal Function: Measure creatinine before and during
treatment. For persistent creatinine elevations, reduce dosage or discontinue
QSYMIA (5.9).
• Serious Skin Reactions: QSYMIA should be discontinued at the first sign ofa rash, unless the rash is clearly not drug-related (5.16).
------------------------------ADVERSE REACTIONS-----------------------------Most common adverse reactions in:• Adults (incidence ≥ 5% and at least 1.5 times placebo) are: paraesthesia,dizziness, dysgeusia, insomnia, constipation, and dry mouth• Pediatric patients aged 12 years and older (incidence ≥4% and greater thanplacebo) are: depression, dizziness, arthralgia, pyrexia, influenza, andligament sprain (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact VIVUS LLC,
at 1-888-998-4887 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS-----------------------------• Oral Contraceptives: Altered exposure of progestin and estrogen may cause
irregular bleeding, but not increased risk of pregnancy. Advise patients not
to discontinue oral contraceptives if spotting occurs (7).
• CNS Depressants Including Alcohol: May potentiate CNS depressanteffects. Avoid excessive use of alcohol (7).
• Non-potassium Sparing Diuretics: May potentiate hypokalemia. Measurepotassium before and during treatment (7).
-----------------------USE IN SPECIFIC POPULATIONS----------------------• Lactation: Breastfeeding not recommended (8.2).
See 17 for PATIENT COUNSELING INFORMATION and
MEDICATION GUIDE
Revised: 06/2023

FULL PRESCRIBING INFORMATION: CONTENTS*
1
2

3
4
5

INDICATIONS AND USAGE
DOSAGE AND ADMINISTRATION
2.1 Patient Selection
2.2 Recommended Testing Prior to Initiation of
QSYMIA
2.3 Recommended Dosage and Administration
2.4 Discontinuation of QSYMIA 15 mg/92 mg
2.5 Recommended Dosage in Patients with Renal
Impairment
2.6 Recommended Dosage in Patients with Hepatic
Impairment
DOSAGE FORM AND STRENGTHSCONTRAINDICATIONSWARNINGS AND PRECAUTIONS
5.1 Embryo-Fetal Toxicity
5.2 Increase in Heart Rate
5.3 Suicidal Behavior and Ideation
5.4 Risk of Ophthalmological Adverse Reactions
5.5 Mood and Sleep Disorders
5.6 Cognitive Impairment
5.7 Slowing of Linear Growth
5.8 Metabolic Acidosis
5.9 Decrease in Renal Function
5.10 Risk of Hypoglycemia in Patients with Type 2
Diabetes Mellitus on Antidiabetic Therapy
5.11 Risk of Hypotension in Patients Treated with
Antihypertensive Medications
5.12 Risk of Seizures with Abrupt Withdrawal of
QSYMIA
5.13 Kidney Stones
5.14 Oligohidrosis and Hyperthermia
5.15 Hypokalemia

5.16 Serious Skin Reactions
5.17 Allergic Reactions Due to Inactive Ingredient
FD&C Yellow No. 5
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
9.2 Abuse
9.3 Dependence
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of
Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION* Sections or subsections omitted from the full prescribing
information are not listed

FULL PRESCRIBING INFORMATION
1

INDICATIONS AND USAGEQSYMIA is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight
management in:•

Adults with an initial body mass index (BMI) of:o 30 kg/m2 or greater (obese), oro 27 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbidity such as
hypertension, type 2 diabetes mellitus, or dyslipidemia•

Pediatric patients aged 12 years and older with an initial BMI in the 95th percentile or greater
standardized for age and sex.

Limitations of Use•

The effect of QSYMIA on cardiovascular morbidity and mortality has not been established.

•

The safety and effectiveness of QSYMIA in combination with other products intended for weight loss,
including prescription drugs, over-the-counter drugs, and herbal preparations, have not been established.

2

DOSAGE AND ADMINISTRATION

2.1

Patient Selection

AdultsSelect adult patients for QSYMIA treatment based on BMI [see Indications and Usage (1)]. Determine thepatient’s BMI by dividing weight (in kilograms) by height (in meters) squared. A BMI conversion table basedon height [inches (in) or centimeters (cm)] and weight [pounds (lb) or kilograms (kg)] is provided below (seeTable 1).

Table 1.
WeightBMI Conversion Chart
(lb)

125

130

135

140

145

150

155

160

165

170

175

180

185

190

195

200

205

210

215

220

225

(kg) 56. 8 59. 1 61. 4 63. 6 65. 9 68. 2 70. 5 72. 7 75. 0 77. 3 79. 5 81. 8 84. 1 86. 4 88. 6 90. 9 93. 2 95. 5 97. 7 100. 0 102. 3

Height
(in)
(cm)
58

147. 3

26

27

28

29

30

31

32

34

35

36

37

38

39

40

41

42

43

44

45

46

47

59

149. 9

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

43

44

45

46

60

152. 4

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

61

154. 9

24

25

26

27

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

62

157. 5

23

24

25

26

27

27

28

29

30

31

32

33

34

35

36

37

38

38

39

40

41

63

160. 0

22

23

24

25

26

27

28

28

29

30

31

32

33

34

35

36

36

37

38

39

40

64

162. 6

22

22

23

24

25

26

27

28

28

29

30

31

32

33

34

34

35

36

37

38

39

65

165. 1

21

22

23

23

24

25

26

27

28

28

29

30

31

32

33

33

34

35

36

37

38

66

167. 6

20

21

22

23

23

24

25

26

27

27

28

29

30

31

32

32

33

34

35

36

36

67

170. 2

20

20

21

22

23

24

24

25

26

27

27

28

29

30

31

31

32

33

34

35

35

68

172. 7

19

20

21

21

22

23

24

24

25

26

27

27

28

29

30

30

31

32

33

34

34

69

175. 3

18

19

20

21

21

22

23

24

24

25

26

27

27

28

29

30

30

31

32

33

33

70

177. 8

18

19

19

20

21

22

22

23

24

24

25

26

27

27

28

29

29

30

31

32

32

71

180. 3

17

18

19

20

20

21

22

22

23

24

24

25

26

27

27

28

29

29

30

31

31

72

182. 9

17

18

18

19

20

20

21

22

22

23

24

24

25

26

27

27

28

29

29

30

31

73

185. 4

17

17

18

19

19

20

20

21

22

22

23

24

24

25

26

26

27

28

28

29

30

74

188. 0

16

17

17

18

19

19

20

21

21

22

23

23

24

24

25

26

26

27

28

28

29

75

190. 5

16

16

17

18

18

19

19

20

21

21

22

23

23

24

24

25

26

26

27

28

28

76

193. 0

15

16

16

17

18

18

19

20

20

21

21

22

23

23

24

24

25

26

26

27

27

Pediatric Patients Aged 12 Years and Older
Select pediatric patients for QSYMIA treatment based on BMI percentile [see Indications and Usage (1)]. See
Table 2 for BMI percentiles by age and sex for pediatric patients aged 12 years and older.
Table 2.

BMI Percentiles by Age and Sex for Pediatric Patients Aged 12 Years and OlderAge (in years)
12
12.5
13
13.5
14
14.5
15
15.5
16
16.5
17
17.5

Male
95th Percentile BMI Value
24.2
24.7
25.2
25.6
26.0
26.5
26.8
27.2
27.6
27.9
28.3
28.6

Female95th Percentile BMI Value
25.3
25.8
26.3
26.8
27.3
27.7
28.1
28.5
28.9
29.3
29.6
30.0

2.2

Recommended Testing Prior to and During Treatment with QSYMIA

Prior to QSYMIA initiation and during treatment with QSYMIA, the following is recommended:
•
•

2.3

Obtain a negative pregnancy test before initiating QSYMIA in patients who can become pregnant andmonthly during QSYMIA therapy. QSYMIA is contraindicated during pregnancy [seeContraindications (4), Warnings and Precautions (5.1) and Use in Specific Populations (8.3)].
Obtain a blood chemistry profile that includes bicarbonate, creatinine, and potassium in all patients, andglucose in patients with type 2 diabetes on antidiabetic medication prior to initiating QSYMIA treatment
and periodically during treatment [Warnings and Precautions (5.8, 5.9, 5.10, 5.15)].
Recommended Dosage and Administration

The recommended dosage, titration, and administration of QSYMIA are as follows:

2.4•

Take QSYMIA orally once daily in the morning with or without food. Avoid administration of
QSYMIA in the evening due to the possibility of insomnia.

•

The recommended starting dosage is QSYMIA 3.75 mg/23 mg (phentermine 3.75 mg/topiramate 23 mg)
orally once daily for 14 days; after 14 days increase to the recommended dosage of QSYMIA
7.5 mg/46 mg (phentermine 7.5 mg/topiramate 46 mg) orally once daily.

•

After 12 weeks of treatment with QSYMIA 7.5 mg/46 mg, evaluate weight loss for adults or BMI
reduction for pediatric patients aged 12 years and older. If an adult patient has not lost at least 3% ofbaseline body weight or a pediatric patient has not experienced a reduction of at least 3% of baseline
BMI, increase the dosage to QSYMIA 11.25 mg/69 mg (phentermine 11.25 mg/topiramate 69 mg)
orally once daily for 14 days; followed by an increase in the dosage to QSYMIA 15 mg/92 mg(phentermine 15 mg/topiramate 92 mg) orally once daily.

•

After 12 weeks of treatment with QSYMIA 15 mg/92 mg, evaluate weight loss for adults or BMI
reduction for pediatric patients aged 12 years and older. If an adult patient has not lost at least 5% ofbaseline body weight or a pediatric patient has not experienced a reduction of at least 5% of baseline
BMI, discontinue QSYMIA [see Dosage and Administration (2.4)], as it is unlikely that the patient willachieve and sustain clinically meaningful weight loss with continued treatment.

•

Monitor the rate of weight loss in pediatric patients. If weight loss exceeds 2 lbs (0.9 kg)/week, consider
dosage reduction.
Discontinuation of QSYMIA 15 mg/92 mg

Discontinue QSYMIA 15 mg/92 mg gradually by taking QSYMIA 15 mg/92 mg once daily every other day forat least 1 week prior to stopping treatment altogether, due to the possibility of precipitating a seizure [seeWarnings and Precautions (5.12) and Drug Abuse and Dependence (9.3)].
2.5

Recommended Dosage in Patients with Renal Impairment

Avoid use of QSYMIA in patients with end-stage renal disease on dialysis.
In patients with severe (creatinine clearance [CrCl] less than 30 mL/min) or moderate (CrCl greater than orequal to 30 and less than 50 mL/min) renal impairment (CrCl calculated using the Cockcroft-Gault equation
with actual body weight), the maximum recommended dosage is QSYMIA 7.5 mg/46 mg once daily.
The recommended dosage in patients with mild (CrCl greater or equal to 50 and less than 80 mL/min) renal
impairment is the same as the recommended dosage for patients with normal renal function [see Warnings andPrecautions (5.9), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

2.6

Recommended Dosage in Patients with Hepatic Impairment

Avoid use of QSYMIA in patients with severe hepatic impairment (Child-Pugh score 10 - 15). In patients withmoderate hepatic impairment (Child-Pugh score 7 - 9), the maximum recommended dosage is QSYMIA
7.5 mg/46 mg once daily.
The recommended dosage of QSYMIA in patients with mild hepatic impairment (Child-Pugh 5 - 6) is the sameas the recommended dosage in patients with normal hepatic function [see Use in Specific Populations (8.7), andClinical Pharmacology (12.3)].
3

DOSAGE FORMS AND STRENGTHSQSYMIA extended-release capsules are available in four strengths (phentermine mg/topiramate mg):•3.75 mg/23 mg - purple cap imprinted with VIVUS and purple body imprinted with 3.75/23•

7.5 mg/46 mg - purple cap imprinted with VIVUS and yellow body imprinted with 7.5/46•

11.25 mg/69 mg - yellow cap imprinted with VIVUS and yellow body imprinted with 11.25/69•

15 mg/92 mg - yellow cap imprinted with VIVUS and white body imprinted with 15/92

4

CONTRAINDICATIONSQSYMIA is contraindicated in patients:•

Who are pregnant [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]•

With glaucoma [see Warnings and Precautions (5.4)]•

With hyperthyroidism•

Taking or within 14 days of stopping a monoamine oxidase inhibitors [see Drug Interactions (7)]•With known hypersensitivity to phentermine, topiramate or excipient in QSYMIA, or idiosyncrasy tothe sympathomimetic amines [see Adverse Reactions (6.2)].

5

WARNINGS AND PRECAUTIONS

5.1

Embryo-Fetal Toxicity

QSYMIA can cause fetal harm. Data from pregnancy registries and epidemiologic studies indicate that a fetus
exposed to topiramate in the first trimester of pregnancy has an increased risk of major congenital
malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for
gestational age (SGA). When multiple species of pregnant animals received topiramate at clinically relevant
doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring.
A negative pregnancy test is recommended before initiating QSYMIA treatment in patients who can become
pregnant and monthly during QSYMIA therapy. Advise patients who can become pregnant of the potential risk
to a fetus and to use effective contraception during QSYMIA therapy [see Use in Specific Populations(8.1,8.3)].
QSYMIA Risk Evaluation and Mitigation Strategy (REMS)
Because of the teratogenic risk associated with QSYMIA therapy, QSYMIA is available through a limited
program under the REMS. Under the QSYMIA REMS, only certified pharmacies may distribute QSYMIA.
Further information is available at www.QSYMIAREMS.com or by telephone at 1-888-998-4887.

5.2

Increase in Heart RateQSYMIA can cause an increase in resting heart rate. A higher percentage of QSYMIA-treated adults andpediatric patients aged 12 years and older experienced heart rate increases from baseline of more than 5, 10, 15,
and 20 beats per minute (bpm) compared to placebo-treated patients [see Adverse Reactions (6.1)]. The clinicalsignificance of a heart rate elevation with QSYMIA treatment is unclear, especially for patients with cardiac
and cerebrovascular disease.
Measure resting heart rate regularly in all patients taking QSYMIA, especially patients with cardiac or
cerebrovascular disease and when initiating or increasing the dosage of QSYMIA. QSYMIA has not beenstudied in patients with recent or unstable cardiac or cerebrovascular disease and therefore use is notrecommended.
Advise patients to inform their healthcare provider of palpitations or feelings of a racing heartbeat while at rest
during QSYMIA treatment. For patients who experience a sustained increase in resting heart rate while taking
QSYMIA, reduce the dosage or discontinue QSYMIA [see Warnings and Precautions (5.12)].
5.3

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including topiramate, increase the risk of suicidal thoughts or behavior in patientstaking these drugs for any indication. Pooled analyses of 199 placebo-controlled clinical studies (monotherapy
and adjunctive therapy, median treatment duration 12 weeks) of 11 different AEDs across several indications
showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk
1.8, 95% CI 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. The
estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%,
compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one caseof suicidal thinking or behavior for every 530 patients treated. There were four suicides in AED-treated patientsin the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about
AED effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as
1 week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because
most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior
beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistentamong drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action
and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did
not vary substantially by age in the clinical trials analyzed.
In a QSYMIA clinical trial of pediatric patients aged 12 years and older, 1 (0.6%) of the 167 QSYMIA-treatedpatients reported suicidal ideation and behavior which required hospitalization. No placebo-treated patients
reported suicidal behavior or ideation.
Monitor all patients for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any
unusual changes in mood or behavior. Discontinue QSYMIA in patients who experience suicidal thoughts or
behaviors [see Warnings and Precautions (5.12)]. Avoid QSYMIA in patients with a history of suicidal
attempts or active suicidal ideation.
5.4

Risk of Ophthalmologic Adverse Reactions

Acute Myopia and Secondary Angle Closure Glaucoma
A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported inpatients treated with topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain.
Ophthalmologic findings can include myopia, mydriasis, anterior chamber shallowing, ocular hyperemia(redness), choroidal detachments, retinal pigment epithelial detachments, macular striae, and increased
intraocular pressure. This syndrome may be associated with supraciliary effusion resulting in anteriordisplacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1month of initiating treatment with topiramate but may occur at any time during therapy. In contrast to primarynarrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with
topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms
is discontinuation of QSYMIA as rapidly as possible in consultation with the treating physician. Elevatedintraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent loss ofvision.
Visual Field Defects
Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and inpostmarketing experience in patients receiving topiramate. In clinical trials, most of these events were reversible
after topiramate discontinuation. If visual problems occur at any time during treatment, consider discontinuing
QSYMIA.
5.5

Mood and Sleep DisordersQSYMIA can cause mood disorders, including depression and anxiety, as well as insomnia. Patients with ahistory of depression may be at increased risk of recurrent depression or other mood disorders while taking
QSYMIA [see Adverse Reactions (6.1)].
Consider dosage reduction or discontinuation of QSYMIA if clinically significant or persistent symptoms
occur. Discontinue QSYMIA if patients have symptoms of suicidal ideation or behavior [see Warnings andPrecautions (5.3)].
5.6

Cognitive Impairment

QSYMIA can cause cognitive dysfunction (e.g., impairment of concentration/attention, difficulty withmemory, and speech or language problems, particularly word-finding difficulties). Rapid titration or highinitial doses of QSYMIA may be associated with higher rates of cognitive events such as attention, memory,and language/word-finding difficulties [see Adverse Reactions (6.1)]. The concomitant use of alcohol orcentral nervous system (CNS) depressant drugs with QSYMIA may potentiate CNS depression or othercentrally mediated effects of these agents, such as dizziness, cognitive adverse reactions, drowsiness, lightheadedness, impaired coordination, and somnolence.
Caution patients about operating hazardous machinery, including automobiles, until they are reasonably
certain QSYMIA therapy does not affect them adversely. Caution patients against excessive alcohol intake
while receiving QSYMIA.
If cognitive dysfunction persists, consider dosage reduction or discontinuation of QSYMIA [see Warnings andPrecautions (5.12)].
5.7

Slowing of Linear Growth

QSYMIA is associated with a reduction in height velocity (centimeters of height gained per year) in obese
pediatric patients 12 to 17 years of age. In a 56-week study, average height increased from baseline in bothQSYMIA- and placebo-treated patients; however, a lower height velocity of -1.3 to -1.4 cm/year was observed
in QSYMIA-treated compared to placebo-treated patients. Monitor height velocity in pediatric patients treatedwith QSYMIA. Consider dosage reduction or discontinuation of QSYMIA if pediatric patients are not growing
or gaining height as expected [see Warnings and Precautions (5.12)].
5.8

Metabolic Acidosis

Hyperchloremic, non-anion gap, metabolic acidosis (decreased serum bicarbonate below the normal reference
range in the absence of chronic respiratory alkalosis) has been reported in patients treated with QSYMIA [see

Adverse Reactions (6.1)]. Manifestations of acute or chronic metabolic acidosis may include hyperventilation,
nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or
stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis andmay also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with anincreased risk for fractures. Chronic metabolic acidosis in pediatric patients may also reduce growth rates,
which may decrease the maximal height achieved.
Conditions or therapies that predispose to acidosis (i.e., renal disease, severe respiratory disorders, statusepilepticus, diarrhea, surgery, or ketogenic diet) may be additive to the bicarbonate lowering effects of
QSYMIA. Concomitant use of QSYMIA and a carbonic anhydrase inhibitor may increase the severity of
metabolic acidosis and may also increase the risk of kidney stone formation [see Warnings and Precautions(5.13)]. Avoid use of QSYMIA with other carbonic anhydrase inhibitors. If concomitant use of QSYMIA withanother carbonic anhydrase inhibitor is unavoidable, the patient should be monitored for the appearance orworsening of metabolic acidosis.
Measure electrolytes including serum bicarbonate prior to starting QSYMIA and during QSYMIA treatment. In
QSYMIA clinical trials, the peak reduction in serum bicarbonate typically occurred within 4 weeks of titration
to the assigned dose, and in most patients there was a correction of bicarbonate by week 56, without any dosage
reduction. However, if persistent metabolic acidosis develops while taking QSYMIA, reduce the dosage or
discontinue QSYMIA [see Warnings and Precautions (5.12)].
5.9

Decrease in Renal FunctionQSYMIA can cause an increase in serum creatinine that reflects a decrease in renal function (glomerular
filtration rate). In clinical trials, peak increases in serum creatinine were observed after 4 to 8 weeks oftreatment. On average, serum creatinine gradually declined but remained elevated over baseline creatinine
values. The changes in serum creatinine (and measured GFR) with short-term (4-weeks) QSYMIA treatment
appear reversible with treatment discontinuation, but the effect of chronic treatment on renal function is notknown.
Measure serum creatinine prior to starting QSYMIA and during QSYMIA treatment. If persistent elevations increatinine occur, reduce the dosage or discontinue QSYMIA [see Warnings and Precautions (5.12), Adverse
Reactions (6.1), Clinical Pharmacology (12.2)].
5.10

Risk of Hypoglycemia in Patients with Type 2 Diabetes Mellitus on Antidiabetic Therapy

Weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with insulin
and/or insulin secretagogues (e.g., sulfonylureas). QSYMIA has not been studied in combination with insulin.
Measure blood glucose levels prior to starting QSYMIA and during QSYMIA treatment in patients with type 2
diabetes on antidiabetic medication. The risk of hypoglycemia may be lowered by a reduction of the dosage ofinsulin and/or insulin secretagogues. If a patient develops hypoglycemia after starting QSYMIA, appropriatechanges should be made to the antidiabetic drug regimen.
5.11

Risk of Hypotension in Patients Treated with Antihypertensive Medications

In hypertensive patients being treated with antihypertensive medications, weight loss may increase the risk ofhypotension and associated symptoms including dizziness, lightheadedness, and syncope. Measure bloodpressure prior to starting QSYMIA and during QSYMIA treatment in patients being treated for hypertension. If
a patient develops symptoms associated with low blood pressure after starting QSYMIA, appropriate changes
should be made to the antihypertensive drug regimen.
5.12

Risk of Seizures with Abrupt Withdrawal of QSYMIA

Abrupt withdrawal of topiramate has been associated with seizures in individuals without a history of seizures
or epilepsy. In situations where immediate termination of QSYMIA is medically required, appropriate

monitoring is recommended. Patients discontinuing QSYMIA 15 mg/92 mg should be gradually tapered toreduce the possibility of precipitating a seizure [see Dosage and Administration (2.4) and Drug Abuse and
Dependence (9.3)].
5.13

Kidney Stones

QSYMIA has been associated with kidney stone formation [see Adverse Reactions (6.1)]. Topiramate inhibits
carbonic anhydrase activity and promotes kidney stone formation by reducing urinary citrate excretion andincreasing urine pH. Patients on a ketogenic diet may be at increased risk for kidney stone formation. An
increase in urinary calcium and a marked decrease in urinary citrate was observed in topiramate-treated
pediatric patients in a one-year, active-controlled study. Increased ratio of urinary calcium/citrate increases therisk of kidney stones and/or nephrocalcinosis.
Avoid the use of QSYMIA with other drugs that inhibit carbonic anhydrase [see Drug Interactions (7)]. Advise
patients to increase fluid intake (to increase urinary output), which may decrease the concentration ofsubstances involved in kidney stone formation.
5.14

Oligohidrosis and Hyperthermia

Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association
with the use of topiramate. Decreased sweating and an elevation in body temperature above normal
characterized these cases. Some of the cases have been reported with topiramate after exposure to elevatedenvironmental temperatures.
The majority of the reports associated with topiramate have been in pediatric patients. Advise all patients andcaregivers to monitor for decreased sweating and increased body temperature during physical activity,
especially in hot weather. Patients on concomitant medications that predispose them to heat-related disorders
may be at increased risk.
5.15

Hypokalemia

QSYMIA can increase the risk of hypokalemia through its inhibition of carbonic anhydrase activity. In addition,
when QSYMIA is used in conjunction with non-potassium sparing diuretics this may further potentiate
potassium-wasting. Measure potassium before and during treatment with QSYMIA. [see Adverse Reactions(6.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].
5.16

Serious Skin Reactions

Serious skin reactions (Stevens-Johnson Syndrome [SJS] and Toxic Epidermal Necrolysis [TEN]) have beenreported in patients receiving topiramate. QSYMIA should be discontinued at the first sign of a rash, unless therash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed
and alternative therapy should be considered. Inform patients about the signs of serious skin reactions.
5.17

Allergic Reactions Due to Inactive Ingredient FD&C Yellow No. 5

This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including
bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5(tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin
hypersensitivity.
6

ADVERSE REACTIONS

The following important adverse reactions are described elsewhere in the labeling:••

Embryo-Fetal Toxicity [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.6)]
Increase in Heart Rate [see Warnings and Precautions (5.2)]

•
•
•
•
•
•
•
•
•
•
•
•
6.1

Suicidal Behavior and Ideation [see Warnings and Precautions (5.3)]
Risk of Ophthalmologic Adverse Reactions [see Warnings and Precautions (5.4)]
Mood and Sleep Disorders [see Warnings and Precautions (5.5)]
Cognitive Impairment [see Warnings and Precautions (5.6)]
Slowing of Linear Growth [see Warnings and Precautions (5.7)]
Metabolic Acidosis [see Warnings and Precautions (5.8)]
Decrease in Renal Function [see Warnings and Precautions (5.9)]
Risk of Seizures with Abrupt Withdrawal of QSYMIA [see Warnings and Precautions (5.12)]
Kidney Stones [see Warnings and Precautions (5.13)]
Oligohydrosis and Hyperthermia [see Warnings and Precautions (5.14)]
Hypokalemia [see Warnings and Precautions (5.15)]
Serious Skin Reactions [see Warnings and Precautions (5.16)]
Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in theclinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may notreflect the rates observed in practice.
The data described herein reflects exposure to QSYMIA in two 1-year, randomized, double-blind, placebocontrolled, multicenter clinical trials and two supportive trials in 2318 adult patients with overweight or obesity(936 [40%] patients with hypertension, 309 [13%] patients with type 2 diabetes, 808 [35%] patients with BMI
greater than 40 kg/m2) exposed for a mean duration of 298 days. Data in this section also describe adverse
reactions from a 1-year, randomized, double-blind, placebo-controlled multicenter clinical trial that evaluated
223 pediatric patients (12 to 17 years old) with obesity [see Clinical Studies (14)].
AdultsAdverse reactions occurring at greater than or equal to 5% and at least 1.5 times placebo in adults include
paraesthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth.
Adverse reactions reported in greater than or equal to 2% of QSYMIA-treated adults and more frequently thanin the placebo group are shown in Table 3.

Table 3.

Adverse Reactions Reported in ≥2% of QSYMIA-Treated Adults with Overweight or Obesityand More Frequently than Placebo in Overall Study Population of 1 Year Duration

Preferred TermParaesthesia
Dry Mouth
Constipation
Upper Respiratory Tract Infection
Headache
Dysgeusia
Insomnia
Nasopharyngitis
Dizziness
Sinusitis
NauseaBack Pain
Fatigue
Diarrhea
Vision Blurred
Bronchitis
Urinary Tract Infection
CoughInfluenza
Depression
AnxietyHypoesthesia
Irritability
Alopecia
Disturbance in Attention
Pain in Extremity
Muscle Spasms
Dyspepsia
Gastroesophageal Reflux Disease
Rash
Hypokalemia
Dry EyeGastroenteritis
Pharyngolaryngeal Pain
Paraesthesia Oral
Eye PainNasal Congestion
ThirstSinus Congestion
Procedural Pain
Palpitations
Musculoskeletal Pain
Decreased Appetite
Neck Pain
Dysmenorrhea
Chest Discomfort

Placebo(N = 1561)
%
2
3
6
13
9
1
5
8
3
6
4
5
4
5
4
4
4
4
4
2
2
1
1
1
1
3
2
2
1
2
0
1
2
2
0
1
1
1
2
2
1
1
1
1
0
0

QSYMIAQSYMIA
3.75 mg/23 mg 7.5 mg/46 mg(N = 240)(N = 498)
%
%
4
14
7
14
8
15
16
12
10
7
1
7
5
6
13
11
3
7
8
7
6
4
5
6
5
4
5
6
6
4
7
4
3
5
3
4
8
5
3
3
3
2
1
4
2
3
2
3
0
2
2
3
3
3
2
2
1
3
2
2
0
1
1
1
1
2
3
1
0
1
2
2
2
1
2
2
3
3
2
2
1
2
1
3
2
2
1
2
2
0
2
0

QSYMIA
15 mg/92 mg(N = 1580)
%
20
19
16
14
11
9
9
9
9
8
7
7
6
6
5
5
5
5
4
4
4
4
4
4
4
3
3
3
3
3
3
3
3
2
2
2
2
2
2
2
2
2
2
1
1
1

Pediatric Patients Aged 12 Years and Older
Adverse reactions occurring in pediatric patients treated with either QSYMIA 15 mg/92 mg or QSYMIA 7.5
mg/46 mg at greater than or equal to 4% and higher than placebo include depression, pyrexia, dizziness,arthralgia, influenza, and ligament sprain.
Adverse reactions reported in greater than or equal to 2% of QSYMIA-treated pediatric patients and more
frequently than in the placebo group from a study in pediatric patients aged 12 years and older are shown in
Table 4.
Table 4.

Adverse Reactions Reported in ≥2% of QSYMIA-Treated Pediatric Patients Aged 12 to 17
Years and More Frequently than Placebo during 56 Weeks of Treatment

Preferred Term
Depression
NauseaPyrexia
Dizziness
Arthralgia
Paraesthesia
Anxiety
Abdominal Pain Upper
Fatigue
Ear Infection
Musculoskeletal Chest Pain
Influenza
Ligament Sprain

Placebo(N = 56)
%
0
4
2
0
0
0
0
0
2
0
0
0
0

QSYMIA
7.5 mg/46 mg(N = 54)
%
2
4
2
2
2
2
2
0
0
2
0
4
4

QSYMIA
15 mg/92 mg(N = 113)
%
4
4
4
4
4
3
3
3
3
3
3
2
2

Increase in Heart Rate
In adult and pediatric clinical trials, there was a higher incidence of heart rate elevations observed in QSYMIAtreated compared to placebo-treated patients.
Table 5 and Table 6 provide the numbers and percentages of adult and pediatric patients, respectively, withelevations in heart rate in clinical studies of up to one year.
Table 5.

Number and Percentage of Adults with Overweight or Obesity with an Increase in Heart Rateat a Single Time Point from Baseline

Greater than 5 bpm
Greater than 10 bpm
Greater than 15 bpm
Greater than 20 bpm

Placebo
N=1561n (%)
1021 (65.4)
657 (42.1)
410 (26.3)
186 (11.9)

QSYMIA
3.75 mg/23 mg
N=240
n (%)
168 (70.0)
120 (50.0)
79 (32.9)
36 (15.0)

QSYMIA
7.5 mg/46 mg
N=498
n (%)
372 (74.7)
251 (50.4)
165 (33.1)
67 (13.5)

QSYMIA
15 mg/92 mg
N=1580n (%)
1228 (77.7)
887 (56.1)
590 (37.3)
309 (19.6)

Table 6.

Number and Percentage of Pediatric Patients with an Increase in Heart Rate at a Single Time
Point from Baseline

Greater than 5 bpm
Greater than 10 bpm
Greater than 15 bpm
Greater than 20 bpm

PlaceboN=56n (%)
37 (66.1)
26 (46.4)
17 (30.4)
10 (17.9)

QSYMIA
7.5 mg/46 mg
N=54
n (%)
38 (70.4)
30 (55.6)
18 (33.3)
10 (18.5)

QSYMIA
15 mg/92 mg
N=113
n (%)
92 (81.4)
73 (64.6)
48 (42.5)
27 (23.9)

Paraesthesia/Dysgeusia
In adult clinical trials, reports of paraesthesia, characterized as tingling in hands, feet, or face, and dysgeusia,
characterized as a metallic taste, occurred (see Table 3). Adverse reactions of paraesthesia were also reported inpediatric patients (see Table 4). QSYMIA-treated adult patients discontinued treatment due to these adverse
reactions (1% for paraesthesia and 0.6% for dysgeusia); no pediatric patients discontinued treatment due toparaesthesia or dysgeusia.
Mood and Sleep Disorders
The proportion of adult patients in 1-year controlled trials of QSYMIA reporting one or more adverse reactions
related to mood and sleep disorders was 15% and 21% with QSYMIA 7.5 mg/46 mg and 15 mg/92 mg,
respectively, compared to 10% with placebo. These events were further categorized into sleep disorders,anxiety, and depression. Reports of sleep disorders were typically characterized as insomnia and occurred in
8.1% and 11% of patients treated with QSYMIA 7.5 mg/46 mg and 15 mg/92 mg, respectively, compared to
5.8% of patients treated with placebo. Reports of anxiety occurred in 4.8% and 7.9% of patients treated withQSYMIA 7.5 mg/46 mg and 15 mg/92 mg, respectively, compared to 2.6% of patients treated with placebo.
Reports of depression/mood problems occurred in 3.8% and 7.6% of patients treated with QSYMIA 7.5 mg/46
mg and 15 mg/92 mg, respectively, compared to 3.4% of patients treated with placebo. Mood and sleep disorderadverse reactions occurred in patients with and without a history of depression.
In a pediatric clinical trial, higher proportions of QSYMIA-treated patients reported one or more adverse
reactions related to mood (e.g., depression, anxiety) and sleep disorders (e.g., insomnia) compared to placebotreated patients (See Table 4).
Cognitive Disorders
In the 1-year controlled trials of QSYMIA in adults, the proportion of patients who experienced one or morecognitive-related adverse reactions was 5.0% for QSYMIA 7.5 mg/46 mg and 7.6% for QSYMIA 15 mg/92 mg,
compared to 1.5% for placebo. These adverse reactions were comprised primarily of reports of problems withattention/concentration, memory, and language (word-finding). These events occurred at any time during
treatment with QSYMIA.
Slowing of Linear Growth
QSYMIA is associated with a reduction in height velocity (centimeters of height gained per year) in obese
pediatric patients 12 to 17 years of age. In a 56-week study, average height increased from baseline in bothQSYMIA- and placebo-treated patients; however, a lower height velocity of -1.3 to -1.4 cm/year was observed
in QSYMIA-treated compared to placebo-treated patients
Decrease in Bone Mineral Density

QSYMIA is associated with less bone mineral acquisition in pediatric patients 12 to 17 years of age. In a
substudy (n=66) evaluating bone mineralization via dual-energy X-ray absorptiometry (DEXA), increases inbone mineral density (BMD) at the lumbar spine and total body less head (TBLH) were smaller in pediatricpatients treated with QSYMIA compared to those treated with placebo after 1 year of treatment. Declines in
BMD Z-scores of -0.5 or greater from baseline for TBLH were observed in 9% of QSYMIA 7.5 mg/46 mgtreated patients and 30% of QSYMIA 15 mg/92 mg-treated patients, compared to 0% of placebo-treatedpatients. The sample size and study duration were too small to determine if fracture risk is increased. Decreased
BMD was not correlated with decreased serum bicarbonate, which commonly occurs with QSYMIA treatment,or changes in body weight. No patient had a BMD Z-score that went below -2.0 during the trial. Similarfindings were observed in a 1 year, active-controlled trial of topiramate in pediatric patients with anothercondition.
Nephrolithiasis
In the 1-year controlled trials of QSYMIA in adults, the incidence of nephrolithiasis was 0.2% for QSYMIA 7.5
mg/46 mg and 1.2% for QSYMIA 15 mg/92 mg, compared to 0.3% for placebo.
Laboratory Abnormalities
Serum Bicarbonate
In the 1-year controlled trials of QSYMIA in adults, the incidence of persistent decreases in serum bicarbonate
below the normal range (levels of less than 21 mEq/L at 2 consecutive visits or at the final visit) was 6.4% for
QSYMIA 7.5 mg/46 mg and 12.8% for QSYMIA 15 mg/92 mg, compared to 2.1% for placebo. The incidenceof persistent, markedly low serum bicarbonate values (levels of less than 17 mEq/L on 2 consecutive visits or at
the final visit) was 0.2% for QSYMIA 7.5 mg/46 mg dose and 0.7% for QSYMIA 15 mg/92 mg dose,compared to 0.1% for placebo. In a pediatric clinical trial, 60 to 70% QSYMIA-treated patients had a persistentbicarbonate level below the normal range (<21 mEq/L) compared to 43% of placebo-treated patients.
Serum Potassium
In the 1-year controlled trials of QSYMIA in adults, the incidence of persistent low serum potassium values(less than 3.5 mEq/L at two consecutive visits or at the final visit) during the trial was 3.6% for QSYMIA 7.5
mg/46 mg dose and 4.9% for QSYMIA 15 mg/92 mg, compared to 1.1% for placebo. Of the subjects who
experienced persistent low serum potassium, 88% were receiving treatment with a non-potassium sparing
diuretic.
The incidence of markedly low serum potassium (less than 3 mEq/L, and a reduction from pre-treatment ofgreater than 0.5 mEq/L) at any time during the trial was 0.2% for QSYMIA 7.5 mg/46 mg dose and 0.7% for
QSYMIA 15 mg/92 mg dose, compared to 0.0% for placebo. Persistent markedly low serum potassium (lessthan 3 mEq/L, and a reduction from pre-treatment of greater than 0.5 mEq/L at two consecutive visits or at the
final visit) occurred in 0.2% receiving QSYMIA 7.5 mg/46 mg dose and 0.1% receiving QSYMIA
15 mg/92 mg dose, compared to 0.0% receiving placebo.
Low serum potassium levels (<3.5 mEq/L) were not observed in a 56-week clinical trial of pediatric patientswith obesity.
Serum Creatinine
In the 1-year controlled trials of QSYMIA in adults and pediatric patients, there was an increase in serum
creatinine from baseline, peaking between Week 4 to 8 in adults and at Week 16 in pediatric patients. Serum
creatinine values declined but remained elevated over baseline over 1 year of treatment. The incidence ofincreases in serum creatinine of greater than or equal to 0.3 mg/dL at any time during treatment in adults was
7.2% for QSYMIA 7.5 mg/46 mg and 8.4% for QSYMIA 15 mg/92 mg, compared to 2.0% for placebo; 17% of
pediatric patients treated with QSYMIA 7.5 mg/46 mg or QSYMIA 15 mg/92 mg and 0% of patients treatedwith placebo had a serum creatinine ≥0.3 mg/dL at any time post-randomization. Increases in serum creatinineof greater than or equal to 50% over baseline occurred in 2.0% of adult subjects receiving QSYMIA 7.5 mg/46
mg and 2.8% receiving QSYMIA 15 mg/92 mg, compared to 0.6% receiving placebo.
Serum Ammonia
Hyperammonemia with or without encephalopathy has been reported with topiramate. The risk for
hyperammonemia with topiramate appears dose related and has been reported more frequently whenconcomitantly used with valproic acid [see Drug Interactions (7)].
The incidence of hyperammonemia in pediatric patients 12 to 17 years of age in clinical trials of anothercondition was 26% in patients taking topiramate at 100 mg/day (1.1 times the maximum recommended dosage
of QSYMIA) and 14% in patients taking topiramate at 50 mg/day (0.6 times the maximum recommended
dosage of QSYMIA), compared to 9% in patients taking placebo. There was also an increased incidence ofmarkedly increased hyperammonemia (defined as 50% above the upper limit of normal reference range) at the
100 mg dose.
6.2

Postmarketing Experience

The following adverse reactions have been reported during post approval use of QSYMIA, phentermine, andtopiramate. Because these reactions are reported voluntarily from a population of uncertain size it is not always
possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
QSYMIA
Psychiatric: suicidal ideation, suicidal behavior
Ophthalmic: acute angle closure glaucoma, increased intraocular pressure
Phentermine
Allergic Reactions: urticaria
Cardiovascular: elevation of blood pressure, ischemic events
Central Nervous System: euphoria, psychosis, tremor
Reproductive: changes in libido, impotence
Topiramate
Dermatologic: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic
epidermal necrolysis), pemphigus
Gastrointestinal: pancreatitis
Hepatic: hepatic failure (including fatalities), hepatitis
Metabolic: hyperammonemia with or without encephalopathy has been reported with concomitant valproic acid[see Drug Interactions (7)], hypothermia
Ophthalmic: maculopathy
7

DRUG INTERACTIONS

Table 7 displays clinically significant drug interactions with QSYMIA.

Table 7.

Clinically Significant Drug Interactions with QSYMIA

Monamine Oxidase Inhibitors
Clinical Impact

Concomitant use of phentermine with monoamine oxidase inhibitors (MAOIs) increases
the risk of hypertensive crisis.

Intervention

Concomitant use of QSYMIA is contraindicated during MAOI treatment and within 14
days of stopping an MAOI.

Oral Contraceptives
Clinical Impact

Co-administration of multiple-dose QSYMIA 15 mg/92 mg once daily with a single doseof oral contraceptive containing 35 µg ethinyl estradiol (estrogen component) and 1 mg
norethindrone (progestin component), in obese otherwise healthy volunteers, decreased
the exposure of ethinyl estradiol by 16% and increased the exposure of norethindrone by
22% [see Clinical Pharmacology (12.3)]. Although this interaction is not anticipated toincrease the risk of pregnancy, irregular bleeding (spotting) may occur more frequently
due to both the increased exposure to the progestin and lower exposure to the estrogen,which tends to stabilize the endometrium.

Intervention

Inform patients not to discontinue their combination oral contraceptive if spotting occurs,
but to notify their healthcare provider if the spotting is troubling to them.

CNS Depressants Including Alcohol
Clinical Impact

The concomitant use of alcohol or CNS depressant drugs (e.g., barbiturates,
benzodiazepines, and sleep medications) with phentermine or topiramate may potentiate
CNS depression such as dizziness or cognitive adverse reactions, or other centrally
mediated effects of these agents.

Intervention

Advise patients not to drive or operate machinery until they have gained sufficientexperience on QSYMIA to gauge whether it adversely affects their mental performance,
motor performance, and/or vision. Caution patients against excessive alcohol intake when
taking QSYMIA. Consider QSYMIA dosage reduction or discontinuation if cognitive
dysfunction persists. [see Warnings and Precautions (5.6)].

Non-Potassium Sparing Diuretics
Clinical Impact

Concurrent use of QSYMIA with non-potassium sparing diuretics may potentiate thepotassium-wasting action of these diuretics. Concomitant administration ofhydrochlorothiazide alone with topiramate alone has been shown to increase the Cmax and
AUC of topiramate by 27% and 29%, respectively.

Intervention

When QSYMIA is used concomitantly with non-potassium-sparing diuretics, measurepotassium before and during QSYMIA treatment[see Warnings and Precautions (5.15)
and Clinical Pharmacology (12.3)].

Antiepileptic Drugs
Clinical Impact

Concomitant administration of phenytoin or carbamazepine with topiramate in patientswith epilepsy, decreased plasma concentrations of topiramate by 48% and 40%,
respectively, when compared to topiramate given alone [see Clinical Pharmacology(12.3)]. Concomitant administration of valproic acid and topiramate has been associatedwith hyperammonemia with and without encephalopathy. Concomitant administration of
topiramate with valproic acid in patients has also been associated with hypothermia (withand without hyperammonemia).

Intervention

Consider measuring blood ammonia in patients in whom the onset of hypothermia or
encephalopathy has been reported [see Clinical Pharmacology (12.3)].

Carbonic Anhydrase Inhibitors
Clinical Impact

Concomitant use of topiramate with any other carbonic anhydrase inhibitor may increase
the severity of metabolic acidosis and may also increase the risk of kidney stone
formation.

Intervention

Avoid the use of QSYMIA with other drugs that inhibit carbonic anhydrase. If
concomitant use of QSYMIA with another carbonic anhydrase inhibitor is unavoidable,monitor patient for the appearance or worsening of metabolic acidosis [see Warnings andPrecautions (5.8, 5.13)].

Pioglitazone
Clinical Impact

A decrease in the exposure of pioglitazone and its active metabolites were noted with theconcurrent use of pioglitazone and topiramate in a clinical trial. The clinical relevance of
these observations is unknown.

Intervention

Consider increased glycemic monitoring when using pioglitazone and QSYMIA
concomitantly [see Clinical Pharmacology (12.3)].

Amitriptyline
Clinical Impact

Some patients may experience a large increase in amitriptyline concentration in thepresence of topiramate.

Intervention

Any adjustments in amitriptyline dose when used with QSYMIA should be madeaccording to the patient's clinical response and not on the basis of amitriptyline levels [seeClinical Pharmacology (12.3)].

8

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy

Risk Summary
QSYMIA is contraindicated in pregnant patients. The use of QSYMIA can cause fetal harm, and weight loss
offers no clear clinical benefit to a pregnant patient (see Clinical Considerations). Available data frompregnancy registries and epidemiologic studies indicate an increased risk of major congenital malformations,
including but not limited to cleft lip and/or cleft palate (oral clefts), and of being SGA in infants exposed inutero to topiramate (see Data). When phentermine and topiramate were co-administered to rats at doses of 3.75
and 25 mg/kg, respectively [approximately 2 times the maximum recommended human dose (MRHD) based onarea under the curve (AUC)], or at the same dose to rabbits (approximately 0.1 times and 1 time, respectively,
the clinical exposures at the MRHD based on AUC), there were no drug-related malformations. However,structural malformations, including craniofacial defects and reduced fetal weights occurred in offspring ofmultiple species of pregnant animals administered topiramate at clinically relevant doses (see Data). Advise
pregnant women of the potential risk to a fetus.
Clinical Considerations
Disease Associated Maternal and/or Embryo/Fetal Risk
Weight loss during pregnancy may result in fetal harm. Appropriate weight gain based on pre-pregnancy weightis currently recommended for all pregnant patients, including those who are already overweight or obese, due tothe obligatory weight gain that occurs in maternal tissues during pregnancy. Maternal obesity increases the risk

for congenital malformations, including neural tube defects, cardiac malformations, oral clefts, and limb
reduction defects.
Fetal/Neonatal Adverse ReactionsQSYMIA can cause metabolic acidosis [see Warnings and Precautions (5.8)]. The effect of topiramate-induced
metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to othercauses) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus’ability to tolerate labor.
Data
Human Data
Data evaluating the risk of major congenital malformations, oral clefts, and being SGA with topiramate
exposure during pregnancy is available from the North American Antiepileptic Drug (NAAED) Pregnancy
Registry and from several larger retrospective epidemiologic studies.
Major Congenital Malformations
The NAAED Pregnancy Registry indicates an increased risk of major congenital malformations, including but
not limited to oral clefts in infants exposed to topiramate during the first trimester of pregnancy. Other than oral
clefts, no specific pattern of major congenital malformations or grouping of major congenital malformation
types were observed. In the NAAED pregnancy registry, when topiramate-exposed infants with only oral clefts
were excluded, the prevalence of major congenital malformations (4.1%) was higher than that in infants
exposed to a reference antiepileptic drug (AED) (1.8%) or in infants with mothers without epilepsy and without
exposure to AEDs (1.1%).
Oral Clefts
In the NAAED Pregnancy Registry, the prevalence of oral clefts among topiramate-exposed infants (1.4%) was
higher than the prevalence in infants exposed to a reference AED (0.3%) or the prevalence in infants withmothers without epilepsy and without exposure to AEDs (0.11%). It was also higher than the backgroundprevalence in United States (0.17%) as estimated by the Centers for Disease Control and Prevention (CDC).
The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 12.5
(95% Confidence Interval [CI] 5.9-26.37) as compared to the risk in a background population of untreated
women. The UK Epilepsy and Pregnancy Register reported a prevalence of oral clefts among infants exposed to
topiramate monotherapy (3.2%) that was 16 times higher than the background rate in the UK (0.2%).
Larger retrospective epidemiology studies showed that topiramate monotherapy exposure in pregnancy is
associated with an approximately two to five-fold increased risk of oral clefts. The FORTRESS study found an
excess risk of 1.5 (95% CI = -1.1 to 4.1) oral cleft cases per 1,000 infants exposed to topiramate during the firsttrimester.
Small for Gestational Age
Data from the NAAED Pregnancy Registry and population-based birth registry cohort indicate that exposure totopiramate in utero is associated with an increased risk of SGA newborns (birth weight <10th percentile). In the
NAAED Pregnancy Registry, 19.7% of topiramate-exposed newborns were SGA compared to 7.9% of
newborns exposed to a reference AED and 5.4% of newborns of mothers without epilepsy and without AED
exposure. In the medical Birth Registry of Norway, a population-based pregnancy registry, 25% of newborns in
the topiramate monotherapy exposure group were SGA compared to 9% in the comparison group unexposed to
AEDs. The long-term consequences of the SGA findings are not known.

Animal Data
Phentermine/Topiramate
Embryo-fetal development studies have been conducted in rats and rabbits with combination phentermine andtopiramate treatment. Phentermine and topiramate co-administered to rats during the period of organogenesis(gestation day (GD) 6 through 17) caused reduced fetal body weights but did not cause fetal malformations at
the maximum dose of 3.75 mg/kg phentermine and 25 mg/kg topiramate [approximately 2 times the maximum
recommended human dose (MRHD) based on area under the curve (AUC) estimates for each active ingredient].
In a similar study in rabbits in which the same doses were administered from GD 6 through 18, no effects onembryo-fetal development were observed at approximately 0.1 times (phentermine) and 1 time (topiramate)clinical exposures at the MRHD based on AUC. Significantly lower maternal body weight gain was recorded atthese doses in rats and rabbits.
A pre- and post-natal development study was conducted in rats with combination phentermine and topiramate
treatment. There were no adverse maternal or offspring effects in rats treated throughout organogenesis andlactation with 1.5 mg/kg/day phentermine and 10 mg/kg/day topiramate (approximately 2- and 3-times clinicalexposures at the MRHD, respectively, based on AUC). Treatment with higher doses of 11.25 mg/kg/day
phentermine and 75 mg/kg/day topiramate (approximately 5 and 6 times maximum clinical doses based on
AUC, respectively) caused reduced maternal body weight gain and offspring toxicity. Offspring effects
included lower pup survival after birth, increased limb and tail malformations, reduced pup body weight anddelayed growth, development, and sexual maturation without affecting learning, memory, or fertility andreproduction. The limb and tail malformations were consistent with results of animal studies conducted with
topiramate alone.
Phentermine
Animal reproduction studies have not been conducted with phentermine. Limited data from studies conductedwith the phentermine/topiramate combination indicate that phentermine alone was not teratogenic but resulted
in lower body weight and reduced survival of offspring in rats at 5-fold the MRHD of QSYMIA, based on
AUC.
Topiramate
Topiramate causes developmental toxicity, including teratogenicity, at clinically relevant doses in multiple
animal species.
Developmental toxicity, including teratogenicity, occurred at clinically relevant doses in multiple animal
species in which topiramate was administered during the period of organogenesis (GD 6 – 15 in rodents, GD 6 –18 in rabbits. In these studies, fetal malformations (primarily craniofacial defects such as cleft palate), limb
malformations (ectrodactyly, micromelia, and amelia), rib/vertebral column anomalies, and/or reduced fetal
weights were observed at dosages > 20 mg/kg in mice (approximately 2 times the MRHD of topiramate in
QSYMIA 15 mg/92 mg on a mg/m2 basis), 20 mg/kg in rats (2 times the MRHD of QSYMIA based on
estimated AUC), and 35 mg/kg in rabbits (2 times the MRHD based on estimated AUC). When rats wereadministered topiramate from GD 15 through lactation day 20, reductions in pre- and/or post-weaning weights
occurred at dosages > 2 mg/kg (2 times the MRHD of QSYMIA based on estimated AUC).
8.2

Lactation

Risk Summary
Topiramate and phentermine are present in human milk. There are no data on the effects of topiramate andphentermine on milk production. Diarrhea and somnolence have been reported in breastfed infants withmaternal use of topiramate. There are no data on the effects of phentermine in breastfed infants. Because of thepotential for serious adverse reactions, including changes in sleep, irritability, hypertension, vomiting, tremor,and weight loss in breastfed infants with maternal use of phentermine, advise patients that breastfeeding is notrecommended during QSYMIA therapy.
8.3

Females and Males of Reproductive Potential

Pregnancy Testing
Pregnancy testing is recommended in patients who can become pregnant before initiating QSYMIA andmonthly during QSYMIA therapy [see Warnings and Precautions (5.1), Use in Specific Populations (8.1)].
Contraception
FemalesQSYMIA can cause fetal harm when administered to a pregnant patient [see Use in Specific Populations (8.1)].
Advise patients who can become pregnant to use effective contraception during therapy with QSYMIA.
For patients taking combined oral contraceptives (COCs), use of QSYMIA may cause irregular bleeding [seeDrug Interactions (7)]. Advise patients not to discontinue taking their COC and to contact their healthcare
provider.
8.4

Pediatric Use

The safety and effectiveness of QSYMIA as an adjunct to a reduced-calorie diet and increased physical activity
for chronic weight management in pediatric patients aged 12 years and older with a BMI in the 95th percentile
or greater standardized for age and sex have been established. Use of QSYMIA for this indication is supported
by a 56-week, double-blind, placebo-controlled study in 223 pediatric patients aged 12 years and above, apharmacokinetic study in pediatric patients, and studies in adults with obesity [see Clinical Pharmacology(12.3) and Clinical Studies (14)].
In a pediatric clinical trial, there was one episode of serious suicidal ideation in a QSYMIA-treated patient
requiring hospitalization and pharmacologic treatment [see Warnings and Precautions (5.3)]; more patientstreated with QSYMIA versus placebo reported adverse reactions related to mood (e.g., depression, anxiety) andsleep disorders (e.g., insomnia) [see Warnings and Precautions (5.5)]. Increases in bone mineral density andlinear growth were attenuated in QSYMIA- versus placebo-treated patients [see Warnings and Precautions(5.7)]. Serious adverse reactions seen in pediatric patients using topiramate include acute angle glaucoma,
oligohidrosis and hyperthermia, metabolic acidosis, cognitive and neuropsychiatric reactions, hyperammonemia
and encephalopathy, and kidney stones.
The safety and effectiveness of QSYMIA in pediatric patients below the age of 12 years have not been
established.
8.5

Geriatric Use

In the QSYMIA clinical trials, a total of 254 (7%) of the patients were 65 to 69 years of age; no patients 70
years of age or older were enrolled.
Clinical studies of QSYMIA did not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects. In general, dose selection for an elderly patient should
be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased
hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
8.6

Renal Impairment

Compared to healthy volunteers with normal renal function, patients with moderate and severe renal impairment
as estimated by the Cockcroft-Gault equation had higher exposures to phentermine and topiramate.

The recommended dosage of QSYMIA in patients with mild renal impairment (CrCl greater or equal to 50 andless than 80 mL/min) is the same as the recommended dosage for patients with normal renal function.
In patients with moderate (CrCl greater than or equal to 30 to less than 50 mL/min) and severe (CrCl less than
30 mL/min) renal impairment, the maximum recommended dosage is QSYMIA 7.5 mg/46 mg once daily.
QSYMIA has not been studied in patients with end-stage renal disease on dialysis. Avoid QSYMIA in thispatient population [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].
8.7

Hepatic Impairment

In patients with mild (Child-Pugh 5 - 6) and moderate (Child-Pugh 7 - 9) hepatic impairment, exposure tophentermine was higher compared to healthy volunteers with normal hepatic function. Exposure to topiramate
was similar among patients with mild and moderate hepatic impairment and healthy volunteers.
The recommended dosage of QSYMIA in patients with mild hepatic impairment (Child-Pugh 5 - 6) is the sameas the recommended dosage in patients with normal hepatic function.
In patients with moderate hepatic impairment, the maximum recommended dosage is QSYMIA 7.5 mg/46 mg
once daily.
QSYMIA has not been studied in patients with severe hepatic impairment (Child-Pugh score 10 - 15). Avoid
QSYMIA in this patient population [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].
9

DRUG ABUSE AND DEPENDENCE

9.1

Controlled SubstanceQSYMIA contains phentermine, a Schedule IV controlled substance, and topiramate, which is not a controlled
substance.
9.2

Abuse

Phentermine has a known potential for abuse. Abuse is the intentional, non-therapeutic use of a drug, even once,
for its desirable psychological or physiological effects.
Phentermine is related chemically and pharmacologically to amphetamines. Amphetamines and other stimulant
drugs have been extensively abused. Abuse of amphetamines and related drugs (e.g., phentermine) may be
associated with impaired control over drug use and severe social dysfunction. There are reports of patients who
have increased the dosage of these drugs to many times higher than recommended. Assess the risk of abuseprior to prescribing QSYMIA as part of a chronic weight management program.
9.3

Dependence

Physical dependence may occur in patients treated with QSYMIA. Physical dependence is a state that develops
as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs andsymptoms after abrupt discontinuation or a significant dose reduction of a drug.
The following adverse reactions have been associated with the abrupt discontinuation of the individualcomponents of QSYMIA:•For topiramate, abrupt discontinuation has been associated with seizures in patients without a history of
seizures or epilepsy [see Warnings and Precautions (5.12)].

•For phentermine, abrupt discontinuation following prolonged high dosage administration results in
extreme fatigue and mental depression; changes are also noted on a sleep electroencephalogram.

Thus, in situations where rapid withdrawal of QSYMIA is required, appropriate medical monitoring is
recommended. Patients discontinuing QSYMIA 15 mg/92 mg should be gradually tapered to reduce thepossibility of precipitating a seizure [see Dosage and Administration (2.4)].
10

OVERDOSAGEIn the event of a significant overdose with QSYMIA, if the ingestion is recent, the stomach should be emptied
immediately by gastric lavage or by induction of emesis. Appropriate supportive treatment should be provided
according to the patient’s clinical signs and symptoms.
Acute overdose of phentermine may be associated with restlessness, tremor, hyperreflexia, rapid respiration,
confusion, aggressiveness, hallucinations, and panic states. Fatigue and depression usually follow the central
stimulation. Cardiovascular effects include arrhythmia, hypertension or hypotension, and circulatory collapse.
Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning usuallyterminates in convulsions and coma. Manifestations of chronic intoxication with anorectic drugs include severedermatoses, marked insomnia, irritability, hyperactivity, and personality changes. A severe manifestation ofchronic intoxication is psychosis, often clinically indistinguishable from schizophrenia.
Management of acute phentermine intoxication is largely symptomatic and includes lavage and sedation with abarbiturate. Acidification of the urine increases phentermine excretion. Intravenous phentolamine has beensuggested for possible acute, severe hypertension, if this complicates phentermine overdosage.
Topiramate overdose has resulted in severe metabolic acidosis. Other signs and symptoms include convulsions,drowsiness, speech disturbance, blurred vision, diplopia, impaired mentation, lethargy, abnormal coordination,
stupor, hypotension, abdominal pain, agitation, dizziness, and depression. The clinical consequences were notsevere in most cases, but deaths have been reported after overdoses involving topiramate. A patient who
ingested a dose between 96 and 110 gm topiramate was admitted to hospital with coma lasting 20 to 24 hours
followed by full recovery after 3 to 4 days.
Hemodialysis is an effective means of removing topiramate from the body.
11

DESCRIPTIONQSYMIA extended-release capsules are comprised of immediate-release phentermine hydrochloride (expressedas the weight of the free base) and extended-release topiramate. QSYMIA contains phentermine hydrochloride,a sympathomimetic amine anorectic, and topiramate, a sulfamate-substituted monosaccharide.
Phentermine Hydrochloride
The chemical name of phentermine hydrochloride is α,α-dimethylphenethylamine hydrochloride. The molecular
formula is C10H15N • HCl and its molecular weight is 185.7 (hydrochloride salt) or 149.2 (free base).
Phentermine hydrochloride is a white, odorless, hygroscopic, crystalline powder that is soluble in water,
methanol, and ethanol. Its structural formula is:
NH2
HCl
H3C

CH3

Topiramate
Topiramate is 2,3:4,5-di-O-isopropylidene-β-D-fructopyranose sulfamate. The molecular formula is
C12H21NO8S and its molecular weight is 339.4. Topiramate is a white to off-white crystalline powder with abitter taste. It is freely soluble in methanol and acetone, sparingly soluble in pH 9 to pH 12 aqueous solutions
and slightly soluble in pH 1 to pH 8 aqueous solutions. Its structural formula is:

O

NH2
S

O

O

O

O

O
O

O

QSYMIAQSYMIA (phentermine and topiramate extended-release capsules) is for oral administration and available infour dosage strengths:•

3.75 mg/23 mg (phentermine 3.75 mg and topiramate 23 mg) (equivalent to 4.67 mg of Phentermine
Hydrochloride USP).

•

7.5 mg/46 mg (phentermine 7.5 mg and topiramate 46 mg) (equivalent to 9.33 mg of Phentermine
Hydrochloride USP).

•

11.25 mg/69 mg (phentermine 11.25 mg and topiramate 69 mg) (equivalent to 14.0 mg of Phentermine
Hydrochloride USP).

•

15 mg/92 mg (phentermine 15 mg and topiramate 92 mg) (equivalent to 18.66 mg of Phentermine
Hydrochloride USP).

Each capsule contains the following inactive ingredients: FD&C Blue #1, FD&C Red #3, FD&C Yellow #5 and#6, ethylcellulose, gelatin, methylcellulose, microcrystalline cellulose, povidone, starch, sucrose, talc, titanium
dioxide, and pharmaceutical black and white inks.
12

CLINICAL PHARMACOLOGY

12.1

Mechanism of Action

Phentermine is a sympathomimetic amine with pharmacologic activity similar to the prototype drugs of thisclass used in obesity, amphetamine (d- and d/l-amphetamine). Drugs of this class used in obesity are commonly
known as "anorectics" or "anorexigenics." The effect of phentermine on chronic weight management is likely
mediated by release of catecholamines in the hypothalamus, resulting in reduced appetite and decreased foodconsumption, but other metabolic effects may also be involved. The exact mechanism of action is not known.
The precise mechanism of action of topiramate on chronic weight management is not known. Topiramate’s
effect on chronic weight management may be due to its effects on both appetite suppression and satiety
enhancement, induced by a combination of pharmacologic effects including augmenting the activity of theneurotransmitter gamma-aminobutyrate, modulation of voltage-gated ion channels, inhibition of AMPA/kainite
excitatory glutamate receptors, or inhibition of carbonic anhydrase.
12.2

Pharmacodynamics

Typical actions of amphetamines include central nervous system stimulation and elevation of blood pressure.
Tachyphylaxis and tolerance have been demonstrated with drugs in this class.
Cardiac Electrophysiology
The effect of QSYMIA on the QTc interval was evaluated in a randomized, double-blind, placebo- and activecontrolled (400 mg moxifloxacin), and parallel group/crossover thorough QT/QTc study. A total of 54 healthy
subjects were administered QSYMIA 7.5 mg/46 mg at steady state and then titrated to QSYMIA 22.5 mg/138
mg at steady state. QSYMIA 22.5 mg/138 mg [a supra-therapeutic dose resulting in a phentermine andtopiramate maximum concentration (Cmax) of 4- and 3- times higher than those at QSYMIA 7.5 mg/46 mg,
respectively] did not affect cardiac repolarization as measured by the change from baseline in QTc.
Glomerular Filtration Rate (GFR)
Healthy obese men and women received QSYMIA daily for 4 weeks (3.75 mg/23 mg on Days 1 to 3, 7.5 mg/46
mg on Days 4 to 6, 11.25 mg/69 mg on Days 7 to 9, and 15 mg/92 mg on Days 10 to 28). The glomerular
filtration rate (GFR) of these participants was assessed via iohexol clearance. On average, GFR decreased
during QSYMIA treatment and returned to baseline within 4 weeks after discontinuing QSYMIA [see Warnings
and Precautions (5.9)]
12.3

Pharmacokinetics

Absorption
Phentermine
Upon oral administration of a single QSYMIA 15 mg/92 mg, the resulting mean plasma phentermine maximum
concentration (Cmax), time to Cmax (Tmax), area under the concentration curve from time zero to the last time withmeasurable concentration (AUC0-t), and area under the concentration curve from time zero to infinity (AUC0-∞)
are 49.1 ng/mL, 6 hr, 1990 ng⋅hr/mL, and 2000 ng⋅hr/mL, respectively. A high fat meal does not affectphentermine pharmacokinetics for QSYMIA 15 mg/92 mg. Phentermine pharmacokinetics are approximately
dose-proportional from QSYMIA 3.75 mg/23 mg to phentermine 15 mg/topiramate 100 mg. Upon dosing
phentermine 15 mg/topiramate 100 mg fixed dose combination capsule to steady state, the mean phentermine
accumulation ratios for AUC and Cmax are both approximately 2.5.
Topiramate
Upon oral administration of a single QSYMIA 15 mg/92 mg, the resulting mean plasma topiramate Cmax, Tmax,
AUC0-t, and AUC0-∞, are 1020 ng/mL, 9 hr, 61600 ng⋅hr/mL, and 68000 ng⋅hr/mL, respectively. A high fat meal
does not affect topiramate pharmacokinetics for QSYMIA 15 mg/92 mg. Topiramate pharmacokinetics areapproximately dose-proportional from QSYMIA 3.75 mg/23 mg to phentermine 15 mg/topiramate 100 mg.
Upon dosing phentermine 15 mg/topiramate 100 mg fixed dose combination capsule to steady state, the mean
topiramate accumulation ratios for AUC and Cmax are both approximately 4.0.
Distribution
Phentermine
Phentermine is 17.5% plasma protein bound. The estimated phentermine apparent volume of distribution (Vd/F)
is 348 L via population pharmacokinetic analysis.
Topiramate
Topiramate is 15 - 41% plasma protein bound over the blood concentration range of 0.5 to 250 µg/mL. The
fraction bound decreased as blood topiramate increased. The estimated topiramate Vc/F (volume of the centralcompartment), and Vp/F (volume of the peripheral compartment) are 50.8 L, and 13.1 L, respectively, via
population pharmacokinetic analysis.

Elimination
Metabolism and Excretion
Phentermine
Phentermine has two metabolic pathways, namely p-hydroxylation on the aromatic ring and N-oxidation on thealiphatic side chain. Cytochrome P450 (CYP) 3A4 primarily metabolizes phentermine but does not show
extensive metabolism. Monoamine oxidase (MAO)-A and MAO-B do not metabolize phentermine. Seventy to
80% of a dose exists as unchanged phentermine in urine when administered alone. The mean phentermine
terminal half-life is about 20 hours. The estimated phentermine oral clearance (CL/F) is 8.79 L/h via population
pharmacokinetic analysis.
Topiramate
Topiramate does not show extensive metabolism. Six topiramate metabolites (via hydroxylation, hydrolysis,
and glucuronidation) exist, none of which constitutes more than 5% of an administered dose. About 70% of adose exists as unchanged topiramate in urine when administered alone. The mean topiramate terminal half-life
is about 65 hours. The estimated topiramate CL/F is 1.17 L/h via population pharmacokinetic analysis.
Specific Populations
Patients with Renal Impairment
A single-dose, open-label study was conducted to evaluate the pharmacokinetics of QSYMIA 15 mg/92 mg in
adult patients with varying degrees of chronic renal impairment compared to healthy volunteers with normal
renal function. The study included patients with renal impairment classified on the basis of creatinine clearance
as mild (greater or equal to 50 and less than 80 mL/min), moderate (greater than or equal to 30 and less than
50 mL/min), and severe (less than 30 mL/min). Creatinine clearance was estimated from serum creatinine basedon the Cockcroft-Gault equation.
Compared to healthy volunteers, phentermine AUC0-inf was 91%, 45%, and 22% higher in patients with severe,
moderate, and mild renal impairment, respectively; phentermine Cmax was 2% to 15% higher. Compared tohealthy volunteers, topiramate AUC0-inf was 126%, 85%, and 25% higher for patients with severe, moderate,
and mild renal impairment, respectively; topiramate Cmax was 6% to 17% higher. An inverse relationshipbetween phentermine or topiramate Cmax or AUC and creatinine clearance was observed.
QSYMIA has not been studied in patients with end-stage renal disease on dialysis [see Dosage andAdministration (2.5), and Use in Specific Populations (8.6)].
Patients with Hepatic Impairment
A single-dose, open-label study was conducted to evaluate the pharmacokinetics of QSYMIA 15 mg/92 mg in
healthy volunteers with normal hepatic function compared with patients with mild (Child-Pugh score 5 - 6) andmoderate (Child-Pugh score 7 - 9) hepatic impairment. In patients with mild and moderate hepatic impairment,
phentermine AUC was 37% and 60% higher compared to healthy volunteers. Pharmacokinetics of topiramate
was not affected in patients with mild and moderate hepatic impairment when compared with healthy
volunteers. QSYMIA has not been studied in patients with severe hepatic impairment (Child-Pughscore 10 - 15) [see Dosage and Administration (2.6), and Use in Specific Populations (8.7)].
Pediatric Patients 12 to 17 years old
A randomized, double-blind, placebo-controlled study was conducted to evaluate the population
pharmacokinetics of QSYMIA using data from 37 pediatric patients (12 to 17 years of age) with obesity.
QSYMIA dosages of 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg were studied. QSYMIA exposure in thepediatric patients appeared comparable to that in adults.

Drug Interaction Studies
In Vitro Assessment of Drug Interactions
Phentermine
Phentermine is not an inhibitor of CYP isozymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, andCYP3A4, and is not an inhibitor of monoamine oxidases. Phentermine is not an inducer of CYP1A2, CYP2B6,
and CYP3A4. Phentermine is not a P-glycoprotein substrate.
Topiramate
Topiramate is not an inhibitor of CYP isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1,
and CYP3A4/5. However, topiramate is a mild inhibitor of CYP2C19. Topiramate is a mild inducer of
CYP3A4. Topiramate is not a P-glycoprotein substrate.
Effects of Phentermine/Topiramate on Other Drugs
Table 8 describes the effect of phentermine/topiramate on the pharmacokinetics of co-administered drugs.
Table 8.

Effect of Phentermine/Topiramate on the Pharmacokinetics of Co-administered Drugs
Phentermine/Topiramate
15 mg/92 mg dose QD for 16 days*
15 mg/92 mg dose QD for 21 days***

15 mg/92 mg dose QD for 15 days

Co-administered Drug and Dosing Regimen
Change in
Drug and Dose (mg)Change in AUC
Cmax
Metformin 500 mg BID for 5 days
↑ 23%
↑ 16%
Sitagliptin 100 mg QD for 5 days
↓ 3%
↓ 9%
Oral contraceptive single dose
norethindrone 1 mg
↑ 16%
↑ 22%
ethinyl estradiol 35 mcg
↓ 16%
↓ 8%

*A single study examined the effect of multiple-dose QSYMIA 15 mg/92 mg once daily on the pharmacokinetics of multiple-

dose 500 mg metformin twice daily and multiple-dose 100 mg sitagliptin once daily in 10 men and 10 women (mean BMI of
27.1 kg/m2 and range of 22.2 – 32.7 kg/m2). The study participants received metformin, sitagliptin, phentermine/topiramate
only, phentermine/topiramate plus probenecid, phentermine/topiramate plus metformin, and phentermine/topiramate plus
sitagliptin on Days 1 – 5, 6 – 10, 11 – 28, 29, 30 – 34, and 35 – 39, respectively. The significance of these interactions are
unknown.
**See Drug Interactions (7)Effect of Other Drugs on Phentermine/Topiramate
Table 9 describes the effect of other drugs on the pharmacokinetics of phentermine/topiramate.
Table 9.

Effect of Co-administered Drugs on the Pharmacokinetics of Phentermine/Topiramate
Co-administered Drug andDosing Regimen
Topiramate 92 mg single dose
Phentermine 15 mg single dose*

Metformin 500 mg BID for 5 days
Sitagliptin 100 mg QD for 5 days*

Probenecid 2 g QD*

Phentermine/Topiramate
Dose (mg)
15 mg phentermine single dose
92 mg topiramate single dose
15 mg/92 mg dose QD for 16 days
phentermine
topiramate
15 mg/92 mg dose QD for 21 days
phentermine
topiramate
15 mg/92 mg dose QD for 11 days
phentermine
topiramate

Change in AUC
↑ 42%
↑ 6%

Change in
Cmax
↑ 13%
↑ 2%

↑ 5%
↓ 5%

↑ 7%
↓ 4%

↑ 9%
↓ 2%

↑ 10%
↓ 2%

↓ 0.3%↑ 0.7%↑ 4%↑ 3%*The same single study examined the effect of multiple-dose 500 mg metformin twice daily, a single-dose 2 g probenecid, andmultiple-dose 100 mg sitagliptin once daily on the pharmacokinetics of multiple-dose phentermine/topiramate 15 mg/92 mg
once daily in 10 men and 10 women (mean BMI of 27.1 kg/m2 and range of 22.2 – 32.7 kg/m2). The study participantsreceived metformin, sitagliptin, phentermine/topiramate only, phentermine/topiramate plus probenecid,
phentermine/topiramate plus metformin, and phentermine/topiramate plus sitagliptin on Days 1 – 5, 6 – 10, 11 – 28, 29, 30 –34, and 35 – 39, respectively.

Effects of Topiramate Alone on Other Drugs and Effects of Other Drugs on Topiramate
Antiepileptic Drugs
Potential interactions between topiramate and standard antiepileptic (AED) drugs were assessed in controlled
clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma
AUCs are summarized in Table 10.
In Table 10, the second column (AED concentration) describes what happens to the concentration of the AED
listed in the first column when topiramate is added. The third column (topiramate concentration) describes how
the co-administration of a drug listed in the first column modifies the concentration of topiramate inexperimental settings when topiramate was given alone [see Drug Interactions (7)].
Table 10.

Summary of AED Interactions with Topiramate

AED
Co-administered
Phenytoin
Carbamazepine (CBZ)
CBZ epoxideb
Valproic acid
Phenobarbital
Primidone
Lamotrigine

AED
Concentration
NC or 25% increasea
NCNC
11% decreaseNC
NC
NC at TPM doses up to 400 mg/day

Topiramate
Concentration
48% decrease
40% decreaseNE
14% decreaseNENE
13% decrease

Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration; NE = Not Evaluated; TPM = topiramateabDigoxin
In a single-dose study, serum digoxin AUC was decreased by 12% with concomitant topiramate administration.
The clinical relevance of this observation has not been established.
Hydrochlorothiazide
A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics ofhydrochlorothiazide (HCTZ) (25 mg q24h) and topiramate (96 mg q12h) when administered alone andconcomitantly. The results of this study indicate that topiramate Cmax increased by 27% and AUC increased by
29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steadystate pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of
topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ
administration, which were greater when HCTZ and topiramate were administered in combination [see Drug
Interactions (7) and Warnings and Precautions (5.15)].
Pioglitazone
A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of
topiramate (96 mg twice daily) and pioglitazone (30 mg daily) when administered alone and concomitantly for
7 days. A 15% decrease in the area under the concentration-time curve during a dosage interval at steady state(AUCτ,ss) of pioglitazone with no alteration in maximum steady-state plasma drug concentration during adosage interval (Cmax,ss) was observed. This finding was not statistically significant. In addition, a 13% and 16%
decrease in Cmax,ss and AUCτ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60%
decrease in Cmax,ss and AUCτ,ss of the active keto-metabolite [see Drug Interactions (7)].
Glyburide
A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state
pharmacokinetics of glyburide (5 mg/day) alone and concomitantly with topiramate (150 mg/day). There was a
22% decrease in Cmax and a 25% reduction in AUC24 for glyburide during topiramate administration. Systemic
exposure (AUC) of the active metabolites, 4-trans-hydroxyglyburide (M1), and 3-cis-hydroxyglyburide (M2),
was reduced by 13% and 15%, and Cmax was reduced by 18% and 25%, respectively. The steady-state
pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide.
Lithium
In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200
mg/day; however, there was an observed increase in systemic exposure of lithium (27% for Cmax and 26% forAUC) following topiramate doses up to 600 mg/day.
Haloperidol
The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of
topiramate (100 mg every 12 hours) in 13 healthy adults (6 males, 7 females).
Amitriptyline
There was a 12% increase in AUC and Cmax for amitriptyline (25 mg per day) in 18 normal subjects (9 males, 9females) receiving 200 mg/day of topiramate [see Drug Interactions (7)].
Sumatriptan
Multiple dosing of topiramate (100 mg every 12 hrs) in 24 healthy volunteers (14 males, 10 females) did notaffect the pharmacokinetics of single-dose sumatriptan either orally (100 mg) or subcutaneously (6 mg).

Risperidone
When administered concomitantly with topiramate at escalating doses of 100, 250, and 400 mg/day, there was a
reduction in risperidone systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg/day
doses of topiramate). No alterations of 9-hydroxyrisperidone levels were observed. Co-administration of
topiramate 400 mg/day with risperidone resulted in a 14% increase in Cmax and a 12% increase in AUC12 of
topiramate. There were no clinically significant changes in the systemic exposure of risperidone plus
9-hydroxyrisperidone or of topiramate; therefore, this interaction is not likely to be of clinical significance.
Propranolol
Multiple dosing of topiramate (200 mg/day) in 34 healthy volunteers (17 males, 17 females) did not affect thepharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg/day in 39
volunteers (27 males, 12 females) had no effect on the exposure to topiramate, at a dose of 200 mg/day of
topiramate.
Dihydroergotamine
Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (12 males, 12 females) did not affect thepharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of
dihydroergotamine did not affect the pharmacokinetics of a 200 mg/day dose of topiramate in the same study.
Diltiazem
Co-administration of diltiazem (240 mg Cardizem CD) with topiramate (150 mg/day) resulted in a 10%
decrease in Cmax and a 25% decrease in diltiazem AUC, a 27% decrease in Cmax and an 18% decrease in desacetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem
resulted in a 16% increase in Cmax and a 19% increase in AUC12 of topiramate.
Venlafaxine
Multiple dosing of topiramate (150 mg/day) in healthy volunteers did not affect the pharmacokinetics ofvenlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg extended release) did notaffect the pharmacokinetics of topiramate.
13

NONCLINICAL TOXICOLOGY

13.1

Carcinogenesis, Mutagenesis, Impairment of Fertility

Phentermine/Topiramate
No animal studies have been conducted with the combination of phentermine/topiramate to evaluate
carcinogenesis, mutagenesis, or impairment of fertility. The following data are based on findings in studies
performed individually with phentermine or topiramate, QSYMIA’s two active ingredients.
Phentermine
Phentermine was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial
mutagenicity assay, a chromosomal aberration test in Chinese hamster lung (CHL-K1) cells, or an in vivo
micronucleus assay.
Rats were administered oral doses of 3, 10, and 30 mg/kg/day phentermine for 2 years. There was no evidenceof carcinogenicity at the highest dose of phentermine (30 mg/kg) which is approximately 11 to 15 times the
maximum recommended clinical dose of QSYMIA 15 mg/92 mg based on AUC exposure.
No animal studies have been conducted with phentermine to determine the potential for impairment of fertility.

Topiramate
Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitro and in vivo assays.
Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increaseunscheduled DNA synthesis in rat hepatocytes in vitro; and it did not increase chromosomal aberrations inhuman lymphocytes in vitro or in rat bone marrow in vivo.
An increase in urinary bladder tumors was observed in mice given topiramate (20, 75, and 300 mg/kg) in thediet for 21 months. The elevated bladder tumor incidence, which was statistically significant in males andfemales receiving 300 mg/kg, was primarily due to the increased occurrence of a smooth muscle tumor
considered histomorphologically unique to mice. Plasma exposures in mice receiving 300 mg/kg wereapproximately 2 to 4 times steady-state exposures measured in patients receiving topiramate monotherapy at the
MRHD of QSYMIA 15 mg/92 mg. The relevance of this finding to human carcinogenic risk is uncertain. No
evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up
to 120 mg/kg (approximately 4 to 10 times the MRHD of QSYMIA based on AUC estimates).
No adverse effects on male or female fertility were observed in rats at doses up to 100 mg/kg (approximately 4
to 8 times male and female MRHD exposures of QSYMIA based on AUC).
14

CLINICAL STUDIESClinical Studies in Adults
The effect of QSYMIA on weight loss in conjunction with reduced caloric intake and increased physicalactivity was studied in two randomized, double-blind, placebo-controlled studies in patients with obesity(Study 1) and patients with obesity or overweight with two or more significant co-morbidities (Study 2). Bothstudies had a 4-week titration period, followed by 52 weeks of treatment. There were two co-primary efficacy
outcomes measured after 1 year of treatment (Week 56): 1) the percent weight loss from baseline; and 2)
treatment response defined as achieving at least 5% weight loss from baseline.
In Study 1, patients with obesity (BMI greater than or equal to 35 kg/m2) were randomized to receive 1 year oftreatment with placebo (N=514), QSYMIA 3.75 mg/23 mg (N=241), or QSYMIA 15 mg/92 mg (N=512) in a
2:1:2 ratio. Patients ranged in age from 18-71 years old (mean age 43) and 83% were female. Approximately
80% were Caucasian, 18% were African American, and 15% were Hispanic/Latino. At the beginning of thestudy the average weight and BMI of patients was 116 kg and 42 kg/m2, respectively. Patients with type 2
diabetes were excluded from participating in Study 1. During the study, a well-balanced, reduced-calorie diet toresult in an approximate 500 kcal/day decrease in caloric intake was recommended to all patients and patientswere offered nutritional and lifestyle modification counseling.
In Study 2, patients with overweight or obesity were randomized to receive 1 year of treatment with placebo(N=994), QSYMIA 7.5 mg/46 mg (N=498), or QSYMIA 15 mg/92 mg (N=995) in a 2:1:2 ratio. Eligible
patients had to have a BMI greater than or equal to 27 kg/m2 and less than or equal to 45 kg/m2 (there was nolower limit on BMI for patients with type 2 diabetes) and two or more of the following obesity-related comorbid conditions:•Elevated blood pressure (greater than or equal to 140/90 mmHg, or greater than or equal to 130/85
mmHg for diabetics) or requirement for greater than or equal to 2 antihypertensive medications;•Triglycerides greater than 200-400 mg/dL or were receiving treatment with 2 or more lipid-lowering
agents;•Elevated fasting blood glucose (greater than 100 mg/dL) or diabetes; and/or•

Waist circumference greater than or equal to 102 cm for men or greater than or equal to 88 cm for
women.

Patients ranged in age from 19-71 years old (mean age 51) and 70% were female. Approximately 86% were
Caucasian, 12% were African American, and 13% were Hispanic/Latino. The average weight and BMI ofpatients at the start of the study was 103 kg and 36.6 kg/m2, respectively. Approximately half (53%) of patients
had hypertension at the start of the study. There were 388 (16%) patients with type 2 diabetes at the start of thestudy. During the study, a well-balanced, reduced-calorie diet to result in an approximate 500 kcal/day decreasein caloric intake was recommended to all patients and patients were offered nutritional and lifestylemodification counseling.
The percentage of randomized patients who withdrew from each study prior to week 56 was 40% in Study 1,
and 31% in Study 2.
Table 11 provides the results for weight loss at 1 year in Studies 1 and 2. After 1 year of treatment withQSYMIA, all dose levels resulted in statistically significant weight loss compared to placebo (see Table 11,
Figure 1 and Figure 2). A statistically significant greater proportion of the patients randomized to QSYMIA
than placebo achieved 5% and 10% weight loss.
Table 11.

Weight Loss at One Year in Adult Patients in Studies 1 and 2

Analysis Method
ITT-LOCF (Primary)*
Weight (kg)Baseline mean (SD)% LS Mean Change frombaseline (SE)**
Difference from placebo(95% CI)
Percentage of patientslosing greater than or equal
to 5% body weight
Risk Difference vs. placebo(95% CI)
Percentage of patientslosing greater than or equal
to 10% body weight
Risk Difference vs. placebo(95% CI)

Placebon = 498

Study 1 (Obesity)
QSYMIA
3.75 mg/23
QSYMIAmg
15 mg/92 mg
n = 234n = 498

Study 2 (Obesity or Overweight with
Co-morbidities)
Placebon = 979QSYMIA
7.5 mg/46 mg
n = 488QSYMIA
15 mg/92 mg
n = 981115.7(21.4)

118.6 (21.9)

115.2 (20.8)

103.3(18.1)

102.8 (18.2)

103.1 (17.6)-1.6 (0.4)-5.1 (0.5)†-10.9 (0.4)†‡-1.2 (0.3)-7.8 (0.4)†-9.8 (0.3)†‡

3.5 (2.4-4.7)

9.4 (8.4-10.3)

6.6 (5.8-7.4)

8.6 (8.0-9.3)

45%†

67%†‡

62%†

70%†‡

27.6 (20.434.8)

49.4 (44.1-54.7)

41.3 (36.346.3)

49.2 (45.453.0)

19%†

47%†‡

37%†

48%†‡

11.4 (5.9-16.9)

39.8 (34.8-44.7)

29.9 (25.334.5)

40.3 (36.743.8)

17%

7%

21%

7%

SD=standard deviation; LS=least-squares; SE=standard error; CI=confidence interval* Uses all available data from subjects in ITT population, including data collected from subjects who discontinued drug but remained on study.
Last Observation Carried Forward (LOCF) method used to impute missing data.
† p < 0.0001 vs. placebo based on least-squares (LS) mean from an analysis of covariance.
‡ p < 0.01 vs. 3.75 mg/23 mg (Study 1) or 7.5 mg/46 mg (Study 2) dose.
Type 1 error was controlled across all pairwise treatment comparisons.
** Adjusted for baseline bodyweight (Study 1) and baseline bodyweight and diabetic status (Study 2).

Figure 1.

Study 1 Percent Weight Change fromBaseline to Week 56 in Adults with
Obesity

Figure 2.

Study 2 Percent Weight Change fromBaseline to Week 56 in Adults with
Obesity or Overweight with Comorbidities

The changes in cardiovascular, metabolic, and anthropometric risk factors associated with obesity from Study 1
and 2 are presented in Table 12 and Table 13. One year of therapy with QSYMIA resulted in relative
improvement over placebo in several risk factors associated with obesity with the exception of heart rate [seeWarnings and Precautions (5.2)].

Table 12.

Least-Squares (LS) Mean† Change from Baseline and Treatment Difference from Placebo in
Cardiometabolic Parameters in Adults Following One Year of Treatment in Study 1(Obesity)

Study 1 (Obesity)
Heart Rate, bpm
Baseline mean (SD)LS Mean Change (SE)
Systolic Blood Pressure, mmHg
Baseline mean (SD)LS Mean Change (SE)Diastolic Blood Pressure, mmHg
Baseline mean (SD)LS Mean Change (SE)Total Cholesterol, %Baseline mean (SD)LS Mean Change (SE)LDL-Cholesterol, %Baseline mean (SD)LS Mean Change (SE)HDL-Cholesterol, %Baseline mean (SD)LS Mean Change (SE)
Triglycerides, %Baseline mean (SD)LS Mean Change (SE)Fasting Glucose, mg/dL
Baseline mean (SD)LS Mean Change (SE)
Waist Circumference, cm
Baseline mean (SD)LS Mean Change (SE)Placebo(N=498)QSYMIA
3.75 mg/23 mg(N=234)QSYMIA
15 mg/92 mg(N=498)73.2 (8.8)-0.8 (0.5)

72.3 (9.2)+0.3 (0.6)

121.9 (11.5)+0.9 (0.6)

QSYMIA – Placebo: LS MeanQSYMIA
3.75 mg/23 mg

QSYMIA
15 mg/92 mg

73.1 (9.6)+1.0 (0.5)

+1.1

+1.8

122.5 (11.1)-1.8 (0.8)

121.9 (11.6)-2.9 (0.6)

-2.8

-3.8

77.2 (7.9)+0.4 (0.4)

77.8 (7.5)-0.1 (0.6)

77.4 (7.7)-1.5 (0.4)

-0.5

-1.9

194.3 (36.7)-3.5 (0.6)

196.3 (36.5)-5.4 (0.9)

192.7 (33.8)-6.0 (0.6)

-1.9

-2.5

120.9 (32.2)-5.5 (1.0)

122.8 (33.4)-7.7 (1.3)

120.0 (30.1)-8.4 (0.9)

-2.2

-2.8

49.5 (13.3)+0.0 (0.8)

50.0 (11.1)+0.5 (1.1)

49.7 (11.7)+3.5 (0.8)

+0.5

+3.5

119.0 (39.3)+9.1 (2.3)

117.5 (40.3)+5.2 (3.1)

114.6 (37.1)-5.2 (2.2)

-3.9

-14.3

93.1 (8.7)+1.9 (0.5)

93.9 (9.2)+0.8 (0.7)

93.0 (9.5)-0.6 (0.5)

-1.2

-2.5

120.5 (14.0)-3.1 (0.5)

121.5 (15.2)-5.6 (0.6)

120.0 (14.7)-10.9 (0.5)

-2.5*

-7.8*

SD=standard deviation; SE=standard error* Statistically significant versus placebo based on the pre-specified method for controlling Type I error across multiple doses† Study 1 adjusted for baseline bodyweightTable 13.

Least-Squares (LS) Mean† Change from Baseline and Treatment Difference from Placebo in
Cardiometabolic Parameters in Adults Following One Year of Treatment in Study 2 (Obeseor Overweight with Comorbidities)

Study 2 (Overweight and Obesewith Comorbidities)
Heart Rate, bpm
Baseline mean (SD)LS Mean Change (SE)
Systolic Blood Pressure, mmHg
Baseline mean (SD)LS Mean Change (SE)Diastolic Blood Pressure, mmHg
Baseline mean (SD)LS Mean Change (SE)Total Cholesterol, %Baseline mean (SD)LS Mean Change (SE)LDL-Cholesterol, %Baseline mean (SD)LS Mean Change (SE)HDL-Cholesterol, %Baseline mean (SD)LS Mean Change (SE)
Triglycerides, %Baseline mean (SD)LS Mean Change (SE)Fasting Insulin, (µIU/mL)
Baseline mean (SD)LS Mean Change (SE)Fasting Glucose, mg/dL
Baseline mean (SD)LS Mean Change (SE)
Waist Circumference, cm
Baseline mean (SD)LS Mean Change (SE)Placebo(N=979)QSYMIA
7.5 mg/46 mg(N=488)QSYMIA
15 mg/92 mg(N=981)

72.1 (9.9)-0.3 (0.3)

72.2 (10.1)+0.3 (0.4)

128.9 (13.5)-2.4 (0.48)

QSYMIA – Placebo: LS MeanQSYMIA
7.5 mg/46 mg

QSYMIA
15 mg/92 mg

72.6 (10.1)+1.4 (0.3)

+0.6

+1.7

128.5 (13.6)-4.7 (0.63)

127.9 (13.4)-5.6 (0.5)

-2.3

-3.2

81.1 (9.2)-2.7 (0.3)

80.6 (8.7)-3.4 (0.4)

80.2 (9.1)-3.8 (0.3)

-0.7

-1.1

205.8 (41.7)-3.3 (0.5)

201.0 (37.9)-4.9 (0.7)

205.4 (40.4)-6.3 (0.5)

-1.6

-3.0

124.2 (36.2)-4.1 (0.9)

120.3 (33.7)-3.7 (1.1)

123.9 (35.6)-6.9 (0.9)

+0.4

-2.8

48.9 (13.8)+1.2 (0.7)

48.5 (12.8)+5.2 (0.9)

49.1 (13.8)+6.8 (0.7)

+4.0

+5.6

163.5 (76.3)+4.7 (1.7)

161.1 (72.2)-8.6 (2.2)

161.9 (73.4)-10.6 (1.7)

-13.3

-15.3

17.8 (13.2)+0.7 (0.8)

18.0 (12.9)-3.5 (1.1)

18.4 (17.5)-4.0 (0.8)

-4.2

-4.7

106.6 (23.7)+2.3 (0.6)

106.2 (21.0)-0.1 (0.8)

105.7 (21.4)-1.3 (0.6)

-2.4

-3.6

113.4 (12.2)-2.4 (0.3)

112.7 (12.4)-7.6 (0.4)

113.2 (12.2)-9.2 (0.3)

-5.2*

-6.8*

SD=standard deviation; SE=standard error* Statistically significant versus placebo based on the pre-specified method for controlling Type I error across multiple doses† Study 2 adjusted for baseline bodyweight and diabetic status

Among the 388 subjects with type 2 diabetes treated in Study 2, reductions in HbA1c from baseline (6.8%)
were 0.1% for placebo compared to 0.4% and 0.4% with QSYMIA 7.5 mg/46 mg and QSYMIA 15 mg/92 mg,
respectively [see Warnings and Precautions (5.10)].
Clinical Studies in Pediatric Patients Aged 12 Years and Older
The effect of QSYMIA on BMI in conjunction with reduced caloric intake and increased physical activity wasevaluated in Study 3 (NCT 03922945), a 56-week, randomized, double-blind, placebo-controlled study inpediatric patients (12 to 17 years of age) with BMI ≥ 95th percentile standardized by age and sex. Patients wererandomized to receive treatment with placebo (N=56), QSYMIA 7.5 mg/46 mg (N=54), or QSYMIA
15 mg/92 mg (N=113) in a 1:1:2 ratio. During the study, a well-balanced, reduced-calorie diet to result in an
approximate 500 kcal/day decrease in caloric intake was recommended to all patients and patients were offereda family-based lifestyle modification program for adolescents.
Patients’ mean age was 14 years old, approximately 55% were female, 67% were Caucasian, 26% were African
American, and 33% were Hispanic/Latino. At the beginning of the study, the average weight and BMI ofpatients was 106 kg and 38 kg/m2, respectively, with approximately 81% considered severely obese (120% ofthe 95th percentile or greater for BMI standardized by age and sex). Thirty-eight (38%) of randomized patients
withdrew from the study prior to week 56.
The primary efficacy parameter was mean percent change in BMI. Table 14 provides results for BMI reduction
at Week 56 in Study 3. After 56 weeks of treatment with QSYMIA, all dose levels resulted in statisticallysignificant reduction in BMI compared to placebo (see Table 14, Figure 3). A greater proportion of patientsrandomized to QSYMIA than placebo achieved 5%, 10%, and 15% BMI reduction.
Table 14. Change in BMI at Week 56 in Pediatric Patients Aged 12 to 17 Years in Study 3 (Obesity)
Analysis Method
ITT-Washout (Primary)*
BMI (kg/m2) Primary Efficacy Endpoint
Baseline mean (SD)% LS Mean Change from baseline (SE)Difference from placebo(95% CI)
Percentage of patients with a reductionof greater than or equal to 5% BMI
Difference vs. placebo(95% CI)
Percentage of patients with a reductionof greater than or equal to 10% BMI
Difference vs. placebo(95% CI)
Percentage of patients with a reductionof greater than or equal to 15% BMI
Difference vs. placebo(95% CI)

Placebon = 56QSYMIA
7.5 mg/46 mg
n = 54QSYMIA
15 mg/92 mg
n = 11336.4 (6.4)+3.3 (1.4)

36.9 (6.7)-4.8 (1.3)

39.0 (7.4)-7.1 (1.0)-8.1 (-11.9, -4.3)-10.4 (-13.9, -7.0)

44.0%

52.2%

29.7% (11.2, 48.3)

38.6% (23.1, 54.1)

33.5%

44.4%

28.8% (13.6, 44.0)

40.5% (28.4, 52.6)

13.6%

28.9%

11.7% (1.3, 22.2)

27.4% (17.7, 37.1)

13.6%

4.5%

2.9%

SD=standard deviation; LS=least-squares; SE=standard error; CI=confidence interval*Missing data were imputed using a washout multiple imputation method based on placebo response.

Figure 3.

Study 3 Percent BMI Change from Baseline to Week 56 in Pediatric Patients Aged 12 to 17
Years with Obesity

Table 15. Change from Baseline and Treatment Difference from Placebo in Cardiometabolic
Parameters in Pediatric Patients Aged 12 to 17 Years Following 56 Weeks of Treatment inStudy 3 (Obesity)
Study 3 (Obesity)
ITT Population

Placebo(N=56)QSYMIA
7.5 mg/46 mg(N=54)QSYMIA
15 mg/92 mg(N=113)QSYMIA – Placebo
QSYMIAQSYMIA
7.5 mg/46 mg
15 mg/92 mg

Heart Rate, bpm*
Baseline mean (SD)76.8 (9.9)
78.6 (9.6)
76.2 (9.6)-5.6
3.2
Mean Change (SD)
2.5 (12.4)-3.1 (8.4)
5.7 (11.4)
Systolic Blood Pressure, mmHg
Baseline mean (SD)117.7 (10.4)
121.4 (9.2)
117.4 (10.2)
-2.8
-1.0
LS Mean Change (SE)+2.9 (1.6)+0.1 (1.5)+1.8 (1.1)
Diastolic Blood Pressure, mmHg
Baseline mean (SD)71.7 (8.3)
75.8 (6.7)
72.9 (7.3)
-3.2
-2.2
LS Mean Change (SE)+3.4 (1.5)+0.2 (1.3)+1.2 (1.0)
Total Cholesterol, mg/dL*
Baseline mean (SD)164.9 (30.9)
160.6 (26.1)
159.4 (32.7)
-1.4
-1.2
Mean % Change (SD)
-1.8 (10.7)-3.2 (13.1)-3.0 (14.5)
LDL-Cholesterol, mg/dL*
Baseline mean (SD)94.1 (26.8)
89.4 (23.7)
90.2 (27.3)
-3.9
-2.5
Mean % Change (SD)
0.2 (23.3)-3.7 (15.5)-2.3 (21.6)
HDL-Cholesterol, mg/dL
Baseline mean (SD)47.2 (9.7)
47.2 (8.9)
46.7 (10.1)
6.4
5.0
LS Mean % Change (SE)-4.3 (15.1)+2.1 (11.5)+0.7 (9.6)
Triglycerides, mg/dL
Baseline mean (SD)118.3 (46.1)
120.1 (61.6)
112.2 (63.2)
-11.7
-11.2
LS Mean % Change (SE)+5.6 (8.4)-6.2 (8.0)-5.6 (7.2)
HbA1c, %*Baseline mean (SD)
5.5 (0.3)
5.6 (0.4)
5.5 (0.4)-0.2
0.0
Mean Change (SD)-0.2 (0.2)-0.4 (0.3)-0.2 (0.3)
Waist Circumference, cm
Baseline mean (SD)111.1 (14.0)
111.9 (15.5)
116.5 (16.8)
-5.6
-7.6
LS Mean Change (SE)+0.6 (1.4)-5.0 (1.4)-7.0 (1.1)
SD=standard deviation; SE=standard error*Parameter was not pre-specified for inferential statistics; descriptive summary of change from baseline provided for
subjects with non-missing data at baseline and Week 56.

16

HOW SUPPLIED/STORAGE AND HANDLINGQSYMIA (phentermine and topiramate extended-release capsules) are available as follows (see Table 16):
Table 16. QSYMIA Presentations
Strength(phentermine mg/topiramate mg)
3.75 mg/23 mg extended-releasecapsules

7.5 mg/46 mg extended-releasecapsules11.25 mg/69 mg extended-releasecapsules

15 mg/92 mg extended-releasecapsules

3.75 mg/23 mg and7.5 mg/46 mg extended-releasecapsules11.25 mg/69 mg and
15 mg/92 mg extended-releasecapsulesDescription

How Supplied

NDC

Purple cap
imprinted with
VIVUS, Purple
body imprinted
with 3.75/23
Purple cap
imprinted with
VIVUS, Yellow
body imprinted
with 7.5/46
Yellow cap
imprinted with
VIVUS, Yellow
body imprinted
with 11.25/69
Yellow cap
imprinted with
VIVUS, White
body imprinted
with 15/92
Purple cap
imprinted with
VIVUS, Purple
body imprinted
with 3.75/23 andPurple cap
imprinted with
VIVUS, Yellow
body imprinted
with 7.5/46
Yellow cap
imprinted with
VIVUS, Yellow
body imprinted
with 11.25/69

Unit of Use Bottle (14 capsules)
Pharmacy Bottle (30 capsules)

62541-201-14
62541-201-30

Unit of Use Bottle (30 capsules)

62541-202-30

Pharmacy Bottle (30 capsules)

62541-203-30

Unit of Use Bottle (30 capsules)

62541-204-30

Starter Pack - Blister
Configuration (28 Capsules)

62541-210-28

Dose Escalation Pack – Blister
Configuration (28 Capsules)

62541-220-28

Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP
Controlled Room Temperature]. Keep container tightly closed and protect from moisture.

17

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Embryo-Fetal Toxicity
Inform patients who can become pregnant that QSYMIA can cause fetal harm and patients should avoid getting
pregnant while taking QSYMIA [see Warnings and Precautions (5.1), Drug Interactions (7), Use in Specific
Populations (8.3)].
Advise patients who can become pregnant:•that pregnancy testing is recommended before initiating QSYMIA and monthly during therapy;•

to use effective contraception during QSYMIA therapy;•

who experience spotting while taking a combined oral contraceptive to notify their healthcare provider;•with a known or suspected pregnancy to stop QSYMIA immediately and notify their healthcare
provider.

Access to QSYMIA
Advise patients that QSYMIA is only available through certified pharmacies that are enrolled in the QSYMIA
certified pharmacy network. Advise patients on how to access QSYMIA through certified pharmacies.
Additional information may be obtained via the website www.QSYMIAREMS.com or by telephone at 1-888998-4887.
Increase in Heart Rate
Inform patients that QSYMIA can increase resting heart rate. Advise patients to report palpitations or feelingsof a racing heartbeat while at rest to their healthcare provider(s) [see Warnings and Precautions (5.2)].
Suicidal Behavior and Ideation and Mood and Sleep Disorders
Inform patients that QSYMIA can increase the risk of mood changes, sleep disorders, depression, and suicidal
ideation. Advise patients to tell their healthcare provider(s) immediately if mood changes, depression, or
suicidal ideation occur [see Warnings and Precautions (5.3, 5.5)].
Ophthalmologic Adverse Reactions
Inform patients that QSYMIA can increase the risk of acute myopia, secondary angle closure glaucoma, andvisual field defects. Advise patients to immediately report symptoms of severe and persistent eye pain or
significant changes in their vision to their healthcare provider(s) [see Warnings and Precautions (5.4)].
Cognitive Impairment
Inform patients that QSYMIA can cause confusion, concentration, and word-finding difficulties. Informpatients that the concomitant use of alcohol or central nervous system (CNS) depressant drugs with QSYMIA,
may increase the risk of dizziness, cognitive adverse reactions, drowsiness, light-headedness, impaired
coordination and somnolence.
Advise patients to tell their healthcare provider(s) about any changes in attention, concentration, memory,difficulty finding words, or other cognitive functions.

Advise patients not to drive or operate machinery until they have gained sufficient experience on QSYMIA togauge whether it adversely affects their mental performance, motor performance, and/or vision. Advise patients
to avoid excessive alcohol intake while taking QSYMIA [see Warnings and Precautions (5.6)].
Slowing of Linear Growth
Discuss with the patient and caregiver that long-term QSYMIA treatment may attenuate growth as reflected byslower height increase in pediatric patients [see Warnings and Precautions (5.7)].
Metabolic Acidosis
Inform patients that QSYMIA can increase the risk of metabolic acidosis. Advise patients to tell their healthcare
provider(s) about any factors that can increase the risk of acidosis (e.g. prolonged diarrhea, surgery, and highprotein/low carbohydrate diet, and/or concomitant medications such as carbonic anhydrase inhibitors) [seeWarnings and Precautions (5.8)].
Risk of Hypoglycemia in Patients with Type 2 Diabetes Mellitus on Antidiabetic Therapy
Inform patients that weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus
treated with insulin and/or insulin secretagogues (e.g., sulfonylureas). Advise patients with type 2 diabetes
mellitus on antidiabetic therapy to monitor their blood glucose levels and report symptoms of hypoglycemia totheir healthcare provider(s) [see Warnings and Precautions (5.10)].
Risk of Hypotension in Patients Treated with Antihypertensive Medications
Advise patients that weight loss may increase the risk of hypotension. Advise patients to report symptoms ofhypotension (e.g., dizziness, lightheadedness, and syncope) to the healthcare provider [see Warnings andPrecautions (5.11)].
Risk of Seizures with Abrupt Withdrawal of QSYMIA
Inform patients that abrupt withdrawal of topiramate has been associated with seizures in individuals without ahistory of seizures or epilepsy. Advise patients not to abruptly stop QSYMIA without first talking to theirhealthcare provider(s) [see Dosage and Administration (2.4), Warnings and Precautions (5.12)].
Kidney Stones
Inform patients that use of QSYMIA has been associated with kidney stone formation. Advise patients toincrease fluid intake to increase urinary output which can decrease the concentration of substances involved in
kidney stone formation. Advise patients to report symptoms of severe side or back pain, and/or blood in theirurine to their healthcare provider(s) [see Warnings and Precautions (5.13) and Adverse Reactions (6.1)].
Oligohidrosis and Hyperthermia
Inform patients that oligohidrosis (decreased sweating) has been reported in association with the use of
topiramate particularly in pediatric patients. Advise patients to monitor for decreased sweating and increased
body temperature during physical activity, especially in hot weather [see Warnings and Precautions (5.14)].
Serious Skin Reactions
Inform patients that serious skin reactions have been reported with use of topiramate. Inform patients of thesigns of serious skin reactions and advise patients to report signs of a skin reaction to their healthcare
provider(s) [see Warning and Precautions (5.16)].
Lactation

Advise patients that breastfeeding is not recommended during QSYMIA treatment [see Use in Specific
Populations (8.2)].
Allergic Reactions Due to Inactive Ingredient FD&C Yellow No. 5
Inform patients that this product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type
reactions (including bronchial asthma) in certain susceptible persons [see Warnings and Precautions (5.17)].
How to Take QSYMIA
Instruct patients on the dosage titration schedule of QSYMIA. Advise patients to take QSYMIA in the morningwith or without food [see Dosage and Administration (2.3)].

Manufactured for VIVUS LLC by Catalent Pharma Solutions, LLC
1100 Enterprise Drive
Winchester, KY 40391
Copyright © 2012 - 2023 VIVUS LLC All rights reserved.
VIVUS LLC
900 E. Hamilton Ave., Suite 550
Campbell, CA 95008 USA

US Patent Numbers: 7,056,890; 7,553,818; 7,659,256; 7,674,776; 8,580,298; 8,580,299; 8,895,057; 8,895,058,
9,011,905; and 9,011,906
QSYMIA IS A REGISTERED TRADEMARK OF VIVUS LLC

MEDICATION GUIDEQSYMIA® (Kyoo sim ee uh)(phentermine and topiramate extended-release capsules)
for oral use, CIV
What is the most important information I should know about QSYMIA?
QSYMIA can cause serious side effects, including:• Birth defects. If you take QSYMIA during pregnancy, your baby has a higher risk for birth defects including cleft lip
and cleft palate. Your baby may also be smaller than expected at birth. The long-term effects of this are not known.
These defects can begin early in pregnancy, even before you know you are pregnant.
Patients who are pregnant must not take QSYMIA.
Patients who can become pregnant should:
1. Have a pregnancy test before taking QSYMIA and every month while taking QSYMIA.
2. Use effective birth control (contraception) consistently while taking QSYMIA. Talk to your healthcare provider
about how to prevent pregnancy.
If you become pregnant while taking QSYMIA, stop taking QSYMIA immediately and tell your healthcare
provider right away. Healthcare providers and patients who become pregnant should report all cases ofpregnancy to: FDA MedWatch at 1-800-FDA-1088
Because of the risk for birth defects (cleft lip and cleft palate), QSYMIA is available through a restricted
program called the QSYMIA Risk Evaluation and Mitigation Strategy (REMS). QSYMIA is only available
through certified pharmacies that participate in the QSYMIA REMS program. Your healthcare provider can give you
information about how to find a certified pharmacy. For more information, go to www.QSYMIAREMS.com or call 1888-998-4887.
•

Increases in heart rate. QSYMIA can increase your heart rate at rest. Your healthcare provider should check yourheart rate while you take QSYMIA. Tell your healthcare provider if you experience, while at rest, a racing or
pounding feeling in your chest lasting several minutes when taking QSYMIA.

•

Suicidal thoughts or actions. Topiramate, an ingredient in QSYMIA, may cause you to have suicidal thoughts or
actions.
Call your healthcare provider right away if you have any of these symptoms, especially if they are new,worse, or worry you:o thoughts about suicide or dyingo attempts to commit suicide
o new or worse depressiono new or worse anxiety
o feeling agitated or restlesso panic attacks
o trouble sleeping (insomnia)
o new or worse irritability
o acting aggressive, being angry, or violent
o acting on dangerous impulses
o an extreme increase in activity and talking (mania)o other unusual changes in behavior or mood
Do not stop QYSMIA without first talking to a healthcare provider.
• Stopping QYSMIA suddenly can cause serious problems.
• Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or
actions, your healthcare provider may check for other causes.
How can I watch for early symptoms of suicidal thoughts and actions?
• Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled.
• Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

•

Serious eye problems which include:o any sudden decrease in vision, with or without eye pain and redness,o a blockage of fluid in the eye causing increased pressure in the eye (secondary angle closure glaucoma).
These problems can lead to permanent vision loss if not treated. Tell your healthcare provider right away if
you have any new eye symptoms.

QSYMIA can have other serious side effects. See “What are the possible side effects of QSYMIA?”
What is QSYMIA?
• QSYMIA is a prescription medicine that contains phentermine and topiramate extended-release that may help
some adults and children 12 years and older with obesity, or some overweight adults who also have weight-related
medical problems lose weight and keep the weight off.
• QSYMIA should be used with a reduced calorie diet and increased physical activity.
• It is not known if QSYMIA changes your risk of heart problems or stroke or of death due to heart problems or
stroke.
• It is not known if QSYMIA is safe and effective when taken with other prescription and over-the-counter medicines,
or herbal weight loss products.
• It is not known if QSYMIA is safe and effective in children under 12 years old.
• QSYMIA is a federally controlled substance (CIV) because it contains phentermine and can be abused or lead todrug dependence. Keep QSYMIA in a safe place, to protect it from theft. Never give your QSYMIA to anyone else,
because it may cause death or harm them. Selling or giving away QSYMIA is against the law.
Who should not take QSYMIA? Do not take QSYMIA if you:• are pregnant, planning to become pregnant, or become pregnant during QSYMIA treatment.
• have glaucoma.
• have thyroid problems (hyperthyroidism).
• are taking certain medicines called monoamine oxidase inhibitors (MAOIs) or have taken MAOIs in the past 14
days.
• are allergic to topiramate, sympathomimetic amines such as phentermine, or any of the ingredients in QSYMIA.
See the end of this Medication Guide for a complete list of ingredients in QSYMIA.
Before taking QSYMIA, tell your healthcare provider about all of your medical conditions, including if you:• have had a heart attack or stroke.
• have or have had an abnormal heart rhythm.
• have or have had depression, mood problems, or suicidal thoughts or behavior.
• have eye problems, especially glaucoma. See “Who should not take QSYMIA?”• have a history of too much acid in the blood (metabolic acidosis) or a condition that puts you at higher risk formetabolic acidosis such aso chronic diarrhea, surgery, a diet high in fat and low in carbohydrates (ketogenic diet), weak, brittle, or softbones (osteoporosis, osteomalacia (rickets), osteopenia), or decreased bone density.
• have type 2 diabetes and take medicine to control your blood sugar.
• have kidney problems, kidney stones, or are getting kidney dialysis.
• have liver problems.
• have seizures or convulsions (epilepsy).
• are breastfeeding or plan to breastfeed. QSYMIA can pass into your breast milk and may harm your baby. You andyour healthcare provider should decide if you will take QSYMIA or breastfeed. You should not do both.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements. QSYMIA taken with other medicines may affect how each medicine
works and may cause side effects.
Especially tell your healthcare provider if you take:• Birth control pills. Tell your healthcare provider if your menstrual bleeding changes while you are taking birthcontrol pills that contain both estrogen and progestin (combination oral contraceptives) and QSYMIA.
• Water pills (diuretics) such as hydrochlorothiazide (HCTZ).
• Any medicines that impair or decrease your thinking, concentration, or muscle coordination.
• Carbonic anhydrase inhibitors such as ZONEGRAN (zonisamide), DIAMOX (acetazolamide) or NEPTAZANE(methazolamide).
• Seizure medicines such as Valproic acid (DEPAKENE or DEPAKOTE).
Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time you get a
new medicine. Do not start a new medicine without talking to your healthcare provider.
How should I take QSYMIA?
• Your healthcare provider should start you on a diet and exercise program when you start taking QSYMIA. Stay on
this program while you are taking QSYMIA.
• Take QSYMIA exactly as your healthcare provider tells you to take it.
• Do not change your dose without talking to your healthcare provider.
• Take QSYMIA daily in the morning.
• QSYMIA can be taken with or without food.

•
•

•

•

•

If you miss a dose of QSYMIA, wait until the next morning to take your usual dose of QSYMIA. Do not double yourdose.
To start treatment with QSYMIAo Take 1 QSYMIA 3.75 mg/23 mg capsule (Figure A) 1 time each morning for the first 14 days.
o After taking QSYMIA 3.75 mg/23 mg capsule for 14 days, then take 1 QSYMIA 7.5 mg/46 mg capsule (FigureB) 1 time each morning.
After taking QSYMIA for 12 weeks
o Your healthcare provider may tell you to increase your dose of QSYMIA if you do not lose a certain amount ofweight or do not have a certain decrease in BMI for children 12 years and older, within the first 12 weeks oftreatment at the recommended dose.
If your healthcare provider increases the dose of QSYMIAo Take 1 QSYMIA 11.25 mg/69 mg capsule (Figure C) 1 time each morning for 14 days.
o After taking 14 days of QSYMIA 11.25 mg/69 mg capsule, then take 1 QSYMIA 15 mg/92 mg capsule (FigureD) 1 time each morning.
Stopping QSYMIA treatment
Your healthcare provider should tell you to stop taking QSYMIA if you have not lost a certain amount of weight or
do not have a certain decrease in BMI for children 12 years and older, after an additional 12 weeks of treatment on
the higher dose.
Do not stop taking QSYMIA without talking to your healthcare provider. Stopping QSYMIA suddenly can cause
serious problems, such as seizures. Your healthcare provider will tell you how to stop taking QSYMIA slowly.

If you take too much QSYMIA, call your healthcare provider or go to the nearest emergency room right away.
What should I avoid while taking QSYMIA?
• Do not get pregnant while taking QSYMIA. See “What is the most important information I should know about
QSYMIA.”• Do not drink too much alcohol while taking QSYMIA. QSYMIA and alcohol can affect each other causing side
effects such as sleepiness or dizziness.
• Do not drive a car, operate heavy machinery, or do other dangerous activities until you know how QSYMIA
affects you. QSYMIA can slow your thinking and motor skills and may affect vision.
What are the possible side effects of QSYMIA?
QSYMIA can cause serious side effects, including:• See “What is the most important information I should know about QSYMIA?”• Mood changes and trouble sleeping. QSYMIA may cause depression or mood problems, and trouble sleeping.
Tell your healthcare provider if symptoms occur.
• Concentration, memory, and speech difficulties. QSYMIA may affect how you think and cause confusion,
problems with concentration, attention, memory, or speech. Tell your healthcare provider if symptoms occur.
• Slowing of growth. QSYMIA may slow the increase in height in children 12 years and older, when used for a longtime.
• Increases of acid in bloodstream (metabolic acidosis). If left untreated, metabolic acidosis can cause brittle orsoft bones (osteoporosis, osteomalacia (rickets), osteopenia), kidney stones, can slow the rate of growth inchildren, and may possibly harm your baby if you are pregnant. Metabolic acidosis can happen with or without
symptoms. Sometimes people with metabolic acidosis will:o feel tired
o not feel hungry (loss of appetite)o feel changes in heartbeato have trouble thinking clearly

Your healthcare provider should do a blood test to measure the level of acid in your blood before and during yourtreatment with QSYMIA.
• Decrease in kidney function. QSYMIA may cause a decrease in kidney function. Your healthcare provider should
do a blood test to measure your kidney function before and during treatment with QSYMIA.
• Low blood sugar (hypoglycemia) in people with type 2 diabetes mellitus who also take medicines used totreat type 2 diabetes mellitus. Weight loss can cause low blood sugar in people with type 2 diabetes mellitus who
also take medicines used to treat type 2 diabetes mellitus (such as insulin or sulfonylureas). You should check yourblood sugar before you start taking QSYMIA and while you take QSYMIA.
• Low blood pressure (hypotension) in people who take high blood pressure medicines. Weight loss cancause low blood pressure in people who take medicines to treat high blood pressure. Call your healthcare provider
if you have symptoms of low blood pressure such as dizziness, feeling lightheaded, and fainting during treatment
with QSYMIA. Your healthcare provider should check your blood pressure before you start taking QSYMIA andwhile you take QSYMIA.
• Possible seizures if you stop taking QSYMIA too fast. Seizures may happen in people who may or may nothave had seizures in the past if you stop QSYMIA too fast. Your healthcare provider will tell you how to stop taking
QSYMIA slowly.
• Kidney stones. Drink plenty of fluids when taking QSYMIA to help decrease your chances of getting kidneystones. If you get severe side or back pain, or blood in your urine, call your healthcare provider.
• Decreased sweating and increased body temperature (fever). People should be watched for signs ofdecreased sweating and fever, especially in hot temperatures. Some people may need to be hospitalized for thiscondition.
• Low potassium. QSYMIA can increase your risk of low potassium levels. Your healthcare provider should do ablood test to measure the level of potassium in your blood before and during treatment with QSYMIA.
• Serious skin reactions. QSYMIA may cause a severe rash with blisters and peeling skin, especially around themouth, nose, eyes, and genitals (Stevens-Johnson Syndrome). QSYMIA may also cause a rash with blisters andpeeling skin over much of the body that may cause death (Toxic Epidermal Necrolysis). Call your healthcare
provider right away if you develop a skin rash or blisters.
• Allergic reaction to FD&C Yellow No. 5. QSYMIA capsules contain the inactive ingredient FD&C Yellow No. 5(tartrazine) which can cause allergic-type reactions (including bronchial asthma) in certain people, especiallypeople who also have an allergy to aspirin.
Common side effects of QSYMIA in adults include:• numbness or tingling in the hands, arms, feet, or face (paraesthesia)• dizziness• change in the way foods taste or loss of taste (dysgeusia)• trouble sleeping (insomnia)• constipation• dry mouth
Common side effects of QSYMIA in children 12 years and older include:• depression• dizziness• joint pain
• fever• flu• ankle sprain
Tell your healthcare provider if you have any side effect that bothers you or does not go away.
These are not all of the possible side effects of QSYMIA. For more information, ask your healthcare provider or
pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
You can also report side effects to VIVUS at 1-888-998-4887.
How should I store QSYMIA?
• Store QSYMIA at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep QSYMIA in a tightly closed container.
• Keep QSYMIA dry and away from moisture.
Keep QSYMIA and all medicines out of the reach of children.
General Information about the safe and effective use of QSYMIA.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use QSYMIA
for a condition for which it was not prescribed. Do not give QSYMIA to other people, even if they have the same
symptoms you have. It may harm them.
You can ask your pharmacist or healthcare provider for information about QSYMIA that is written for healthprofessionals.

What are the ingredients in QSYMIA?
Active Ingredient: phentermine hydrochloride and topiramate extended-release.
Inactive Ingredients: FD&C Blue #1, FD&C Red #3, FD&C Yellow #5 and #6, ethylcellulose, gelatin, methylcellulose,
microcrystalline cellulose, povidone, starch, sucrose, talc, titanium dioxide, and pharmaceutical black and white inks.
Copyright © 2012 - 2023 VIVUS LLC All rights reserved.
VIVUS LLC
900 E. Hamilton Ave., Suite 550
Campbell, CA 95008 USA

US Patent Numbers: 7,056,890; 7,553,818; 7,659,256; 7,674,776; 8,580,298; 8,580,299; 8,895,057; 8,895,058; 9,011,905; and 9,011,906.
QSYMIA is a registered trademark of VIVUS LLC.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
PH-03-002-14

Revised: 06/2023