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.

2.1 Patient Selection

2.2 Recommended Testing Prior to and During Treatment with QSYMIA

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

• Obtain a negative pregnancy test before initiating QSYMIA in patients who can become pregnant and monthly during QSYMIA therapy. QSYMIA is contraindicated during pregnancy [see Contraindications (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, and glucose 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)].

2.3 Recommended Dosage and Administration

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

• 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% of baseline 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% of baseline 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 will achieve 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.

2.4 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 for at least 1 week prior to stopping treatment altogether, due to the possibility of precipitating a seizure [see Warnings 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 or equal 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 and Precautions (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 with moderate 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 same as the recommended dosage in patients with normal hepatic function [see Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)] .

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)] .

5.2 Increase in Heart Rate

QSYMIA can cause an increase in resting heart rate. A higher percentage of QSYMIA-treated adults and pediatric 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 clinical significance 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 been studied in patients with recent or unstable cardiac or cerebrovascular disease and therefore use is not recommended.

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 patients taking 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 case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in AED-treated patients in 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 consistent among 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-treated patients 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

5.5 Mood and Sleep Disorders

QSYMIA can cause mood disorders, including depression and anxiety, as well as insomnia. Patients with a history 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 and Precautions (5.3)] .

5.6 Cognitive Impairment

QSYMIA can cause cognitive dysfunction (e.g., impairment of concentration/attention, difficulty with memory, and speech or language problems, particularly word-finding difficulties). Rapid titration or high initial 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 or central nervous system (CNS) depressant drugs with QSYMIA may potentiate CNS depression or other centrally mediated effects of these agents, such as dizziness, cognitive adverse reactions, drowsiness, light-headedness, 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 and Precautions (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 both QSYMIA- 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 treated with 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 and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased 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, status epilepticus, 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 with another carbonic anhydrase inhibitor is unavoidable, the patient should be monitored for the appearance or worsening 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 Function

QSYMIA 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 of treatment. 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 not known.

Measure serum creatinine prior to starting QSYMIA and during QSYMIA treatment. If persistent elevations in creatinine 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 of insulin and/or insulin secretagogues. If a patient develops hypoglycemia after starting QSYMIA, appropriate changes 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 of hypotension and associated symptoms including dizziness, lightheadedness, and syncope. Measure blood pressure 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 to reduce 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 and increasing 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 the risk 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 of substances 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 elevated environmental temperatures.

The majority of the reports associated with topiramate have been in pediatric patients. Advise all patients and caregivers 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 been reported in patients receiving topiramate. QSYMIA should be discontinued at the first sign of a rash, unless the rash 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.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The data described herein reflects exposure to QSYMIA in two 1-year, randomized, double-blind, placebo-controlled, 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/m 2) 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)] .

6.2 Postmarketing Experience

The following adverse reactions have been reported during post approval use of QSYMIA, phentermine, and topiramate. 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.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

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, a pharmacokinetic 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 patients treated with QSYMIA versus placebo reported adverse reactions related to mood (e.g., depression, anxiety) and sleep disorders (e.g., insomnia) [see Warnings and Precautions (5.5)] . Increases in bone mineral density and linear 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 and less 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 this patient 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 to phentermine 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 same as 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)] .

9.1 Controlled Substance

QSYMIA 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 abuse prior 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 and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

The following adverse reactions have been associated with the abrupt discontinuation of the individual components 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 the possibility of precipitating a seizure [see Dosage and Administration (2.4)] .

Phentermine Hydrochloride

The chemical name of phentermine hydrochloride is α,α-dimethylphenethylamine hydrochloride. The molecular formula is C 10H 15N ∙ 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:

Topiramate

Topiramate is 2,3:4,5-di-O-isopropylidene-β-D-fructopyranose sulfamate. The molecular formula is C 12H 21NO 8S and its molecular weight is 339.4. Topiramate is a white to off-white crystalline powder with a bitter 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:

QSYMIA

QSYMIA (phentermine and topiramate extended-release capsules) is for oral administration and available in four 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.

12.1 Mechanism of Action

Phentermine is a sympathomimetic amine with pharmacologic activity similar to the prototype drugs of this class 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 food consumption, 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 the neurotransmitter 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.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Clinical Studies in Adults

The effect of QSYMIA on weight loss in conjunction with reduced caloric intake and increased physical activity 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). Both studies 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/m 2) were randomized to receive 1 year of treatment 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 the study the average weight and BMI of patients was 116 kg and 42 kg/m 2, respectively. Patients with type 2 diabetes were excluded from participating in Study 1. 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 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/m 2and less than or equal to 45 kg/m 2(there was no lower limit on BMI for patients with type 2 diabetes) and two or more of the following obesity-related co-morbid 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 of patients at the start of the study was 103 kg and 36.6 kg/m 2, 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 the study. 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 offered nutritional and lifestyle modification 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 with QSYMIA, all dose levels resulted in statistically significant weight loss compared to placebo (see Table 11, Figure 1and Figure 2). A statistically significant greater proportion of the patients randomized to QSYMIA than placebo achieved 5% and 10% weight loss.

	Figure 1. Study 1 Percent Weight Change from Baseline to Week 56 in Adults with Obesity		Figure 2. Study 2 Percent Weight Change from Baseline to Week 56 in Adults with Obesity or Overweight with Co-morbidities

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 [see Warnings and Precautions (5.2)] .

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 was evaluated in Study 3 (NCT 03922945), a 56-week, randomized, double-blind, placebo-controlled study in pediatric patients (12 to 17 years of age) with BMI ≥ 95 thpercentile standardized by age and sex. Patients were randomized 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 offered a 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 of patients was 106 kg and 38 kg/m 2, respectively, with approximately 81% considered severely obese (120% of the 95 thpercentile 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 statistically significant reduction in BMI compared to placebo (see Table 14, Figure 3). A greater proportion of patients randomized to QSYMIA than placebo achieved 5%, 10%, and 15% BMI reduction.

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.

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 1-888-998-4887.

Increase in Heart Rate

Inform patients that QSYMIA can increase resting heart rate. Advise patients to report palpitations or feelings of 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, and visual 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. Inform patients 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 to gauge 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 by slower 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 high protein/low carbohydrate diet, and/or concomitant medications such as carbonic anhydrase inhibitors) [see Warnings 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 to their 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 of hypotension (e.g., dizziness, lightheadedness, and syncope) to the healthcare provider [see Warnings and Precautions (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 a history of seizures or epilepsy. Advise patients not to abruptly stop QSYMIA without first talking to their healthcare 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 to increase 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 their urine 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 the signs 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 morning with or without food [see Dosage and Administration (2.3)] .