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 and over-the-counter drugs and herbal preparations have not been established.

2.1 General Dosing and Administration

Determine the patient's BMI. BMI is calculated by dividing weight (in kilograms) by height (in meters) squared. A BMI conversion chart (Table 1) based on height [inches (in) or centimeters (cm)] and weight [pounds (lb) or kilograms (kg)] is provided below.

Table 1. BMI Conversion Chart

In adults with an initial BMI of 30 kg/m2 or greater or 27 kg/m2 or greater when accompanied by weight-related co-morbidities such as hypertension, type 2 diabetes mellitus, or dyslipidemia prescribe Qsymia as follows:

• Take Qsymia once daily in the morning with or without food. Avoid dosing with Qsymia in the evening due to the possibility of insomnia.
• Start treatment with Qsymia 3.75 mg/23 mg (phentermine 3.75 mg/topiramate 23 mg extended-release) daily for 14 days; after 14 days increase to the recommended dose of Qsymia 7.5 mg/46 mg (phentermine 7.5 mg/topiramate 46 mg extended-release) once daily.
• Evaluate weight loss after 12 weeks of treatment with Qsymia 7.5 mg/46 mg.
  If a patient has not lost at least 3% of baseline body weight on Qsymia 7.5 mg/46 mg, discontinue Qsymia or escalate the dose, as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss at the Qsymia 7.5 mg/46 mg dose.
  To escalate the dose: Increase to Qsymia 11.25 mg/69 mg (phentermine 11.25 mg/topiramate 69 mg extended-release) daily for 14 days; followed by dosing Qsymia 15 mg/92 mg (phentermine 15 mg/topiramate 92 mg extended-release) once daily.
• Evaluate weight loss following dose escalation to Qsymia 15 mg/92 mg after an additional 12 weeks of treatment.
  If a patient has not lost at least 5% of baseline body weight on Qsymia 15 mg/92 mg, discontinue Qsymia as directed, as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.
• Qsymia 3.75 mg/23 mg and Qsymia 11.25 mg/69 mg are for titration purposes only.

2.2 Dosing in Patients with Renal Impairment

In patients with moderate (creatinine clearance [CrCl] greater than or equal to 30 and less than 50 mL/min) or severe (CrCl less than 30 mL/min) renal impairment dosing should not exceed Qsymia 7.5 mg/46 mg once daily. Renal impairment is determined by calculating CrCl using the Cockcroft-Gault equation with actual body weight [see Warnings and Precautions (5.13) and Clinical Pharmacology (12.3)].

2.3 Dosing in Patients with Hepatic Impairment

In patients with moderate hepatic impairment (Child-Pugh score 7 - 9), dosing should not exceed Qsymia 7.5 mg/46 mg once daily [see Warnings and Precautions (5.14) and Clinical Pharmacology (12.3)].

5.1 Fetal Toxicity

Qsymia can cause fetal harm. Data from pregnancy registries and epidemiology studies indicate that a fetus exposed to topiramate, a component of Qsymia, in the first trimester of pregnancy has an increased risk of oral clefts (cleft lip with or without cleft palate). If Qsymia is used during pregnancy or if a patient becomes pregnant while taking Qsymia, treatment should be discontinued immediately, and the patient should be apprised of the potential hazard to a fetus. Females of reproductive potential should have a negative pregnancy test before starting Qsymia and monthly thereafter during Qsymia therapy. Females of reproductive potential should use effective contraception during Qsymia therapy [see Use in Specific Populations (8.1) and (8.6)] .

5.2 Increase in Heart Rate

Qsymia can cause an increase in resting heart rate.

A higher percentage of Qsymia-treated overweight and obese adults experienced heart rate increases from baseline of more than 5, 10, 15, and 20 beats per minute (bpm) compared to placebo-treated overweight and obese adults. Table 2 provides the numbers and percentages of patients with elevations in heart rate in clinical studies of up to one year.

The clinical significance of a heart rate elevation with Qsymia treatment is unclear, especially for patients with cardiac and cerebrovascular disease (such as patients with a history of myocardial infarction or stroke in the previous 6 months, life-threatening arrhythmias, or congestive heart failure).

Regular measurement of resting heart rate is recommended for all patients taking Qsymia, especially patients with cardiac or cerebrovascular disease or when initiating or increasing the dose of Qsymia. Qsymia has not been studied in patients with recent or unstable cardiac or cerebrovascular disease and therefore use is not recommended.

Patients should inform healthcare providers 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, the dose should be reduced or Qsymia discontinued.

5.3 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including topiramate, a component of Qsymia, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with Qsymia should be monitored 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.

Avoid Qsymia in patients with a history of suicidal attempts or active suicidal ideation.

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% Confidence Interval [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 (5 to 100 years) in the clinical trials analyzed.

5.4 Acute Myopia and Secondary Angle Closure Glaucoma

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients treated with topiramate, a component of Qsymia. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness), and increased intraocular pressure. Mydriasis may or may not be present. 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 1 month of initiating treatment with topiramate but may occur at any time during therapy. The primary treatment to reverse symptoms is immediate discontinuation of Qsymia. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious adverse events including permanent loss of vision.

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. The majority of these mood and sleep disorders resolved spontaneously, or resolved upon discontinuation of dosing [see Adverse Reactions (6.1)].

For clinically significant or persistent symptoms consider dose reduction or withdrawal of Qsymia. If patients have symptoms of suicidal ideation or behavior, discontinue Qsymia.

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)] .

Since Qsymia has the potential to impair cognitive function, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain Qsymia therapy does not affect them adversely. If cognitive dysfunction persists consider dose reduction or withdrawal of Qsymia for symptoms that are moderate to severe, bothersome, or those which fail to resolve with dose reduction.

5.7 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)].

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 topiramate. Concomitant use of Qsymia and a carbonic anhydrase inhibitor (e.g., zonisamide, acetazolamide, or dichlorphenamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, if Qsymia is given concomitantly with another carbonic anhydrase inhibitor to a patient with a predisposing condition for metabolic acidosis the patient should be monitored for the appearance or worsening of metabolic acidosis.

Some 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. The effect of Qsymia on growth and bone-related sequelae has not been systematically investigated in long-term, placebo-controlled trials.

Measurement of electrolytes including serum bicarbonate prior to starting Qsymia and during Qsymia treatment is recommended. In Qsymia clinical trials, the peak reduction in serum bicarbonate occurred by week 4, and in most subjects there was a correction of bicarbonate by week 56, without any change to study drug. However, if persistent metabolic acidosis develops while taking Qsymia, reduce the dose or discontinue Qsymia.

5.8 Elevation in Creatinine

Qsymia can cause an increase in serum creatinine that reflects a decrease in renal function (glomerular filtration rate). In phase 3 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 Qsymia treatment appear reversible with treatment discontinuation, but the effect of chronic treatment on renal function is not known. Therefore, measurement of serum creatinine prior to starting Qsymia and during Qsymia treatment is recommended. If persistent elevations in creatinine occur while taking Qsymia, reduce the dose or discontinue Qsymia [see Adverse Reactions (6.1), Pharmacodynamics (12.2)].

5.9 Potential Risk of Hypoglycemia in Patients with Type 2 Diabetes Mellitus on Anti-Diabetic 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. Measurement of blood glucose levels prior to starting Qsymia and during Qsymia treatment is recommended in patients with type 2 diabetes. Decreases in medication doses for antidiabetic medications which are non-glucose-dependent should be considered to mitigate the risk of hypoglycemia. If a patient develops hypoglycemia after starting Qsymia, appropriate changes should be made to the antidiabetic drug regimen.

5.10 Potential 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. Measurement of blood pressure prior to starting Qsymia and during Qsymia treatment is recommended 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.

5.11 CNS Depression with Concomitant CNS Depressants Including Alcohol

The concomitant use of alcohol or central nervous system (CNS) depressant drugs (e.g., barbiturates, benzodiazepines, and sleep medications) with phentermine or topiramate 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. Therefore, avoid concomitant use of alcohol with Qsymia.

5.12 Potential Seizures with Abrupt Withdrawal of Qsymia

Abrupt withdrawal of topiramate, a component of Qsymia, 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 as recommended to reduce the possibility of precipitating a seizure [see Dosage and Administration (2.1)] .

5.13 Patients with Renal Impairment

Phentermine and topiramate, the components of Qsymia, are cleared by renal excretion. Therefore, exposure to phentermine and topiramate is higher in patients with moderate (creatinine clearance [CrCl] greater than or equal to 30 and less than 50 mL/min) or severe (CrCl less than 30 mL/min) renal impairment. Adjust dose of Qsymia for both patient populations.

Qsymia has not been studied in patients with end-stage renal disease on dialysis. Avoid use of Qsymia in this patient population [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)] .

5.14 Patients with Hepatic Impairment

In patients with mild (Child-Pugh score 5 - 6) or moderate (Child-Pugh score 7 - 9) hepatic impairment, exposure to phentermine was higher compared to healthy volunteers. Adjust dose of Qsymia for patients with moderate hepatic impairment.

Qsymia has not been studied in patients with severe hepatic impairment (Child-Pugh score 10 - 15). Avoid use of Qsymia in this patient population [see Dosage and Administration (2.3), and Clinical Pharmacology (12.3)].

5.15 Kidney Stones

Use of Qsymia has been associated with kidney stone formation. Topiramate, a component of Qsymia, inhibits carbonic anhydrase activity and promotes kidney stone formation by reducing urinary citrate excretion and increasing urine pH.

Avoid the use of Qsymia with other drugs that inhibit carbonic anhydrase (e.g., zonisamide, acetazolamide, or methazolamide).

Use of topiramate by patients on a ketogenic diet may also result in a physiological environment that increases the likelihood of kidney stone formation.

Increase fluid intake to increase urinary output which can decrease the concentration of substances involved in kidney stone formation [see Adverse Reactions (6.1)].

5.16 Oligohidrosis and Hyperthermia

Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with the use of topiramate, a component of Qsymia. 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.

Patients treated with Qsymia should be advised to monitor for decreased sweating and increased body temperature during physical activity, especially in hot weather. Caution should be used when Qsymia is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity.

5.17 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 such as furosemide (loop diuretic) or hydrochlorothiazide (thiazide-like diuretic) this may further potentiate potassium-wasting. When prescribing Qsymia, patients should be monitored for hypokalemia [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)] .

5.18 Monitoring: Laboratory Tests

Qsymia was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies.

Obtain a blood chemistry profile that includes bicarbonate, creatinine, potassium, and glucose at baseline and periodically during treatment [s ee Warnings and Precautions (5.7), (5.8), (5.9), and (5.17)].

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 Phase 2 supportive trials in 2318 adult patients (936 [40.4%] patients with hypertension, 309 [13.3%] patients with type 2 diabetes, 808 [34.9%] patients with BMI greater than 40 kg/m 2) exposed for a mean duration of 298 days.

6.2 Postmarketing Experience

The following adverse reactions have been reported during post approval use of phentermine and topiramate, the components of Qsymia. 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 Disorders
• Suicidal ideation, Suicidal behavior

• Ophthalmic disorders

• Acute angle closure glaucoma
  Increased intraocular pressure

Phentermine

• Allergic adverse reactions
• Urticaria
• Cardiovascular adverse reactions
• Elevation of blood pressure, Ischemic events
• Central nervous system adverse reactions
• Euphoria, Psychosis, Tremor
• Reproductive adverse reactions
• Changes in libido, Impotence

Topiramate

• Dermatologic disorders
• Bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), Pemphigus
• Gastrointestinal disorders
• Pancreatitis
• Hepatic disorders
• Hepatic failure (including fatalities), Hepatitis
• Metabolic disorders
• Hyperammonemia
• Hypothermia
• Ophthalmic disorders
• Maculopathy

7.1 Monoamine Oxidase Inhibitors

Use of phentermine is contraindicated during or within 14 days following the administration of monoamine oxidase inhibitors because of the risk of hypertensive crisis.

7.2 Oral Contraceptives

Co-administration of multiple-dose Qsymia 15 mg/92 mg once daily with a single dose of 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 study did not specifically address the impact of the interaction on contraceptive efficacy, an increased risk of pregnancy is not anticipated. The primary determinant of contraceptive efficacy is the progestin component of the combination oral contraceptive, so higher exposure to the progestin would not be expected to be deleterious.

However, 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. Patients should be informed not to discontinue their combination oral contraceptive if spotting occurs, but to notify their healthcare provider if the spotting is troubling to them.

7.3 CNS Depressants Including Alcohol

Specific drug interaction studies of Qsymia and alcohol or other CNS depressant drugs have not been performed. 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. Therefore, if Qsymia is used with alcohol or other CNS depressants, the patient should be counseled regarding possible increased risk of CNS depression or side effects.

7.4 Non-Potassium Sparing Diuretics

Concurrent use of Qsymia with non-potassium sparing diuretics may potentiate the potassium-wasting action of these diuretics. Concomitant administration of hydrochlorothiazide alone with topiramate alone has been shown to increase the C max and AUC of topiramate by 27% and 29%, respectively. When prescribing Qsymia in the presence of non-potassium-sparing medicinal products, patients should be monitored for hypokalemia [see Warnings and Precautions (5.17) and Clinical Pharmacology (12.3)] .

7.5 Antiepileptic Drugs

Concomitant administration of phenytoin or carbamazepine with topiramate in patients with 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 associated with hyperammonemia with and without encephalopathy. Concomitant administration of topiramate with valproic acid in patients has also been associated with hypothermia (with and without hyperammonemia). It may be prudent to examine blood ammonia in patients in whom the onset of hypothermia or encephalopathy has been reported [see Clinical Pharmacology (12.3)] .

7.6 Carbonic Anhydrase Inhibitors

Concomitant use of topiramate, a component of Qsymia, with any other carbonic anhydrase inhibitor (e.g., zonisamide, acetazolamide, or dichlorphenamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Avoid the use of Qsymia with other drugs that inhibit carbonic anhydrase [see Warnings and Precautions (5.7)] .

7.7 Pioglitazone

A decrease in the exposure of pioglitazone and its active metabolites were noted with the concurrent use of pioglitazone and topiramate in a clinical trial. The clinical relevance of these observations is unknown; however, when Qsymia is added to pioglitazone therapy or pioglitazone is added to Qsymia therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state [see Clinical Pharmacology (12.3)] .

8.1 Pregnancy

8.2 Labor and Delivery

The effect of Qsymia on labor and delivery in humans is unknown. The development of Qsymia-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus's ability to tolerate labor.

8.3 Nursing Mothers

Qsymia may be present in human milk because topiramate and amphetamines (phentermine has pharmacologic activity and a chemical structure similar to amphetamines) are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness of Qsymia in pediatric patients below the age of 18 years have not been established and the use of Qsymia is not recommended in pediatric patients. Serious adverse reactions seen in pediatric patients using topiramate, a component of Qsymia, include acute angle glaucoma, oligohidrosis and hyperthermia, metabolic acidosis, cognitive and neuropsychiatric reactions, hyperammonemia and encephalopathy, and kidney stones.

8.5 Geriatric Use

In the Qsymia clinical trials, a total of 254 (7%) of the patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

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 Females of Reproductive Potential

Qsymia can cause fetal harm. Data from pregnancy registries and epidemiology studies indicate that a fetus exposed to topiramate, a component of Qsymia, in the first trimester of pregnancy has an increased risk of oral clefts (cleft lip with or without cleft palate).

Females who become pregnant during Qsymia therapy should stop Qsymia treatment immediately and notify their healthcare provider.

8.7 Renal Impairment

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

No dose adjustments are necessary in patients with mild renal impairment. 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 dose should not exceed 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 (2.2) and Clinical Pharmacology (12.3)] .

8.8 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. Exposure to topiramate, a component of Qsymia, was similar among patients with mild and moderate hepatic impairment and healthy volunteers.

No dose adjustments are necessary in patients with mild hepatic impairment. In patients with moderate hepatic impairment, the dose should not exceed 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 (2.3) and Clinical Pharmacology (12.3)] .

9.1 Controlled Substance

Qsymia is controlled in Schedule IV of the Controlled Substances Act because it contains phentermine a Schedule IV drug. Any material, compound, mixture, or preparation that contains any quantity of phentermine is controlled as a Schedule IV drug.

Topiramate is not controlled in the Controlled Substances Act.

9.2 Abuse

Phentermine, a component of Qsymia, has a known potential for abuse.

Phentermine, a component of Qsymia, is related chemically and pharmacologically to the amphetamines. Amphetamines and other stimulant drugs have been extensively abused and the possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including Qsymia as part of a weight reduction program. 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 than recommended.

9.3 Dependence

Qsymia has not been systematically studied for its potential to produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use. Physical dependence manifests by drug-class-specific withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Limited information on the potential for physical dependence for the individual components of Qsymia is available. For topiramate, abrupt discontinuation has been associated with seizures in patients without a history of seizures or epilepsy. For phentermine, abrupt cessation 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.

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 is available in four dosage strengths:

• Qsymia 3.75 mg/23 mg (phentermine 3.75 mg and topiramate 23 mg extended-release) capsules;
• Qsymia 7.5 mg/46 mg (phentermine 7.5 mg and topiramate 46 mg extended-release) capsules;
• Qsymia 11.25 mg/69 mg (phentermine 11.25 mg and topiramate 69 mg extended-release) capsules;
• Qsymia 15 mg/92 mg (phentermine 15 mg and topiramate 92 mg extended-release) capsules.

Each capsule contains the following inactive ingredients: methylcellulose, sucrose, starch, microcrystalline cellulose, ethylcellulose, povidone, gelatin, talc, titanium dioxide, FD&C Blue #1, FD&C Red #3, FD&C Yellow #5 and #6, 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 all drugs of this class in which these phenomena have been looked for.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.3 Reproductive and Developmental Toxicology

Store at controlled room temperature, 15°C to 25°C (59°F to 77°F). Keep container tightly closed and protect from moisture.

Adjunctive Treatment

Qsymia is indicated for chronic weight management in conjunction with a reduced-calorie diet and increased physical activity.

Access to Qsymia

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 .

Concomitant Use with Other Products

Advise patients to tell healthcare provider(s) about all medications, nutritional supplements, and vitamins (including any weight loss products) that are being taken or may be taken while on Qsymia.

How to take Qsymia

Advise patients to take Qsymia in the morning with or without food.

Advise patients to start treatment with Qsymia as follows:

• Take one Qsymia 3.75 mg/23 mg capsule once daily – in the morning - for the first 14 days
• After the first 14 days is complete, take one Qsymia 7.5 mg/46 mg capsule once daily – in the morning
• Do not take Qsymia 3.75 mg/23 mg and Qsymia 7.5/46 mg capsules together

If an increase in Qsymia dose is prescribed after medical evaluation, advise patients to increase the dose of Qsymia as follows:

• Take one Qsymia 11.25 mg/69 mg capsule once daily – in the morning - for 14 days
• After the 14 days is complete, take one Qsymia 15 mg/92 mg capsule once daily – in the morning
• Do not take Qsymia 11.25/69 mg and Qsymia 15 mg/92 mg capsules together

Advise patients to discontinue the Qsymia 15 mg/92 mg dose gradually by taking one Qsymia 15 mg/92 mg capsule every other day for at least one week before stopping in order to avoid a seizure.

Females of Reproductive Potential

Qsymia can cause fetal harm and patients should avoid getting pregnant while taking Qsymia [see Warnings and Precautions (5.1)]

• Pregnancy testing is recommended before starting Qsymia and monthly thereafter during therapy.
• Advise patients about effective methods of contraception, as well as the importance of using effective contraception consistently during Qsymia therapy. Advise females who become pregnant during Qsymia therapy to stop Qsymia immediately and tell their healthcare provider(s).

Nursing Mothers

Either discontinue nursing or discontinue Qsymia [see Use in Specific Populations (8.3)].

Elevation in Heart Rate

• Qsymia can increase resting heart rate [see Warnings and Precautions (5.2)].
• Advise patients to report symptoms of sustained periods of heart pounding or racing while at rest to their health care provider(s).

Suicidal Behavior and Ideation; Changes in Mood or Depression

Qsymia can increase the risk of mood changes, depression, and suicidal ideation [see Warnings and Precautions (5.5)].

• Advise patients to tell their healthcare provider(s) immediately if mood changes, depression, and suicidal ideation occur.

Acute Angle Closure Glaucoma

Qsymia can increase the risk of acute myopia and secondary angle closure glaucoma [see Warnings and Precautions (5.4)] .

• Advise patients to report symptoms of severe and persistent eye pain or significant changes in their vision to their healthcare provider(s).

Cognitive Adverse Reactions

Qsymia can cause dizziness, confusion, concentration, and word-finding difficulties, or visual changes [see Warnings and Precautions (5.6)] .

• Advise patients to tell their healthcare provider(s) about any changes in attention, concentration, memory, and/or difficulty finding words.
• 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.

Metabolic Acidosis

Qsymia can increase the risk of metabolic acidosis [see Warnings and Precautions (5.7)].

• 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).

Hypoglycemia in Patients with Type 2 Diabetes Mellitus on Anti-diabetic 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) [see Warnings and Precautions (5.9)] .

• Advise patients with type 2 diabetes mellitus on anti-diabetic therapy to monitor their blood glucose levels and report symptoms of hypoglycemia to their healthcare provider(s)

CNS Depression with Concomitant CNS Depressants including Alcohol

The concomitant use of alcohol or central nervous system (CNS) depressant drugs (e.g., barbiturates, benzodiazepines, and sleep medications) with phentermine or topiramate 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 [see Warnings and Precautions (5.11)] .

• Advise patients not to drink alcohol while taking Qsymia.

Potential Seizures with Abrupt Withdrawal of Qsymia

Abrupt withdrawal of topiramate, a component of Qsymia, 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 (2.1)]

Kidney stones

Use of Qsymia has been associated with kidney stone formation [see Warnings and Precautions (5.15) and Adverse Reactions (6.1)] .

• 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) .

Oligohidrosis and Hyperthermia

Oligohidrosis (decreased sweating) has been reported in association with the use of topiramate, a component of Qsymia. Decreased sweating and an elevation in body temperature above normal characterized these cases.

• Advise patients to monitor for decreased sweating and increased body temperature during physical activity, especially in hot weather.