Qsymia extended-release capsules

Qsymia extended-release capsules is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index (BMI) of

• 30 kg/m² or greater (obese), or
• 27 kg/m² or greater (overweight) in the presence of at least one weight related comorbidity such as hypertension, type 2 diabetes mellitus, or dyslipidemia

Limitations of Use

The effect of Qsymia extended-release capsules on cardiovascular morbidity and mortality has not been established.

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

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 extended-release capsules as follows:

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

Discontinuing Qsymia extended-release capsules

• Discontinue Qsymia extended-release capsules 15 mg/92 mg gradually by taking a dose every other day for at least 1 week prior to stopping treatment altogether, due to the possibility of precipitating a seizure.

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 extended-release capsules 7.5 mg/46 mg once daily. Renal impairment is determined by calculating CrCl using the Cockcroft-Gault equation with actual body weight.

Dosing In Patients With Hepatic Impairment

In patients with moderate hepatic impairment (Child-Pugh score 7 -9), dosing should not exceed Qsymia extended-release capsules 7.5 mg/46 mg once daily.

Qsymia extended-release capsules is contraindicated in the following conditions:

• Pregnancy
• Glaucoma
• Hyperthyroidism
• During or within 14 days following the administration of monoamine oxidase inhibitors
• Known hypersensitivity or idiosyncrasy to the sympathomimetic amines.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Fetal Toxicity

Qsymia extended-release capsules can cause fetal harm. Data from pregnancy registries and epidemiology studies indicate that a fetus exposed to topiramate, a component of Qsymia extended-release capsules, in the first trimester of pregnancy has an increased risk of oral clefts (cleft lip with or without cleft palate). If Qsymia extended-release capsules is used during pregnancy or if a patient becomes pregnant while taking Qsymia extended-release capsules, 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 extended-release capsules and monthly thereafter during Qsymia extended-release capsules therapy. Females of reproductive potential should use effective contraception during Qsymia extended-release capsules therapy.

Qsymia extended-release capsules Risk Evaluation and Mitigation Strategy (REMS)

Because of the teratogenic risk associated with Qsymia extended-release capsules therapy, Qsymia extended-release capsules is available through a limited program under the REMS. Under the Qsymia extended-release capsules REMS, only certified pharmacies may distribute Qsymia extended-release capsules. Further information, is available at www.Qsymia extended-release capsulesREMS.com or by telephone at 1-888-998-4887.

Increase In Heart Rate

Qsymia extended-release capsules can cause an increase in resting heart rate.

A higher percentage of Qsymia extended-release capsules-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.

Table 2: Number and Percentage of Patients with an Increase in Heart Rate at a Single Time Point from Baseline

The clinical significance of a heart rate elevation with Qsymia extended-release capsules 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 extended-release capsules, especially patients with cardiac or cerebrovascular disease or when initiating or increasing the dose of Qsymia extended-release capsules. Qsymia extended-release capsules 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 extended-release capsules treatment. For patients who experience a sustained increase in resting heart rate while taking Qsymia extended-release capsules, the dose should be reduced or Qsymia extended-release capsules discontinued.

Suicidal Behavior And Ideation

Antiepileptic drugs (AEDs), including topiramate, a component of Qsymia extended-release capsules, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with Qsymia extended-release capsules 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 extended-release capsules in patients who experience suicidal thoughts or behaviors.

Avoid Qsymia extended-release capsules 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.

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 extended-release capsules. 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 extended-release capsules. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious adverse events including permanent loss of vision.

Mood And Sleep Disorders

Qsymia extended-release capsules 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 extended-release capsules. The majority of these mood and sleep disorders resolved spontaneously, or resolved upon discontinuation of dosing.

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

Cognitive Impairment

Qsymia extended-release capsules 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 extended-release capsules may be associated with higher rates of cognitive events such as attention, memory, and language/word-finding difficulties.

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

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 extended-release capsules.

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 extended-release capsules 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 extended-release capsules 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 extended-release capsules 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 extended-release capsules and during Qsymia extended-release capsules treatment is recommended. In Qsymia extended-release capsules 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 extended-release capsules, reduce the dose or discontinue Qsymia extended-release capsules.

Elevation In Creatinine

Qsymia extended-release capsules can cause an increase in serum creatinine. 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. Elevations in serum creatinine often signify a decrease in renal function, but the cause for Qsymia extended-release capsules-associated changes in serum creatinine has not been definitively established. Therefore, measurement of serum creatinine prior to starting Qsymia extended-release capsules and during Qsymia extended-release capsules treatment is recommended. If persistent elevations in creatinine occur while taking Qsymia extended-release capsules, reduce the dose or discontinue Qsymia extended-release capsules.

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 extended-release capsules has not been studied in combination with insulin. Measurement of blood glucose levels prior to starting Qsymia extended-release capsules and during Qsymia extended-release capsules 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 extended-release capsules, appropriate changes should be made to the antidiabetic drug regimen.

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 extended-release capsules and during Qsymia extended-release capsules treatment is recommended in patients being treated for hypertension. If a patient develops symptoms associated with low blood pressure after starting Qsymia extended-release capsules, appropriate changes should be made to the antihypertensive drug regimen.

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 extended-release capsules.

Potential Seizures With Abrupt Withdrawal Of Qsymia extended-release capsules

Abrupt withdrawal of topiramate, a component of Qsymia extended-release capsules, has been associated with seizures in individuals without a history of seizures or epilepsy. In situations where immediate termination of Qsymia extended-release capsules is medically required, appropriate monitoring is recommended. Patients discontinuing Qsymia extended-release capsules 15 mg/92 mg should be gradually tapered as recommended to reduce the possibility of precipitating a seizure.

Patients With Renal Impairment

Phentermine and topiramate, the components of Qsymia extended-release capsules, 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 extended-release capsules for both patient populations.

Qsymia extended-release capsules has not been studied in patients with end-stage renal disease on dialysis. Avoid use of Qsymia extended-release capsules in this patient population.

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 extended-release capsules for patients with moderate hepatic impairment.

Qsymia extended-release capsules has not been studied in patients with severe hepatic impairment (Child-Pugh score 10 -15). Avoid use of Qsymia extended-release capsules in this patient population.

Kidney Stones

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

Avoid the use of Qsymia extended-release capsules 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.

Oligohidrosis And Hyperthermia

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

Hypokalemia

Qsymia extended-release capsules can increase the risk of hypokalemia through its inhibition of carbonic anhydrase activity. In addition, when Qsymia extended-release capsules 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 extended-release capsules, patients should be monitored for hypokalemia.

Monitoring: Laboratory Tests

Qsymia extended-release capsules 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.

Patient Counseling Information

See FDA-approved patient labeling (Medication Guide).

Advise patients of the following:

Adjunctive Treatment

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

Access to Qsymia extended-release capsules

Qsymia extended-release capsules is only available through certified pharmacies that are enrolled in the Qsymia extended-release capsules certified pharmacy network. Advise patients on how to access Qsymia extended-release capsules through certified pharmacies. Additional information may be obtained via the website www.Qsymia extended-release capsulesREMS.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 extended-release capsules.

How to take Qsymia extended-release capsules

Advise patients to take Qsymia extended-release capsules in the morning with or without food.

Advise patients to start treatment with Qsymia extended-release capsules as follows:

• Take one Qsymia extended-release capsules 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 extended-release capsules 7.5 mg/46 mg capsule once daily – in the morning
• Do not take Qsymia extended-release capsules 3.75 mg/23 mg and Qsymia extended-release capsules 7.5/46 mg capsules together

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

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

Advise patients to discontinue the Qsymia extended-release capsules 15 mg/92 mg dose gradually by taking one Qsymia extended-release capsules 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 extended-release capsules can cause fetal harm and patients should avoid getting pregnant while taking Qsymia extended-release capsules

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

Nursing Mothers

Either discontinue nursing or discontinue Qsymia extended-release capsules.

Elevation in Heart Rate

• Qsymia extended-release capsules can increase resting heart rate.
• Advise patients to report symptoms of sustained periods of heart pounding or racing while at rest to their healthcare provider(s).

Suicidal Behavior and Ideation; Changes in Mood or Depression

Qsymia extended-release capsules can increase the risk of mood changes, depression, and suicidal ideation.

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

Acute Angle Closure Glaucoma

Qsymia extended-release capsules can increase the risk of acute myopia and secondary angle closure glaucoma.

• 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 extended-release capsules can cause dizziness, confusion, concentration, and word-finding difficulties, or visual changes.

• 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 extended-release capsules to gauge whether it adversely affects their mental performance, motor performance, and/or vision.

Metabolic Acidosis

Qsymia extended-release capsules 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).

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).

• 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.

• Advise patients not to drink alcohol while taking Qsymia extended-release capsules.

Potential Seizures with Abrupt Withdrawal of Qsymia extended-release capsules

Abrupt withdrawal of topiramate, a component of Qsymia extended-release capsules, has been associated with seizures in individuals without a history of seizures or epilepsy.

• Advise patients not to abruptly stop Qsymia extended-release capsules without first talking to their healthcare provider(s)

Kidney stones

Use of Qsymia extended-release capsules 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).

Oligohidrosis and Hyperthermia

Oligohidrosis (decreased sweating) has been reported in association with the use of topiramate, a component of Qsymia extended-release capsules. 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Phentermine/Topiramate

No animal studies have been conducted with phentermine/topiramate, the combined products in Qsymia extended-release capsules, to evaluate carcinogenesis, mutagenesis, or impairment of fertility. The following data are based on findings in studies performed individually with phentermine or topiramate, Qsymia extended-release capsules'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 evidence of carcinogenicity at the highest dose of phentermine (30 mg/kg) which is approximately 11 to 15 times the maximum recommended clinical dose of Qsymia extended-release capsules 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 increase unscheduled DNA synthesis in rat hepatocytes in vitro; and it did not increase chromosomal aberrations in human 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 the diet for 21 months. The elevated bladder tumor incidence, which was statistically significant in males and females 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 were approximately 2 to 4 times steady-state exposures measured in patients receiving topiramate monotherapy at the MRHD of Qsymia extended-release capsules 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 extended-release capsules based on AUC estimates).

No adverse effects on male or female fertility were observed in rats at doses up to 100 mg/kg or approximately 4 to 8 times male and female MRHD exposures of Qsymia extended-release capsules based on AUC.

Use In Specific Populations

Pregnancy

Pregnancy Category X

Risk Summary

Qsymia extended-release capsules is contraindicated in pregnant women. The use of Qsymia extended-release capsules can cause fetal harm and weight loss offers no potential benefit to a pregnant woman. Available epidemiologic data indicate an increased risk in oral clefts (cleft lip with or without cleft palate) with first trimester exposure to topiramate, a component of Qsymia extended-release capsules. When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring.

If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, treatment should be discontinued immediately and the patient should be apprised of the potential hazard to a fetus.

There is a Qsymia extended-release capsules Pregnancy Surveillance Program to monitor maternal-fetal outcomes of pregnancies that occur during Qsymia extended-release capsules therapy. Healthcare providers and patients are encouraged to report pregnancies by calling 1-888-998-4887.

Clinical Considerations

Oral clefts occur from the fifth through the ninth week of gestation. The lip is formed between the beginning of the fifth week to the seventh week of gestation, and the palate is formed between the beginning of the sixth week through the ninth week of gestation.

A minimum weight gain, and no weight loss, is currently recommended for all pregnant women, including those who are already overweight or obese, due to the obligatory weight gain that occurs in maternal tissues during pregnancy.

Qsymia extended-release capsules can cause metabolic acidosis. The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus' ability to tolerate labor.

Human Data

Data evaluating the risk of major congenital malformations and oral clefts with topiramate (a component of Qsymia extended-release capsules) exposure during pregnancy is available from the North American Anti-Epileptic Drug (NAAED) Pregnancy Registry and from several larger retrospective epidemiologic studies. The NAAED Pregnancy Registry suggested an estimated increase in risk for oral clefts of 9.60 (95% CI 3.60 -25.70). 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 (Table 5). The FORTRESS study, sponsored by the maker of Qsymia extended-release capsules, 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 first trimester.

Table 5: Summary of Studies Evaluating the Association of Topiramate in Utero Exposure and Oral Clefts and Major Congenital Malformations

Animal Data

Phentermine/Topiramate

Embryo-fetal development studies have been conducted in rats and rabbits with combination phentermine and topiramate treatment. Phentermine and topiramate co-administered to rats during the period of organogenesis 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, no effects on embryo-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 at these 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 and lactation with 1.5 mg/kg/day phentermine and 10 mg/kg/day topiramate (approximately 2 and 3 times clinical exposures 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 and delayed growth, development, and sexual maturation without affecting learning, memory, or fertility and reproduction. 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 conducted with 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 extended-release capsules, based on AUC.

Topiramate

Topiramate causes developmental toxicity, including teratogenicity, at clinically relevant doses.

Labor And Delivery

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

Nursing Mothers

Qsymia extended-release capsules may be present in human milk because topiramate and amphetamines (phentermine has pharmacologic activity and a chemic

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

• Fetal Toxicity:
• Elevation in Heart Rate
• Suicidal Behavior and Ideation
• Acute Angle Closure Glaucoma
• Mood and Sleep Disorders
• Cognitive Impairment
• Metabolic Acidosis

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 extended-release capsules 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/m²) exposed for a mean duration of 298 days.

Common Adverse Reactions

Adverse reactions occurring at a rate of greater than or equal to 5% and at a rate at least 1.5 times placebo include paraesthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth.

Adverse reactions reported in greater than or equal to 2% of Qsymia extended-release capsules-treated patients and more frequently than in the placebo group are shown in Table 3.

Table 3: Adverse Reactions Reported in Greater Than or Equal to 2% of Patients and More Frequently than Placebo during 1 Year of Treatment – Overall Study Population

Paraesthesia/Dysgeusia

Reports of paraesthesia, characterized as tingling in hands, feet, or face, occurred in 4.2%, 13.7%, and 19.9% of patients treated with Qsymia extended-release capsules 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 1.9% of patients treated with placebo. Dysgeusia was characterized as a metallic taste, and occurred in 1.3%, 7.4%, and 9.4% of patients treated with Qsymia extended-release capsules 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 1.1% of patients treated with placebo. The majority of these events first occurred within the initial 12 weeks of drug therapy; however, in some patients, events were reported later in the course of treatment. Only Qsymia extended-release capsules-treated patients discontinued treatment due to these events (1% for paraesthesia and 0.6% for dysgeusia).

Mood and Sleep Disorders

The proportion of patients in 1-year controlled trials of Qsymia extended-release capsules reporting one or more adverse reactions related to mood and sleep disorders was 15.8%, 14.5%, and 20.6% with Qsymia extended-release capsules 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 10.3% 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 6.7%, 8.1%, and 11.1% of patients treated with Qsymia extended-release capsules 3.75 mg/23 mg, 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 4.6%, 4.8%, and 7.9% of patients treated with Qsymia extended-release capsules 3.75 mg/23 mg, 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 5.0%, 3.8%, and 7.6% of patients treated with Qsymia extended-release capsules 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 3.4% of patients treated with placebo. The majority of these events first occurred within the initial 12 weeks of drug therapy; however, in some patients, events were reported later in the course of treatments. In the Qsymia extended-release capsules clinical trials, the overall prevalence of mood and sleep adverse reactions was approximately twice as great in patients with a history of depression compared to patients without a history of depression; however, the proportion of patients on active treatment versus placebo who reported mood and sleep adverse reactions was similar in these two subgroups. Occurrence of depression-related events was more frequent in patients with a past history of depression across all treatment groups. However, the placebo-adjusted difference in incidence of these events remained constant between groups regardless of previous depression history.

Cognitive Disorders

In the 1-year controlled trials of Qsymia extended-release capsules, the proportion of patients who experienced one or more cognitive-related adverse reactions was 2.1% for Qsymia extended-release capsules 3.75 mg/23 mg, 5.0% for Qsymia extended-release capsules 7.5 mg/46 mg, and 7.6% for Qsymia extended-release capsules 15 mg/92 mg, compared to 1.5% for placebo. These adverse reactions were comprised primarily of reports of problems with attention/concentration, memory, and language (word finding). These events typically began within the first 4 weeks of treatment, had a median duration of approximately 28 days or less, and were reversible upon discontinuation of treatment; however, individual patients did experience events later in treatment, and events of longer duration.

Laboratory Abnormalities

Serum Bicarbonate

In the 1-year controlled trials of Qsymia extended-release capsules, the incidence of persistent treatment-emergent 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 8.8% for Qsymia extended-release capsules 3.75 mg/23 mg, 6.4% for Qsymia extended-release capsules 7.5 mg/46 mg, and 12.8% for Qsymia extended-release capsules 15 mg/92 mg, compared to 2.1% for placebo. The incidence of persistent, markedly low serum bicarbonate values (levels of less than 17 mEq/L on 2 consecutive visits or at the final visit) was 1.3% for Qsymia extended-release capsules 3.75 mg/23 mg, 0.2% for Qsymia extended-release capsules 7.5 mg/46 mg dose, and 0.7% for Qsymia extended-release capsules 15 mg/92 mg dose, compared to 0.1% for placebo. Generally, decreases in serum bicarbonate levels were mild (average 1-3 mEq/L) and occurred early in treatment (4-week visit), however severe decreases and decreases later in treatment occurred.

Serum Potassium

In the 1-year controlled trials of Qsymia extended-release capsules, 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 0.4% for Qsymia extended-release capsules 3.75 mg/23 mg, 3.6% for Qsymia extended-release capsules 7.5 mg/46 mg dose, and 4.9% for Qsymia extended-release capsules 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 of greater than 0.5 mEq/L) at any time during the trial was 0.0% for Qsymia extended-release capsules 3.75 mg/23 mg, 0.2% for Qsymia extended-release capsules 7.5 mg/46 mg dose, and 0.7% for Qsymia extended-release capsules 15 mg/92 mg dose, compared to 0.0% for placebo. Persistent markedly low serum potassium (less than 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 0.0% of subjects receiving Qsymia extended-release capsules 3.75 mg/23 mg, 0.2% receiving Qsymia extended-release capsules 7.5 mg/46 mg dose, and 0.1% receiving Qsymia extended-release capsules 15 mg/92 mg dose, compared to 0.0% receiving placebo.

Hypokalemia was reported by 0.4% of subjects treated with Qsymia extended-release capsules 3.75 mg/23 mg, 1.4% of subjects treated with Qsymia extended-release capsules 7.5 mg/46 mg, and 2.5% of subjects treated with Qsymia extended-release capsules 15 mg/92 mg compared to 0.4% of subjects treated with placebo. “Blood potassium decreased” was reported by 0.4% of subjects treated with Qsymia extended-release capsules 3.75 mg/23 mg, 0.4% of subjects treated with Qsymia extended-release capsules 7.5 mg/46 mg, 1.0% of subjects treated with Qsymia extended-release capsules 15 mg/92 mg, and 0.0% of subjects treated with placebo.

Serum Creatinine

In the 1-year controlled trials of Qsymia extended-release capsules, there was a dose-related increase from baseline, peaking between Week 4 to 8, which declined but remained elevated over baseline over 1 year of treatment. The incidence of increases in serum creatinine of greater than or equal to 0.3 mg/dL at any time during treatment was 2.1% for Qsymia extended-release capsules 3.75 mg/23 mg, 7.2% for Qsymia extended-release capsules 7.5 mg/46 mg, and 8.4% for Qsymia extended-release capsules 15 mg/92 mg, compared to 2.0% for placebo. Increases in serum creatinine of greater than or equal to 50% over baseline occurred in 0.8% of subjects receiving Qsymia extended-release capsules 3.75 mg/23 mg, 2.0% receiving Qsymia extended-release capsules 7.5 mg/46 mg, and 2.8% receiving Qsymia extended-release capsules 15 mg/92 mg, compared to 0.6% receiving placebo.

Nephrolithiasis

In the 1-year controlled trials of Qsymia extended-release capsules, the incidence of nephrolithiasis was 0.4% for Qsymia extended-release capsules 3.75 mg/23 mg, 0.2% for Qsymia extended-release capsules 7.5 mg/46 mg, and 1.2% for Qsymia extended-release capsules 15 mg/92 mg, compared to 0.3% for placebo.

Drug Discontinuation Due to Adverse Reactions

In the 1-year placebo-controlled clinical studies, 11.6% of Qsymia extended-release capsules 3.75 mg/23 mg, 11.6% of Qsymia extended-release capsules 7.5 mg/46 mg, 17.4% of Qsymia extended-release capsules 15 mg/92 mg, and 8.4% of placebo-treated patients discontinued treatment due to reported adverse reactions. The most common adverse reactions that led to discontinuation of treatment are shown in Table 4.

Table 4: Adverse Reactions Greater Than or Equal To 1% Leading to Treatment Discontinuation (1-Year Clinical Trials)

Postmarketing Experience

The following adverse reactions have been reported during post approval use of phentermine and topiramate, the components of Qsymia extended-release capsules. 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 extended-release capsules

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

In the event of a significant overdose with Qsymia extended-release capsules, 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 usually terminates in convulsions and coma. Manifestations of chronic intoxication with anorectic drugs include severe dermatoses, marked insomnia, irritability, hyperactivity, and personality changes. A severe manifestation of chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia.

Management of acute phentermine intoxication is largely symptomatic and includes lavage and sedation with a barbiturate. Acidification of the urine increases phentermine excretion. Intravenous phentolamine has been suggested 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, mentation impaired, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness, and depression. The clinical consequences were not severe in most cases, but deaths have been reported after poly-drug overdoses involving gram amounts of topiramate. A patient who ingested a dose between 96 and 110 grams topiramate was admitted to hospital with coma lasting 20 to 24 hours followed by full recovery after 3 to 4 days.

Activated charcoal has been shown to adsorb topiramate in vitro. Hemodialysis is an effective means of removing topiramate from the body.

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.

Cardiac Electrophysiology

The effect of Qsymia extended-release capsules on the QTc interval was evaluated in a randomized, double-blind, placebo-and active-controlled (400 mg moxifloxacin), and parallel group/crossover thorough QT/QTc study. A total of 54 healthy subjects were administered Qsymia extended-release capsules 7.5 mg/46 mg at steady state and then titrated to Qsymia extended-release capsules 22.5 mg/138 mg at steady state. Qsymia extended-release capsules 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 extended-release capsules 7.5 mg/46 mg, respectively] did not affect cardiac repolarization as measured by the change from baseline in QTc.

Phentermine

Upon oral administration of a single Qsymia extended-release capsules 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 with measureable 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 affect phentermine pharmacokinetics for Qsymia extended-release capsules 15 mg/92 mg. Phentermine pharmacokinetics is approximately dose-proportional from Qsymia extended-release capsules 3.75 mg/23 mg to phentermine 15 mg/topiramate 100 mg. Upon dosing phentermine/topiramate 15/100 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 extended-release capsules 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 extended-release capsules 15 mg/92 mg. Topiramate pharmacokinetics is approximately dose-proportional from Qsymia extended-release capsules 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 central compartment), and Vp/F (volume of the peripheral compartment) are 50.8 L, and 13.1 L, respectively, via population pharmacokinetic analysis.

Metabolism and Excretion

Phentermine

Phentermine has two metabolic pathways, namely p-hydroxylation on the aromatic ring and N-oxidation on the aliphatic 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 a dose 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.