Phentermine And Topiramate

1 INDICATIONS AND USAGE QSYMIA is indicated in combination with a reduced-calorie diet and increased physical activity to reduce excess body weight and maintain weight reduction long term in: Adults and pediatric patients aged 12 years and older with obesity Adults with overweight in the presence of at least one weight-related comorbid condition QSYMIA is a combination of phentermine, a sympathomimetic amine anorectic, and topiramate, indicated in combination with a reduced-calorie diet and increased physical activity to reduce excess body weight and maintain weight reduction long term in: Adults and pediatric patients aged 12 years and older with obesity ( 1 ) Adults with overweight in the presence of at least one weight-related comorbid condition ( 1 ) Limitations of Use: The effect of QSYMIA on cardiovascular morbidity and mortality has not been established ( 1 ). 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 ( 1 ). Limitations of Use The effect of QSYMIA on cardiovascular morbidity and mortality has not been established. The safety and effectiveness of QSYMIA in combination with other products intended for weight loss, including prescription drugs, over-the-counter drugs, and herbal preparations, have not been established.

2 DOSAGE AND ADMINISTRATION Take orally once daily in morning. Avoid administration in evening to prevent insomnia ( 2.2 ). Recommended starting dosage is 3.75 mg/23 mg (phentermine mg/topiramate mg) daily for 14 days; then increase to 7.5 mg/46 mg daily ( 2.2 ). Escalate dosage based on weight loss in adults or BMI reduction in pediatric patients. See the Full Prescribing Information for details regarding discontinuation or dosage escalation ( 2.2 ). Gradually discontinue 15 mg/92 mg dosage to prevent possible seizure ( 2.3 ). Do not exceed 7.5 mg/46 mg dosage for patients with moderate or severe renal impairment or patients with moderate hepatic impairment ( 2.4 , 2.5 ). 2.1 Recommended Testing Prior to and During Treatment with QSYMIA Prior to QSYMIA initiation and during treatment with QSYMIA, the following is recommended: Obtain a negative pregnancy test before initiating QSYMIA in patients who can become pregnant and monthly during QSYMIA therapy. QSYMIA is contraindicated during pregnancy [see Contraindications (4) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.3) ] . Obtain a blood chemistry profile that includes bicarbonate, creatinine, and potassium in all patients, and glucose in patients with type 2 diabetes mellitus on antidiabetic medication prior to initiating QSYMIA treatment and periodically during treatment [see Warnings and Precautions (5.7 , 5.8 , 5.12) ] . 2.2 Recommended Dosage and Administration The recommended dosage, titration, and administration of QSYMIA are as follows: Take QSYMIA orally once daily in the morning with or without food. Avoid administration of QSYMIA in the evening due to the possibility of insomnia. The recommended starting dosage of QSYMIA is one capsule (containing 3.75 mg of phentermine and 23 mg of topiramate) (3.75 mg/23 mg) taken orally once daily for 14 days; after 14 days increase to the recommended dosage of QSYMIA 7.5 mg/46 mg orally once daily. After 12 weeks of treatment with QSYMIA 7.5 mg/46 mg, evaluate weight loss for adults or BMI reduction for pediatric patients aged 12 years and older. If an adult patient has not lost at least 3% of baseline body weight or a pediatric patient has not experienced a reduction of at least 3% of baseline BMI, increase the dosage to QSYMIA 11.25 mg/69 mg orally once daily for 14 days; followed by an increase in the dosage to QSYMIA 15 mg/92 mg orally once daily. After 12 weeks of treatment with QSYMIA 15 mg/92 mg, evaluate weight loss for adults or BMI reduction for pediatric patients aged 12 years and older. If an adult patient has not lost at least 5% of baseline body weight or a pediatric patient has not experienced a reduction of at least 5% of baseline BMI, discontinue QSYMIA [see Dosage and Administration (2.3) ] , as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment. Monitor the rate of weight loss in pediatric patients. If weight loss exceeds 2 lbs (0.9 kg)/week, consider dosage reduction. 2.3 Discontinuation of QSYMIA 15 mg/92 mg Discontinue QSYMIA 15 mg/92 mg gradually by taking QSYMIA 15 mg/92 mg orally once daily every other day for at least 1 week prior to stopping treatment altogether, due to the possibility of precipitating a seizure [see Warnings and Precautions (5.9) and Drug Abuse and Dependence (9.3) ] . 2.4 Recommended Dosage in Patients with Renal Impairment The recommended dosage in patients with mild (CrCl greater or equal to 50 and less than 80 mL/min) renal impairment is the same as the recommended dosage for patients with normal renal function [see Warnings and Precautions (5.9) , Use in Specific Populations (8.6) , and Clinical Pharmacology (12.3) ] . In patients with severe [creatinine clearance (CrCl) less than 30 mL/min] or moderate (CrCl greater than or equal to 30 and less than 50 mL/min) renal impairment (CrCl calculated using the Cockcroft-Gault equation with actual body weight), the maximum recommended dosage is QSYMIA 7.5 mg/46 mg once daily. Avoid use of QSYMIA in patients with end-stage renal disease on dialysis. 2.5 Recommended Dosage in Patients with Hepatic Impairment The recommended dosage of QSYMIA in patients with mild hepatic impairment (Child-Pugh 5 - 6) is the same as the recommended dosage in patients with normal hepatic function [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] . In patients with moderate hepatic impairment (Child-Pugh score 7 - 9), the maximum recommended dosage is QSYMIA 7.5 mg/46 mg orally once daily. Avoid use of QSYMIA in patients with severe hepatic impairment (Child-Pugh score 10 - 15).

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Embryo-Fetal Toxicity [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1 , 8.6) ] Suicidal Behavior and Ideation [see Warnings and Precautions (5.2) ] Risk of Ophthalmologic Adverse Reactions [see Warnings and Precautions (5.3) ] Mood and Sleep Disorders [see Warnings and Precautions (5.4) ] Cognitive Impairment [see Warnings and Precautions (5.5) ] Slowing of Linear Growth [see Warnings and Precautions (5.6) ] Metabolic Acidosis [see Warnings and Precautions (5.7) ] Decrease in Renal Function [see Warnings and Precautions (5.8) ] Risk of Seizures with Abrupt Withdrawal of QSYMIA [see Warnings and Precautions (5.9) ] Kidney Stones [see Warnings and Precautions (5.10) ] Oligohydrosis and Hyperthermia [see Warnings and Precautions (5.11) ] Hypokalemia [see Warnings and Precautions (5.12) ] Serious Skin Reactions [see Warnings and Precautions (5.13) ] Most common adverse reactions in: Adults (incidence ≥ 5% and at least 1.5 times placebo) are: paraesthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth ( 6.1 ). Pediatric patients aged 12 years and older (incidence ≥4% and greater than placebo) are: depression, dizziness, arthralgia, pyrexia, influenza, and ligament sprain ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact VIVUS LLC, at 1-888-998-4887 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 reflect exposure to QSYMIA in two 1-year, randomized, double-blind, placebo-controlled, multicenter clinical trials and two supportive trials in 2,318 adult patients with overweight or obesity [936 (40%) patients with hypertension, 309 (13%) patients with type 2 diabetes mellitus, 808 (35%) patients with BMI greater than 40 kg/m 2 ] exposed for a mean duration of 298 days. Data in this section also describe adverse reactions from a 1-year, randomized, double-blind, placebo-controlled multicenter clinical trial that evaluated 223 pediatric patients (12 to 17 years old) with obesity [see Clinical Studies (14) ] . Adults Adverse reactions occurring at greater than or equal to 5% and at least 1.5 times placebo in adults include paraesthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth. Adverse reactions reported in greater than or equal to 2% of QSYMIA-treated adults and more frequently than in the placebo group are shown in Table 1. Table 1. Adverse Reactions Reported in ≥2% of QSYMIA-Treated Adults with Overweight or Obesity and More Frequently than Placebo in Overall Study Population of 1 Year Duration Adverse Reaction Placebo (N = 1561) % QSYMIA 3.75 mg/23 mg (N = 240) % QSYMIA 7.5 mg/46 mg (N = 498) % QSYMIA 15 mg/92 mg (N = 1,580) % Paraesthesia 2 4 14 20 Dry Mouth 3 7 14 19 Constipation 6 8 15 16 Upper Respiratory Tract Infection 13 16 12 14 Headache 9 10 7 11 Dysgeusia 1 1 7 9 Insomnia 5 5 6 9 Nasopharyngitis 8 13 11 9 Dizziness 3 3 7 9 Sinusitis 6 8 7 8 Nausea 4 6 4 7 Back Pain 5 5 6 7 Fatigue 4 5 4 6 Diarrhea 5 5 6 6 Vision Blurred 4 6 4 5 Bronchitis 4 7 4 5 Urinary Tract Infection 4 3 5 5 Cough 4 3 4 5 Influenza 4 8 5 4 Depression 2 3 3 4 Anxiety 2 3 2 4 Hypoesthesia 1 1 4 4 Irritability 1 2 3 4 Alopecia 1 2 3 4 Disturbance in Attention 1 0 2 4 Pain in Extremity 3 2 3 3 Muscle Spasms 2 3 3 3 Dyspepsia 2 2 2 3 Gastroesophageal Reflux Disease 1 1 3 3 Rash 2 2 2 3 Hypokalemia 0 0 1 3 Dry Eye 1 1 1 3 Gastroenteritis 2 1 2 3 Pharyngolaryngeal Pain 2 3 1 2 Paraesthesia Oral 0 0 1 2 Eye Pain 1 2 2 2 Nasal Congestion 1 2 1 2 Thirst 1 2 2 2 Sinus Congestion 2 3 3 2 Procedural Pain 2 2 2 2 Palpitations 1 1 2 2 Musculoskeletal Pain 1 1 3 2 Decreased Appetite 1 2 2 2 Neck Pain 1 1 2 1 Dysmenorrhea 0 2 0 1 Chest Discomfort 0 2 0 1 Pediatric Patients Aged 12 Years and Older Adverse reactions occurring in pediatric patients treated with either QSYMIA 15 mg/92 mg or QSYMIA 7.5 mg/46 mg at greater than or equal to 4% and higher than placebo include depression, pyrexia, dizziness, arthralgia, influenza, and ligament sprain. Adverse reactions reported in greater than or equal to 2% of QSYMIA-treated pediatric patients and more frequently than in the placebo group from a study in pediatric patients aged 12 years and older are shown in Table 2. Table 2. Adverse Reactions Reported in ≥2% of QSYMIA-Treated Pediatric Patients Aged 12 to 17 Years and More Frequently than Placebo during 56 Weeks of Treatment Adverse Reaction Placebo (N = 56) % QSYMIA 7.5 mg/46 mg (N = 54) % QSYMIA 15 mg/92 mg (N = 113) % Depression 0 2 4 Nausea 4 4 4 Pyrexia 2 2 4 Dizziness 0 2 4 Arthralgia 0 2 4 Paraesthesia 0 2 3 Anxiety 0 2 3 Abdominal Pain Upper 0 0 3 Fatigue 2 0 3 Ear Infection 0 2 3 Musculoskeletal Chest Pain 0 0 3 Influenza 0 4 2 Ligament Sprain 0 4 2 Increase in Heart Rate In adult and pediatric clinical trials, there was a higher incidence of heart rate elevations observed in QSYMIA-treated compared to placebo-treated patients. In an 8-week ambulatory blood pressure monitoring (ABPM) study in adults, QSYMIA increased the 24-hr average heart rate by 3.6 beats per minute (bpm) (95% CI 2.1, 5.2) compared to the placebo group [see Clinical Pharmacology (12.2) ] . In clinical trials, a higher percentage of QSYMIA-treated adults and pediatric patients aged 12 years and older experienced heart rate increases from baseline of more than 5, 10, 15, and 20 bpm compared to placebo-treated patients. Table 3 and Table 4 provide the numbers and percentages of adult and pediatric patients, respectively, with elevations in heart rate in clinical studies of up to one year. Table 3. Number and Percentage of Adults with Overweight or Obesity with an Increase in Heart Rate at a Single Time Point from Baseline Placebo N=1561 n (%) QSYMIA 3.75 mg/23 mg N=240 n (%) QSYMIA 7.5 mg/46 mg N=498 n (%) QSYMIA 15 mg/92 mg N=1580 n (%) Greater than 5 bpm 1021 (65.4) 168 (70.0) 372 (74.7) 1228 (77.7) Greater than 10 bpm 657 (42.1) 120 (50.0) 251 (50.4) 887 (56.1) Greater than 15 bpm 410 (26.3) 79 (32.9) 165 (33.1) 590 (37.3) Greater than 20 bpm 186 (11.9) 36 (15.0) 67 (13.5) 309 (19.6) Table 4. Number and Percentage of Pediatric Patients with an Increase in Heart Rate at a Single Time Point from Baseline Placebo N=56 n (%) QSYMIA 7.5 mg/46 mg N=54 n (%) QSYMIA 15 mg/92 mg N=113 n (%) Greater than 5 bpm 37 (66.1) 38 (70.4) 92 (81.4) Greater than 10 bpm 26 (46.4) 30 (55.6) 73 (64.6) Greater than 15 bpm 17 (30.4) 18 (33.3) 48 (42.5) Greater than 20 bpm 10 (17.9) 10 (18.5) 27 (23.9) Paraesthesia/Dysgeusia In adult clinical trials, reports of paraesthesia, characterized as tingling in hands, feet, or face, and dysgeusia, characterized as a metallic taste, occurred (see Table 1 ). Adverse reactions of paraesthesia were also reported in pediatric patients (see Table 2 ). QSYMIA-treated adult patients discontinued treatment due to these adverse reactions (1% for paraesthesia and 0.6% for dysgeusia); no pediatric patients discontinued treatment due to paraesthesia or dysgeusia. Mood and Sleep Disorders The proportion of adult patients in 1-year controlled trials of QSYMIA reporting one or more adverse reactions related to mood and sleep disorders was 15% and 21% with QSYMIA 7.5 mg/46 mg and 15 mg/92 mg, respectively, compared to 10% with placebo. These events were further categorized into sleep disorders, anxiety, and depression. Reports of sleep disorders were typically characterized as insomnia and occurred in 8.1% and 11% of patients treated with QSYMIA 7.5 mg/46 mg and 15 mg/92 mg, respectively, compared to 5.8% of patients treated with placebo. Reports of anxiety occurred in 4.8% and 7.9% of patients treated with QSYMIA 7.5 mg/46 mg and 15 mg/92 mg, respectively, compared to 2.6% of patients treated with placebo. Reports of depression/mood problems occurred in 3.8% and 7.6% of patients treated with QSYMIA 7.5 mg/46 mg and 15 mg/92 mg, respectively, compared to 3.4% of patients treated with placebo. Mood and sleep disorder adverse reactions occurred in patients with and without a history of depression. In a pediatric clinical trial, higher proportions of QSYMIA-treated patients reported one or more adverse reactions related to mood (e.g., depression, anxiety) and sleep disorders (e.g., insomnia) compared to placebo-treated patients (see Table 2 ). Cognitive Disorders In the 1-year controlled trials of QSYMIA in adults, the proportion of patients who experienced one or more cognitive-related adverse reactions was 5.0% for QSYMIA 7.5 mg/46 mg and 7.6% for QSYMIA 15 mg/92 mg, compared to 1.5% for placebo. These adverse reactions were comprised primarily of reports of problems with attention/concentration, memory, and language (word-finding). These events occurred at any time during treatment with QSYMIA. Slowing of Linear Growth QSYMIA is associated with a reduction in height velocity (centimeters of height gained per year) in obese pediatric patients 12 to 17 years of age. In a 56-week study, average height increased from baseline in both QSYMIA- and placebo-treated patients; however, a lower height velocity of -1.3 to -1.4 cm/year was observed in QSYMIA-treated compared to placebo-treated patients. Decrease in Bone Mineral Density QSYMIA is associated with less bone mineral acquisition in pediatric patients 12 to 17 years of age. In a substudy (n=66) evaluating bone mineralization via dual-energy X-ray absorptiometry (DEXA), increases in bone mineral density (BMD) at the lumbar spine and total body less head (TBLH) were smaller in pediatric patients treated with QSYMIA compared to those treated with placebo after 1 year of treatment. Declines in BMD Z-scores of -0.5 or greater from baseline for TBLH were observed in 9% of QSYMIA 7.5 mg/46 mg-treated patients and 30% of QSYMIA 15 mg/92 mg-treated patients, compared to 0% of placebo-treated patients. The sample size and study duration were too small to determine if fracture risk is increased. Decreased BMD was not correlated with decreased serum bicarbonate, which commonly occurs with QSYMIA treatment, or changes in body weight. No patient had a BMD Z-score that went below -2.0 during the trial. Similar findings were observed in a 1 year, active-controlled trial of topiramate in pediatric patients with another condition. Nephrolithiasis In the 1-year controlled trials of QSYMIA in adults, the incidence of nephrolithiasis was 0.2% for QSYMIA 7.5 mg/46 mg and 1.2% for QSYMIA 15 mg/92 mg, compared to 0.3% for placebo. Laboratory Abnormalities Serum Bicarbonate In the 1-year controlled trials of QSYMIA in adults, the incidence of persistent decreases in serum bicarbonate below the normal range (levels of less than 21 mEq/L at 2 consecutive visits or at the final visit) was 6.4% for QSYMIA 7.5 mg/46 mg and 12.8% for QSYMIA 15 mg/92 mg, compared to 2.1% for placebo. The 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 0.2% for QSYMIA 7.5 mg/46 mg dose and 0.7% for QSYMIA 15 mg/92 mg dose, compared to 0.1% for placebo. In a pediatric clinical trial, 60 to 70% QSYMIA-treated patients had a persistent bicarbonate level below the normal range (<21 mEq/L) compared to 43% of placebo-treated patients. Serum Potassium In the 1-year controlled trials of QSYMIA in adults, the incidence of persistent low serum potassium values (less than 3.5 mEq/L at two consecutive visits or at the final visit) during the trial was 3.6% for QSYMIA 7.5 mg/46 mg dose and 4.9% for QSYMIA 15 mg/92 mg, compared to 1.1% for placebo. Of the subjects who experienced persistent low serum potassium, 88% were receiving treatment with a non-potassium sparing diuretic. The incidence of markedly low serum potassium (less than 3 mEq/L, and a reduction from pre-treatment of greater than 0.5 mEq/L) at any time during the trial was 0.2% for QSYMIA 7.5 mg/46 mg dose and 0.7% for QSYMIA 15 mg/92 mg dose, compared to 0.0% for placebo. Persistent markedly low serum potassium (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 0.2% receiving QSYMIA 7.5 mg/46 mg dose and 0.1% receiving QSYMIA 15 mg/92 mg dose, compared to 0.0% receiving placebo. Low serum potassium levels (<3.5 mEq/L) were not observed in a 56-week clinical trial of pediatric patients with obesity. Serum Creatinine In the 1-year controlled trials of QSYMIA in adults and pediatric patients, there was an increase in serum creatinine from baseline, peaking between Week 4 to 8 in adults and at Week 16 in pediatric patients. Serum creatinine values declined but remained elevated over baseline over 1 year of treatment. The incidence of increases in serum creatinine of greater than or equal to 0.3 mg/dL at any time during treatment in adults was 7.2% for QSYMIA 7.5 mg/46 mg and 8.4% for QSYMIA 15 mg/92 mg, compared to 2.0% for placebo; 17% of pediatric patients treated with QSYMIA 7.5 mg/46 mg or QSYMIA 15 mg/92 mg and 0% of patients treated with placebo had a serum creatinine ≥0.3 mg/dL at any time post-randomization. Increases in serum creatinine of greater than or equal to 50% over baseline occurred in 2.0% of adult subjects receiving QSYMIA 7.5 mg/46 mg and 2.8% receiving QSYMIA 15 mg/92 mg, compared to 0.6% receiving placebo. Serum Ammonia Hyperammonemia with or without encephalopathy has been reported with topiramate. The risk for hyperammonemia with topiramate appears dose related and has been reported more frequently when concomitantly used with valproic acid [see Drug Interactions (7) ] . The incidence of hyperammonemia in pediatric patients 12 to 17 years of age in clinical trials of another condition was 26% in patients taking topiramate at 100 mg/day (1.1 times the maximum recommended dosage of QSYMIA) and 14% in patients taking topiramate at 50 mg/day (0.6 times the maximum recommended dosage of QSYMIA), compared to 9% in patients taking placebo. There was also an increased incidence of markedly increased hyperammonemia (defined as 50% above the upper limit of normal reference range) at the 100 mg dose. 6.2 Postmarketing Experience The following adverse reactions have been reported during post approval use of QSYMIA, phentermine, and topiramate. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. QSYMIA Psychiatric: suicidal ideation, suicidal behavior Ophthalmic: acute angle closure glaucoma, increased intraocular pressure Phentermine Allergic Reactions: urticaria Cardiovascular: elevation of blood pressure, ischemic events Central Nervous System: euphoria, psychosis, tremor Reproductive: changes in libido, impotence Topiramate Dermatologic: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), pemphigus Gastrointestinal: pancreatitis Hepatic: hepatic failure (including fatalities), hepatitis Metabolic: hyperammonemia with or without encephalopathy has been reported with concomitant valproic acid [see Drug Interactions (7) ] , hypothermia Ophthalmic: maculopathy

12.3 Pharmacokinetics Absorption Phentermine Upon oral administration of a single QSYMIA 15 mg/92 mg, the resulting mean plasma phentermine maximum concentration (C max ), time to C max (T max ), area under the concentration curve from time zero to the last time with measurable concentration (AUC 0-t ), and area under the concentration curve from time zero to infinity (AUC 0-∞ ) 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 15 mg/92 mg. Phentermine pharmacokinetics are approximately dose-proportional from QSYMIA 3.75 mg/23 mg to phentermine 15 mg/topiramate 100 mg. Upon dosing phentermine 15 mg/topiramate 100 mg fixed dose combination capsule to steady state, the mean phentermine accumulation ratios for AUC and C max are both approximately 2.5. Topiramate Upon oral administration of a single QSYMIA 15 mg/92 mg, the resulting mean plasma topiramate C max , T max , AUC 0-t , and AUC 0-∞ , are 1020 ng/mL, 9 hr, 61600 ng∙hr/mL, and 68000 ng∙hr/mL, respectively. A high fat meal does not affect topiramate pharmacokinetics for QSYMIA 15 mg/92 mg. Topiramate pharmacokinetics are approximately dose-proportional from QSYMIA 3.75 mg/23 mg to phentermine 15 mg/topiramate 100 mg. Upon dosing phentermine 15 mg/topiramate 100 mg fixed dose combination capsule to steady state, the mean topiramate accumulation ratios for AUC and C max 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. Elimination 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. Specific Populations Patients with Renal Impairment A single-dose, open-label study was conducted to evaluate the pharmacokinetics of QSYMIA 15 mg/92 mg in adult patients with varying degrees of chronic renal impairment compared to healthy volunteers with normal renal function. The study included patients with renal impairment classified on the basis of creatinine clearance as mild (greater or equal to 50 and less than 80 mL/min), moderate (greater than or equal to 30 and less than 50 mL/min), and severe (less than 30 mL/min). Creatinine clearance was estimated from serum creatinine based on the Cockcroft-Gault equation. Compared to healthy volunteers, phentermine AUC 0-inf was 91%, 45%, and 22% higher in patients with severe, moderate, and mild renal impairment, respectively; phentermine C max was 2% to 15% higher. Compared to healthy volunteers, topiramate AUC 0-inf was 126%, 85%, and 25% higher for patients with severe, moderate, and mild renal impairment, respectively; topiramate C max was 6% to 17% higher. An inverse relationship between phentermine or topiramate C max or AUC and creatinine clearance was observed. QSYMIA has not been studied in patients with end-stage renal disease on dialysis [see Dosage and Administration (2.4) and Use in Specific Populations (8.6) ] . Patients with Hepatic Impairment A single-dose, open-label study was conducted to evaluate the pharmacokinetics of QSYMIA 15 mg/92 mg in healthy volunteers with normal hepatic function compared with patients with mild (Child-Pugh score 5 - 6) and moderate (Child-Pugh score 7 - 9) hepatic impairment. In patients with mild and moderate hepatic impairment, phentermine AUC was 37% and 60% higher compared to healthy volunteers. Pharmacokinetics of topiramate was not affected in patients with mild and moderate hepatic impairment when compared with healthy volunteers. QSYMIA has not been studied in patients with severe hepatic impairment (Child-Pugh score 10 - 15) [see Dosage and Administration (2.5) and Use in Specific Populations (8.7) ] . Pediatric Patients 12 to 17 years old A randomized, double-blind, placebo-controlled study was conducted to evaluate the population pharmacokinetics of QSYMIA using data from 37 pediatric patients (12 to 17 years of age) with obesity. QSYMIA dosages of 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg were studied. QSYMIA exposure in the pediatric patients appeared comparable to that in adults. Drug Interaction Studies In Vitro Assessment of Drug Interactions Phentermine Phentermine is not an inhibitor of CYP isozymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4, and is not an inhibitor of monoamine oxidases. Phentermine is not an inducer of CYP1A2, CYP2B6, and CYP3A4. Phentermine is not a P-glycoprotein substrate. Topiramate Topiramate is not an inhibitor of CYP isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4/5. However, topiramate is a mild inhibitor of CYP2C19. Topiramate is a mild inducer of CYP3A4. Topiramate is not a P-glycoprotein substrate. Effects of Phentermine/Topiramate on Other Drugs Table 7 describes the effect of phentermine/topiramate on the pharmacokinetics of co-administered drugs. Table 7. Effect of Phentermine/Topiramate on the Pharmacokinetics of Co-administered Drugs Phentermine/Topiramate Co-administered Drug and Dosing Regimen Drug and Dose (mg) Change in AUC Change in C max A single study examined the effect of multiple-dose QSYMIA 15 mg/92 mg once daily on the pharmacokinetics of multiple-dose 500 mg metformin twice daily and multiple-dose 100 mg sitagliptin once daily in 10 males and 10 females (mean BMI of 27.1 kg/m 2 and range of 22.2 – 32.7 kg/m 2). The study participants received metformin, sitagliptin, phentermine/topiramate only, phentermine/topiramate plus probenecid, phentermine/topiramate plus metformin, and phentermine/topiramate plus sitagliptin on Days 1 – 5, 6 – 10, 11 – 28, 29, 30 – 34, and 35 – 39, respectively. The significance of these interactions is unknown. 15 mg/92 mg dose QD for 16 days Metformin 500 mg BID for 5 days ↑ 23% ↑ 16% 15 mg/92 mg dose QD for 21 days Sitagliptin 100 mg QD for 5 days ↓ 3% ↓ 9% See Drug Interactions (7) 15 mg/92 mg dose QD for 15 days Oral contraceptive single dose norethindrone 1 mg ethinyl estradiol 35 mcg ↑ 16% ↓ 16% ↑ 22% ↓ 8% Effect of Other Drugs on Phentermine/Topiramate Table 8 describes the effect of other drugs on the pharmacokinetics of phentermine/topiramate. Table 8. Effect of Co-administered Drugs on the Pharmacokinetics of Phentermine/Topiramate Co-administered Drug and Dosing Regimen Phentermine/Topiramate Dose (mg) Change in AUC Change in C max Topiramate 92 mg single dose 15 mg phentermine single dose ↑ 42% ↑ 13% Phentermine 15 mg single dose 92 mg topiramate single dose ↑ 6% ↑ 2% The same single study examined the effect of multiple-dose 500 mg metformin twice daily, a single-dose 2 g probenecid, and multiple-dose 100 mg sitagliptin once daily on the pharmacokinetics of multiple-dose phentermine/topiramate 15 mg/92 mg once daily in 10 males and 10 females (mean BMI of 27.1 kg/m 2 and range of 22.2 – 32.7 kg/m 2). The study participants received metformin, sitagliptin, phentermine/topiramate only, phentermine/topiramate plus probenecid, phentermine/topiramate plus metformin, and phentermine/topiramate plus sitagliptin on Days 1 – 5, 6 – 10, 11 – 28, 29, 30 – 34, and 35 – 39, respectively. Metformin 500 mg BID for 5 days 15 mg/92 mg dose QD for 16 days phentermine topiramate ↑ 5% ↓ 5% ↑ 7% ↓ 4% Sitagliptin 100 mg QD for 5 days 15 mg/92 mg dose QD for 21 days phentermine topiramate ↑ 9% ↓ 2% ↑ 10% ↓ 2% Probenecid 2 g QD 15 mg/92 mg dose QD for 11 days phentermine topiramate ↓ 0.3% ↑ 0.7% ↑ 4% ↑ 3% Effects of Topiramate Alone on Other Drugs and Effects of Other Drugs on Topiramate Antiepileptic Drugs Potential interactions between topiramate and standard antiepileptic (AED) drugs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in Table 9. In Table 9, the second column (AED concentration) describes what happens to the concentration of the AED listed in the first column when topiramate is added. The third column (topiramate concentration) describes how the co-administration of a drug listed in the first column modifies the concentration of topiramate in experimental settings when topiramate was given alone [see Drug Interactions (7) ] . Table 9. Summary of AED Interactions with Topiramate AED Co-administered AED Concentration Topiramate Concentration NC = Less than 10% change in plasma concentration; NE = Not Evaluated; TPM = topiramate Phenytoin NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease Carbamazepine (CBZ) NC 40% decrease CBZ epoxide Is not administered but is an active metabolite of carbamazepine. NC NE Valproic acid 11% decrease 14% decrease Phenobarbital NC NE Primidone NC NE Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease Digoxin In a single-dose study, serum digoxin AUC was decreased by 12% with concomitant topiramate administration. The clinical relevance of this observation has not been established. Hydrochlorothiazide A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg q24h) and topiramate (96 mg q12h) when administered alone and concomitantly. The results of this study indicate that topiramate C max increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination [see Drug Interactions (7) and Warnings and Precautions (5.12) ] . Pioglitazone A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate (96 mg twice daily) and pioglitazone (30 mg daily) when administered alone and concomitantly for 7 days. A 15% decrease in the area under the concentration-time curve during a dosage interval at steady state (AUC τ,ss ) of pioglitazone with no alteration in maximum steady-state plasma drug concentration during a dosage interval (C max,ss ) was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in C max,ss and AUC τ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in C max,ss and AUC τ,ss of the active keto-metabolite [see Drug Interactions (7) ] . Glyburide A drug-drug interaction study conducted in patients with type 2 diabetes mellitus evaluated the steady-state pharmacokinetics of glyburide (5 mg/day) alone and concomitantly with topiramate (150 mg/day). There was a 22% decrease in C max and a 25% reduction in AUC 24 for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4- trans -hydroxyglyburide (M1), and 3- cis -hydroxyglyburide (M2), was reduced by 13% and 15%, and C max was reduced by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide. Lithium In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg/day; however, there was an observed increase in systemic exposure of lithium (27% for C max and 26% for AUC) following topiramate doses up to 600 mg/day. Haloperidol The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hours) in 13 healthy adults (6 males, 7 females). Amitriptyline There was a 12% increase in AUC and C max for amitriptyline (25 mg per day) in 18 normal subjects (9 males, 9 females) receiving 200 mg/day of topiramate [see Drug Interactions (7) ] . Sumatriptan Multiple dosing of topiramate (100 mg every 12 hrs) in 24 healthy volunteers (14 males, 10 females) did not affect the pharmacokinetics of single-dose sumatriptan either orally (100 mg) or subcutaneously (6 mg). Risperidone When administered concomitantly with topiramate at escalating doses of 100, 250, and 400 mg/day, there was a reduction in risperidone systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg/day doses of topiramate). No alterations of 9-hydroxyrisperidone levels were observed. Co-administration of topiramate 400 mg/day with risperidone resulted in a 14% increase in C max and a 12% increase in AUC 12 of topiramate. There were no clinically significant changes in the systemic exposure of risperidone plus 9-hydroxyrisperidone or of topiramate; therefore, this interaction is not likely to be of clinical significance. Propranolol Multiple dosing of topiramate (200 mg/day) in 34 healthy volunteers (17 males, 17 females) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg/day in 39 volunteers (27 males, 12 females) had no effect on the exposure to topiramate, at a dose of 200 mg/day of topiramate. Dihydroergotamine Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (12 males, 12 females) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg/day dose of topiramate in the same study. Diltiazem Co-administration of diltiazem hydrochloride extended-release with topiramate (150 mg/day) resulted in a 10% decrease in C max and a 25% decrease in diltiazem AUC, a 27% decrease in C max and an 18% decrease in des-acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem hydrochloride extended-release resulted in a 16% increase in C max and a 19% increase in AUC 12 of topiramate. Venlafaxine Multiple dosing of topiramate (150 mg/day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg extended release) did not affect the pharmacokinetics of topiramate.