PHENTERMINE AND TOPIRAMATE

Phentermine and topiramate extended-release capsules are comprised of immediate-release phentermine hydrochloride (expressed as the weight of the free base) and extended-release topiramate. Phentermine and topiramate extended-release capsules contain phentermine hydrochloride USP, a sympathomimetic amine anorectic, and topiramate USP, a sulfamate-substituted monosaccharide. Phentermine Hydrochloride, USP The chemical name of phentermine hydrochloride, USP is α,α-dimethylphenethylamine hydrochloride. The molecular formula is C 10 H 15 N • HCl and its molecular weight is 185.7 (hydrochloride salt) or 149.2 (free base). Phentermine hydrochloride, USP is a white, odorless, hygroscopic, crystalline powder that is soluble in water, methanol, and ethanol. Its structural formula is: Topiramate, USP Topiramate, USP is 2,3:4,5-di-O-isopropylidene-β-D-fructopyranose sulfamate. The molecular formula is C 12 H 21 NO 8 S and its molecular weight is 339.4. Topiramate, USP 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: Phentermine and topiramate extended-release capsules are for oral administration and available in four dosage strengths: 3.75 mg/23 mg (phentermine 3.75 mg and topiramate 23 mg extended-release) (equivalent to 4.67 mg of phentermine hydrochloride, USP). 7.5 mg/46 mg (phentermine 7.5 mg and topiramate 46 mg extended-release) (equivalent to 9.33 mg of phentermine hydrochloride, USP). 11.25 mg/69 mg (phentermine 11.25 mg and topiramate 69 mg extended-release) (equivalent to 14.0 mg of phentermine hydrochloride, USP). 15 mg/92 mg (phentermine 15 mg and topiramate 92 mg extended-release) (equivalent to 18.66 mg of phentermine hydrochloride, USP). Each capsule contains the following inactive ingredients: colloidal silicon dioxide, copovidone, ethylcellulose, gelatin, hypromellose, microcrystalline cellulose, polysorbate 80, povidone K-30, sugar spheres (which contain sucrose and corn starch), talc, and titanium dioxide. The 3.75 mg/23 mg strength also contains iron oxide red and iron oxide yellow. The 7.5 mg/46 mg strength also contains FD&C Blue #2 and iron oxide yellow. The 11.25 mg/69 mg strength also contains iron oxide yellow. The 15 mg/92 mg strength also contains iron oxide red. The imprinting ink contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac glaze. 1 1

Phentermine and topiramate extended-release capsules are 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 Limitations of Use The effect of phentermine and topiramate extended-release capsules on cardiovascular morbidity and mortality has not been established. The safety and effectiveness of phentermine and topiramate extended-release capsules in combination with other products intended for weight loss, including prescription drugs, over-the-counter drugs, and herbal preparations, have not been established. Phentermine and topiramate extended-release capsules are 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 phentermine and topiramate extended-release capsules on cardiovascular morbidity and mortality has not been established ( 1 ). The safety and effectiveness of phentermine and topiramate 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 ( 1 ).

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 Phentermine and Topiramate Extended-Release Capsules Prior to phentermine and topiramate extended-release capsule initiation and during treatment with phentermine and topiramate extended-release capsules, the following is recommended: Obtain a negative pregnancy test before initiating phentermine and topiramate extended-release capsules in patients who can become pregnant and monthly during phentermine and topiramate extended-release capsule therapy. Phentermine and topiramate extended-release capsules are 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 phentermine and topiramate extended-release capsule 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 phentermine and topiramate extended-release capsules are as follows: Take phentermine and topiramate extended-release capsules orally once daily in the morning with or without food. Avoid administration of phentermine and topiramate extended-release capsules in the evening due to the possibility of insomnia. The recommended starting dosage of phentermine and topiramate extended-release capsules 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 phentermine and topiramate extended-release capsules 7.5 mg/46 mg orally once daily. After 12 weeks of treatment with phentermine and topiramate extended-release capsules 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 phentermine and topiramate extended-release capsules 11.25 mg/69 mg orally once daily for 14 days; followed by an increase in the dosage to phentermine and topiramate extended-release capsules 15 mg/92 mg orally once daily. After 12 weeks of treatment with phentermine and topiramate extended-release capsules 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 phentermine and topiramate extended-release capsules [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 Phentermine and Topiramate Extended-Release Capsules 15 mg/92 mg Discontinue phentermine and topiramate extended-release capsules 15 mg/92 mg gradually by taking phentermine and topiramate extended-release capsules 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 phentermine and topiramate extended-release capsules 7.5 mg/46 mg once daily. Avoid use of phentermine and topiramate extended-release capsules in patients with end-stage renal disease on dialysis. 2.5 Recommended Dosage in Patients with Hepatic Impairment The recommended dosage of phentermine and topiramate extended-release capsules in patients with mild hepatic impairment (Child-Pugh 5 to 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 to 9), the maximum recommended dosage is phentermine and topiramate extended-release capsules 7.5 mg/46 mg orally once daily. Avoid use of phentermine and topiramate extended-release capsules in patients with severe hepatic impairment (Child-Pugh score 10 to 15).

Phentermine and topiramate extended-release capsules are contraindicated in patients: Who are pregnant [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.1 )] With glaucoma [see Warnings and Precautions ( 5.3 )] With hyperthyroidism Taking or within 14 days of stopping a monoamine oxidase inhibitors [see Drug Interactions ( 7 )] With known hypersensitivity to phentermine, topiramate or any of the excipients in phentermine and topiramate extended-release capsules, or idiosyncrasy to the sympathomimetic amines [see Adverse Reactions ( 6.2 )] . Pregnancy ( 4 ) Glaucoma ( 4 ) Hyperthyroidism ( 4 ) Taking or within 14 days of stopping monoamine oxidase inhibitors ( 4 ) Known hypersensitivity to any component of phentermine and topiramate extended-release capsules or idiosyncrasy to sympathomimetic amines ( 4 )

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 Phentermine and Topiramate Extended-Release Capsules [see Warnings and Precautions ( 5.9 )] Kidney Stones [see Warnings and Precautions ( 5.10 )] Oligohidrosis 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 Teva at 1-888-838-2872 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 phentermine and topiramate extended-release capsules 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 phentermine and topiramate extended-release capsule-treated adults and more frequently than in the placebo group are shown in Table 1. Table 1. Adverse Reactions Reported in ≥2% of Phentermine and Topiramate Extended-Release Capsule-Treated Adults with Overweight or Obesity and More Frequently than Placebo in Overall Study Population of 1 Year Duration Placebo (N = 1,561) Phentermine and Topiramate Extended-Release Capsules 3.75 mg/23 mg (N = 240) Phentermine and Topiramate Extended-Release Capsules 7.5 mg/46 mg (N = 498) Phentermine and Topiramate Extended-Release Capsules 15 mg/92 mg (N = 1,580) Adverse Reaction % % % % 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 phentermine and topiramate extended-release capsules 15 mg/92 mg or phentermine and topiramate extended-release capsules 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 phentermine and topiramate extended-release capsule-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 Phentermine and Topiramate Extended-Release Capsule-Treated Pediatric Patients Aged 12 to 17 Years and More Frequently than Placebo during 56 Weeks of Treatment Placebo (N = 56) Phentermine and Topiramate Extended-Release Capsules 7.5 mg/46 mg (N = 54) Phentermine and Topiramate Extended-Release Capsules 15 mg/92 mg (N = 113) Adverse Reaction % % % 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 phentermine and topiramate extended-release capsule-treated 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=1,561 n (%) Phentermine and Topiramate Extended-Release Capsules 3.75 mg/23 mg N=240 n (%) Phentermine and Topiramate Extended-Release Capsules 7.5 mg/46 mg N=498 n (%) Phentermine and Topiramate Extended-Release Capsules 15 mg/92 mg N=1,580 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 (%) Phentermine and Topiramate Extended-Release Capsules 7.5 mg/46 mg N=54 n (%) Phentermine and Topiramate Extended-Release Capsules 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). Phentermine and topiramate extended-release capsule-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 phentermine and topiramate extended-release capsules reporting one or more adverse reactions related to mood and sleep disorders was 15% and 21% with phentermine and topiramate extended-release capsules 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 phentermine and topiramate extended-release capsules 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 phentermine and topiramate extended-release capsules 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 phentermine and topiramate extended-release capsules 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 phentermine and topiramate extended-release capsule-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 phentermine and topiramate extended-release capsules in adults, the proportion of patients who experienced one or more cognitive-related adverse reactions was 5.0% for phentermine and topiramate extended-release capsules 7.5 mg/46 mg and 7.6% for phentermine and topiramate 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 occurred at any time during treatment with phentermine and topiramate extended-release capsules. Slowing of Linear Growth Phentermine and topiramate extended-release capsules are 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 phentermine and topiramate extended-release capsule- and placebo-treated patients; however, a lower height velocity of -1.3 to -1.4 cm/year was observed in phentermine and topiramate extended-release capsule-treated compared to placebo-treated patients. Decrease in Bone Mineral Density Phentermine and topiramate extended-release capsules are 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 phentermine and topiramate extended-release capsules 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 phentermine and topiramate extended-release capsules 7.5 mg/46 mg-treated patients and 30% of phentermine and topiramate extended-release capsules 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 phentermine and topiramate extended-release capsules 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 phentermine and topiramate extended-release capsules in adults, the incidence of nephrolithiasis was 0.2% for phentermine and topiramate extended-release capsules 7.5 mg/46 mg and 1.2% for phentermine and topiramate extended-release capsules 15 mg/92 mg, compared to 0.3% for placebo. Laboratory Abnormalities Serum Bicarbonate In the 1-year controlled trials of phentermine and topiramate extended-release capsules 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 phentermine and topiramate extended-release capsules 7.5 mg/46 mg and 12.8% for phentermine and topiramate 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 0.2% for phentermine and topiramate extended-release capsules 7.5 mg/46 mg dose and 0.7% for phentermine and topiramate extended-release capsules 15 mg/92 mg dose, compared to 0.1% for placebo. In a pediatric clinical trial, 60 to 70% phentermine and topiramate extended-release capsule-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 phentermine and topiramate extended-release capsules 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 phentermine and topiramate extended-release capsules 7.5 mg/46 mg dose and 4.9% for phentermine and topiramate 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 0.2% for phentermine and topiramate extended-release capsules 7.5 mg/46 mg dose and 0.7% for phentermine and topiramate 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 0.2% receiving phentermine and topiramate extended-release capsules 7.5 mg/46 mg dose and 0.1% receiving phentermine and topiramate extended-release capsules 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 phentermine and topiramate extended-release capsules 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 phentermine and topiramate extended-release capsules 7.5 mg/46 mg and 8.4% for phentermine and topiramate extended-release capsules 15 mg/92 mg, compared to 2.0% for placebo; 17% of pediatric patients treated with phentermine and topiramate extended-release capsules 7.5 mg/46 mg or phentermine and topiramate extended-release capsules 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 phentermine and topiramate extended-release capsules 7.5 mg/46 mg and 2.8% receiving phentermine and topiramate extended-release capsules 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 phentermine and topiramate extended-release capsules) and 14% in patients taking topiramate at 50 mg/day (0.6 times the maximum recommended dosage of phentermine and topiramate extended-release capsules), 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 phentermine and topiramate extended-release capsules, 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. Phentermine and Topiramate Extended-Release Capsules 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

Table 5 displays clinically significant drug interactions with phentermine and topiramate extended-release capsules. Table 5. Clinically Significant Drug Interactions with Phentermine and Topiramate Extended-Release Capsules Monoamine Oxidase Inhibitors Clinical Impact Concomitant use of phentermine with monoamine oxidase inhibitors (MAOIs) increases the risk of hypertensive crisis. Intervention Concomitant use of phentermine and topiramate extended-release capsules is contraindicated during MAOI treatment and within 14 days of stopping an MAOI. Oral Contraceptives Clinical Impact Coadministration of multiple-dose phentermine and topiramate extended-release capsules 15 mg/92 mg once daily with a single dose of oral contraceptive containing 35 mcg ethinyl estradiol (estrogen component) and 1 mg norethindrone (progestin component), in obese otherwise healthy volunteers, decreased the exposure of ethinyl estradiol by 16% and increased the exposure of norethindrone by 22% [see Clinical Pharmacology ( 12.3 )] . Although this interaction is not anticipated to increase the risk of pregnancy, irregular bleeding (spotting) may occur more frequently due to both the increased exposure to the progestin and lower exposure to the estrogen, which tends to stabilize the endometrium. Intervention Inform patients not to discontinue their combination oral contraceptive if spotting occurs, but to notify their health care provider if the spotting is troubling to them. CNS Depressants Including Alcohol Clinical Impact The concomitant use of alcohol or CNS depressant drugs (e.g., barbiturates, benzodiazepines, and sleep medications) with phentermine or topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Intervention Advise patients not to drive or operate machinery until they have gained sufficient experience on phentermine and topiramate extended-release capsules to gauge whether it adversely affects their mental performance, motor performance, and/or vision. Caution patients against excessive alcohol intake when taking phentermine and topiramate extended-release capsules. Consider phentermine and topiramate extended-release capsule dosage reduction or discontinuation if cognitive dysfunction persists [see Warnings and Precautions ( 5.5 )] . Non-Potassium Sparing Diuretics Clinical Impact Concurrent use of phentermine and topiramate extended-release capsules 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. Intervention When phentermine and topiramate extended-release capsules are used concomitantly with non-potassium-sparing diuretics, measure potassium before and during phentermine and topiramate extended-release capsule treatment [see Warnings and Precautions ( 5.12 ) and Clinical Pharmacology ( 12.3 )] . Antiepileptic Drugs Clinical Impact 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). Intervention Consider measuring blood ammonia in patients in whom the onset of hypothermia or encephalopathy has been reported [see Clinical Pharmacology ( 12.3 )] . Carbonic Anhydrase Inhibitors Clinical Impact Concomitant use of topiramate with any other carbonic anhydrase inhibitor may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Intervention Avoid the use of phentermine and topiramate extended-release capsules with other drugs that inhibit carbonic anhydrase. If concomitant use of phentermine and topiramate extended-release capsules with another carbonic anhydrase inhibitor is unavoidable, monitor patient for the appearance or worsening of metabolic acidosis [see Warnings and Precautions ( 5.7 , 5.10 )] . Pioglitazone Clinical Impact 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. Intervention Consider increased glycemic monitoring when using pioglitazone and phentermine and topiramate extended-release capsules concomitantly [see Clinical Pharmacology ( 12.3 )] . Amitriptyline Clinical Impact Some patients may experience a large increase in amitriptyline concentration in the presence of topiramate. Intervention Any adjustments in amitriptyline dose when used with phentermine and topiramate extended-release capsules should be made according to the patient's clinical response and not on the basis of amitriptyline levels [see Clinical Pharmacology ( 12.3 )] . Oral Contraceptives: Altered exposure of progestin and estrogen may cause irregular bleeding, but not increased risk of pregnancy. Advise patients not to discontinue oral contraceptives if spotting occurs ( 7 ). CNS Depressants Including Alcohol: May potentiate CNS depressant effects. Avoid excessive use of alcohol ( 7 ). Non-potassium Sparing Diuretics: May potentiate hypokalemia. Measure potassium before and during treatment ( 7 ).