1 INDICATIONS AND USAGE 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: Adult patients 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: Adult patients with obesity ( 1 ) 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 ( 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 ).

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 Phentermine and Topiramate Extended-Release Capsules [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 )] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions [see Warnings and Precautions ( 5.13 )] Serious Skin Reactions [see Warnings and Precautions ( 5.14 )] Anaphylaxis and Angioedema [see Warnings and Precautions ( 5.15 )] Allergic Reactions Due to Inactive Ingredients FD&C Yellow No.

5 [see Warnings and Precautions ( 5.16 )] 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).

To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories, Inc.

at 1-888-375-3784 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 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 [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-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-Treated Adults with Overweight or Obesity and More Frequently than Placebo in Overall Study Population of 1 Year Duration Adverse Reaction Placebo (N = 1561) % Phentermine and topiramate extended-release 3.75 mg/23 mg (N = 240) % Phentermine and topiramate extended-release 7.5 mg/46 mg (N = 498) % Phentermine and topiramate extended-release 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 Increase in Heart Rate In adult clinical trials, there was a higher incidence of heart rate elevations observed in phentermine and topiramate extended-release-treated compared to placebo-treated patients.

In clinical trials, a higher percentage of phentermine and topiramate extended-release-treated adult patients experienced heart rate increases from baseline of more than 5, 10, 15, and 20 bpm compared to placebo-treated patients.

Table 3 provides the numbers and percentages of adult patients 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 (%) Phentermine and topiramate extended-release 3.75 mg/23 mg N = 240 n (%) Phentermine and topiramate extended-release 7.5 mg/46 mg N = 498 n (%) Phentermine and topiramate extended-release 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) 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).

Phentermine and topiramate extended-release-treated adult patients discontinued treatment due to these adverse reactions (1% for paraesthesia and 0.6% for dysgeusia).

Mood and Sleep Disorders The proportion of adult patients in 1-year controlled trials of phentermine and topiramate extended-release reporting one or more adverse reactions related to mood and sleep disorders was 15% and 21% with phentermine and topiramate extended-release 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 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 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 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.

Cognitive Disorders In the 1-year controlled trials of phentermine and topiramate extended-release in adults, the proportion of patients who experienced one or more cognitive-related adverse reactions was 5% for phentermine and topiramate extended-release 7.5 mg/46 mg and 7.6% for phentermine and topiramate extended-release 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.

Nephrolithiasis In the 1-year controlled trials of phentermine and topiramate extended-release in adults, the incidence of nephrolithiasis was 0.2% for phentermine and topiramate extended-release 7.5 mg/46 mg and 1.2% for phentermine and topiramate extended-release 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 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 7.5 mg/46 mg, and 12.8% for phentermine and topiramate extended-release 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 7.5 mg/46 mg dose, and 0.7% for phentermine and topiramate extended-release 15 mg/92 mg dose, compared to 0.1% for placebo.

Serum Potassium In the 1-year controlled trials of phentermine and topiramate extended-release 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 7.5 mg/46 mg dose and 4.9% for phentermine and topiramate extended-release 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 7.5 mg/46 mg dose and 0.7% for phentermine and topiramate extended-release 15 mg/92 mg dose, compared to 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 7.5 mg/46 mg dose and 0.1% receiving phentermine and topiramate extended-release 15 mg/92 mg dose, compared to 0% receiving placebo.

Serum Creatinine In the 1-year controlled trials of phentermine and topiramate extended-release in adults there was an increase in serum creatinine from baseline, peaking between Week 4 to 8 in adult 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 7.5 mg/46 mg and 8.4% for phentermine and topiramate extended-release 15 mg/92 mg, compared to 2% for placebo.

Increases in serum creatinine of greater than or equal to 50% over baseline occurred in 2% of adult subjects receiving phentermine and topiramate extended-release 7.5 mg/46 mg and 2.8% receiving phentermine and topiramate extended-release 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) and 14% in patients taking topiramate at 50 mg/day (0.6 times the maximum recommended dosage of phentermine and topiramate extended-release), 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,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 Hypersensitivity: immediate hypersensitivity reactions (including anaphylaxis and angioedema, delayed hypersensitivity reactions (including facial swelling, lip swelling, periorbital swelling, tongue swelling) anaphylaxis, angioedema, facial swelling, lip swelling, tongue swelling, periorbital edema Dermatologic : bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), pemphigus, urticaria 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