Phentermine and Topiramate Extended-release

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 ).

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. 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 capsules 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 capsules 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 capsules 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. If an adult patient has not lost at least 3% of baseline body weight, 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. If an adult patient has not lost at least 5% of baseline body weight, 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. 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 ( 5.8 ), 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).

WARNINGS AND PRECAUTIONS • Embryo-Fetal Toxicity: Can cause fetal harm. Inpatients who can become pregnant, a negative pregnancy test is recommended before initiating phentermine and topiramate extended-release capsules and monthly during therapy; advise use of effective contraception. Phentermine and topiramate extended-release capsules are available through a limited program under a Risk Evaluation and Mitigation Strategy (REMS) ( 5.1 ). • Suicidal Behavior and Ideation : Monitor for depression or suicidal thoughts. Discontinue phentermine and topiramate extended-release capsules if symptoms develop ( 5.2 ). • Risk of Ophthalmologic Adverse Reactions : Acute myopia and secondary angle closure glaucoma have been reported. Immediately discontinue phentermine and topiramate extended-release capsules if symptoms develop. Consider phentermine and topiramate extended-release capsules discontinuation if visual field defects occur. ( 5.3 ). • Mood and Sleep Disorders : Consider dosage reduction or discontinuation for clinically significant or persistent mood or sleep disorder symptoms ( 5.4 ). • Cognitive Impairment: May cause disturbances in attention or memory, or speech/language problems. Caution patients about operating automobiles or hazardous machinery when starting treatment ( 5.5 ). • Slowing of Linear Growth : Consider dosage reduction or discontinuation if pediatric patients are not growing or gaining height as expected ( 5.6 ). • Metabolic Acidosis: Measure electrolytes before and during treatment. If persistent metabolic acidosis develops, reduce dosage or discontinue phentermine and topiramate extended-release capsules ( 5.7 ). • Decrease in Renal Function: Measure creatinine before and during treatment. For persistent creatinine elevations, reduce dosage or discontinue phentermine and topiramate extended-release capsules ( 5.8 ). • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity, serious skin reactions (SJS or TEN), anaphylaxis, and angioedema: Discontinue phentermine and topiramate extended-release capsules if an alternative etiology cannot be established ( 5.13 , 5.14, 5.15 ). 5.1 Embryo-Fetal Toxicity Phentermine and topiramate extended-release capsules can cause fetal harm. Data from pregnancy registries and epidemiologic studies indicate that a fetus exposed to topiramate in the first trimester of pregnancy has an increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA). When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring. A negative pregnancy test is recommended before initiating phentermine and topiramate extended-release capsules treatment in patients who can become pregnant and monthly during phentermine and topiramate extended-release capsules therapy. Advise patients who can become pregnant of the potential risk to a fetus and to use effective contraception during phentermine and topiramate extended-release capsules therapy [see Use in Specific Populations ( 8.1 , 8.3 )] . Phentermine and Topiramate Extended-Release Capsules Risk Evaluation and Mitigation Strategy (REMS) Because of the teratogenic risk associated with phentermine and topiramate extended-release capsules therapy, phentermine and topiramate extended-release capsules are available through a limited program under the REMS. Under the phentermine and topiramate extended-release capsules REMS, only certified pharmacies may distribute phentermine and topiramate extended-release capsules. Further information is available at www.PhenTopREMS.com or by telephone at 1‐800‐269‐6816. 5.2 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including topiramate, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. 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% 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 in the clinical trials analyzed. Monitor all patients for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Discontinue phentermine and topiramate extended-release capsules in patients who experience suicidal thoughts or behaviors [see Warnings and Precautions ( 5.9 )]. Avoid phentermine and topiramate extended-release capsules in patients with a history of suicidal attempts or active suicidal ideation. 5.3 Risk of Ophthalmological Adverse Reactions 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. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, mydriasis, anterior chamber shallowing, ocular hyperemia (redness), choroidal detachments, retinal pigment epithelial detachments, macular striae, and increased intraocular pressure. 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. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of phentermine and topiramate extended-release capsules as rapidly as possible in consultation with the treating physician. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent loss of vision. Visual Field Defects Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during treatment, consider discontinuing phentermine and topiramate extended-release capsules. 5.4 Mood and Sleep Disorders Phentermine and topiramate 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

CONTRAINDICATIONS 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 )] • Wjith 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 amine. Anaphylaxis and angioedema have occurred with topiramate [see Warnings and Precautions ( 5.15 )]. • 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 )

DRUG INTERACTIONS 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 are contraindicated during MAOI treatment and within 14 days of stopping an MAOI. Oral Contraceptives Clinical Impact Co-administration of multiple-dose phentermine and topiramate extended-release 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 capsules 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 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 capsules 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 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 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 )..

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, com

Mechanism of Action Phentermine is a sympathomimetic amine with pharmacologic activity similar to the prototype drugs of this class used in obesity, amphetamine (d- and d/l-amphetamine). Drugs of this class used in obesity are commonly known as "anorectics" or "anorexigenics." The effect of phentermine on weight reduction and long-term maintenance of body weight is likely mediated by release of catecholamines in the hypothalamus, resulting in reduced appetite and decreased food consumption, but other metabolic effects may also be involved. The exact mechanism of action is not known. The precise mechanism of action of topiramate on weight reduction and long-term maintenance of body weight is not known. Topiramate’s effect on weight reduction and long-term maintenance of body weight may be due to its effects on both appetite suppression and satiety enhancement, induced by a combination of pharmacologic effects including augmenting the activity of the neurotransmitter gamma-aminobutyrate, modulation of voltage-gated ion channels, inhibition of AMPA/kainite excitatory glutamate receptors, or inhibition of carbonic anhydrase.