PHENTERMINE AND TOPIRAMATE EXTENDED-RELEASE 7.5 MG-46 MG CAPSULE | RED (RED OPAQUE CAP), WHITE (WHITE OPAQUE BODY) CAPSULE DRL 625 DR.REDDYS LABORATORIES INC 4359862530

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). Serious Skin Reactions: Phentermine and topiramate extended-release capsules should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related (5.13).

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. Pediatric use information is approved for Vivus LLC's Qsymia (phentermine and topiramate) extended-release capsules. However, due to Vivus LLC's marketing exclusivity rights, this drug product is not labeled with that information.

Hyperchloremic, non-anion gap, metabolic acidosis (decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) has been reported in patients treated with phentermine and topiramate extended-release capsules [see Adverse Reactions ( 6.1 )]. Manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures. Chronic metabolic acidosis in pediatric patients may also reduce growth rates, which may decrease the maximal height achieved. Conditions or therapies that predispose to acidosis (i.e., renal disease, severe respiratory disorders, status epilepticus, diarrhea, surgery, or ketogenic diet) may be additive to the bicarbonate lowering effects of phentermine and topiramate extended-release. Concomitant use of phentermine and topiramate extended-release capsules and a carbonic anhydrase inhibitor may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation [see Warnings and Precautions ( 5.10 )]. Avoid use of phentermine and topiramate extended-release capsules with other carbonic anhydrase inhibitors. If concomitant use of phentermine and topiramate extended-release capsules with another carbonic anhydrase inhibitor is unavoidable, the patient should be monitored for the appearance or worsening of metabolic acidosis. Measure electrolytes including serum bicarbonate prior to starting phentermine and topiramate extended-release capsules and during phentermine and topiramate extended-release treatment. In phentermine and topiramate extended-release clinical trials, the peak reduction in serum bicarbonate typically occurred within 4 weeks of titration to the assigned dose, and in most patients, there was a correction of bicarbonate by week 56, without any dosage reduction. However, if persistent metabolic acidosis develops while taking phentermine and topiramate extended-release capsules, reduce the dosage or discontinue phentermine and topiramate extended-release capsules [see Warnings and Precautions ( 5.9 )].

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/m2] 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 adults 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. Pediatric use information is approved for Vivus LLC's Qsymia (phentermine and topiramate) extended-release capsules. However, due to Vivus LLC's marketing exclusivity rights, this drug product is not labeled with that information.

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 Cmax 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)..

Risk Summary Phentermine and topiramate extended-release capsules are contraindicated in pregnant patients. The use of phentermine and topiramate extended-release capsules can cause fetal harm and weight loss offers no clear clinical benefit to a pregnant patient (see Clinical Considerations). Available data from pregnancy registries and epidemiologic studies indicate an increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being SGA in infants exposed in utero to topiramate (see Data). When phentermine and topiramate were co-administered to rats at doses of 3.75 and 25 mg/kg, respectively [approximately 2 times the maximum recommended human dose (MRHD) based on area under the curve (AUC)], or at the same dose to rabbits (approximately 0.1 times and 1 time, respectively, the clinical exposures at the MRHD based on AUC), there were no drug-related malformations. However, structural malformations, including craniofacial defects and reduced fetal weights occurred in offspring of multiple species of pregnant animals administered topiramate at clinically relevant doses (see Data). Advise pregnant women of the potential risk to a fetus. Clinical Considerations Disease Associated Maternal and/or Embryo/Fetal Risk Weight loss during pregnancy may result in fetal harm. Appropriate weight gain based on pre-pregnancy weight is currently recommended for all pregnant patients, including those who are already overweight or obese, due to the obligatory weight gain that occurs in maternal tissues during pregnancy. Maternal obesity increases the risk for congenital malformations, including neural tube defects, cardiac malformations, oral clefts, and limb reduction defects. Fetal/Neonatal Adverse Reactions Phentermine and topiramate extended-release capsules can cause metabolic acidosis [see Warnings and Precautions ( 5.7 )]. The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus ability to tolerate labor. Data Human Data Data evaluating the risk of major congenital malformations, oral clefts, and being SGA with topiramate exposure during pregnancy is available from the North American Antiepileptic Drug (NAAED) Pregnancy Registry and from several larger retrospective epidemiologic studies. Major Congenital Malformations The NAAED Pregnancy Registry indicates an increased risk of major congenital malformations, including but not limited to oral clefts in infants exposed to topiramate during the first trimester of pregnancy. Other than oral clefts, no specific pattern of major congenital malformations or grouping of major congenital malformation types were observed. In the NAAED pregnancy registry, when topiramate-exposed infants with only oral clefts were excluded, the prevalence of major congenital malformations (4.1%) was higher than that in infants exposed to a reference antiepileptic drug (AED) (1.8%) or in infants with mothers without epilepsy and without exposure to AEDs (1.1%). Oral Clefts In the NAAED Pregnancy Registry, the prevalence of oral clefts among topiramate-exposed infants (1.4%) was higher than the prevalence in infants exposed to a reference AED (0.3%) or the prevalence in infants with mothers without epilepsy and without exposure to AEDs (0.11%). It was also higher than the background prevalence in United States (0.17%) as estimated by the Centers for Disease Control and Prevention (CDC). The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 12.5 (95% Confidence Interval [CI] 5.9-26.37) as compared to the risk in a background population of untreated women. The UK Epilepsy and Pregnancy Register reported a prevalence of oral clefts among infants exposed to topiramate monotherapy (3.2%) that was 16 times higher than the background rate in the UK (0.2%). Larger retrospective epidemiology studies showed that topiramate monotherapy exposure in pregnancy is associated with an approximately two to five-fold increased risk of oral clefts. The FORTRESS study found an excess risk of 1.5 (95% CI = -1.1 to 4.1) oral cleft cases per 1,000 infants exposed to topiramate during the first trimester. Small for Gestational Age Data from the NAAED Pregnancy Registry and population-based birth registry cohort indicate that exposure to topiramate in utero is associated with an increased risk of SGA newborns (birth weight <10th percentile). In the NAAED Pregnancy Registry, 19.7% of topiramate-exposed newborns were SGA compared to 7.9% of newborns exposed to a reference AED and 5.4% of newborns of mothers without epilepsy and without AED exposure. In the medical Birth Registry of Norway, a population-based pregnancy registry, 25% of newborns in the topiramate monotherapy exposure group were SGA compared to 9% in the comparison group unexposed to AEDs. The long-term consequences of the SGA findings are not known. Animal Data Phentermine/Topiramate Embryo-fetal development studies have been conducted in rats and rabbits with combination phentermine and topiramate treatment. Phentermine and topiramate co-administered to rats during the period of organogenesis (gestation day (GD) 6 through 17) caused reduced fetal body weights but did not cause fetal malformations at the maximum dose of 3.75 mg/kg phentermine and 25 mg/kg topiramate [approximately 2 times the maximum recommended human dose (MRHD) based on area under the curve (AUC) estimates for each active ingredient]. In a similar study in rabbits in which the same doses were administered from GD 6 through 18, no effects on embryo-fetal development were observed at approximately 0.1 times (phentermine) and 1 time (topiramate) clinical exposures at the MRHD based on AUC. Significantly lower maternal body weight gain was recorded at these doses in rats and rabbits. A pre- and post-natal development study was conducted in rats with combination phentermine and topiramate treatment. There were no adverse maternal or offspring effects in rats treated throughout organogenesis and lactation with 1.5 mg/kg/day phentermine and 10 mg/kg/day topiramate (approximately 2- and 3-times clinical exposures at the MRHD, respectively, based on AUC). Treatment with higher doses of 11.25 mg/kg/day phentermine and 75 mg/kg/day topiramate (approximately 5 and 6 times maximum clinical doses based on AUC, respectively) caused reduced maternal body weight gain and offspring toxicity. Offspring effects included lower pup survival after birth, increased limb and tail malformations, reduced pup body weight and delayed growth, development, and sexual maturation without affecting learning, memory, or fertility and reproduction. The limb and tail malformations were consistent with results of animal studies conducted with topiramate alone. Phentermine Animal reproduction studies have not been conducted with phentermine. Limited data from studies conducted with the phentermine/topiramate combination indicate that phentermine alone was not teratogenic but resulted in lower body weight and reduced survival of offspring in rats at 5-fold the MRHD of phentermine and topiramate extended-release, based on AUC. Topiramate Topiramate causes developmental toxicity, including teratogenicity, at clinically relevant doses in multiple animal species. Developmental toxicity, including teratogenicity, occurred at clinically relevant doses in multiple animal species in which topiramate was administered during the period of organogenesis (GD 6 to 15 in rodents, GD 6 to 18 in rabbits. In these studies, fetal malformations (primarily craniofacial defects such as cleft palate), limb malformations (ectrodactyly, micromelia, and amelia), rib/vertebral column anomalies, and/or reduced fetal weights were observed at dosages > 20 mg/kg in mice (approximately 2 times the MRHD of topiramate in phentermine and topiramate extended-release 15 mg/92 mg on a mg/m2 basis), 20 mg/kg in rats (2 times the MRHD of phentermine and topiramate extended-release based on estimated AUC), and 35 mg/kg in rabbits (2 times the MRHD based on estimated AUC). When rats were administered topiramate from GD 15 through lactation day 20, reductions in pre- and/or post-weaning weights occurred at dosages > 2 mg/kg (2 times the MRHD of phentermine and topiramate extended-release based on estimated AUC).

In the event of a significant overdose with phentermine and topiramate extended-release capsules, if the ingestion is recent, the stomach should be emptied immediately by gastric lavage or by induction of emesis. Appropriate supportive treatment should be provided according to the patient s clinical signs and symptoms. In the event of an overdose of phentermine and topiramate extended-release capsules, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Acute overdose of phentermine may be associated with restlessness, tremor, hyperreflexia, rapid respiration, confusion, aggressiveness, hallucinations, and panic states. Fatigue and depression usually follow the central stimulation. Cardiovascular effects include arrhythmia, hypertension or hypotension, and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning usually terminates in convulsions and coma. Manifestations of chronic intoxication with anorectic drugs include severe dermatoses, marked insomnia, irritability, hyperactivity, and personality changes. A severe manifestation of chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia. Management of acute phentermine intoxication is largely symptomatic and includes lavage and sedation with a barbiturate. Acidification of the urine increases phentermine excretion. Intravenous phentolamine has been suggested for possible acute, severe hypertension, if this complicates phentermine overdosage. Topiramate overdose has resulted in severe metabolic acidosis. Other signs and symptoms include convulsions, drowsiness, speech disturbance, blurred vision, diplopia, impaired mentation, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness, and depression. The clinical consequences were not severe in most cases, but deaths have been reported after overdoses involving topiramate. A patient who ingested a dose between 96 and 110 grams topiramate was admitted to hospital with coma lasting 20 to 24 hours followed by full recovery after 3 to 4 days. Hemodialysis is an effective means of removing topiramate from the body.

Phentermine and topiramate extended-release capsules are comprised of immediate-release phentermine hydrochloride, USP (expressed as the weight of the free base) and extended-release topiramate, USP. 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 , -dimethylphenethylamine hydrochloride. The molecular formula is C10H16ClN and its molecular weight is 185.69 g mol-1 (hydrochloride salt) or 149.2 (free base). Phentermine hydrochloride, USP is a white, odourless, hygroscopic, crystalline powder that is soluble in water and lower alcohols. It is also slightly soluble in chloroform and insoluble in ether. Its structural formula is: Topiramate, USP Topiramate, USP is 2,3:4,5-di-O-isopropylidene- -D-fructopyranose sulfamate. The molecular formula is C12H21NO8S and its molecular weight is 339.36.Topiramate, USP is a white to off-white powder. It is freely soluble in dichloromethane. Its structural formula is: Phentermine and Topiramate Extended-Release Capsules 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 USP, 23 mg) (equivalent to 4.665 mg of Phentermine Hydrochloride, USP). 7.5 mg/46 mg (phentermine 7.5 mg and topiramate USP, 46 mg) (equivalent to 9.33 mg of Phentermine Hydrochloride, USP). 11.25 mg/69 mg (phentermine 11.25 mg and topiramate USP, 69 mg) (equivalent to 14 mg of Phentermine Hydrochloride, USP). 15 mg/92 mg (phentermine 15 mg and topiramate USP, 92 mg) (equivalent to 18.66 mg of Phentermine Hydrochloride, USP). Each capsule contains the following inactive ingredients: ethocel, gelatin, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, talc and titanium dioxide. In addition, the 7.5 mg/46 mg contains FD&C Red No. 40 and FD&C Yellow #6, 11.25 mg/69 mg contains FD&C Yellow #5 and FD&C Blue #1, 15 mg/92 mg contains FD&C Yellow #6 and D&C Red #28. The imprinting ink opacode Black contains shellac, iron oxide black, propylene glycol, FD&C Blue #2, FD&C Red No. 40, D&C Yellow #10, FD&C Blue #1..

Absorption Phentermine Upon oral administration of a single phentermine and topiramate extended-release capsule 15 mg/92 mg, the resulting mean plasma phentermine maximum concentration (Cmax), time to Cmax (Tmax), area under the concentration curve from time zero to the last time with measurable concentration (AUC0-t), and area under the concentration curve from time zero to infinity (AUC0 ) are 49.1 ng/mL, 6 hr, 1,990 ng hr/mL, and 2,000 ng hr/mL, respectively. A high fat meal does not affect phentermine pharmacokinetics for phentermine and topiramate extended-release 15 mg/92 mg. Phentermine pharmacokinetics are approximately dose-proportional from phentermine and topiramate extended-release 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 Cmax are both approximately 2.5. Topiramate Upon oral administration of a single phentermine and topiramate extended-release capsule 15 mg/92 mg, the resulting mean plasma topiramate Cmax, Tmax, AUC0-t, and AUC0- , are 1,020 ng/mL, 9 hr, 61,600 ng hr/mL, and 68,000 ng hr/mL, respectively. A high fat meal does not affect topiramate pharmacokinetics for phentermine and topiramate extended-release 15 mg/92 mg. Topiramate pharmacokinetics are approximately dose-proportional from phentermine and topiramate extended-release 3.75 mg/23 mg to phentermine 15 mg/topiramate 100 mg. Upon dosing phentermine 15 mg/topiramate 100 mg fixed dose combination capsule to steady state, the mean topiramate accumulation ratios for AUC and Cmax are both approximately 4. 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 to 41% plasma protein bound over the blood concentration range of 0.5 to 250 mcg/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 phentermine and topiramate extended-release 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 AUC0-inf was 91%, 45%, and 22% higher in patients with severe, moderate, and mild renal impairment, respectively; phentermine Cmax was 2% to 15% higher. Compared to healthy volunteers, topiramate AUC0-inf was 126%, 85%, and 25% higher for patients with severe, moderate, and mild renal impairment, respectively; topiramate Cmax was 6% to 17% higher. An inverse relationship between phentermine or topiramate Cmax or AUC and creatinine clearance was observed. Phentermine and topiramate extended-release capsules have 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 phentermine and topiramate extended-release 15 mg/92 mg in healthy volunteers with normal hepatic function compared with patients with mild (Child-Pugh score 5 to 6) and moderate (Child-Pugh score 7 to 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. Phentermine and topiramate extended-release capsules have not been studied in patients with severe hepatic impairment (Child-Pugh score 10 to 15) [see Dosage and Administration ( 2.5 ), and Use in Specific Populations ( 8.7 )]. 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 Cmax *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% **15 mg/92 mg dose QD for 15 days Oral contraceptive single dose norethindrone 1 mg ethinyl estradiol 35 mcg 16% 16% 22% 8% * A single study examined the effect of multiple-dose phentermine and topiramate extended-release 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/m2 and range of 22.2 to 32.7 kg/m2). 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 to 5, 6 to 10, 11 to 28, 29, 30 to 34, and 35 to 39, respectively. The significance of these interaction is unknown. **See Drug Interactions ( 7 ) 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 Cmax Topiramate 92 mg single dose 15 mg phentermine single dose 42% 13% Phentermine 15 mg single dose 92 mg topiramate single dose 6% 2% *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 grams QD 15 mg/92 mg dose QD for 11 days phentermine topiramate 0.3% 0.7% 4% 3% * The same single study examined the effect of multiple-dose 500 mg metformin twice daily, a single-dose 2 grams 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/m2 and range of 22.2 to 32.7 kg/m2). 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 to 5, 6 to 10, 11 to 28, 29, 30 to 34, and 35 to 39, respectively. 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 Phenytoin NC or 25% increasea 48% decrease Carbamazepine (CBZ) NC 40% decrease CBZ epoxideb 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 a Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. b Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration; NE = Not Evaluated; TPM = topiramate . 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 Cmax 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 ,ss) of pioglitazone with no alteration in maximum steady-state plasma drug concentration during a dosage interval (Cmax,ss) was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in Cmax,ss and AUC ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in Cmax,ss and AUC ,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 Cmax and a 25% reduction in AUC24 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 Cmax 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 Cmax 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 Cmax 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 Cmax and a 12% increase in AUC12 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 Cmax and a 25% decrease in diltiazem AUC, a 27% decrease in Cmax 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 Cmax and a 19% increase in AUC12 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. Pediatric use information is approved for Vivus LLC's Qsymia (phentermine and topiramate) extended-release capsules. However, due to Vivus LLC's marketing exclusivity rights, this drug product is not labeled with that information.

Phentermine/Topiramate No animal studies have been conducted with the combination of phentermine/topiramate to evaluate carcinogenesis, mutagenesis, or impairment of fertility. The following data are based on findings in studies performed individually with phentermine or topiramate, phentermine and topiramate extended-release capsule's two active ingredients. Phentermine Phentermine was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a chromosomal aberration test in Chinese hamster lung (CHL-K1) cells, or an in vivo micronucleus assay. Rats were administered oral doses of 3, 10, and 30 mg/kg/day phentermine for 2 years. There was no evidence of carcinogenicity at the highest dose of phentermine (30 mg/kg) which is approximately 11 to 15 times the maximum recommended clinical dose of phentermine and topiramate extended-release 15 mg/92 mg based on AUC exposure. No animal studies have been conducted with phentermine to determine the potential for impairment of fertility. Topiramate Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitro and in vivo assays. Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increase unscheduled DNA synthesis in rat hepatocytes in vitro; and it did not increase chromosomal aberrations in human lymphocytes in vitro or in rat bone marrow in vivo. An increase in urinary bladder tumors was observed in mice given topiramate (20, 75, and 300 mg/kg) in the diet for 21 months. The elevated bladder tumor incidence, which was statistically significant in males and females receiving 300 mg/kg, was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. Plasma exposures in mice receiving 300 mg/kg were approximately 2 to 4 times steady-state exposures measured in patients receiving topiramate monotherapy at the MRHD of phentermine and topiramate extended-release 15 mg/92 mg. The relevance of this finding to human carcinogenic risk is uncertain. No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/kg (approximately 4 to 10 times the MRHD of phentermine and topiramate extended-release based on AUC estimates). No adverse effects on male or female fertility were observed in rats at doses up to 100 mg/kg (approximately 4 to 8 times male and female MRHD exposures of phentermine and topiramate extended-release based on AUC).

Clinical Studies in Adults The effect of phentermine and topiramate extended-release on weight loss in conjunction with reduced caloric intake and increased physical activity was studied in two randomized, double-blind, placebo-controlled studies in patients with obesity (Study 1) and patients with obesity or overweight with two or more significant co-morbidities (Study 2). Both studies had a 4-week titration period, followed by 52 weeks of treatment. There were two co-primary efficacy outcomes measured after 1 year of treatment (Week 56): 1) the percent weight loss from baseline; and 2) treatment response defined as achieving at least 5% weight loss from baseline. In Study 1 (NCT00554216), patients with obesity (BMI greater than or equal to 35 kg/m2) were randomized to receive 1 year of treatment with placebo (N=514), phentermine and topiramate extended-release 3.75 mg/23 mg (N=241), or phentermine and topiramate extended-release 15 mg/92 mg (N=512) in a 2:1:2 ratio. Patients ranged in age from 18 to 71 years old (mean age 43) and 83% were female. Approximately 80% were White, 18% were Black or African American, and 15% were Hispanic or Latino ethnicity. At the beginning of the study the average weight and BMI of patients was 116 kg and 42 kg/m2, respectively. Patients with type 2 diabetes mellitus were excluded from participating in Study 1. During the study, a well-balanced, reduced-calorie diet to result in an approximate 500 kcal/day decrease in caloric intake was recommended to all patients and patients were offered nutritional and lifestyle modification counseling. In Study 2 (NCT00553787), patients with overweight or obesity were randomized to receive 1 year of treatment with placebo (N=994), phentermine and topiramate extended-release 7.5 mg/46 mg (N=498), or phentermine and topiramate extended-release 15 mg/92 mg (N=995) in a 2:1:2 ratio. Eligible patients had to have a BMI greater than or equal to 27 kg/m2 and less than or equal to 45 kg/m2 (there was no lower limit on BMI for patients with type 2 diabetes mellitus) and two or more of the following obesity-related co-morbid conditions: Elevated blood pressure (greater than or equal to 140/90 mmHg, or greater than or equal to 130/85 mmHg for diabetics) or requirement for greater than or equal to 2 antihypertensive medications; Triglycerides greater than 200 to 400 mg/dL or were receiving treatment with 2 or more lipid-lowering agents; Elevated fasting blood glucose (greater than 100 mg/dL) or diabetes; and/or Waist circumference greater than or equal to 102 cm for men or greater than or equal to 88 cm for females. Patients ranged in age from 19 to 71 years of age (mean age 51) and 70% were female. Approximately 86% were White, 12% were Black or African American, and 13% were Hispanic/ or Latino ethnicity. The average weight and BMI of patients at the start of the study was 103 kg and 36.6 kg/m2, respectively. Approximately half (53%) of patients had hypertension at the start of the study. There were 388 (16%) patients with type 2 diabetes mellitus at the start of the study. During the study, a well-balanced, reduced-calorie diet to result in an approximate 500 kcal/day decrease in caloric intake was recommended to all patients and patients were offered nutritional and lifestyle modification counseling. The percentage of randomized patients who withdrew from each study prior to week 56 was 40% in Study 1, and 31% in Study 2. Table 10 provides the results for weight loss at 1 year in Studies 1 and 2. After 1 year of treatment with phentermine and topiramate extended-release, all dose levels resulted in statistically significant weight loss compared to placebo (see Table 10, Figure 1 and Figure 2). A statistically significant greater proportion of the patients randomized to phentermine and topiramate extended-release than placebo achieved 5% and 10% weight loss. Table 10. Weight Loss at One Year in Adult Patients in Studies 1 and 2 Study 1 (Obesity) Study 2 (Obesity or Overweight with Co-morbidities) Analysis Method Placebo Phentermine and topiramate extended-release 3.75 mg/23 mg Phentermine and topiramate extended-release 15 mg/92 mg Placebo Phentermine and topiramate extended-release 7.5 mg/46 mg Phentermine and topiramate extended-release 15 mg/92 mg ITT-LOCF (Primary)* n = 498 n = 234 n = 498 n = 979 n = 488 n = 981 Weight (kg) Baseline mean (SD) 115.7 (21.4) 118.6 (21.9) 115.2 (20.8) 103.3 (18.1) 102.8 (18.2) 103.1 (17.6) % LS Mean Change from baseline (SE)** -1.6 (0.4) -5.1 (0.5) -10.9 (0.4) -1.2 (0.3) -7.8 (0.4) -9.8 (0.3) Difference from placebo (95% CI) 3.5 (2.4 to 4.7) 9.4 (8.4 to 10.3) 6.6 (5.8 to 7.4) 8.6 (8.0 to 9.3) Percentage of patients losing greater than or equal to 5% body weight 17% 45% 67% 21% 62% 70% Risk Difference vs. placebo (95% CI) 27.6(20.4 to 34.8) 49.4 (44.1 to 54.7) 41.3(36.3 to 46.3) 49.2 (45.4 to 53.0) Percentage of patients losing greater than or equal to 10% body weight 7% 19% 47% 7% 37% 48% Risk Difference vs. placebo (95% CI) 11.4 (5.9 to 16.9) 39.8(34.8 to 44.7) 29.9(25.3 to 34.5) 40.3(36.7 to 43.8) SD=standard deviation; LS=least-squares; SE=standard error; CI=confidence interval * Uses all available data from subjects in ITT population, including data collected from subjects who discontinued drug but remained on study. Last Observation Carried Forward (LOCF) method used to impute missing data. p < 0.0001 vs. placebo based on least-squares (LS) mean from an analysis of covariance. p < 0.01 vs. 3.75 mg/23 mg (Study 1) or 7.5 mg/46 mg (Study 2) dose. Type 1 error was controlled across all pairwise treatment comparisons. ** Adjusted for baseline bodyweight (Study 1) and baseline bodyweight and diabetic status (Study 2). Figure 1. Study 1 Percent Weight Change from Baseline to Week 56 in Adults with Obesity Figure 2. Study 2 Percent Weight Change from Baseline to Week 56 in Adults with Obesity or Overweight with Comorbidities p < 0.0001 for all three phentermine and topiramate extended-release doses vs placebo, and 15 mg/92 mg vs 7.5 mg/46 mg or 3.75 mg/23 mg at all time points for both completers and ITT-LOCF The changes in cardiovascular, metabolic, and anthropometric risk factors associated with obesity from Study 1 and 2 are presented in Table 11 and Table 12. Table 11. Least-Squares (LS) Mean Change from Baseline and Treatment Difference from Placebo in Cardiometabolic Parameters in Adults Following One Year of Treatment in Study 1 (Obesity) Study 1 (Obesity) Placebo (N = 498) Phentermine and topiramate extended-release 3.75 mg/23 mg (N = 234) Phentermine and topiramate extended-release 15 mg/ 92 mg (N = 498) Phentermine and topiramate extended-release Placebo: LS Mean Phentermine and topiramate extended-release 3.75 mg/23 mg Phentermine and topiramate extended-release 15 mg/92 mg Heart Rate, bpm Baseline mean (SD)LS Mean Change (SE) 73.2 (8.8) -0.8 (0.5) 72.3 (9.2)+0.3 (0.6) 73.1 (9.6)+1.0 (0.5) +1.1 +1.8 Systolic Blood Pressure, mmHg Baseline mean (SD)LS Mean Change (SE) 121.9 (11.5) +0.9 (0.6) 122.5 (11.1)-1.8 (0.8) 121.9 (11.6)-2.9 (0.6) -2.8 -3.8 Diastolic blood pressure, mmHg Baseline mean (SD)LS Mean Change (SE) 77.2 (7.9) +0.4 (0.4) 77.8 (7.5)-0.1 (0.6) 77.4 (7.7)-1.5 (0.4) -0.5 -1.9 Total Cholesterol, % Baseline mean (SD)LS Mean Change (SE) 194.3 (36.7) -3.5 (0.6) 196.3 (36.5)-5.4 (0.9) 192.7 (33.8)-6.0 (0.6) -1.9 -2.5 LDL-Cholesterol, % Baseline mean (SD)LS Mean Change (SE) 120.9 (32.2) -5.5 (1.0) 122.8 (33.4)-7.7 (1.3) 120.0 (30.1)-8.4 (0.9) -2.2 -2.8 HDL-Cholesterol, % Baseline mean (SD)LS Mean Change (SE) 49.5 (13.3) +0.0 (0.8) 50.0 (11.1)+0.5 (1.1) 49.7 (11.7)+3.5 (0.8) +0.5 +3.5 Triglycerides, % Baseline mean (SD)LS Mean Change (SE) 119.0 (39.3) +9.1 (2.3) 117.5 (40.3)+5.2 (3.1) 114.6 (37.1)-5.2 (2.2) -3.9 -14.3 Fasting Glucose, mg/dL Baseline mean (SD)LS Mean Change (SE) 93.1 (8.7) +1.9 (0.5) 93.9 (9.2)+0.8 (0.7) 93.0 (9.5)-0.6 (0.5) -1.2 -2.5 Waist Circumference, cm Baseline mean (SD)LS Mean Change (SE) 120.5 (14.0) -3.1 (0.5) 121.5 (15.2)-5.6 (0.6) 120.0 (14.7)-10.9 (0.5) -2.5* -7.8* SD=standard deviation; SE=standard error * Statistically significant versus placebo based on the pre-specified method for controlling Type I error across multiple doses Study 1 adjusted for baseline bodyweight Table 12. Least-Squares (LS) Mean Change from Baseline and Treatment Difference from Placebo in Cardiometabolic Parameters in Adults Following One Year of Treatment in Study 2 (Obese or Overweight with Comorbidities) Study 2 (Overweight and Obese with Comorbidities) Placebo (N = 979) Phentermine and topiramate extended-release 7.5 mg/46 mg (N = 488) Phentermine and topiramate extended-release 15 mg/ 92 mg (N = 981) Phentermine and topiramate extended-release Placebo: LS Mean Phentermine and topiramate extended-release 7.5 mg/46 mg Phentermine and topiramate extended-release 15 mg/92 mg Heart Rate, bpm Baseline mean (SD) LS Mean Change (SE) 72.1 (9.9)-0.3 (0.3) 72.2 (10.1)+0.3 (0.4) 72.6 (10.1)+1.4 (0.3) +0.6 +1.7 Systolic Blood Pressure, mmHg Baseline mean (SD)LS Mean Change (SE) 128.9 (13.5)-2.4 (0.48) 128.5 (13.6) -4.7 (0.63) 127.9 (13.4)-5.6 (0.5) -2.3 -3.2 Diastolic Blood Pressure, mmHg Baseline mean (SD)LS Mean Change (SE) 81.1 (9.2)-2.7 (0.3) 80.6 (8.7) -3.4 (0.4) 80.2 (9.1)-3.8 (0.3) -0.7 -1.1 Total Cholesterol, % Baseline mean (SD)LS Mean Change (SE) 205.8 (41.7) -3.3 (0.5) 201.0 (37.9)-4.9 (0.7) 205.4 (40.4)-6.3 (0.5) -1.6 -3.0 LDL-Cholesterol, % Baseline mean (SD)LS Mean Change (SE) 124.2 (36.2) -4.1 (0.9) 120.3 (33.7)-3.7 (1.1) 123.9 (35.6)-6.9 (0.9) +0.4 -2.8 HDL-Cholesterol, % Baseline mean (SD)LS Mean Change (SE) 48.9 (13.8) +1.2 (0.7) 48.5 (12.8)+5.2 (0.9) 49.1 (13.8)+6.8 (0.7) +4.0 +5.6 Triglycerides, % Baseline mean (SD)LS Mean Change (SE) 163.5 (76.3) +4.7 (1.7) 161.1 (72.2)-8.6 (2.2) 161.9 (73.4)-10.6 (1.7) -13.3 -15.3 Fasting Insulin, ( IU/mL) Baseline mean (SD)LS Mean Change (SE) 17.8 (13.2)+0.7 (0.8) 18.0 (12.9)-3.5 (1.1) 18.4 (17.5)-4.0 (0.8) -4.2 -4.7 Fasting Glucose, mg/dL Baseline mean (SD)LS Mean Change (SE) 106.6 (23.7)+2.3 (0.6) 106.2 (21.0)-0.1 (0.8) 105.7 (21.4)-1.3 (0.6) -2.4 -3.6 Waist Circumference, cm Baseline mean (SD)LS Mean Change (SE) 113.4 (12.2)-2.4 (0.3) 112.7 (12.4)-7.6 (0.4) 113.2 (12.2)-9.2 (0.3) -5.2* -6.8* SD=standard deviation; SE=standard error * Statistically significant versus placebo based on the pre-specified method for controlling Type I error across multiple doses Study 2 adjusted for baseline bodyweight and diabetic status Among the 388 subjects with type 2 diabetes mellitus treated in Study 2, reductions in HbA1c from baseline (6.8%) were 0.1% for placebo compared to 0.4% and 0.4% with phentermine and topiramate extended-release 7.5 mg/46 mg and phentermine and topiramate extended-release 15 mg/92 mg, respectively. Pediatric use information is approved for Vivus LLC's Qsymia (phentermine and topiramate) extended-release capsules. However, due to Vivus LLC's marketing exclusivity rights, this drug product is not labeled with that information.

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Embryo-Fetal Toxicity Inform patients who can become pregnant that phentermine and topiramate extended-release capsules can cause fetal harm and patients should avoid getting pregnant while taking phentermine and topiramate extended-release capsules [see Warnings and Precautions ( 5.1 ), Drug Interactions ( 7 ), and Use in Specific Populations ( 8.3 )]. Advise patients who can become pregnant: that pregnancy testing is recommended before initiating phentermine and topiramate extended-release capsules and monthly during therapy; to use effective contraception during phentermine and topiramate extended-release capsules therapy; who experience spotting while taking a combined oral contraceptive to notify their health care provider; with a known or suspected pregnancy to stop phentermine and topiramate extended-release capsules immediately and notify their health care provider. Access to Phentermine and Topiramate Extended-Release Capsules Advise patients that phentermine and topiramate extended-release capsules are only available through certified pharmacies that are enrolled in the phentermine and topiramate extended-release capsules certified pharmacy network. Advise patients on how to access phentermine and topiramate extended-release capsules through certified pharmacies. Additional information may be obtained via the website www.PhenTopREMS .com or by telephone at 1 800 269 6816. Suicidal Behavior and Ideation and Mood and Sleep Disorders Inform patients that phentermine and topiramate extended-release capsules can increase the risk of mood changes, sleep disorders, depression, and suicidal ideation. Advise patients to tell their health care provider(s) immediately if mood changes, depression, or suicidal ideation occur [see Warnings and Precautions ( 5.2, 5.4 )]. Ophthalmologic Adverse Reactions Inform patients that phentermine and topiramate extended-release capsules can increase the risk of acute myopia, secondary angle closure glaucoma, and visual field defects. Advise patients to immediately report symptoms of severe and persistent eye pain or significant changes in their vision to their health care provider(s) [see Warnings and Precautions ( 5.3 )]. Cognitive Impairment Inform patients that phentermine and topiramate extended-release capsules can cause confusion, concentration, and word-finding difficulties. Inform patients that the concomitant use of alcohol or central nervous system (CNS) depressant drugs with phentermine and topiramate extended-release capsules, may increase the risk of dizziness, cognitive adverse reactions, drowsiness, light-headedness, impaired coordination and somnolence. Advise patients to tell their health care provider(s) about any changes in attention, concentration, memory, difficulty finding words, or other cognitive functions. 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. Advise patients to avoid excessive alcohol intake while taking phentermine and topiramate extended-release capsules [see Warnings and Precautions ( 5.5 )]. Slowing of Linear Growth Discuss with the patient and caregiver that long-term phentermine and topiramate extended-release capsules treatment may attenuate growth as reflected by slower height increase in pediatric patients [see Warnings and Precautions ( 5.6 )]. Metabolic Acidosis Inform patients that phentermine and topiramate extended-release capsules can increase the risk of metabolic acidosis. Advise patients to tell their health care provider(s) about any factors that can increase the risk of acidosis (e.g. prolonged diarrhea, surgery, and high protein/low carbohydrate diet, and/or concomitant medications such as carbonic anhydrase inhibitors) [see Warnings and Precautions ( 5.7 )]. Risk of Seizures with Abrupt Withdrawal of Phentermine and Topiramate Extended-Release Capsules Inform patients that abrupt withdrawal of topiramate has been associated with seizures in individuals without a history of seizures or epilepsy. Advise patients not to abruptly stop phentermine and topiramate extended-release capsules without first talking to their health care provider(s) [see Dosage and Administration ( 2.3 ) and Warnings and Precautions ( 5.9 )]. Kidney Stones Inform patients that use of phentermine and topiramate extended-release capsules has been associated with kidney stone formation. Advise patients to increase fluid intake to increase urinary output which can decrease the concentration of substances involved in kidney stone formation. Advise patients to report symptoms of severe side or back pain, and/or blood in their urine to their health care provider(s) [see Warnings and Precautions ( 5.10 ) and Adverse Reactions ( 6.1 )]. Oligohidrosis and Hyperthermia Inform patients that oligohidrosis (decreased sweating) has been reported in association with the use of topiramate. Advise patients to monitor for decreased sweating and increased body temperature during physical activity, especially in hot weather [see Warnings and Precautions ( 5.11 )]. Serious Skin Reactions Inform patients that serious skin reactions have been reported with use of topiramate. Inform patients of the signs of serious skin reactions and advise patients to report signs of a skin reaction to their health care provider(s) [see Warning and Precautions ( 5.13 )]. Lactation Advise patients that breastfeeding is not recommended during phentermine and topiramate extended-release capsules treatment [see Use in Specific Populations ( 8.2 )]. Allergic Reactions Due to Inactive Ingredient FD&C Yellow No. 5 Inform patients that this product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons [see Warnings and Precautions ( 5.14 )]. How to Take Phentermine and Topiramate Extended-Release Capsules Instruct patients on the dosage titration schedule of phentermine and topiramate extended-release capsules. Advise patients to take phentermine and topiramate extended-release capsules in the morning with or without food [see Dosage and Administration ( 2.2 )] . Rx only Distributed by: Dr. Reddy s Laboratories Inc., Princeton, NJ 08540 Made in India Issued: 11/2024

MEDICATION GUIDE Phentermine (FEN-ter-meen) and Topiramate (toe-PIE-rah-mate) Extended-Release Capsules, for oral use, CIV This Medication Guide has been approved by the U.S. Food and Drug Administration. To reorder additional Medication Guides, contact Dr. Reddy s Customer Service at 1-866-733-3952. The brands listed are trademarks of their respective owners and are not trademarks of Dr. Reddy s Laboratories Limited. Rx only Distributed by: Dr. Reddy s Laboratories Inc., Princeton, NJ 08540 Made in India Issued: 11/2024 What is the most important information I should know about phentermine and topiramate extended-release capsules? Phentermine and topiramate extended-release capsules can cause serious side effects, including : Birth defects.If you take phentermine and topiramate extended-release capsules during pregnancy, your baby has a higher risk for birth defects including cleft lip and cleft palate. Your baby may also be smaller than expected at birth. The long-term effects of this are not known. These defects can begin early in pregnancy, even before you know you are pregnant. Patients who are pregnant must not take phentermine and topiramate extended-release capsules. Patients who can become pregnant should: Have a pregnancy test before taking phentermine and topiramate extended-release capsules and every month while taking phentermine and topiramate extended-release capsules. Use effective birth control (contraception) consistently while taking phentermine and topiramate extended-release capsules. Talk to your health care provider about how to prevent pregnancy. If you become pregnant while taking phentermine and topiramate extended-release capsules, stop taking phentermine and topiramate extended-release capsules immediately and tell your health care provider right away. Health care providers and patients who become pregnant should report all cases of pregnancy to: FDA MedWatch at 1-800-FDA-1088 Because of the risk for birth defects (cleft lip and cleft palate), phentermine and topiramate extended-release capsules are available through a restricted program called the phentermine and topiramate extended-release capsules Risk Evaluation and Mitigation Strategy (REMS). Phentermine and topiramate extended-release capsules are only available through certified pharmacies that participate in the phentermine and topiramate extended-release capsules REMS program. Your health care provider can give you information about how to find a certified pharmacy. For more information, go to www.PhenTopREMS or call 1 800 269 6816. Suicidal thoughts or actions.Topiramate, an ingredient in phentermine and topiramate extended-release capsules, may cause you to have suicidal thoughts or actions. Call your health care provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying attempts to commit suicide new or worse depression new or worse anxiety feeling agitated or restless panic attacks trouble sleeping (insomnia) new or worse irritability acting aggressive, being angry, or violent acting on dangerous impulses an extreme increase in activity and talking (mania) other unusual changes in behavior or mood Do not stop phentermine and topiramate extended-release capsules without first talking to a health care provider. Stopping phentermine and topiramate extended-release capsules suddenly can cause serious problems. Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your health care provider may check for other causes. How can I watch for early symptoms of suicidal thoughts and actions? Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings. Keep all follow-up visits with your health care provider as scheduled. Call your health care provider between visits as needed, especially if you are worried about symptoms. Serious eye problemswhich include: any sudden decrease in vision, with or without eye pain and redness, a blockage of fluid in the eye causing increased pressure in the eye (secondary angle closure glaucoma). These problems can lead to permanent vision loss if not treated. Tell your health care provider right away if you have any new eye symptoms. Phentermine and topiramate extended-release capsules can have other serious side effects. See " What are the possible side effects of p hentermine and topiramate extended-release capsules ? " What are phentermine and topiramate extended-release capsules? Phentermine and topiramate extended-release capsules are a prescription medicine that contains phentermine and topiramate extended-release. Phentermine and topiramate extended-release capsules may help adults with obesity or some adults with overweight who also have weight-related medical problems, to help them lose excess body weight and keep the weight off. Phentermine and topiramate extended-release capsules should be used with a reduced calorie diet and increased physical activity. It is not known if phentermine and topiramate extended-release capsules changes your risk of heart problems or stroke or of death due to heart problems or stroke. It is not known if phentermine and topiramate extended-release capsules are safe and effective when taken with other prescription and over-the-counter medicines, or herbal weight loss products. It is not known if phentermine and topiramate extended-release capsules are safe and effective in children under 12 years old. Phentermine and topiramate extended-release capsules are a federally controlled substance (CIV) because it contains phentermine and can be abused or lead to drug dependence. Keep phentermine and topiramate extended-release capsules in a safe place, to protect them from theft. Never give your phentermine and topiramate extended-release capsules to anyone else, because they may cause death or harm them. Selling or giving away phentermine and topiramate extended-release capsules is against the law. Who should not take phentermine and topiramate extended-release capsules? Do not take phentermine and topiramate extended-release capsules if you: are pregnant, planning to become pregnant, or become pregnant during phentermine and topiramate extended-release capsules treatment. have glaucoma. have thyroid problems (hyperthyroidism). are taking certain medicines called monoamine oxidase inhibitors (MAOIs) or have taken MAOIs in the past 14 days. are allergic to topiramate, sympathomimetic amines such as phentermine, or any of the ingredients in phentermine and topiramate extended-release capsules. See the end of this Medication Guide for a complete list of ingredients in phentermine and topiramate extended-release capsules. Before taking phentermine and topiramate extended-release capsules, tell your health care provider about all of your medical conditions, including if you: have or have had depression, mood problems, or suicidal thoughts or behavior. have eye problems, especially glaucoma. See " Who should not take phentermine and topiramate extended-release capsules? " have a history of too much acid in the blood (metabolic acidosis) or a condition that puts you at higher risk for metabolic acidosis such as chronic diarrhea, surgery, a diet high in fat and low in carbohydrates (ketogenic diet), weak, brittle, or soft bones (osteoporosis, osteomalacia (rickets), osteopenia), or decreased bone density. have kidney problems, kidney stones, or are getting kidney dialysis. have liver problems. have seizures or convulsions (epilepsy). are breastfeeding or plan to breastfeed. Phentermine and topiramate can pass into your breast milk and may harm your baby. You and your health care provider should decide if you will take phentermine and topiramate extended-release capsules or breastfeed. You should not do both. Tell your health care provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Phentermine and topiramate extended-release capsules taken with other medicines may affect how each medicine works and may cause side effects. Especially tell your health care provider if you take: Birth control pills. Tell your health care provider if your menstrual bleeding changes while you are taking birth control pills that contain both estrogen and progestin (combination oral contraceptives) and phentermine and topiramate extended-release capsules. Water pills(diuretics) such as hydrochlorothiazide (HCTZ). Any medicines that impair or decrease your thinking, concentration, or muscle coordination. Carbonic anhydrase inhibitorssuch as ZONEGRAN (zonisamide), DIAMOX (acetazolamide) or NEPTAZANE (methazolamide). Seizure medicinessuch as Valproic acid (DEPAKENE or DEPAKOTE). Ask your health care provider or pharmacist for a list of these medicines, if you are not sure. Know the medicines you take. Keep a list of them to show your health care provider and pharmacist each time you get a new medicine. Do not start a new medicine without talking to your health care provider. How should I take phentermine and topiramate extended-release capsules? Your health care provider should start you on a diet and exercise program when you start taking phentermine and topiramate extended-release capsules. Stay on this program while you are taking phentermine and topiramate extended-release capsules. Take phentermine and topiramate extended-release capsules exactly as your health care provider tells you to take them. Do not change your dose without talking to your health care provider. Take phentermine and topiramate extended-release capsules daily in the morning. Phentermine and topiramate extended-release capsules can be taken with or without food. If you miss a dose of phentermine and topiramate extended-release capsules, wait until the next morning to take your usual dose of phentermine and topiramate extended-release capsules. Do not double your dose. To start treatment with phentermine and topiramate extended-release capsules Take 1 phentermine and topiramate extended-release capsule 3.75 mg/23 mg (Figure A) 1 time each morning for the first 14 days. After taking phentermine and topiramate extended-release capsules 3.75 mg/23 mg for 14 days, then take 1 phentermine and topiramate extended-release capsule 7.5 mg/46 mg (Figure B) 1 time each morning. After taking phentermine and topiramate extended-release capsules for 12 weeks Your health care provider may tell you to increase your dose of phentermine and topiramate extended-release capsules if you do not lose a certain amount of weight within the first 12 weeks of treatment at the recommended dose. If your health care provider increases the dose of phentermine and topiramate extended-release capsules Take 1 phentermine and topiramate extended-release capsule 11.25 mg/69 mg (Figure C) 1 time each morning for 14 days. After taking 14 days of phentermine and topiramate extended-release capsules 11.25 mg/69 mg, then take 1 phentermine and topiramate extended-release capsule 15 mg/92 mg (Figure D) 1 time each morning. Stopping phentermine and topiramate extended-release capsules treatment Your health care provider should tell you to stop taking phentermine and topiramate extended-release capsules if you have not lost a certain amount of weight after an additional12 weeks of treatment on the higher dose. Do not stop taking phentermine and topiramate extended-release capsules without talking to your health care provider. Stopping phentermine and topiramate extended-release capsules suddenly can cause serious problems, such as seizures. Your health care provider will tell you how to stop taking phentermine and topiramate extended-release capsules slowly. If you take too much phentermine and topiramate extended-release capsules, call your health care provider or Poison Help line at 1-800-222-1222 or go to the nearest emergency room right away. What should I avoid while taking phentermine and topiramate extended-release capsules? Do not get pregnant while taking phentermine and topiramate extended-release capsules. See " What is the most important information I should know about phentermine and topiramate extended-release capsules." Do not drink too much alcohol while taking phentermine and topiramate extended-release capsules. Phentermine and topiramate extended-release capsules and alcohol can affect each other causing side effects such as sleepiness or dizziness. Do not drive a car, operate heavy machinery, or do other dangerous activities until you know how phentermine and topiramate extended-release capsules affects you. Phentermine and topiramate extended-release capsules can slow your thinking and motor skills and may affect vision. What are the possible side effects of phentermine and topiramate extended-release capsules? Phentermine and topiramate extended-release capsules can cause serious side effects, including: See " What is the most important information I should know about phentermine and topiramate extended-release capsules?" Mood changes and trouble sleeping. Phentermine and topiramate extended-release capsules may cause depression or mood problems, and trouble sleeping. Tell your health care provider if symptoms occur. Concentration, memory, and speech difficulties. Phentermine and topiramate extended-release capsules may affect how you think and cause confusion, problems with concentration, attention, memory, or speech. Tell your health care provider if symptoms occur. Slowing of growth. Phentermine and topiramate extended-release capsules may slow the increase in height in children when used for a long time. Increases of acid in bloodstream (metabolic acidosis).If left untreated, metabolic acidosis can cause brittle or soft bones (osteoporosis, osteomalacia (rickets), osteopenia), kidney stones, can slow the rate of growth in children, and may possibly harm your baby if you are pregnant. Metabolic acidosis can happen with or without symptoms. Sometimes people with metabolic acidosis will: feel tired not feel hungry (loss of appetite) feel changes in heartbeat have trouble thinking clearly Your health care provider should do a blood test to measure the level of acid in your blood before and during your treatment with phentermine and topiramate extended-release capsules. Decrease in kidney function. Phentermine and topiramate extended-release capsules may cause a decrease in kidney function. Your health care provider should do a blood test to measure your kidney function before and during treatment with phentermine and topiramate extended-release capsules. Possible seizures if you stop taking phentermine and topiramate extended-release capsules too fast. Seizures may happen in people who may or may not have had seizures in the past if you stop phentermine and topiramate extended-release capsules too fast. Your health care provider will tell you how to stop taking phentermine and topiramate extended-release capsules slowly. Kidney stones. Drink plenty of fluids when taking phentermine and topiramate extended-release capsules to help decrease your chances of getting kidney stones. If you get severe side or back pain, or blood in your urine, call your health care provider. Decreased sweating and increased body temperature (fever). People should be watched for signs of decreased sweating and fever, especially in hot temperatures. Some people may need to be hospitalized for this condition. Low potassium. Phentermine and topiramate extended-release capsules can increase your risk of low potassium levels. Your health care provider should do a blood test to measure the level of potassium in your blood before and during treatment with phentermine and topiramate extended-release capsules. Serious skin reactions. Phentermine and topiramate extended-release capsules may cause a severe rash with blisters and peeling skin, especially around the mouth, nose, eyes, and genitals (Stevens-Johnson Syndrome). Phentermine and topiramate extended-release capsules may also cause a rash with blisters and peeling skin over much of the body that may cause death (Toxic Epidermal Necrolysis). Call your health care provider right away if you develop a skin rash or blisters. Allergic reaction to FD&C Yellow No. 5. Phentermine and topiramate extended-release capsules,11.25 mg/69 mg contain the inactive ingredient FD&C Yellow No. 5 (tartrazine) which can cause allergic-type reactions (including bronchial asthma) in certain people, especially people who also have an allergy to aspirin. Common side effects of phentermine and topiramate extended-release capsules in adults include: numbness or tingling in the hands, arms, feet, or face (paraesthesia) dizziness change in the way foods taste or loss of taste (dysgeusia) trouble sleeping (insomnia) constipation dry mouth Tell your health care provider if you have any side effect that bothers you or does not go away. These are not all of the possible side effects of phentermine and topiramate extended-release capsules. For more information, ask your health care provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.You can also report side effects to Dr. Reddy s Laboratories Limited at 1 888-375-3784. How should I store phentermine and topiramate extended-release capsules? Store phentermine and topiramate extended-release capsules at room temperature between 20 C to 25 C (68 F to 77 F). Keep phentermine and topiramate extended-release capsules in a tightly closed container. Keep phentermine and topiramate extended-release capsules dry and away from moisture. Keep phentermine and topiramate extended-release capsules and all medicines out of the reach of children. General Information about the safe and effective use of phentermine and topiramate extended-release capsules. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use phentermine and topiramate extended-release capsules for a condition for whichthey were not prescribed. Do not give phentermine and topiramate extended-release capsules to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or health care provider for information about phentermine and topiramate extended-release capsules that is written for health professionals. What are the ingredients in phentermine and topiramate extended-release capsules? Active Ingredient: phentermine hydrochloride and topiramate extended-release. Inactive Ingredients: ethocel, gelatin, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, talc and titanium dioxide. In addition, the 7.5 mg/46 mg contains FD&C Red No. 40 and FD&C Yellow #6, 11.25 mg/69 mg contains FD&C Yellow #5 and FD&C Blue #1, 15 mg/92 mg contains FD&C Yellow #6 and D&C Red #28. The imprinting ink Opacode Black contains shellac, iron oxide black, propylene glycol, FD&C Blue #2, FD&C Red No. 40, D&C Yellow #10, FD&C Blue #1. Pediatric use information is approved for Vivus LLC's Qsymia (phentermine and topiramate) extended-release capsules. However, due to Vivus LLC's marketing exclusivity rights, this drug product is not labeled with that information.

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