Data from FDA (Food and Drug Administration, USA) - Curated by Toby Galbraith - Last updated 10 October 2017

Indication(s)

1 INDICATIONS AND USAGE Qsymia is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index (BMI) of 30 kg/m 2 or greater (obese), or 27 kg/m 2 or greater (overweight) in the presence of at least one weight related comorbidity such as hypertension, type 2 diabetes mellitus, or dyslipidemia Qsymia is a combination of phentermine, a sympathomimetic amine anorectic, and topiramate extended-release, an antiepileptic drug, indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m 2 or greater (obese) ( 1) or 27 kg/m 2 or greater (overweight) in the presence of at least one weight-related comorbidity such as hypertension, type 2 diabetes mellitus, or dyslipidemia ( 1) Limitations of Use: The effect of Qsymia on cardiovascular morbidity and mortality has not been established ( 1). The safety and effectiveness of Qsymia in combination with other products intended for weight loss, including prescription and over-the-counter drugs, and herbal preparations, have not been established ( 1). Limitations of Use The effect of Qsymia on cardiovascular morbidity and mortality has not been established. The safety and effectiveness of Qsymia in combination with other products intended for weight loss, including prescription and over-the-counter drugs and herbal preparations have not been established.

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Advisory information

contraindications
4 CONTRAINDICATIONS Qsymia is contraindicated in the following conditions: Pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)] Glaucoma [see Warnings and Precautions (5.4)] Hyperthyroidism During or within 14 days following the administration of monoamine oxidase inhibitors [see Drug Interactions (7.1)] Known hypersensitivity or idiosyncrasy to the sympathomimetic amines [see Adverse Reactions (6.2)]. Pregnancy ( 4) Glaucoma ( 4) Hyperthyroidism ( 4) During or within 14 days of taking monoamine oxidase inhibitors ( 4) Known hypersensitivity or idiosyncrasy to sympathomimetic amines ( 4)
Adverse reactions
6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Fetal Toxicity: [ see Warnings and Precautions (5.1) and Use in Specific Populations (8.1), (8.6)] Elevation in Heart Rate [ see Warnings and Precautions (5.2) ] Suicidal Behavior and Ideation [see Warnings and Precautions (5.3)] Acute Angle Closure Glaucoma [see Warnings and Precautions (5.4)] Mood and Sleep Disorders [see Warnings and Precautions (5.5)] Cognitive Impairment [see Warnings and Precautions (5.6)] Metabolic Acidosis [see Warnings and Precautions (5.7)] Most common adverse reactions (incidence greater than or equal to 5% and at a rate at least 1.5 times placebo) are: paraesthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth ( 6.1). To report SUSPECTED ADVERSE REACTIONS, contact VIVUS, Inc., at 1-888-998-4887 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The data described herein reflects exposure to Qsymia in two, 1-year, randomized, double-blind, placebo-controlled, multicenter clinical trials, and two Phase 2 supportive trials in 2318 adult patients (936 [40.4%] patients with hypertension, 309 [13.3%] patients with type 2 diabetes, 808 [34.9%] patients with BMI greater than 40 kg/m 2) exposed for a mean duration of 298 days. Common Adverse Reactions: Adverse reactions occurring at a rate of greater than or equal to 5% and at a rate at least 1.5 times placebo include paraesthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth. Adverse reactions reported in greater than or equal to 2% of Qsymia-treated patients and more frequently than in the placebo group are shown in Table 3. Table 3. Adverse Reactions Reported in Greater Than or Equal to 2% of Patients and More Frequently than Placebo during 1 Year of Treatment – Overall Study Population System Organ Class Preferred Term Placebo (N = 1561) % Qsymia 3.75 mg/23 mg (N = 240) % Qsymia 7.5 mg/46 mg (N = 498) % Qsymia 15 mg/92 mg (N = 1580) % Nervous System Disorders Paraesthesia 1.9 4.2 13.7 19.9 Headache 9.3 10.4 7.0 10.6 Dizziness 3.4 2.9 7.2 8.6 Dysgeusia 1.1 1.3 7.4 9.4 Hypoesthesia 1.2 0.8 3.6 3.7 Disturbance in Attention 0.6 0.4 2.0 3.5 Psychiatric Disorders Insomnia 4.7 5.0 5.8 9.4 Depression 2.2 3.3 2.8 4.3 Anxiety 1.9 2.9 1.8 4.1 Gastrointestinal Disorders Constipation 6.1 7.9 15.1 16.1 Dry Mouth 2.8 6.7 13.5 19.1 Nausea 4.4 5.8 3.6 7.2 Diarrhea 4.9 5.0 6.4 5.6 Dyspepsia 1.7 2.1 2.2 2.8 Gastroesophageal Reflux Disease 1.3 0.8 3.2 2.6 Paraesthesia Oral 0.3 0.4 0.6 2.2 General Disorders and Administration Site Conditions Fatigue 4.3 5.0 4.4 5.9 Irritability 0.7 1.7 2.6 3.7 Thirst 0.7 2.1 1.8 2.0 Chest Discomfort 0.4 2.1 0.2 0.9 Eye Disorders Vision Blurred 3.5 6.3 4.0 5.4 Eye Pain 1.4 2.1 2.2 2.2 Dry Eye 0.8 0.8 1.4 2.5 Cardiac Disorders Palpitations 0.8 0.8 2.4 1.7 Skin and Subcutaneous Tissue Disorders Rash 2.2 1.7 2.0 2.6 Alopecia 0.7 2.1 2.6 3.7 Metabolism and Nutrition Disorders Hypokalemia 0.4 0.4 1.4 2.5 Decreased Appetite 0.6 2.1 1.8 1.5 Reproductive System and Breast Disorders Dysmenorrhea 0.2 2.1 0.4 0.8 Infections and Infestations Upper Respiratory Tract Infection 12.8 15.8 12.2 13.5 Nasopharyngitis 8.0 12.5 10.6 9.4 Sinusitis 6.3 7.5 6.8 7.8 Bronchitis 4.2 6.7 4.4 5.4 Influenza 4.4 7.5 4.6 4.4 Urinary Tract Infection 3.6 3.3 5.2 5.2 Gastroenteritis 2.2 0.8 2.2 2.5 Musculoskeletal and Connective Tissue Disorders Back Pain 5.1 5.4 5.6 6.6 Pain in Extremity 2.8 2.1 3.0 3.0 Muscle Spasms 2.2 2.9 2.8 2.9 Musculoskeletal Pain 1.2 0.8 3.0 1.6 Neck Pain 1.3 1.3 2.2 1.2 Respiratory, Thoracic, and Mediastinal Disorders Cough 3.5 3.3 3.8 4.8 Sinus Congestion 2.0 2.5 2.6 2.0 Pharyngolaryngeal Pain 2.0 2.5 1.2 2.3 Nasal Congestion 1.4 1.7 1.2 2.0 Injury, Poisoning, and Procedural Complications Procedural Pain 1.7 2.1 2.4 1.9 Paraesthesia/Dysgeusia Reports of paraesthesia, characterized as tingling in hands, feet, or face, occurred in 4.2%, 13.7%, and 19.9% of patients treated with Qsymia 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 1.9% of patients treated with placebo. Dysgeusia was characterized as a metallic taste, and occurred in 1.3%, 7.4%, and 9.4% of patients treated with Qsymia 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 1.1% of patients treated with placebo. The majority of these events first occurred within the initial 12 weeks of drug therapy; however, in some patients, events were reported later in the course of treatment. Only Qsymia-treated patients discontinued treatment due to these events (1% for paraesthesia and 0.6% for dysgeusia). Mood and Sleep Disorders The proportion of patients in 1-year controlled trials of Qsymia reporting one or more adverse reactions related to mood and sleep disorders was 15.8%, 14.5%, and 20.6% with Qsymia 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 10.3% 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 6.7%, 8.1%, and 11.1% of patients treated with Qsymia 3.75 mg/23 mg, 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 4.6%, 4.8%, and 7.9% of patients treated with Qsymia 3.75 mg/23 mg, 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 5.0%, 3.8%, and 7.6% of patients treated with Qsymia 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 3.4% of patients treated with placebo. The majority of these events first occurred within the initial 12 weeks of drug therapy; however, in some patients, events were reported later in the course of treatments. In the Qsymia clinical trials, the overall prevalence of mood and sleep adverse reactions was approximately twice as great in patients with a history of depression compared to patients without a history of depression; however, the proportion of patients on active treatment versus placebo who reported mood and sleep adverse reactions was similar in these two subgroups. Occurrence of depression-related events was more frequent in patients with a past history of depression across all treatment groups. However, the placebo-adjusted difference in incidence of these events remained constant between groups regardless of previous depression history. Cognitive Disorders In the 1-year controlled trials of Qsymia, the proportion of patients who experienced one or more cognitive-related adverse reactions was 2.1% for Qsymia 3.75 mg/23 mg, 5.0% for Qsymia 7.5 mg/46 mg, and 7.6% for Qsymia 15 mg/92 mg, compared to 1.5% for placebo. These adverse reactions were comprised primarily of reports of problems with attention/concentration, memory, and language (word finding). These events typically began within the first 4 weeks of treatment, had a median duration of approximately 28 days or less, and were reversible upon discontinuation of treatment; however, individual patients did experience events later in treatment, and events of longer duration. Laboratory Abnormalities Serum Bicarbonate In the 1-year controlled trials of Qsymia, the incidence of persistent treatment-emergent 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 8.8% for Qsymia 3.75 mg/23 mg, 6.4% for Qsymia 7.5 mg/46 mg, and 12.8% for Qsymia 15 mg/92 mg, compared to 2.1% for placebo. The incidence of persistent, markedly low serum bicarbonate values (levels of less than 17 mEq/L on 2 consecutive visits or at the final visit) was 1.3% for Qsymia 3.75 mg/23 mg, 0.2% for Qsymia 7.5 mg/46 mg dose, and 0.7% for Qsymia 15 mg/92 mg dose, compared to 0.1% for placebo. Generally, decreases in serum bicarbonate levels were mild (average 1-3 mEq/L) and occurred early in treatment (4-week visit), however severe decreases and decreases later in treatment occurred. Serum Potassium In the 1-year controlled trials of Qsymia, 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 0.4% for Qsymia 3.75 mg/23 mg, 3.6% for Qsymia 7.5 mg/46 mg dose, and 4.9% for Qsymia 15 mg/92 mg, compared to 1.1% for placebo. Of the subjects who experienced persistent low serum potassium, 88% were receiving treatment with a non-potassium sparing diuretic. The incidence of markedly low serum potassium (less than 3 mEq/L, and a reduction from pre-treatment of greater than 0.5 mEq/L) at any time during the trial was 0.0% for Qsymia 3.75 mg/23 mg, 0.2% for Qsymia 7.5 mg/46 mg dose, and 0.7% for Qsymia 15 mg/92 mg dose, compared to 0.0% for placebo. Persistent markedly low serum potassium (less than 3 mEq/L, and a reduction from pre-treatment of greater than 0.5 mEq/L at two consecutive visits or at the final visit) occurred in 0.0% of subjects receiving Qsymia 3.75 mg/23 mg, 0.2% receiving Qsymia 7.5 mg/46 mg dose, and 0.1% receiving Qsymia 15 mg/92 mg dose, compared to 0.0% receiving placebo. Hypokalemia was reported by 0.4% of subjects treated with Qsymia 3.75 mg/23 mg, 1.4% of subjects treated with Qsymia 7.5 mg/46 mg, and 2.5% of subjects treated with Qsymia 15 mg/92 mg compared to 0.4% of subjects treated with placebo. "Blood potassium decreased" was reported by 0.4% of subjects treated with Qsymia 3.75 mg/23 mg, 0.4% of subjects treated with Qsymia 7.5 mg/46 mg, 1.0% of subjects treated with Qsymia 15 mg/92 mg, and 0.0% of subjects treated with placebo. Serum Creatinine In the 1-year controlled trials of Qsymia, there was a dose-related increase from baseline, peaking between Week 4 to 8, which 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 was 2.1% for Qsymia 3.75 mg/23 mg, 7.2% for Qsymia 7.5 mg/46 mg, and 8.4% for Qsymia 15 mg/92 mg, compared to 2.0% for placebo. Increases in serum creatinine of greater than or equal to 50% over baseline occurred in 0.8% of subjects receiving Qsymia 3.75 mg/23 mg, 2.0% receiving Qsymia 7.5 mg/46 mg, and 2.8% receiving Qsymia 15 mg/92 mg, compared to 0.6% receiving placebo. Nephrolithiasis In the 1-year controlled trials of Qsymia, the incidence of nephrolithiasis was 0.4% for Qsymia 3.75 mg/23 mg, 0.2% for Qsymia 7.5 mg/46 mg, and 1.2% for Qsymia 15 mg/92 mg, compared to 0.3% for placebo. Drug Discontinuation Due to Adverse Reactions In the 1-year placebo-controlled clinical studies, 11.6% of Qsymia 3.75 mg/23 mg, 11.6% of Qsymia 7.5 mg/46 mg, 17.4% of Qsymia 15 mg/92 mg, and 8.4% of placebo-treated patients discontinued treatment due to reported adverse reactions. The most common adverse reactions that led to discontinuation of treatment are shown in Table 4. Table 4. Adverse Reactions Greater Than or Equal To 1% Leading to Treatment Discontinuation (1-Year Clinical Trials) Adverse Reaction Leading to Treatment Discontinuation greater than or equal to 1% in any treatment group Placebo (N=1561) % Qsymia 3.75 mg/23 mg (N=240) % Qsymia 7.5 mg/46 mg (N=498) % Qsymia 15 mg/92 mg (N=1580) % Vision blurred 0.5 2.1 0.8 0.7 Headache 0.6 1.7 0.2 0.8 Irritability 0.1 0.8 0.8 1.1 Dizziness 0.2 0.4 1.2 0.8 Paraesthesia 0.0 0.4 1.0 1.1 Insomnia 0.4 0.0 0.4 1.6 Depression 0.2 0.0 0.8 1.3 Anxiety 0.3 0.0 0.2 1.1 6.2 Postmarketing Experience The following adverse reactions have been reported during post approval use of phentermine and topiramate, the components of Qsymia. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Qsymia Psychiatric Disorders Suicidal ideation, Suicidal behavior Ophthalmic disorders Acute angle closure glaucoma Increased intraocular pressure Phentermine Allergic adverse reactions Urticaria Cardiovascular adverse reactions Elevation of blood pressure, Ischemic events Central nervous system adverse reactions Euphoria, Psychosis, Tremor Reproductive adverse reactions Changes in libido, Impotence Topiramate Dermatologic disorders Bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), Pemphigus Gastrointestinal disorders Pancreatitis Hepatic disorders Hepatic failure (including fatalities), Hepatitis Metabolic disorders Hyperammonemia Hypothermia Ophthalmic disorders Maculopathy

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Take once daily in morning. Avoid evening dose to prevent insomnia ( 2.1). Recommended dose: Qsymia 3.75 mg/23 mg (phentermine 3.75 mg/topiramate 23 mg extended-release) daily for 14 days; then increase to 7.5 mg/46 mg daily ( 2.1). Discontinue or escalate dose (as described) if 3% weight loss is not achieved after 12 weeks on 7.5 mg/46 mg dose ( 2.1). Discontinue Qsymia if 5% weight loss is not achieved after 12 weeks on maximum daily dose of 15 mg/92 mg ( 2.1). Discontinue 15 mg/92 mg dose gradually (as described) to prevent possible seizure ( 2.1). Do not exceed 7.5 mg/46 mg dose for patients with moderate or severe renal impairment or patients with moderate hepatic impairment ( 2.2, 2.3). 2.1 General Dosing and Administration Determine the patient's BMI. BMI is calculated by dividing weight (in kilograms) by height (in meters) squared. A BMI conversion chart (Table 1) based on height [inches (in) or centimeters (cm)] and weight [pounds (lb) or kilograms (kg)] is provided below. Table 1. BMI Conversion Chart In adults with an initial BMI of 30 kg/m2 or greater or 27 kg/m2 or greater when accompanied by weight-related co-morbidities such as hypertension, type 2 diabetes mellitus, or dyslipidemia prescribe Qsymia as follows: Take Qsymia once daily in the morning with or without food. Avoid dosing with Qsymia in the evening due to the possibility of insomnia. Start treatment with Qsymia 3.75 mg/23 mg (phentermine 3.75 mg/topiramate 23 mg extended-release) daily for 14 days; after 14 days increase to the recommended dose of Qsymia 7.5 mg/46 mg (phentermine 7.5 mg/topiramate 46 mg extended-release) once daily. Evaluate weight loss after 12 weeks of treatment with Qsymia 7.5 mg/46 mg. If a patient has not lost at least 3% of baseline body weight on Qsymia 7.5 mg/46 mg, discontinue Qsymia or escalate the dose, as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss at the Qsymia 7.5 mg/46 mg dose. To escalate the dose: Increase to Qsymia 11.25 mg/69 mg (phentermine 11.25 mg/topiramate 69 mg extended-release) daily for 14 days; followed by dosing Qsymia 15 mg/92 mg (phentermine 15 mg/topiramate 92 mg extended-release) once daily. Evaluate weight loss following dose escalation to Qsymia 15 mg/92 mg after an additional 12 weeks of treatment. If a patient has not lost at least 5% of baseline body weight on Qsymia 15 mg/92 mg, discontinue Qsymia as directed, as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment. Qsymia 3.75 mg/23 mg and Qsymia 11.25 mg/69 mg are for titration purposes only. Table 1 Discontinuing Qsymia Discontinue Qsymia 15 mg/92 mg gradually by taking a dose 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 (5.12)]. 2.2 Dosing in Patients with Renal Impairment In patients with moderate (creatinine clearance [CrCl] greater than or equal to 30 and less than 50 mL/min) or severe (CrCl less than 30 mL/min) renal impairment dosing should not exceed Qsymia 7.5 mg/46 mg once daily. Renal impairment is determined by calculating CrCl using the Cockcroft-Gault equation with actual body weight [see Warnings and Precautions (5.13) and Clinical Pharmacology (12.3)]. 2.3 Dosing in Patients with Hepatic Impairment In patients with moderate hepatic impairment (Child-Pugh score 7 - 9), dosing should not exceed Qsymia 7.5 mg/46 mg once daily [see Warnings and Precautions (5.14) and Clinical Pharmacology (12.3) ].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Nursing Mothers: Discontinue drug or nursing ( 8.3). Pediatric Use: Safety and effectiveness not established and use not recommended ( 8.4). 8.1 Pregnancy Pregnancy Category X Risk Summary Qsymia is contraindicated in pregnant women. The use of Qsymia can cause fetal harm and weight loss offers no potential benefit to a pregnant woman. Available epidemiologic data indicate an increased risk in oral clefts (cleft lip with or without cleft palate) with first trimester exposure to topiramate, a component of Qsymia. When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, treatment should be discontinued immediately and the patient should be apprised of the potential hazard to a fetus. There is a Qsymia Pregnancy Surveillance Program to monitor maternal-fetal outcomes of pregnancies that occur during Qsymia therapy. Healthcare providers and patients are encouraged to report pregnancies by calling 1-888-998-4887. Clinical Considerations Oral clefts occur from the fifth through the ninth week of gestation. The lip is formed between the beginning of the fifth week to the seventh week of gestation, and the palate is formed between the beginning of the sixth week through the ninth week of gestation. A minimum weight gain, and no weight loss, is currently recommended for all pregnant women, including those who are already overweight or obese, due to the obligatory weight gain that occurs in maternal tissues during pregnancy. Qsymia can cause metabolic acidosis. 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 [see Warnings and Precautions (5.7)] . Human Data Data evaluating the risk of major congenital malformations and oral clefts with topiramate (a component of Qsymia) exposure during pregnancy is available from the North American Anti-Epileptic Drug (NAAED) Pregnancy Registry and from several larger retrospective epidemiologic studies. The NAAED Pregnancy Registry suggested an estimated increase in risk for oral clefts of 9.60 (95% CI 3.60 - 25.70). 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 (Table 5). The FORTRESS study, sponsored by the maker of Qsymia, 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. Table 5. Summary of Studies Evaluating the Association of Topiramate in Utero Exposure and Oral Clefts and Major Congenital Malformations Epidemiology Study Oral clefts Major Congenital Malformations Estimated Increase in Risk 95% CI Estimated Increase in Risk 95% CI CI = confidence interval Wolters Kluwer Sponsored by the maker of Qsymia 1.47 0.36 – 6.06 1.12 0.81 – 1.55 FORTRESS 2.22 0.78 – 6.36 1.21 0.99 – 1.47 Slone/CDC 5.36 1.49 – 20.07 1.01 0.37 – 3.22 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 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, 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 [see Nonclinical Toxicology (13.3)] . 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 Qsymia, based on AUC. Topiramate Topiramate causes developmental toxicity, including teratogenicity, at clinically relevant doses [see Nonclinical Toxicology (13.3)] . 8.2 Labor and Delivery The effect of Qsymia on labor and delivery in humans is unknown. The development of Qsymia-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus's ability to tolerate labor. 8.3 Nursing Mothers Qsymia may be present in human milk because topiramate and amphetamines (phentermine has pharmacologic activity and a chemical structure similar to amphetamines) are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness of Qsymia in pediatric patients below the age of 18 years have not been established and the use of Qsymia is not recommended in pediatric patients. Serious adverse reactions seen in pediatric patients using topiramate, a component of Qsymia, include acute angle glaucoma, oligohidrosis and hyperthermia, metabolic acidosis, cognitive and neuropsychiatric reactions, hyperammonemia and encephalopathy, and kidney stones. Juvenile Animal Studies Juvenile animal studies have not been conducted with Qsymia. When topiramate (30, 90, or 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose. 8.5 Geriatric Use In the Qsymia clinical trials, a total of 254 (7%) of the patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. Clinical studies of Qsymia did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Females of Reproductive Potential Qsymia can cause fetal harm. Data from pregnancy registries and epidemiology studies indicate that a fetus exposed to topiramate, a component of Qsymia, in the first trimester of pregnancy has an increased risk of oral clefts (cleft lip with or without cleft palate). Females who become pregnant during Qsymia therapy should stop Qsymia treatment immediately and notify their healthcare provider. Pregnancy Testing Females of reproductive potential should have a negative pregnancy test before starting Qsymia and monthly thereafter during Qsymia therapy. Contraception Females of reproductive potential should use effective contraception during Qsymia therapy. 8.7 Renal Impairment Compared to healthy volunteers, patients with moderate and severe renal impairment as estimated by the Cockcroft-Gault equation had higher phentermine and topiramate exposures. No dose adjustments are necessary in patients with mild renal impairment. In patients with moderate (CrCl greater than or equal to 30 to less than 50 mL/min) and severe (CrCl less than 30 mL/min) renal impairment, the dose should not exceed Qsymia 7.5 mg/46 mg once daily. Qsymia has not been studied in patients with end-stage renal disease on dialysis. Avoid Qsymia in this patient population [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)] . 8.8 Hepatic Impairment In patients with mild (Child-Pugh 5 - 6) and moderate (Child-Pugh 7 - 9) hepatic impairment, exposure to phentermine was higher compared to healthy volunteers. Exposure to topiramate, a component of Qsymia, was similar among patients with mild and moderate hepatic impairment and healthy volunteers. No dose adjustments are necessary in patients with mild hepatic impairment. In patients with moderate hepatic impairment, the dose should not exceed Qsymia 7.5 mg/46 mg once daily. Qsymia has not been studied in patients with severe hepatic impairment (Child-Pugh score 10 - 15). Avoid Qsymia in this patient population [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)] .
Pregnancy and lactation
8.3 Nursing Mothers Qsymia may be present in human milk because topiramate and amphetamines (phentermine has pharmacologic activity and a chemical structure similar to amphetamines) are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Interactions

7 DRUG INTERACTIONS Oral contraceptives: Altered exposure may cause irregular bleeding but not increased risk of pregnancy. Advise patients not to discontinue oral contraceptives if spotting occurs ( 7.2). CNS depressants including alcohol: Potentiate CNS depressant effects. Avoid concomitant use of alcohol ( 7.3). Non-potassium sparing diuretics: May potentiate hypokalemia. Measure potassium before/during treatment ( 7.4). 7.1 Monoamine Oxidase Inhibitors Use of phentermine is contraindicated during or within 14 days following the administration of monoamine oxidase inhibitors because of the risk of hypertensive crisis. 7.2 Oral Contraceptives Co-administration of multiple-dose Qsymia 15 mg/92 mg once daily with a single dose of oral contraceptive containing 35 µg 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 study did not specifically address the impact of the interaction on contraceptive efficacy, an increased risk of pregnancy is not anticipated. The primary determinant of contraceptive efficacy is the progestin component of the combination oral contraceptive, so higher exposure to the progestin would not be expected to be deleterious. However, 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. Patients should be informed not to discontinue their combination oral contraceptive if spotting occurs, but to notify their health care provider if the spotting is troubling to them. 7.3 CNS Depressants Including Alcohol Specific drug interaction studies of Qsymia and alcohol or other CNS depressant drugs have not been performed. 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. Therefore, if Qsymia is used with alcohol or other CNS depressants, the patient should be counseled regarding possible increased risk of CNS depression or side effects. 7.4 Non-Potassium Sparing Diuretics Concurrent use of Qsymia 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. When prescribing Qsymia in the presence of non-potassium-sparing medicinal products, patients should be monitored for hypokalemia [see Warnings and Precautions (5.17) and Clinical Pharmacology (12.3)] . 7.5 Antiepileptic Drugs 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). It may be prudent to examine blood ammonia in patients in whom the onset of hypothermia or encephalopathy has been reported [see Clinical Pharmacology (12.3)] . 7.6 Carbonic Anhydrase Inhibitors Concomitant use of topiramate, a component of Qsymia, with any other carbonic anhydrase inhibitor (e.g., zonisamide, acetazolamide, or dichlorphenamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Avoid the use of Qsymia with other drugs that inhibit carbonic anhydrase [see Warnings and Precautions (5.7)] .

More information

Category Value
Authorisation number NDA022580
Agency product number 0H73WJJ391
Orphan designation No
Product NDC 62541-204,62541-201,62541-202,62541-203
Date Last Revised 27-06-2017
Type HUMAN PRESCRIPTION DRUG
Storage and handling Store at controlled room temperature, 15°C to 25°C (59°F to 77°F). Keep container tightly closed and protect from moisture.
Marketing authorisation holder Vivus, Inc.
Warnings Qsymia is a federally controlled substance (CIV) because it contains phentermine and can be abused or lead to drug dependence. Keep Qsymia in a safe place, to protect it from theft. Never give your Qsymia to anyone else, because it may cause death or harm them. Selling or giving away this medicine is against the law.