Qsymia

Phentermine and topiramate combination is used together with a reduced-calorie diet and proper exercise to help you lose weight. It is also used in overweight people who may also have diabetes, high blood pressure, high cholesterol, or heart disease.

This medicine is available only under a special restricted distribution program called Qsymia™ REMS program.

This product is available in the following dosage forms:

• Capsule, Extended Release

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/m² or greater (obese), or
• 27 kg/m² or greater (overweight) in the presence of at least one weight related comorbidity such as hypertension, type 2 diabetes mellitus, or dyslipidemia

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.

Qsymia is a prescription medication used to help adults who are obese or overweight and have weight-related medical problems. Qsymia helps these adults lose weight and maintain a healthy weight.

It is a single product containing 2 medications: phentermine and topiramate.

Phentermine belongs to a group of drugs called anorectics. These work by reducing appetite and help to decrease food consumption. Topiramate belongs to a group of drugs called anticonvulsants. These work by reducing appetite and increasing a feeling of fullness after eating.

This medication comes in extended-release capsule form and is taken 1 time a day, with or without food. Take Qsymia in the morning.

Common side effects of Qsymia include changes in the way foods taste, trouble sleeping, constipation, dry mouth, and numbness or tingling in the hands, arms, feet, or face.

Qsymia can also cause blurred vision, drowsiness, and dizziness. Do not drive or operate heavy machinery until you know how Qsymia affects you.

If you take too much Qsymia, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If Qsymia is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

• Store Qsymia at room temperature.
• Keep this and all medicines out of the reach of children.
• Qsymia is not available at retail pharmacies. This medication is available only through specific mail order pharmacies.

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.

Phentermine is an appetite suppressant similar to an amphetamine. Topiramate is a seizure medication, also called an anticonvulsant.

Phentermine and topiramate is a combination medicine used together with diet and exercise to treat obesity. This medicine is sometimes used to treat obesity that may be related to diabetes, high cholesterol, or high blood pressure. Phentermine and topiramate will not treat any these underlying conditions. Keep using any other medicines your doctor has prescribed to treat these conditions.

Phentermine and topiramate may also be used for purposes not listed in this medication guide.

• Store at room temperature.
• Keep lid tightly closed.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

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/m2 or greater (obese), or
• 27 kg/m2 or greater (overweight) in the presence of at least one weight related comorbidity such as hypertension, type 2 diabetes mellitus, or dyslipidemia

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.

Qsymia capsules are formulated in the following four strength combinations (phentermine mg/topiramate mg extended-release):

• 3.75 mg/23 mg [Purple cap imprinted with VIVUS, Purple body imprinted with 3.75/23]
• 7.5 mg/46 mg [Purple cap imprinted with VIVUS, Yellow body imprinted with 7.5/46]
• 11.25 mg/69 mg [Yellow cap imprinted with VIVUS, Yellow body imprinted with 11.25/69]
• 15 mg/92 mg [Yellow cap imprinted with VIVUS, White body imprinted with 15/92]

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)]

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/m2) 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.

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.

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

Phentermine

Topiramate

Carcinogenesis, Mutagenesis, Impairment of Fertility

Phentermine/Topiramate

No animal studies have been conducted with phentermine/topiramate, the combined products in Qsymia, to evaluate carcinogenesis, mutagenesis, or impairment of fertility. The following data are based on findings in studies performed individually with phentermine or topiramate, Qsymia'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 Qsymia 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 Qsymia 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 Qsymia based on AUC estimates).

No adverse effects on male or female fertility were observed in rats at doses up to 100 mg/kg or approximately 4 to 8 times male and female MRHD exposures of Qsymia based on AUC.

Reproductive and Developmental Toxicology

Topiramate

Topiramate, a component of Qsymia, causes developmental toxicity, including teratogenicity, in multiple animal species at clinically relevant doses.

When oral doses of 20, 100, or 500 mg/kg were administered to pregnant mice during the period of organogenesis, the incidence of fetal malformations (primarily craniofacial defects) was increased at all doses. The low dose of topiramate in this study (20 mg/kg) is approximately 2 times the MRHD of topiramate in Qsymia 15 mg/92 mg on a mg/m2 basis. Fetal body weights and skeletal ossification were reduced at 500 mg/kg in conjunction with decreased maternal body weight gain.

In rat studies (oral doses of 20, 100, and 500 mg/kg or 0.2, 2.5, 30, and 400 mg/kg), the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased among the offspring of dams treated with 400 mg/kg (34 times the MRHD of Qsymia based on AUC estimates) or greater during the organogenesis period of pregnancy. Embryotoxicity (reduced fetal body weights, increased incidence of structural variations) was observed at doses as low as 20 mg/kg (2 times the MRHD of Qsymia based on estimated AUC). Clinical signs of maternal toxicity were seen at 400 mg/kg and above, and maternal body weight gain was reduced during treatment with 100 mg/kg or greater.

In rabbit studies (20, 60, and 180 mg/kg or 10, 35, and 120 mg/kg orally during organogenesis), embryo/fetal mortality was increased at 35 mg/kg (2 times the MRHD based on estimated AUC) or greater, and teratogenic effects (primarily rib and vertebral malformations) were observed at 120 mg/kg (6 times the MRHD of Qsymia based on estimated AUC). Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg and above.

When female rats were treated during the latter part of gestation and throughout lactation (0.2, 4, 20, and 100 mg/kg or 2, 20, and 200 mg/kg), offspring exhibited decreased viability and delayed physical development at 200 mg/kg (16 times the MRHD of Qsymia based on estimated AUC) and reductions in pre-and/or post-weaning body weight gain at 2 mg/kg (2 times the MRHD of Qsymia based on estimated AUC) and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg or greater.

In a rat embryo/fetal development study with a postnatal component (0.2, 2.5, 30, or 400 mg/kg during organogenesis; noted above), pups exhibited delayed physical development at 400 mg/kg (34 times the MRHD of Qsymia based on estimated AUC) and persistent reductions in body weight gain at 30 mg/kg (2 times the MRHD of Qsymia based on estimated AUC) and higher.

Common side effects of Qsymia include: constipation, insomnia, nasopharyngitis, paresthesia, mood disorder, sleep disorder, and xerostomia. Other side effects include: urinary tract infection, anxiety, blurred vision, depression, dizziness, fatigue, influenza, nausea, increased serum creatinine, and dysgeusia. See below for a comprehensive list of adverse effects.

Applies to phentermine / topiramate: oral capsule extended release

Nervous system

Very common (10% or more): Paraesthesia (up to 19.9%), headache (up to 10.6%)
Common (1% to 10%): Dysgeusia, dizziness, hypoesthesia, disturbance in attention, cognitive impairment

Phentermine:
Postmarketing reports: Euphoria, psychosis, tremor[Ref]

Psychiatric

Common (1% to 10%): Insomnia, anxiety, depression/mood problems, irritability
Postmarketing reports: Suicidal ideation, suicidal behavior

Phentermine:
Postmarketing reports: Libido changes, impotence[Ref]

Metabolic

Very common (10% or more): Decreased serum bicarbonate (up to 12.8%)
Common (1% to 10%): Hypokalemia, decreased serum potassium, decreased appetite

Topiramate:
Postmarketing reports: Hyperammonemia[Ref]

Renal

Common (1% to 10%): Elevated serum creatinine, nephrolithiasis[Ref]

Cardiovascular

Very common (10% or more): Elevated resting heart rate (up to 77.7%)
Common (1% to 10%): Palpitations

Phentermine:
Postmarketing reports: Elevated blood pressure, ischemic events[Ref]

Ocular

Common (1% to 10%): Blurred vision, dry eye, eye pain
Postmarketing reports: Acute angle closure glaucoma, increased intraocular pressure

Topiramate:
Postmarketing reports: Maculopathy[Ref]

Other

Common (1% to 10%): Fatigue, thirst, chest discomfort, procedural pain

Topiramate:
Postmarketing reports: Hypothermia[Ref]

General

Common adverse reactions occurring at a rate of 5% or more and at a rate of at least 1.5 times placebo include paraesthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth.[Ref]

Dermatologic

Common (1% to 10%): Alopecia, rash

Topiramate:
Postmarketing reports: Bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), pemphigus[Ref]

Gastrointestinal

Very common (10% or more): Dry mouth (up to 19.1%), constipation (up to 16.1%)
Common (1% to 10%): Nausea, diarrhea, gastroesophageal reflux disease, dyspepsia, oral paraesthesia, gastroenteritis

Topiramate:
Postmarketing reports: Pancreatitis[Ref]

Genitourinary

Common (1% to 10%): Dysmenorrhea, urinary tract infection[Ref]

Hepatic

Topiramate:
Postmarketing reports: Hepatic failure (including fatalities), hepatitis[Ref]

Hypersensitivity

Phentermine:
Postmarketing reports: Urticaria[Ref]

Immunologic

Common (1% to 10%): Influenza[Ref]

Musculoskeletal

Common (1% to 10%): Back pain, extremity pain, muscle spasms, musculoskeletal pain, neck pain[Ref]

Respiratory

Very common (10% or more): Upper respiratory tract infection (up to 15.8%), nasopharyngitis (up to 12.5%)
Common (1% to 10%): Sinusitis, bronchitis, cough, sinus congestion, pharyngolaryngeal pain, nasal congestion[Ref]

Some side effects of Qsymia may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.