Qsymia (Phentermine Hydrochloride / Topiramate) - Side Effects and Adverse Reactions

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.

Table 3. Adverse Reactions Reported in Greater Than or Equal to 2% of Patients and More Frequently with 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

Paraesthesias/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 Discontinuationgreater 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

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.

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