Qsymia Side Effects Center

SIDE EFFECTS

The following important adverse reactions are described elsewhere in the labeling:

• Embryo-Fetal Toxicity [see WARNINGS AND PRECAUTIONS and Use In Specific Populations]
• Increase in Heart Rate [see WARNINGS AND PRECAUTIONS]
• Suicidal Behavior and Ideation [see WARNINGS AND PRECAUTIONS]
• Risk of Ophthalmologic Adverse Reactions [see WARNINGS AND PRECAUTIONS]
• Mood and Sleep Disorders [see WARNINGS AND PRECAUTIONS]
• Cognitive Impairment [see WARNINGS AND PRECAUTIONS]
• Slowing of Linear Growth [see WARNINGS AND PRECAUTIONS]
• Metabolic Acidosis [see WARNINGS AND PRECAUTIONS]
• Decrease in Renal Function [see WARNINGS AND PRECAUTIONS]
• Risk of Seizures with Abrupt Withdrawal of QSYMIA [see WARNINGS AND PRECAUTIONS]
• Kidney Stones [see WARNINGS AND PRECAUTIONS]
• Oligohydrosis and Hyperthermia [see WARNINGS AND PRECAUTIONS]
• Hypokalemia [see WARNINGS AND PRECAUTIONS]
• Serious Skin Reactions [see WARNINGS AND PRECAUTIONS]

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, placebocontrolled, multicenter clinical trials and two supportive trials in 2318 adult patients with overweight or obesity (936 [40%] patients with hypertension, 309 [13%] patients with type 2 diabetes, 808 [35%] patients with BMI greater than 40 kg/m²) exposed for a mean duration of 298 days. Data in this section also describe adverse reactions from a 1-year, randomized, double-blind, placebo-controlled multicenter clinical trial that evaluated 223 pediatric patients (12 to 17 years old) with obesity [see Clinical Studies].

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 QSYMIA-treated adults and more frequently than in the placebo group are shown in Table 3.

Table 3: Adverse Reactions Reported in ≥2% of QSYMIA-Treated Adults with Overweight or Obesity and More Frequently than Placebo in Overall Study Population of 1 Year Duration

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) %
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

Pediatric Patients Aged 12 Years And Older

Adverse reactions occurring in pediatric patients treated with either QSYMIA 15 mg/92 mg or QSYMIA 7.5 mg/46 mg at greater than or equal to 4% and higher than placebo include depression, pyrexia, dizziness, arthralgia, influenza, and ligament sprain.

Adverse reactions reported in greater than or equal to 2% of QSYMIA-treated pediatric patients and more frequently than in the placebo group from a study in pediatric patients aged 12 years and older are shown in Table 4.

Table 4: Adverse Reactions Reported in ≥2% of QSYMIA-Treated Pediatric Patients Aged 12 to 17 Years and More Frequently than Placebo during 56 Weeks of Treatment

Preferred Term	Placebo (N = 56) %	QSYMIA 7.5 mg/46 mg (N = 54) %	QSYMIA 15 mg/92 mg (N = 113) %
Depression	0	2	4
Nausea	4	4	4
Pyrexia	2	2	4
Dizziness	0	2	4
Arthralgia	0	2	4
Paraesthesia	0	2	3
Anxiety	0	2	3
Abdominal Pain Upper	0	0	3
Fatigue	2	0	3
Ear Infection	0	2	3
Musculoskeletal Chest Pain	0	0	3
Influenza	0	4	2
Ligament Sprain	0	4	2

Increase In Heart Rate

In adult and pediatric clinical trials, there was a higher incidence of heart rate elevations observed in QSYMIAtreated compared to placebo-treated patients.

Table 5 and Table 6 provide the numbers and percentages of adult and pediatric patients, respectively, with elevations in heart rate in clinical studies of up to one year.

Table 5: 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 (%)	QSYMIA 3.75 mg/23 mg N=240 n (%)	QSYMIA 7.5 mg/46 mg N=498 n (%)	QSYMIA 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)

Table 6: Number and Percentage of Pediatric Patients with an Increase in Heart Rate at a Single Time Point from Baseline

	Placebo N=56 n (%)	QSYMIA 7.5 mg/46 mg N=54 n (%)	QSYMIA 15 mg/92 mg N=113 n (%)
Greater than 5 bpm	37 (66.1)	38 (70.4)	92 (81.4)
Greater than 10 bpm	26 (46.4)	30 (55.6)	73 (64.6)
Greater than 15 bpm	17 (30.4)	18 (33.3)	48 (42.5)
Greater than 20 bpm	10 (17.9)	10 (18.5)	27 (23.9)

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 3). Adverse reactions of paraesthesia were also reported in pediatric patients (see Table 4). QSYMIA-treated adult patients discontinued treatment due to these adverse reactions (1% for paraesthesia and 0.6% for dysgeusia); no pediatric patients discontinued treatment due to paraesthesia or dysgeusia.

Mood And Sleep Disorders

The proportion of adult patients in 1-year controlled trials of QSYMIA reporting one or more adverse reactions related to mood and sleep disorders was 15% and 21% with QSYMIA 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 QSYMIA 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 QSYMIA 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 QSYMIA 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.

In a pediatric clinical trial, higher proportions of QSYMIA-treated patients reported one or more adverse reactions related to mood (e.g., depression, anxiety) and sleep disorders (e.g., insomnia) compared to placebotreated patients (See Table 4).

Cognitive Disorders

In the 1-year controlled trials of QSYMIA in adults, the proportion of patients who experienced one or more cognitive-related adverse reactions was 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 occurred at any time during treatment with QSYMIA.

Slowing Of Linear Growth

QSYMIA is associated with a reduction in height velocity (centimeters of height gained per year) in obese pediatric patients 12 to 17 years of age. In a 56-week study, average height increased from baseline in both QSYMIA- and placebo-treated patients; however, a lower height velocity of -1.3 to -1.4 cm/year was observed in QSYMIA-treated compared to placebo-treated patients

Decrease In Bone Mineral Density

QSYMIA is associated with less bone mineral acquisition in pediatric patients 12 to 17 years of age. In a substudy (n=66) evaluating bone mineralization via dual-energy X-ray absorptiometry (DEXA), increases in bone mineral density (BMD) at the lumbar spine and total body less head (TBLH) were smaller in pediatric patients treated with QSYMIA compared to those treated with placebo after 1 year of treatment. Declines in BMD Z-scores of -0.5 or greater from baseline for TBLH were observed in 9% of QSYMIA 7.5 mg/46 mgtreated patients and 30% of QSYMIA 15 mg/92 mg-treated patients, compared to 0% of placebo-treated patients. The sample size and study duration were too small to determine if fracture risk is increased. Decreased BMD was not correlated with decreased serum bicarbonate, which commonly occurs with QSYMIA treatment, or changes in body weight. No patient had a BMD Z-score that went below -2.0 during the trial. Similar findings were observed in a 1 year, active-controlled trial of topiramate in pediatric patients with another condition.

Nephrolithiasis

In the 1-year controlled trials of QSYMIA in adults, the incidence of nephrolithiasis was 0.2% for QSYMIA 7.5 mg/46 mg and 1.2% for QSYMIA 15 mg/92 mg, compared to 0.3% for placebo.

Laboratory Abnormalities

Serum Bicarbonate

In the 1-year controlled trials of QSYMIA 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 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 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. In a pediatric clinical trial, 60 to 70% QSYMIA-treated patients had a persistent bicarbonate level below the normal range (<21 mEq/L) compared to 43% of placebo-treated patients.

Serum Potassium

In the 1-year controlled trials of QSYMIA 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 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 0.2% 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 0.2% receiving QSYMIA 7.5 mg/46 mg dose and 0.1% receiving QSYMIA 15 mg/92 mg dose, compared to 0.0% receiving placebo.

Low serum potassium levels (<3.5 mEq/L) were not observed in a 56-week clinical trial of pediatric patients with obesity.

Serum Creatinine

In the 1-year controlled trials of QSYMIA in adults and pediatric patients, there was an increase in serum creatinine from baseline, peaking between Week 4 to 8 in adults and at Week 16 in pediatric 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 QSYMIA 7.5 mg/46 mg and 8.4% for QSYMIA 15 mg/92 mg, compared to 2.0% for placebo; 17% of pediatric patients treated with QSYMIA 7.5 mg/46 mg or QSYMIA 15 mg/92 mg and 0% of patients treated with placebo had a serum creatinine ≥0.3 mg/dL at any time post-randomization. Increases in serum creatinine of greater than or equal to 50% over baseline occurred in 2.0% of adult subjects receiving QSYMIA 7.5 mg/46 mg and 2.8% receiving QSYMIA 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].

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 QSYMIA) and 14% in patients taking topiramate at 50 mg/day (0.6 times the maximum recommended dosage of QSYMIA), 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.

Postmarketing Experience

The following adverse reactions have been reported during post approval use of QSYMIA, phentermine, and topiramate. 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: suicidal ideation, suicidal behavior

Ophthalmic: acute angle closure glaucoma, increased intraocular pressure

Phentermine

Allergic Reactions: urticaria

Cardiovascular: elevation of blood pressure, ischemic events

Central Nervous System: euphoria, psychosis, tremor

Reproductive: changes in libido, impotence

Topiramate

Dermatologic: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), pemphigus

Gastrointestinal: pancreatitis

Hepatic: hepatic failure (including fatalities), hepatitis

Metabolic: hyperammonemia with or without encephalopathy has been reported with concomitant valproic acid [see DRUG INTERACTIONS], hypothermia

Ophthalmic: maculopathy

DRUG INTERACTIONS

Table 7 displays clinically significant drug interactions with QSYMIA.

Table 7: Clinically Significant Drug Interactions with QSYMIA

Monamine Oxidase Inhibitors
Clinical Impact	Concomitant use of phentermine with monoamine oxidase inhibitors (MAOIs) increases the risk of hypertensive crisis.
Intervention	Concomitant use of QSYMIA is contraindicated during MAOI treatment and within 14 days of stopping an MAOI.
Oral Contraceptives
Clinical Impact	Co-administration of multiple-dose QSYMIA 15 mg/92 mg once daily with a single dose of oral contraceptive containing 35μg 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]. 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 healthcare 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 QSYMIA to gauge whether it adversely affects their mental performance, motor performance, and/or vision. Caution patients against excessive alcohol intake when taking QSYMIA. Consider QSYMIA dosage reduction or discontinuation if cognitive dysfunction persists. [see WARNINGS AND PRECAUTIONS].
Non-Potassium Saparing Diuretics
Clinical Impact	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 Cmax and AUC of topiramate by 27% and 29%, respectively.
Intervention	When QSYMIA is used concomitantly with non-potassium-sparing diuretics, measure potassium before and during QSYMIA treatment[see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
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]. 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].
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 QSYMIA with other drugs that inhibit carbonic anhydrase. If concomitant use of QSYMIA with another carbonic anhydrase inhibitor is unavoidable, monitor patient for the appearance or worsening of metabolic acidosis [see WARNINGS AND PRECAUTIONS].
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 QSYMIA concomitantly [see CLINICAL PHARMACOLOGY].
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 QSYMIA should be made according to the patient's clinical response and not on the basis of amitriptyline levels [see CLINICAL PHARMACOLOGY].

Drug Abuse And Dependence

Controlled Substance

QSYMIA contains phentermine, a Schedule IV controlled substance, and topiramate, which is not a controlled substance.

Abuse

Phentermine has a known potential for abuse. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Phentermine is related chemically and pharmacologically to amphetamines. Amphetamines and other stimulant drugs have been extensively abused. Abuse of amphetamines and related drugs (e.g., phentermine) may be associated with impaired control over drug use and severe social dysfunction. There are reports of patients who have increased the dosage of these drugs to many times higher than recommended. Assess the risk of abuse prior to prescribing QSYMIA as part of a chronic weight management program.

Dependence

Physical dependence may occur in patients treated with QSYMIA. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

The following adverse reactions have been associated with the abrupt discontinuation of the individual components of QSYMIA:

• For topiramate, abrupt discontinuation has been associated with seizures in patients without a history of seizures or epilepsy [see WARNINGS AND PRECAUTIONS].
• For phentermine, abrupt discontinuation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on a sleep electroencephalogram.

Thus, in situations where rapid withdrawal of QSYMIA is required, appropriate medical monitoring is recommended. Patients discontinuing QSYMIA 15 mg/92 mg should be gradually tapered to reduce the possibility of precipitating a seizure [see DOSAGE AND ADMINISTRATION].

Read the entire FDA prescribing information for Qsymia (Phentermine and Topiramate)