Source: FDA, National Drug Code (US) Revision Year: 2022
QSYMIA is contraindicated in patients:
QSYMIA can cause fetal harm. Data from a pregnancy registry and epidemiologic studies indicate that a fetus exposed to topiramate in the first trimester of pregnancy has an increased risk of oral clefts (cleft lip with or without cleft palate). A negative pregnancy test is recommended before initiating QSYMIA treatment in patients who can become pregnant and monthly during QSYMIA therapy. Advise patients who can become pregnant of the potential risk to a fetus and to use effective contraception during QSYMIA therapy [see Use in Specific Populations (8.1, 8.3)].
Because of the teratogenic risk associated with QSYMIA therapy, QSYMIA is available through a limited program under the REMS. Under the QSYMIA REMS, only certified pharmacies may distribute QSYMIA. Further information is available at www.QSYMIAREMS.com or by telephone at 1-888-998-4887.
QSYMIA can cause an increase in resting heart rate. A higher percentage of QSYMIA-treated adults and pediatric patients aged 12 years and older experienced heart rate increases from baseline of more than 5, 10, 15, and 20 beats per minute (bpm) compared to placebo-treated patients [see Adverse Reactions (6.1)]. The clinical significance of a heart rate elevation with QSYMIA treatment is unclear, especially for patients with cardiac and cerebrovascular disease.
Measure resting heart rate regularly in all patients taking QSYMIA, especially patients with cardiac or cerebrovascular disease and when initiating or increasing the dosage of QSYMIA. QSYMIA has not been studied in patients with recent or unstable cardiac or cerebrovascular disease and therefore use is not recommended.
Advise patients to inform their healthcare provider of palpitations or feelings of a racing heartbeat while at rest during QSYMIA treatment. For patients who experience a sustained increase in resting heart rate while taking QSYMIA, reduce the dosage or discontinue QSYMIA [see Warnings and Precautions (5.12)] .
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.
In a QSYMIA clinical trial of pediatric patients aged 12 years and older, 1 (0.6%) of the 167 QSYMIA-treated patients reported suicidal ideation and behavior which required hospitalization. No placebo-treated patients reported suicidal behavior or ideation.
Monitor all patients for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Discontinue QSYMIA in patients who experience suicidal thoughts or behaviors [see Warnings and Precautions (5.12)]. Avoid QSYMIA in patients with a history of suicidal attempts or active suicidal ideation.
A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients treated with topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, mydriasis, anterior chamber shallowing, ocular hyperemia (redness), choroidal detachments, retinal pigment epithelial detachments, macular striae, and increased intraocular pressure. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating treatment with topiramate but may occur at any time during therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of QSYMIA as rapidly as possible [see Warnings and Precautions (5.12)]. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious adverse reactions including permanent loss of vision.
Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during treatment, consider discontinuing QSYMIA.
QSYMIA can cause mood disorders, including depression and anxiety, as well as insomnia. Patients with a history of depression may be at increased risk of recurrent depression or other mood disorders while taking QSYMIA [see Adverse Reactions (6.1)].
Consider dosage reduction or discontinuation of QSYMIA if clinically significant or persistent symptoms occur. Discontinue QSYMIA if patients have symptoms of suicidal ideation or behavior [see Warnings and Precautions (5.3)].
QSYMIA can cause cognitive dysfunction (e.g., impairment of concentration/attention, difficulty with memory, and speech or language problems, particularly word-finding difficulties). Rapid titration or high initial doses of QSYMIA may be associated with higher rates of cognitive events such as attention, memory, and language/word-finding difficulties [see Adverse Reactions (6.1)]. The concomitant use of alcohol or central nervous system (CNS) depressant drugs with QSYMIA may potentiate CNS depression or other centrally mediated effects of these agents, such as dizziness, cognitive adverse reactions, drowsiness, light-headedness, impaired coordination, and somnolence.
Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain QSYMIA therapy does not affect them adversely. Caution patients against excessive alcohol intake while receiving QSYMIA.
If cognitive dysfunction persists, consider dosage reduction or discontinuation of QSYMIA [see Warnings and Precautions (5.12)].
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. Monitor height velocity in pediatric patients treated with QSYMIA. Consider dosage reduction or discontinuation of QSYMIA if pediatric patients are not growing or gaining height as expected [see Warnings and Precautions (5.12)].
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 QSYMIA [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 QSYMIA. Concomitant use of QSYMIA 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 (5.13)]. Avoid use of QSYMIA with other carbonic anhydrase inhibitors. If concomitant use of QSYMIA 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 QSYMIA and during QSYMIA treatment. In QSYMIA 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 QSYMIA, reduce the dosage or discontinue QSYMIA [see Warnings and Precautions (5.12)].
QSYMIA can cause an increase in serum creatinine that reflects a decrease in renal function (glomerular filtration rate). In clinical trials, peak increases in serum creatinine were observed after 4 to 8 weeks of treatment. On average, serum creatinine gradually declined but remained elevated over baseline creatinine values. The changes in serum creatinine (and measured GFR) with short-term (4-weeks) QSYMIA treatment appear reversible with treatment discontinuation, but the effect of chronic treatment on renal function is not known.
Measure serum creatinine prior to starting QSYMIA and during QSYMIA treatment. If persistent elevations in creatinine occur, reduce the dosage or discontinue QSYMIA [see Warnings and Precautions (5.12), Adverse Reactions (6.1), Clinical Pharmacology (12.2)].
Weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with insulin and/or insulin secretagogues (e.g., sulfonylureas). QSYMIA has not been studied in combination with insulin. Measure blood glucose levels prior to starting QSYMIA and during QSYMIA treatment in patients with type 2 diabetes on antidiabetic medication. The risk of hypoglycemia may be lowered by a reduction of the dosage of insulin and/or insulin secretagogues. If a patient develops hypoglycemia after starting QSYMIA, appropriate changes should be made to the antidiabetic drug regimen.
In hypertensive patients being treated with antihypertensive medications, weight loss may increase the risk of hypotension and associated symptoms including dizziness, lightheadedness, and syncope. Measure blood pressure prior to starting QSYMIA and during QSYMIA treatment in patients being treated for hypertension. If a patient develops symptoms associated with low blood pressure after starting QSYMIA, appropriate changes should be made to the antihypertensive drug regimen.
Abrupt withdrawal of topiramate has been associated with seizures in individuals without a history of seizures or epilepsy. In situations where immediate termination of QSYMIA is medically required, appropriate 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 (2.4) and Drug Abuse and Dependence (9.3)].
QSYMIA has been associated with kidney stone formation [see Adverse Reactions (6.1)]. Topiramate inhibits carbonic anhydrase activity and promotes kidney stone formation by reducing urinary citrate excretion and increasing urine pH. Patients on a ketogenic diet may be at increased risk for kidney stone formation. An increase in urinary calcium and a marked decrease in urinary citrate was observed in topiramate-treated pediatric patients in a one-year, active-controlled study. Increased ratio of urinary calcium/citrate increases the risk of kidney stones and/or nephrocalcinosis.
Avoid the use of QSYMIA with other drugs that inhibit carbonic anhydrase [see Drug Interactions (7)]. Advise patients to increase fluid intake (to increase urinary output), which may decrease the concentration of substances involved in kidney stone formation.
Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with the use of topiramate. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases have been reported with topiramate after exposure to elevated environmental temperatures.
The majority of the reports associated with topiramate have been in pediatric patients. Advise all patients and caregivers to monitor for decreased sweating and increased body temperature during physical activity, especially in hot weather. Patients on concomitant medications that predispose them to heat-related disorders may be at increased risk.
QSYMIA can increase the risk of hypokalemia through its inhibition of carbonic anhydrase activity. In addition, when QSYMIA is used in conjunction with non-potassium sparing diuretics this may further potentiate potassium-wasting. Measure potassium before and during treatment with QSYMIA. [see Adverse Reactions (6.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].
Serious skin reactions (Stevens-Johnson Syndrome [SJS] and Toxic Epidermal Necrolysis [TEN]) have been reported in patients receiving topiramate. QSYMIA should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. Inform patients about the signs of serious skin reactions.
This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.
The following important adverse reactions are described elsewhere in the labeling:
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 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 (14)].
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 |
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 |
In adult and pediatric clinical trials, there was a higher incidence of heart rate elevations observed in QSYMIA-treated 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) |
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.
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 placebo-treated patients (See Table 4).
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.
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
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 mg-treated 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.
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.
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.
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.
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.
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 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.
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.
Psychiatric: suicidal ideation, suicidal behavior
Ophthalmic: acute angle closure glaucoma, increased intraocular pressure
Allergic Reactions: urticaria
Cardiovascular: elevation of blood pressure, ischemic events
Central Nervous System: euphoria, psychosis, tremor
Reproductive: changes in libido, impotence
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 (7)], hypothermia
Ophthalmic: maculopathy
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 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 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 (5.6)]. |
| Non-Potassium Sparing 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 C max 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 (5.15) 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 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 (5.8, 5.13)]. |
| 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 (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 QSYMIA should be made according to the patient’s clinical response and not on the basis of amitriptyline levels [see Clinical Pharmacology (12.3)]. |
QSYMIA is contraindicated in pregnant patients. The use of QSYMIA can cause fetal harm and weight loss offers no clear clinical benefit to a pregnant patient (see Clinical Considerations). Available data from a pregnancy registry and epidemiologic studies indicate an increased risk in oral clefts (cleft lip with or without cleft palate) with first trimester exposure to topiramate, a component of QSYMIA (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.
Maternal obesity increases the risk for congenital malformations, including neural tube defects, cardiac malformations, oral clefts, and limb reduction defects. In addition, 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.
QSYMIA can cause metabolic acidosis [see Warnings and Precautions (5.8)]. 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 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 Antiepileptic 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. 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.
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 QSYMIA, 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 6–15 in rodents, GD 6–18 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 QSYMIA 15 mg/92 mg on a mg/m² basis), 20 mg/kg in rats (2 times the MRHD of QSYMIA 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 QSYMIA based on estimated AUC).
Topiramate and phentermine, components of QSYMIA, are present in human milk. There are no data on the effects of topiramate and phentermine on milk production. Diarrhea and somnolence have been reported in breastfed infants with maternal use of topiramate. There are no data on the effects of phentermine in breastfed infants. Because of the potential for serious adverse reactions, including changes in sleep, irritability, hypertension, vomiting, tremor, and weight loss in breastfed infants with maternal use of phentermine, advise patients that breastfeeding is not recommended during QSYMIA therapy.
Pregnancy testing is recommended in patients who can become pregnant before initiating QSYMIA and monthly during QSYMIA therapy [see Warnings and Precautions (5.1), Use in Specific Populations (8.1)].
QSYMIA can cause fetal harm when administered to a pregnant patient [see Use in Specific Populations (8.1)]. Advise patients who can become pregnant to use effective contraception during therapy with QSYMIA.
For patients taking combined oral contraceptives (COCs), use of QSYMIA may cause irregular bleeding [see Drug Interactions (7)]. Advise patients not to discontinue taking their COC and to contact their healthcare provider.
The safety and effectiveness of QSYMIA as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in pediatric patients aged 12 years and older with a BMI in the 95th percentile or greater standardized for age and sex have been established. Use of QSYMIA for this indication is supported by a 56-week, double-blind, placebo-controlled study in 223 pediatric patients aged 12 years and above, a pharmacokinetic study in pediatric patients, and studies in adults with obesity [see Clinical Pharmacology (12.3) and Clinical Studies (14)].
In a pediatric clinical trial, there was one episode of serious suicidal ideation in a QSYMIA-treated patient requiring hospitalization and pharmacologic treatment [see Warnings and Precautions (5.3)]; more patients treated with QSYMIA versus placebo reported adverse reactions related to mood (e.g., depression, anxiety) and sleep disorders (e.g., insomnia) [see Warnings and Precautions (5.5)]. Increases in bone mineral density and linear growth were attenuated in QSYMIA-versus placebo-treated patients [see Warnings and Precautions (5.7)]. Serious adverse reactions seen in pediatric patients using topiramate include acute angle glaucoma, oligohidrosis and hyperthermia, metabolic acidosis, cognitive and neuropsychiatric reactions, hyperammonemia and encephalopathy, and kidney stones.
The safety and effectiveness of QSYMIA in pediatric patients below the age of 12 years have not been established.
In the QSYMIA clinical trials, a total of 254 (7%) of the patients were 65 to 69 years of age; no patients 70 years of age or older were enrolled.
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.
Compared to healthy volunteers with normal renal function, patients with moderate and severe renal impairment as estimated by the Cockcroft-Gault equation had higher exposures to phentermine and topiramate.
The recommended dosage of QSYMIA in patients with mild renal impairment (CrCl greater or equal to 50 and less than 80 mL/min) is the same as the recommended dosage for patients with normal renal function.
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 maximum recommended dosage is 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 (2.5) and Clinical Pharmacology (12.3)].
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 with normal hepatic function. Exposure to topiramate was similar among patients with mild and moderate hepatic impairment and healthy volunteers.
The recommended dosage of QSYMIA in patients with mild hepatic impairment (Child-Pugh 5-6) is the same as the recommended dosage in patients with normal hepatic function.
In patients with moderate hepatic impairment, the maximum recommended dosage is 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 (2.6) and Clinical Pharmacology (12.3)].
QSYMIA contains phentermine, a Schedule IV controlled substance, and topiramate, which is not a controlled substance.
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.
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:
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 (2.4)].
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