Included as part of the "PRECAUTIONS" Section
Qsymia can cause fetal harm. Data from pregnancy registries and epidemiology studies indicate that a fetus exposed to topiramate, a component of Qsymia, in the first trimester of pregnancy has an increased risk of oral clefts (cleft lip with or without cleft palate). If Qsymia is used during pregnancy or if a patient becomes pregnant while taking Qsymia, treatment should be discontinued immediately, and the patient should be apprised of the potential hazard to a fetus. Females of reproductive potential should have a negative pregnancy test before starting Qsymia and monthly thereafter during Qsymia therapy. Females of reproductive potential should use effective contraception during Qsymia therapy [see Use In Specific Populations].
Qsymia Risk Evaluation And Mitigation Strategy (REMS)
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.
Increase In Heart Rate
Qsymia can cause an increase in resting heart rate.
A higher percentage of Qsymia-treated overweight and obese adults experienced heart rate increases from baseline of more than 5, 10, 15, and 20 beats per minute (bpm) compared to placebo-treated overweight and obese adults. Table 2 provides the numbers and percentages of patients with elevations in heart rate in clinical studies of up to one year.
Table 2. Number and Percentage of Patients with an Increase in Heart Rate at a Single Time Point from Baseline
3.75 mg/23 mg
7.5 mg/46 mg
15 mg/92 mg
|Greater than 5 bpm
|Greater than 10 bpm
|Greater than 15 bpm
|Greater than 20 bpm
The clinical significance of a heart rate elevation with Qsymia treatment is unclear, especially for patients with cardiac and cerebrovascular disease (such as patients with a history of myocardial infarction or stroke in the previous 6 months, life-threatening arrhythmias, or congestive heart failure).
Regular measurement of resting heart rate is recommended for all patients taking Qsymia, especially patients with cardiac or cerebrovascular disease or when initiating or increasing the dose of Qsymia. Qsymia has not been studied in patients with recent or unstable cardiac or cerebrovascular disease and therefore use is not recommended.
Patients should inform healthcare providers 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, the dose should be reduced or Qsymia discontinued.
Suicidal Behavior And Ideation
Antiepileptic drugs (AEDs), including topiramate, a component of Qsymia, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with Qsymia should be monitored 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.
Avoid Qsymia in patients with a history of suicidal attempts or active suicidal ideation.
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% Confidence Interval [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 (5 to 100 years) in the clinical trials analyzed.
Acute Myopia And Secondary Angle Closure Glaucoma
A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients treated with topiramate, a component of Qsymia. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness), and increased intraocular pressure. Mydriasis may or may not be present. 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. The primary treatment to reverse symptoms is immediate discontinuation of Qsymia. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious adverse events including permanent loss of vision.
Mood And Sleep Disorders
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. The majority of these mood and sleep disorders resolved spontaneously, or resolved upon discontinuation of dosing [see ADVERSE REACTIONS].
For clinically significant or persistent symptoms consider dose reduction or withdrawal of Qsymia. If patients have symptoms of suicidal ideation or behavior, discontinue Qsymia.
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].
Since Qsymia has the potential to impair cognitive function, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain Qsymia therapy does not affect them adversely. If cognitive dysfunction persists consider dose reduction or withdrawal of Qsymia for symptoms that are moderate to severe, bothersome, or those which fail to resolve with dose reduction.
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].
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 topiramate. Concomitant use of Qsymia and a carbonic anhydrase inhibitor (e.g., zonisamide, acetazolamide, or dichlorphenamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, if Qsymia is given concomitantly with another carbonic anhydrase inhibitor to a patient with a predisposing condition for metabolic acidosis the patient should be monitored for the appearance or worsening of metabolic acidosis.
Some 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. The effect of Qsymia on growth and bone-related sequelae has not been systematically investigated in long-term, placebo-controlled trials.
Measurement of electrolytes including serum bicarbonate prior to starting Qsymia and during Qsymia treatment is recommended. In Qsymia clinical trials, the peak reduction in serum bicarbonate occurred by week 4, and in most subjects there was a correction of bicarbonate by week 56, without any change to study drug. However, if persistent metabolic acidosis develops while taking Qsymia, reduce the dose or discontinue Qsymia.
Elevation In Creatinine
Qsymia can cause an increase in serum creatinine. 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. Elevations in serum creatinine often signify a decrease in renal function, but the cause for Qsymia-associated changes in serum creatinine has not been definitively established. Therefore, measurement of serum creatinine prior to starting Qsymia and during Qsymia treatment is recommended. If persistent elevations in creatinine occur while taking Qsymia, reduce the dose or discontinue Qsymia [see ADVERSE REACTIONS].
Potential Risk Of Hypoglycemia In Patients With Type 2 Diabetes Mellitus On Anti-Diabetic Therapy
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. Measurement of blood glucose levels prior to starting Qsymia and during Qsymia treatment is recommended in patients with type 2 diabetes. Decreases in medication doses for antidiabetic medications which are non-glucose-dependent should be considered to mitigate the risk of hypoglycemia. If a patient develops hypoglycemia after starting Qsymia, appropriate changes should be made to the antidiabetic drug regimen.
Potential Risk Of Hypotension In Patients Treated With Antihypertensive Medications
In hypertensive patients being treated with antihypertensive medications, weight loss may increase the risk of hypotension, and associated symptoms including dizziness, lightheadedness, and syncope. Measurement of blood pressure prior to starting Qsymia and during Qsymia treatment is recommended 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.
CNS Depression With Concomitant CNS Depressants Including Alcohol
The concomitant use of alcohol or central nervous system (CNS) depressant drugs (e.g., barbiturates, benzodiazepines, and sleep medications) with phentermine or topiramate 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. Therefore, avoid concomitant use of alcohol with Qsymia.
Potential Seizures With Abrupt Withdrawal Of Qsymia
Abrupt withdrawal of topiramate, a component of Qsymia, 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 as recommended to reduce the possibility of precipitating a seizure [see DOSAGE AND ADMINISTRATION].
Patients With Renal Impairment
Phentermine and topiramate, the components of Qsymia, are cleared by renal excretion. Therefore, exposure to phentermine and topiramate is higher in patients with moderate (creatinine clearance [CrCl] greater than or equal to 30 and less than 50 mL/min) or severe (CrCl less than 30 mL/min) renal impairment. Adjust dose of Qsymia for both patient populations.
Qsymia has not been studied in patients with end-stage renal disease on dialysis. Avoid use of Qsymia in this patient population [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
Patients With Hepatic Impairment
In patients with mild (Child-Pugh score 5 - 6) or moderate (Child-Pugh score 7 - 9) hepatic impairment, exposure to phentermine was higher compared to healthy volunteers. Adjust dose of Qsymia for patients with moderate hepatic impairment.
Qsymia has not been studied in patients with severe hepatic impairment (Child-Pugh score 10 - 15). Avoid use of Qsymia in this patient population [see DOSAGE AND ADMINISTRATION, and CLINICAL PHARMACOLOGY].
Use of Qsymia has been associated with kidney stone formation. Topiramate, a component of Qsymia, inhibits carbonic anhydrase activity and promotes kidney stone formation by reducing urinary citrate excretion and increasing urine pH.
Avoid the use of Qsymia with other drugs that inhibit carbonic anhydrase (e.g., zonisamide, acetazolamide, or methazolamide).
Use of topiramate by patients on a ketogenic diet may also result in a physiological environment that increases the likelihood of kidney stone formation.
Increase fluid intake to increase urinary output which can decrease the concentration of substances involved in kidney stone formation [see ADVERSE REACTIONS].
Oligohidrosis And Hyperthermia
Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with the use of topiramate, a component of Qsymia. 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.
Patients treated with Qsymia should be advised to monitor for decreased sweating and increased body temperature during physical activity, especially in hot weather. Caution should be used when Qsymia is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity.
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 such as furosemide (loop diuretic) or hydrochlorothiazide (thiazide-like diuretic) this may further potentiate potassium-wasting. When prescribing Qsymia, patients should be monitored for hypokalemia [see ADVERSE REACTIONS and CLINICAL PHARMACOLOGY].
Qsymia was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies.
Obtain a blood chemistry profile that includes bicarbonate, creatinine, potassium, and glucose at baseline and periodically during treatment [see Metabolic Acidosis, Elevation In Creatinine, Potential Risk Of Hypoglycemia In Patients With Type 2 Diabetes Mellitus On Anti-Diabetic Therapy and Hypokalemia].
Patient Counseling Information
See FDA-approved patient labeling (PATIENT INFORMATION).
Advise patients of the following:
Qsymia is indicated for chronic weight management in conjunction with a reduced-calorie diet and increased physical activity.
Access To Qsymia
Qsymia is only available through certified pharmacies that are enrolled in the Qsymia certified pharmacy network. Advise patients on how to access Qsymia through certified pharmacies. Additional information may be obtained via the website www.QsymiaREMS.com or by telephone at 1-888-998-4887.
Concomitant Use With Other Products
Advise patients to tell healthcare provider(s) about all medications, nutritional supplements, and vitamins (including any weight loss products) that are being taken or may be taken while on Qsymia.
How To Take Qsymia
Advise patients to take Qsymia in the morning with or without food.
Advise patients to start treatment with Qsymia as follows:
- Take one Qsymia 3.75 mg/23 mg capsule once daily – in the morning - for the first 14 days
- After the first 14 days is complete, take one Qsymia 7.5 mg/46 mg capsule once daily – in the morning
- Do not take Qsymia 3.75 mg/23 mg and Qsymia 7.5/46 mg capsules together
If an increase in Qsymia dose is prescribed after medical evaluation, advise patients to increase the dose of Qsymia as follows:
- Take one Qsymia 11.25 mg/69 mg capsule once daily – in the morning - for 14 days
- After the 14 days is complete, take one Qsymia 15 mg/92 mg capsule once daily – in the morning
- Do not take Qsymia 11.25/69 mg and Qsymia 15 mg/92 mg capsules together
Advise patients to discontinue the Qsymia 15 mg/92 mg dose gradually by taking one Qsymia 15 mg/92 mg capsule every other day for at least one week before stopping in order to avoid a seizure.
Females Of Reproductive Potential
Qsymia can cause fetal harm and patients should avoid getting pregnant while taking Qsymia [see WARNINGS AND PRECAUTIONS]
- Pregnancy testing is recommended before starting Qsymia and monthly thereafter during therapy.
- Advise patients about effective methods of contraception, as well as the importance of using effective contraception consistently during Qsymia therapy. Advise females who become pregnant during Qsymia therapy to stop Qsymia immediately and tell their healthcare provider(s).
Either discontinue nursing or discontinue Qsymia [see Use In Specific Populations].
Elevation In Heart Rate
- Qsymia can increase resting heart rate [see WARNINGS AND PRECAUTIONS].
- Advise patients to report symptoms of sustained periods of heart pounding or racing while at rest to their healthcare provider(s).
Suicidal Behavior And Ideation; Changes In Mood Or Depression
Qsymia can increase the risk of mood changes, depression, and suicidal ideation [see WARNINGS AND PRECAUTIONS].
- Advise patients to tell their healthcare provider(s) immediately if mood changes, depression, and suicidal ideation occur.
Acute Angle Closure Glaucoma
Qsymia can increase the risk of acute myopia and secondary angle closure glaucoma [see WARNINGS AND PRECAUTIONS].
- Advise patients to report symptoms of severe and persistent eye pain or significant changes in their vision to their healthcare provider(s).
Cognitive Adverse Reactions
Qsymia can cause dizziness, confusion, concentration, and word-finding difficulties, or visual changes [see WARNINGS AND PRECAUTIONS].
- Advise patients to tell their healthcare provider(s) about any changes in attention, concentration, memory, and/or difficulty finding words.
- 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.
Qsymia can increase the risk of metabolic acidosis [see WARNINGS AND PRECAUTIONS].
- Advise patients to tell their healthcare provider(s) about any factors that can increase the risk of acidosis (e.g. prolonged diarrhea, surgery, and high protein/low carbohydrate diet, and/or concomitant medications such as carbonic anhydrase inhibitors).
Hypoglycemia In Patients With Type 2 Diabetes Mellitus On Anti-Diabetic Therapy
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) [see WARNINGS AND PRECAUTIONS].
- Advise patients with type 2 diabetes mellitus on anti-diabetic therapy to monitor their blood glucose levels and report symptoms of hypoglycemia to their healthcare provider(s)
CNS Depression With Concomitant CNS Depressants Including Alcohol
The concomitant use of alcohol or central nervous system (CNS) depressant drugs (e.g., barbiturates, benzodiazepines, and sleep medications) with phentermine or topiramate 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 [see WARNINGS AND PRECAUTIONS].
- Advise patients not to drink alcohol while taking Qsymia.
Potential Seizures With Abrupt Withdrawal Of Qsymia
Abrupt withdrawal of topiramate, a component of Qsymia, has been associated with seizures in individuals without a history of seizures or epilepsy.
- Advise patients not to abruptly stop Qsymia without first talking to their healthcare provider(s) [see DOSAGE AND ADMINISTRATION]
Use of Qsymia has been associated with kidney stone formation [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].
- Advise patients to increase fluid intake to increase urinary output which can decrease the concentration of substances involved in kidney stone formation.
- Advise patients to report symptoms of severe side or back pain, and/or blood in their urine to their healthcare provider(s).
Oligohidrosis And Hyperthermia
Oligohidrosis (decreased sweating) has been reported in association with the use of topiramate, a component of Qsymia. Decreased sweating and an elevation in body temperature above normal characterized these cases.
- Advise patients to monitor for decreased sweating and increased body temperature during physical activity, especially in hot weather.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
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 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 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.
Use In Specific Populations
Pregnancy Category X
Qsymia is contraindicated in pregnant women. The use of Qsymia can cause fetal harm and weight loss offers no potential benefit to a pregnant woman. Available epidemiologic data indicate an increased risk in oral clefts (cleft lip with or without cleft palate) with first trimester exposure to topiramate, a component of Qsymia. When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring.
If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, treatment should be discontinued immediately and the patient should be apprised of the potential hazard to a fetus.
There is a Qsymia Pregnancy Surveillance Program to monitor maternal-fetal outcomes of pregnancies that occur during Qsymia therapy. Healthcare providers and patients are encouraged to report pregnancies by calling 1-888-998-4887.
Oral clefts occur from the fifth through the ninth week of gestation. The lip is formed between the beginning of the fifth week to the seventh week of gestation, and the palate is formed between the beginning of the sixth week through the ninth week of gestation.
A minimum weight gain, and no weight loss, is currently recommended for all pregnant women, including those who are already overweight or obese, due to the obligatory weight gain that occurs in maternal tissues during pregnancy.
Qsymia can cause metabolic acidosis. The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus’ ability to tolerate labor [see WARNINGS AND PRECAUTIONS].
Data evaluating the risk of major congenital malformations and oral clefts with topiramate (a component of Qsymia) exposure during pregnancy is available from the North American Anti-Epileptic Drug (NAAED) Pregnancy Registry and from several larger retrospective epidemiologic studies. The NAAED Pregnancy Registry suggested an estimated increase in risk for oral clefts of 9.60 (95% CI 3.60 - 25.70). Larger retrospective epidemiology studies showed that topiramate monotherapy exposure in pregnancy is associated with an approximately two to five-fold increased risk of oral clefts (Table 5). The FORTRESS study, sponsored by the maker of Qsymia, found an excess risk of 1.5 (95% CI = -1.1 to 4.1) oral cleft cases per 1,000 infants exposed to topiramate during the first trimester.
Table 5. Summary of Studies Evaluating the Association of Topiramate in Utero Exposure and Oral Clefts and Major Congenital Malformations
||Major Congenital Malformations
|Estimated Increase in Risk
||Estimated Increase in Risk
||0.36 – 6.06
||0.81 – 1.55
||0.78 – 6.36
||0.99 – 1.47
||1.49 – 20.07
||0.37 – 3.22
a Sponsored by the maker of Qsymia
CI = confidence interval
Embryo-fetal development studies have been conducted in rats and rabbits with combination phentermine and topiramate treatment. Phentermine and topiramate co-administered to rats during the period of organogenesis caused reduced fetal body weights but did not cause fetal malformations at the maximum dose of 3.75 mg/kg phentermine and 25 mg/kg topiramate [approximately 2 times the maximum recommended human dose (MRHD) based on area under the curve (AUC) estimates for each active ingredient]. In a similar study in rabbits, no effects on embryo-fetal development were observed at approximately 0.1 times (phentermine) and 1 time (topiramate) clinical exposures at the MRHD based on AUC. Significantly lower maternal body weight gain was recorded at these doses in rats and rabbits.
A pre- and post-natal development study was conducted in rats with combination phentermine and topiramate treatment. There were no adverse maternal or offspring effects in rats treated throughout organogenesis and lactation with 1.5 mg/kg/day phentermine and 10 mg/kg/day topiramate (approximately 2 and 3 times clinical exposures at the MRHD, respectively, based on AUC). Treatment with higher doses of 11.25 mg/kg/day phentermine and 75 mg/kg/day topiramate (approximately 5 and 6 times maximum clinical doses based on AUC, respectively) caused reduced maternal body weight gain and offspring toxicity. Offspring effects included lower pup survival after birth, increased limb and tail malformations, reduced pup body weight and
delayed growth, development, and sexual maturation without affecting learning, memory, or fertility and reproduction. The limb and tail malformations were consistent with results of animal studies conducted with topiramate alone [see Nonclinical Toxicology].
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 causes developmental toxicity, including teratogenicity, at clinically relevant doses [see Nonclinical Toxicology].
Labor And Delivery
The effect of Qsymia on labor and delivery in humans is unknown. The development of Qsymia-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus’s ability to tolerate labor.
Qsymia may be present in human milk because topiramate and amphetamines (phentermine has pharmacologic activity and a chemical structure similar to amphetamines) are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Safety and effectiveness of Qsymia in pediatric patients below the age of 18 years have not been established and the use of Qsymia is not recommended in pediatric patients. Serious adverse reactions seen in pediatric patients using topiramate, a component of Qsymia, include acute angle glaucoma, oligohidrosis and hyperthermia, metabolic acidosis, cognitive and neuropsychiatric reactions, hyperammonemia and encephalopathy, and kidney stones.
Juvenile Animal Studies
Juvenile animal studies have not been conducted with Qsymia. When topiramate (30, 90, or 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose.
In the Qsymia clinical trials, a total of 254 (7%) of the patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
Clinical studies of Qsymia did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Females Of Reproductive Potential
Qsymia can cause fetal harm. Data from pregnancy registries and epidemiology studies indicate that a fetus exposed to topiramate, a component of Qsymia, in the first trimester of pregnancy has an increased risk of oral clefts (cleft lip with or without cleft palate).
Females who become pregnant during Qsymia therapy should stop Qsymia treatment immediately and notify their healthcare provider.
Females of reproductive potential should have a negative pregnancy test before starting Qsymia and monthly thereafter during Qsymia therapy.
Females of reproductive potential should use effective contraception during Qsymia therapy.
Compared to healthy volunteers, patients with moderate and severe renal impairment as estimated by the Cockcroft-Gault equation had higher phentermine and topiramate exposures.
No dose adjustments are necessary in patients with mild renal impairment. In patients with moderate (CrCl greater than or equal to 30 to less than 50 mL/min) and severe (CrCl less than 30 mL/min) renal impairment, the dose should not exceed Qsymia 7.5 mg/46 mg once daily.
Qsymia has not been studied in patients with end-stage renal disease on dialysis. Avoid Qsymia in this patient population [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
In patients with mild (Child-Pugh 5 - 6) and moderate (Child-Pugh 7 - 9) hepatic impairment, exposure to phentermine was higher compared to healthy volunteers. Exposure to topiramate, a component of Qsymia, was similar among patients with mild and moderate hepatic impairment and healthy volunteers.
No dose adjustments are necessary in patients with mild hepatic impairment. In patients with moderate hepatic impairment, the dose should not exceed Qsymia 7.5 mg/46 mg once daily.
Qsymia has not been studied in patients with severe hepatic impairment (Child-Pugh score 10 - 15). Avoid Qsymia in this patient population [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].