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mechanism of action is Cytochrome P450 2C19 Inhibitors [MoA] or Cytochrome P450 3A4 Inducers [MoA]

Qsymia (Phentermine And Topiramate)

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Dosage & administration

* Take orally once daily in morning. Avoid administration in evening to prevent insomnia (

2.2 Recommended Dosage and Administration

The recommended dosage, titration, and administration of QSYMIA are as follows:

* Take QSYMIA orally once daily in the morning with or without food. Avoid administration of QSYMIA in the evening due to the possibility of insomnia.
* The recommended starting dosage of QSYMIA is one capsule (containing 3.75 mg of phentermine and 23 mg of topiramate) (3.75 mg/23 mg) taken orally once daily for 14 days; after 14 days increase to the recommended dosage of QSYMIA 7.5 mg/46 mg orally once daily.
* After 12 weeks of treatment with QSYMIA 7.5 mg/46 mg, evaluate weight loss for adults or BMI reduction for pediatric patients aged 12 years and older. If an adult patient has not lost at least 3% of baseline body weight or a pediatric patient has not experienced a reduction of at least 3% of baseline BMI, increase the dosage to QSYMIA 11.25 mg/69 mg orally once daily for 14 days; followed by an increase in the dosage to QSYMIA 15 mg/92 mg orally once daily.
* After 12 weeks of treatment with QSYMIA 15 mg/92 mg, evaluate weight loss for adults or BMI reduction for pediatric patients aged 12 years and older. If an adult patient has not lost at least 5% of baseline body weight or a pediatric patient has not experienced a reduction of at least 5% of baseline BMI, discontinue QSYMIA

[see Dosage and Administration (2.3)]

, as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.
* Monitor the rate of weight loss in pediatric patients. If weight loss exceeds 2 lbs (0.9 kg)/week, consider dosage reduction.

).

* Recommended starting dosage is 3.75 mg/23 mg (phentermine mg/topiramate mg) daily for 14 days; then increase to 7.5 mg/46 mg daily (

2.2 Recommended Dosage and Administration

The recommended dosage, titration, and administration of QSYMIA are as follows:

[see Dosage and Administration (2.3)]

).

* Escalate dosage based on weight loss in adults or BMI reduction in pediatric patients. See the Full Prescribing Information for details regarding discontinuation or dosage escalation (

2.2 Recommended Dosage and Administration

The recommended dosage, titration, and administration of QSYMIA are as follows:

[see Dosage and Administration (2.3)]

).

* Gradually discontinue 15 mg/92 mg dosage to prevent possible seizure (

2.3 Discontinuation of QSYMIA 15 mg/92 mg

Discontinue QSYMIA 15 mg/92 mg gradually by taking QSYMIA 15 mg/92 mg orally once daily every other day for at least 1 week prior to stopping treatment altogether, due to the possibility of precipitating a seizure

[see Warnings and Precautions (5.9)and Drug Abuse and Dependence (9.3)]

).

* Do not exceed 7.5 mg/46 mg dosage for patients with moderate or severe renal impairment or patients with moderate hepatic impairment (

2.4 Recommended Dosage in Patients with Renal Impairment

* The recommended dosage in patients with mild (CrCl greater or equal to 50 and less than 80 mL/min) renal impairment is the same as the recommended dosage for patients with normal renal function

[see Warnings and Precautions (5.9), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)]

.
* In patients with severe [creatinine clearance (CrCl) less than 30 mL/min] or moderate (CrCl greater than or equal to 30 and less than 50 mL/min) renal impairment (CrCl calculated using the Cockcroft-Gault equation with actual body weight), the maximum recommended dosage is QSYMIA 7.5 mg/46 mg once daily.
* Avoid use of QSYMIA in patients with end-stage renal disease on dialysis.

2.5 Recommended Dosage in Patients with Hepatic Impairment

* 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

[see Use in Specific Populations (8.7)and Clinical Pharmacology (12.3)]

.
* In patients with moderate hepatic impairment (Child-Pugh score 7 - 9), the maximum recommended dosage is QSYMIA 7.5 mg/46 mg orally once daily.
* Avoid use of QSYMIA in patients with severe hepatic impairment (Child-Pugh score 10 - 15).

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Qsymia prescribing information

Take orally once daily in morning. Avoid administration in evening to prevent insomnia (
2.2 Recommended Dosage and Administration
The recommended dosage, titration, and administration of QSYMIA are as follows:
- Take QSYMIA orally once daily in the morning with or without food. Avoid administration of QSYMIA in the evening due to the possibility of insomnia.
- The recommended starting dosage of QSYMIA is one capsule (containing 3.75 mg of phentermine and 23 mg of topiramate) (3.75 mg/23 mg) taken orally once daily for 14 days; after 14 days increase to the recommended dosage of QSYMIA 7.5 mg/46 mg orally once daily.
- After 12 weeks of treatment with QSYMIA 7.5 mg/46 mg, evaluate weight loss for adults or BMI reduction for pediatric patients aged 12 years and older. If an adult patient has not lost at least 3% of baseline body weight or a pediatric patient has not experienced a reduction of at least 3% of baseline BMI, increase the dosage to QSYMIA 11.25 mg/69 mg orally once daily for 14 days; followed by an increase in the dosage to QSYMIA 15 mg/92 mg orally once daily.
- After 12 weeks of treatment with QSYMIA 15 mg/92 mg, evaluate weight loss for adults or BMI reduction for pediatric patients aged 12 years and older. If an adult patient has not lost at least 5% of baseline body weight or a pediatric patient has not experienced a reduction of at least 5% of baseline BMI, discontinue QSYMIA
  [see Dosage and Administration (2.3)]
  , as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.
- Monitor the rate of weight loss in pediatric patients. If weight loss exceeds 2 lbs (0.9 kg)/week, consider dosage reduction.
).
Recommended starting dosage is 3.75 mg/23 mg (phentermine mg/topiramate mg) daily for 14 days; then increase to 7.5 mg/46 mg daily (
2.2 Recommended Dosage and Administration
The recommended dosage, titration, and administration of QSYMIA are as follows:
- Take QSYMIA orally once daily in the morning with or without food. Avoid administration of QSYMIA in the evening due to the possibility of insomnia.
- The recommended starting dosage of QSYMIA is one capsule (containing 3.75 mg of phentermine and 23 mg of topiramate) (3.75 mg/23 mg) taken orally once daily for 14 days; after 14 days increase to the recommended dosage of QSYMIA 7.5 mg/46 mg orally once daily.
- After 12 weeks of treatment with QSYMIA 7.5 mg/46 mg, evaluate weight loss for adults or BMI reduction for pediatric patients aged 12 years and older. If an adult patient has not lost at least 3% of baseline body weight or a pediatric patient has not experienced a reduction of at least 3% of baseline BMI, increase the dosage to QSYMIA 11.25 mg/69 mg orally once daily for 14 days; followed by an increase in the dosage to QSYMIA 15 mg/92 mg orally once daily.
- After 12 weeks of treatment with QSYMIA 15 mg/92 mg, evaluate weight loss for adults or BMI reduction for pediatric patients aged 12 years and older. If an adult patient has not lost at least 5% of baseline body weight or a pediatric patient has not experienced a reduction of at least 5% of baseline BMI, discontinue QSYMIA
  [see Dosage and Administration (2.3)]
  , as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.
- Monitor the rate of weight loss in pediatric patients. If weight loss exceeds 2 lbs (0.9 kg)/week, consider dosage reduction.
).
Escalate dosage based on weight loss in adults or BMI reduction in pediatric patients. See the Full Prescribing Information for details regarding discontinuation or dosage escalation (
2.2 Recommended Dosage and Administration
The recommended dosage, titration, and administration of QSYMIA are as follows:
- Take QSYMIA orally once daily in the morning with or without food. Avoid administration of QSYMIA in the evening due to the possibility of insomnia.
- The recommended starting dosage of QSYMIA is one capsule (containing 3.75 mg of phentermine and 23 mg of topiramate) (3.75 mg/23 mg) taken orally once daily for 14 days; after 14 days increase to the recommended dosage of QSYMIA 7.5 mg/46 mg orally once daily.
- After 12 weeks of treatment with QSYMIA 7.5 mg/46 mg, evaluate weight loss for adults or BMI reduction for pediatric patients aged 12 years and older. If an adult patient has not lost at least 3% of baseline body weight or a pediatric patient has not experienced a reduction of at least 3% of baseline BMI, increase the dosage to QSYMIA 11.25 mg/69 mg orally once daily for 14 days; followed by an increase in the dosage to QSYMIA 15 mg/92 mg orally once daily.
- After 12 weeks of treatment with QSYMIA 15 mg/92 mg, evaluate weight loss for adults or BMI reduction for pediatric patients aged 12 years and older. If an adult patient has not lost at least 5% of baseline body weight or a pediatric patient has not experienced a reduction of at least 5% of baseline BMI, discontinue QSYMIA
  [see Dosage and Administration (2.3)]
  , as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.
- Monitor the rate of weight loss in pediatric patients. If weight loss exceeds 2 lbs (0.9 kg)/week, consider dosage reduction.
).
Gradually discontinue 15 mg/92 mg dosage to prevent possible seizure (
2.3 Discontinuation of QSYMIA 15 mg/92 mg
Discontinue QSYMIA 15 mg/92 mg gradually by taking QSYMIA 15 mg/92 mg orally once daily every other day for at least 1 week prior to stopping treatment altogether, due to the possibility of precipitating a seizure
[see Warnings and Precautions (5.9)and Drug Abuse and Dependence (9.3)]
.
).
Do not exceed 7.5 mg/46 mg dosage for patients with moderate or severe renal impairment or patients with moderate hepatic impairment (
2.4 Recommended Dosage in Patients with Renal Impairment
- The recommended dosage in patients with mild (CrCl greater or equal to 50 and less than 80 mL/min) renal impairment is the same as the recommended dosage for patients with normal renal function
  [see Warnings and Precautions (5.9), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)]
  .
- In patients with severe [creatinine clearance (CrCl) less than 30 mL/min] or moderate (CrCl greater than or equal to 30 and less than 50 mL/min) renal impairment (CrCl calculated using the Cockcroft-Gault equation with actual body weight), the maximum recommended dosage is QSYMIA 7.5 mg/46 mg once daily.
- Avoid use of QSYMIA in patients with end-stage renal disease on dialysis.
,
2.5 Recommended Dosage in Patients with Hepatic Impairment
- 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
  [see Use in Specific Populations (8.7)and Clinical Pharmacology (12.3)]
  .
- In patients with moderate hepatic impairment (Child-Pugh score 7 - 9), the maximum recommended dosage is QSYMIA 7.5 mg/46 mg orally once daily.
- Avoid use of QSYMIA in patients with severe hepatic impairment (Child-Pugh score 10 - 15).
).

QSYMIA extended-release capsules are available in four strengths (phentermine mg/topiramate mg):

3.75 mg/23 mg - purple cap imprinted with VIVUS and purple body imprinted with 3.75/23
7.5 mg/46 mg - purple cap imprinted with VIVUS and yellow body imprinted with 7.5/46
11.25 mg/69 mg - yellow cap imprinted with VIVUS and yellow body imprinted with 11.25/69
15 mg/92 mg - yellow cap imprinted with VIVUS and white body imprinted with 15/92

Lactation
: Breastfeeding not recommended (

8.2 Lactation
Risk Summary
Topiramate and phentermine 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.
).

QSYMIA is contraindicated in patients:

Who are pregnant

[see

5.1 Embryo-Fetal Toxicity
QSYMIA can cause fetal harm. Data from pregnancy registries and epidemiologic studies indicate that a fetus exposed to topiramate in the first trimester of pregnancy has an increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA). When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring. 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)]
.
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.
and

8.1 Pregnancy
Risk Summary
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 pregnancy registries and epidemiologic studies indicate an increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being SGA in infants exposed
in utero
to topiramate
(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.
Clinical Considerations
Disease Associated Maternal and/or Embryo/Fetal Risk
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. Maternal obesity increases the risk for congenital malformations, including neural tube defects, cardiac malformations, oral clefts, and limb reduction defects.
Fetal/Neonatal Adverse Reactions
QSYMIA can cause metabolic acidosis
[see Warnings and Precautions (5.7)]
. 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
Human Data
Data evaluating the risk of major congenital malformations, oral clefts, and being SGA with topiramate exposure during pregnancy is available from the North American Antiepileptic Drug (NAAED) Pregnancy Registry and from several larger retrospective epidemiologic studies.
Major Congenital Malformations
The NAAED Pregnancy Registry indicates an increased risk of major congenital malformations, including but not limited to oral clefts in infants exposed to topiramate during the first trimester of pregnancy. Other than oral clefts, no specific pattern of major congenital malformations or grouping of major congenital malformation types were observed. In the NAAED pregnancy registry, when topiramate-exposed infants with only oral clefts were excluded, the prevalence of major congenital malformations (4.1%) was higher than that in infants exposed to a reference antiepileptic drug (AED) (1.8%) or in infants with mothers without epilepsy and without exposure to AEDs (1.1%).
Oral Clefts
In the NAAED Pregnancy Registry, the prevalence of oral clefts among topiramate-exposed infants (1.4%) was higher than the prevalence in infants exposed to a reference AED (0.3%) or the prevalence in infants with mothers without epilepsy and without exposure to AEDs (0.11%). It was also higher than the background prevalence in United States (0.17%) as estimated by the Centers for Disease Control and Prevention (CDC). The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 12.5 (95% Confidence Interval [CI] 5.9-26.37) as compared to the risk in a background population of untreated women. The UK Epilepsy and Pregnancy Register reported a prevalence of oral clefts among infants exposed to topiramate monotherapy (3.2%) that was 16 times higher than the background rate in the UK (0.2%).
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.
Small for Gestational Age
Data from the NAAED Pregnancy Registry and population-based birth registry cohort indicate that exposure to topiramate in utero is associated with an increased risk of SGA newborns (birth weight <10^thpercentile). In the NAAED Pregnancy Registry, 19.7% of topiramate-exposed newborns were SGA compared to 7.9% of newborns exposed to a reference AED and 5.4% of newborns of mothers without epilepsy and without AED exposure. In the medical Birth Registry of Norway, a population-based pregnancy registry, 25% of newborns in the topiramate monotherapy exposure group were SGA compared to 9% in the comparison group unexposed to AEDs. The long-term consequences of the SGA findings are not known.
Animal Data
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/m²basis), 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).
]
With glaucoma

[see

5.3 Risk of Ophthalmologic Adverse Reactions
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. 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 in consultation with the treating physician. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent loss of vision.
Visual Field Defects
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.
]
With hyperthyroidism

Taking or within 14 days of stopping a monoamine oxidase inhibitors

[see

7 DRUG INTERACTIONS

Table 5 displays clinically significant drug interactions with QSYMIA.

Table 5. Clinically Significant Drug Interactions with QSYMIA
Monoamine 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 health care 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 (5.5)].
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_maxand 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 (5.12)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 (5.7, 5.10)] .
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)] .

Oral Contraceptives
: Altered exposure of progestin and estrogen may cause irregular bleeding, but not increased risk of pregnancy. Advise patients not to discontinue oral contraceptives if spotting occurs .
CNS Depressants Including Alcohol
: May potentiate CNS depressant effects. Avoid excessive use of alcohol .
Non-potassium Sparing Diuretics
: May potentiate hypokalemia. Measure potassium before and during treatment .

]

With known hypersensitivity to phentermine, topiramate or any of the excipients in QSYMIA, or idiosyncrasy to the sympathomimetic amines

[see

6.2 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 (7)]
, hypothermia
Ophthalmic:
maculopathy
]

.

Embryo-Fetal Toxicity
: Can cause fetal harm. In patients who can become pregnant, a negative pregnancy test is recommended before initiating QSYMIA and monthly during therapy; advise use of effective contraception. QSYMIA is available through a limited program under a Risk Evaluation and Mitigation Strategy (REMS) (

5.1 Embryo-Fetal Toxicity
QSYMIA can cause fetal harm. Data from pregnancy registries and epidemiologic studies indicate that a fetus exposed to topiramate in the first trimester of pregnancy has an increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA). When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring. 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)]
.
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.
).
Suicidal Behavior and Ideation
: Monitor for depression or suicidal thoughts. Discontinue QSYMIA if symptoms develop (

5.2 Suicidal Behavior and Ideation
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 (5.9)]
. Avoid QSYMIA in patients with a history of suicidal attempts or active suicidal ideation.
).
Risk of Ophthalmologic Adverse Reactions
: Acute myopia and secondary angle closure glaucoma have been reported. Immediately discontinue QSYMIA if symptoms develop. Consider QSYMIA discontinuation if visual field defects occur (

5.3 Risk of Ophthalmologic Adverse Reactions
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. 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 in consultation with the treating physician. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent loss of vision.
Visual Field Defects
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.
).
Mood and Sleep Disorders
: Consider dosage reduction or discontinuation for clinically significant or persistent mood or sleep disorder symptoms (

5.4 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
[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 (5.2)]
.
).
Cognitive Impairment
: May cause disturbances in attention or memory, or speech/language problems. Caution patients about operating automobiles or hazardous machinery when starting treatment (

5.5 Cognitive Impairment
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 (5.9)]
.
).
Slowing of Linear Growth
: Consider dosage reduction or discontinuation if pediatric patients are not growing or gaining height as expected (

5.6 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. 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 (5.9)]
.
).
Metabolic Acidosis
: Measure electrolytes before and during treatment. If persistent metabolic acidosis develops, reduce dosage or discontinue QSYMIA (

5.7 Metabolic Acidosis
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 (5.10)]
. 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 (5.9)]
.
).
Decrease in Renal Function
: Measure creatinine before and during treatment. For persistent creatinine elevations, reduce dosage or discontinue QSYMIA (

5.8 Decrease in Renal Function
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 (5.9), Adverse Reactions (6.1), and Clinical Pharmacology (12.2)]
.
).
Serious Skin Reactions:
QSYMIA should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related (

5.13 Serious Skin Reactions
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.
).

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