QSYMIA- phentermine and topiramate capsule, extended release

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

PHENTERMINE HYDROCHLORIDE (UNII: 0K2I505OTV) (PHENTERMINE - UNII:C045TQL4WP), TOPIRAMATE (UNII: 0H73WJJ391) (TOPIRAMATE - UNII:0H73WJJ391)

Available from:

Vivus LLC

INN (International Name):

PHENTERMINE HYDROCHLORIDE

Composition:

PHENTERMINE 3.75 mg

Administration route:

ORAL

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

QSYMIA is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in: - Adults with an initial body mass index (BMI) of: 30 kg/m 2 or greater (obese), or 27 kg/m 2 or greater (overweight) in the presence of at least one weight-related comorbidity such as hypertension, type 2 diabetes mellitus, or dyslipidemia - 30 kg/m 2 or greater (obese), or - 27 kg/m 2 or greater (overweight) in the presence of at least one weight-related comorbidity such as hypertension, type 2 diabetes mellitus, or dyslipidemia - Pediatric patients aged 12 years and older with an initial BMI in the 95 th percentile or greater standardized for age and sex. Limitations of Use - The effect of QSYMIA on cardiovascular morbidity and mortality has not been established. - The safety and effectiveness of QSYMIA in combination with other products intended for weight loss, including prescription drugs, over-the-counter drugs, and herbal preparations, have not been established. QSYMIA is contraindicated in patients: - Who are pregnant [see Warnings and Precautions (5.1)and Use in Specific Populations (8.1)] - With glaucoma [see Warnings and Precautions (5.4)] - With hyperthyroidism - Taking or within 14 days of stopping a monoamine oxidase inhibitors [see Drug Interactions (7)] - With known hypersensitivity to phentermine, topiramate or excipient in QSYMIA, or idiosyncrasy to the sympathomimetic amines [see Adverse Reactions (6.2)]. 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 (5.8)] . 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 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 th percentile). 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/m 2 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). 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. Pregnancy Testing 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)] . Contraception Females 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: - For topiramate, abrupt discontinuation has been associated with seizures in patients without a history of seizures or epilepsy [see Warnings and Precautions (5.12)] . - For phentermine, abrupt discontinuation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on a sleep electroencephalogram. Thus, in situations where rapid withdrawal of QSYMIA is required, appropriate medical monitoring is recommended. Patients discontinuing QSYMIA 15 mg/92 mg should be gradually tapered to reduce the possibility of precipitating a seizure [see Dosage and Administration (2.4)] .

Product summary:

QSYMIA (phentermine and topiramate extended-release capsules) are available as follows (see Table 16): Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Keep container tightly closed and protect from moisture.

Authorization status:

New Drug Application

Patient Information leaflet

QSYMIA- PHENTERMINE AND TOPIRAMATE CAPSULE, EXTENDED RELEASE
Vivus LLC
----------
MEDICATION GUIDE
QSYMIA ®(KYOO SIM EE UH)
(PHENTERMINE AND TOPIRAMATE EXTENDED-RELEASE CAPSULES)
FOR ORAL USE, CIV
This Medication Guide has been approved by the U.S. Food and
Drug Administration.
PH-03-002-14
Revised: 06/2023
What is the most important information I should know about QSYMIA?
QSYMIA can cause serious side effects, including :
•
Birth defects.If you take QSYMIA during pregnancy, your baby has a
higher risk for birth defects
including cleft lip and cleft palate. Your baby may also be smaller
than expected at birth. The
long-term effects of this are not known. These defects can begin early
in pregnancy, even before
you know you are pregnant.
Patients who are pregnant must not take QSYMIA.
Patients who can become pregnant should:
1.
Have a pregnancy test before taking QSYMIA and every month while
taking QSYMIA.
2.
Use effective birth control (contraception) consistently while taking
QSYMIA. Talk to
your healthcare provider about how to prevent pregnancy.
If you become pregnant while taking QSYMIA, stop taking QSYMIA
immediately and tell your
healthcare provider right away.Healthcare providers and patients who
become pregnant should
report all cases of pregnancy to:
3.
FDA MedWatch at 1-800-FDA-1088
Because of the risk for birth defects (cleft lip and cleft palate),
QSYMIA is available through a
restricted program called the QSYMIA Risk Evaluation and Mitigation
Strategy (REMS).
QSYMIA is only available through certified pharmacies that participate
in the QSYMIA REMS
program. Your healthcare provider can give you information about how
to find a certified
pharmacy. For more information, go to www.QSYMIAREMS.com or call
1-888-998-4887.
•
Increases in heart rate.QSYMIA can increase your heart rate at rest.
Your healthcare provider
should check your heart rate while you take QSYMIA. Tell your
healthcare provider if you
experience, while at rest, a racing or pounding feeling in your chest
lasting several minutes when
tak

Summary of Product characteristics

QSYMIA- PHENTERMINE AND TOPIRAMATE CAPSULE, EXTENDED RELEASE
QSYMIA- PHENTERMINE AND TOPIRAMATE CAPSULE, EXTENDED RELEASE
VIVUS LLC
----------
HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
QSYMIA
SAFELY AND
EFFECTIVELY. SEE FULL PRESCRIBING INFORMATION FOR QSYMIA.
QSYMIA (PHENTERMINE AND TOPIRAMATE EXTENDED-RELEASE CAPSULES), FOR
ORAL USE, CIV
INITIAL U.S. APPROVAL: 2012
INDICATIONS AND USAGE
QSYMIA is a combination of phentermine, a sympathomimetic amine
anorectic, and topiramate, indicated
as an adjunct to a reduced-calorie diet and increased physical
activity for chronic weight management in:
Adults with an initial body mass index (BMI) of:
30 kg/m
or greater (obese) ( 1) or
27 kg/m
or greater (overweight) in the presence of at least one weight-related
comorbidity such as
hypertension, type 2 diabetes mellitus, or dyslipidemia ( 1)
Pediatric patients aged 12 years and older with BMI in the 95
percentile or greater standardized for
age and sex.
Limitations of Use:
The effect of QSYMIA on cardiovascular morbidity and mortality has not
been established ( 1).
The safety and effectiveness of QSYMIA in combination with other
products intended for weight loss,
including prescription and over-the-counter drugs, and herbal
preparations, have not been established (
1).
DOSAGE AND ADMINISTRATION
Take orally once daily in morning. Avoid administration in evening to
prevent insomnia ( 2.3).
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 ( 2.3).
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 ( 2.3).
Gradually discontinue 15 mg/92 mg dosage to prevent possible seizure (
2.4).
Do not exceed 7.5 mg/46 mg dosage for patients with moderate or severe
renal impairment or patients
with moderate hepatic impairment ( 2.5, 2.6).
DOSAGE FORMS AND STRENGTHS
Extend