Phentermine/topiramate

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Phentermine/topiramate
Fentermina.svg
Topiramate.svg
Combination of
Phentermine Appetite suppressant/stimulant of the amphetamine and phenethylamine class
Topiramate Anticonvulsant
Clinical data
Trade names Qsymia
Pregnancy cat. X (US)
Legal status Schedule IV (US) Rx only
Routes Oral
Identifiers
CAS number  YesY
ATC code None
PubChem CID 56842108
 YesY (what is this?)  (verify)

The combination of the drugs phentermine and topiramate (trade name Qsymia, formerly Qnexa) is a medication indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults[1] with an initial body mass index (BMI) of at least 30 kg/m2 or at least 27 kg/m2 (overweight) in the presence of at least one weight-related comorbidity such as hypertension, type 2 diabetes mellitus, or dyslipidemia.[2] In clinical trials, Qsymia was associated with significant weight loss when compared with placebo.[3] This weight loss was associated with improvements in weight-related comorbidities such as improved glycemia, decreased blood pressure, and improved cholesterol.[4]

Qsymia was developed by Vivus, Inc., a California pharmaceutical company.[5] Phentermine is a sympathomimetic amine which acts as an appetite suppressant and stimulant.[6] Topiramate is an anticonvulsant that has weight loss side effects.[7] The exact mechanism of action for both drugs is unknown.[8]

On February 22, 2012, U.S. Food and Drug Administration (FDA) advisors voted 20 to 2 to recommend that the FDA adopt phentermine/topiramate ER for chronic weight management.[9] On July 17, 2012, the U.S. FDA approved Qsymia 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/m2 or ≥27 kg/m2 (overweight) in the presence of at least one weight-related comorbidity such as hypertension, type 2 diabetes mellitus, or dyslipidemia.[10] Qsymia is available in certified retail pharmacies nationwide and also available through a certified mail-order pharmacy network.[11]

Available Doses[edit]

The following doses of phentermine IR (immediate-release) and topiramate ER were used in Phase 3 testing:[12]

• Top dose: phentermine 15 mg and topiramate ER 92 mg

• Recommended dose: phentermine 7.5 mg and topiramate ER 46 mg

• Starting dose: phentermine 3.75 mg and topiramate ER 23 mg

Safety and effectiveness[edit]

Qsymia clinical trials have shown significant weight loss among subjects receiving Qsymia when compared with placebo.[13] The Phase 3 56-week EQUIP and CONQUER studies showed an average weight loss of 8% to 11% with the recommended dose or top dose (ITT-LOCF).[14] In addition, 62% to 70% of subjects receiving the recommended dose or top dose of Qsymia achieved ≥5% weight by week 56 (ITT-LOCF).[15]

The most common adverse events which occurred at a rate ≥5% and ≥1.5 times placebo included paraesthesia (tingling in fingers/toes), dizziness, dysgeusia, insomnia, constipation, and dry mouth.[16]

Qsymia is contraindicated in pregnancy, glaucoma, hyperthyroidism, during or within 14 days of taking monoamine oxidase inhibitors, and in patients with hypersensitivity or idiosyncrasy to sympathomimetic amines. Qsymia can cause an increase in resting heart rate.[17]

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).[18] 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.[19]

As cited in the approval letter, Qsymia is required to do 11 post marketing studies. Five of these are related to potential use in pediatric patients in the future. The FDA is concerned with potential impact on behavior, learning and memory, ocular toxicity, general nervous system and bone teeth development. The other required studies are outlined below 1. An in vitro study to determine the inhibition potential of both phentermine and topiramate extended-release individually and in combination on the following human transporters: organic cation transporter2 (OCT2) and OCT3; organic anion transporter3 (OAT3) and OAT4; multidrug and toxin extrusion protein1 (MATE1) and MATE2-K. 2. A prospective cohort study to a) determine the frequency of pregnancy in women of child-bearing age prescribed Qsymia and b) compare the risk of oral clefts, major congenital malformations, and low birth weight in offspring of women exposed to Qsymia during pregnancy with offspring of similar women not exposed to Qsymia during pregnancy. 3. A drug-use study conducted annually for 7 years with nationally representative and projected data to provide a denominator in order to assess adverse event reporting rates of the known serious risk of congenital malformation (specifically orofacial clefts) in infants exposed to Qsymia during the first trimester of pregnancy, and to assess possible risk factors contributing to the risk. Provide the following about patients prescribed Qsymia: a) the estimated total number of prescriptions and patients dispensed Qsymia per year; b) distribution of patients by age, sex, and BMI; c) distribution of prescribers by specialty; d) average, median, and range for duration of use; e) average and median size of prescriptions; f) prescribed average daily dose; g) frequencies of top 10 concomitant diagnoses (including pregnancy) by age and sex; h) frequencies of top 10 concomitant drugs by age and sex (including contraceptive medications for females of childbearing age). 4. A randomized, placebo- and active-controlled trial to evaluate changes in renal function in obese adults, who will be randomized to Qsymia (3 dosage strengths) or placebo. The primary objective of the trial will be to assess the change in measured GFR (assessed as urinary clearance of 125I-sodium iothalamate). Depending on the results of short-term Qsymia exposure on measured GFR, longer follow-up of affected individuals may be required. 5. A randomized, double-blind, placebo-controlled trial to evaluate the effect of long-term treatment with Qsymia on the incidence of major adverse cardiovascular events (non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death) in obese and overweight subjects with cardiovascular disease or multiple cardiovascular risk factors. A subset of individuals should have measurements of bone health assessed by serial radiographic and laboratory measurements. Measurements of autonomic function (heart rate variability, baroreceptor sensitivity) and dynamic testing (24-hour blood pressure and heart rate monitoring) should also be assessed in a subset of individuals.

<FDA NDA Approval letter><7/17/2012>

Qsymia Risk Evaluation and Mitigation Strategy (REMS)[edit]

Qsymia was approved with a REMS to assure that benefits of treatment outweigh the risks.[20] 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.[21]

Key Publications[edit]

EQUIP Investigated the safety and efficacy of the combination for 56 weeks in severely obese patients (BMI ≥35 kg/m2); published in Obesity.[22]

CONQUER A 56-week safety and efficacy trial, evaluating obese or overweight patients (BMI ≥27 and ≤45 kg/m2) with ≥2 weight-related comorbidities (such as type 2 diabetes, hypertension, dyslipidemia); published in The Lancet.[23]

SEQUEL A 52-week extension of CONQUER, collecting long-term data over 108 weeks.[24]

Approval history[edit]

In December 2009 VIVUS submitted a new drug application (NDA) to the FDA and on March 1, 2010, Vivus announced that the FDA accepted the NDA for review.[25]

In October 2010, the FDA announced its decision to not approve Qsymia in its current form and issued a Complete Response Letter (CRL) to VIVUS due to lack of long-term data and concerns about side effects including elevated heart rate, major adverse cardiovascular events, and birth defects.[26]

The FDA expressed concerns about the potential for Qsymia to cause birth defects and requested that Vivus assess the feasibility of analyzing existing healthcare databases to determine the historical incidence of oral cleft in offspring of women treated with topiramate for migraine prophylaxis (100 mg).[27]

In October 2011, VIVUS resubmitted the NDA to the FDA with responses to the issues addressed in the CRL. The FDA accepted the NDA in November 2011.[28]

On February 22, 2012, US FDA advisors on the Endocrine and Metabolism Advisory Committee voted 20 to 2 to recommend that the FDA adopt phentermine/topiramate ER for chronic weight management.[29]

The drug’s name was changed from Qnexa to Qsymia, and approved by the FDA on July 17, 2012.[30]

On September 18, 2012, Qsymia became available on the US market.[31]

Patents and other indications[edit]

Vivus currently has four U.S. patents covering Qsymia.[32] These patents are related to the product and methods of using the drug in various therapeutic applications.

Qsymia is also in phase 2 clinical development for the treatment of type 2 diabetes and obstructive sleep apnea (OSA). A phase 2 safety and efficacy study evaluating Qsymia in patients with OSA showed that patients who took Qsymia had improvements in sleep apnea events (apnea-hypopnea events) and lost more weight than those who took placebo.[33]

Further analyses from clinical studies demonstrated that Qsymia improves blood pressure.[34] Dr. Suzanne Oparil of the University of Alabama at Birmingham stated “The higher the dose, the more weight loss and the more blood pressure went down” presented at the American Society of Hypertension’s 25th annual meeting in New York.[35] Her co-authored study was subsequently accepted and published by the American Journal of Cardiology.19[36]

References[edit]

  1. ^ Sherafat-Kazemzadeh, Roya; Susan Z Yanovski, and Jack A Yanovski (August 28, 2012). "Pharmacotherapy for childhood obesity: present and future prospects". International Journal of Obesity 37 (1): 1-15. doi:10.1038/ijo.2012.144. PMID 22929210. 
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  10. ^ http://ir.vivus.com/releasedetail.cfm?ReleaseID=692685
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  14. ^ [11]
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  23. ^ [Gadde KM, et al. Lancet. 2011;377(9774):1341-1352.]
  24. ^ [Garvey WT, et al. Am J Clin Nutr. 201;95(2):297-308.]
  25. ^ http://ir.vivus.com/releasedetail.cfm?ReleaseID=447799
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  27. ^ [20]
  28. ^ http://ir.vivus.com/releasedetail.cfm?ReleaseID=620724
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  30. ^ http://usatoday30.usatoday.com/news/health/story/2012-07-18/qsymia-diet-drug-approval/56271594/1
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External links[edit]