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 - extended release
Clinical data
Trade names Qsymia
Pregnancy cat.
Legal status
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 extended-release (ER) (trade name Qsymia) is a medication used for weight loss. In clinical trials, phentermine/topiramate ER was associated with modest but statistically significant weight loss when compared with placebo.[1] This weight loss was associated with improvements in weight-related comorbidities such as improved glycemia, decreased blood pressure, and improved cholesterol.[1]

Phentermine/topiramate ER was developed by Vivus, Inc., a California pharmaceutical company.[2] Phentermine is a sympathomimetic amine which acts as an appetite suppressant and stimulant.[1] Topiramate is an anticonvulsant that has weight loss side effects.[1] The exact mechanism of action for both drugs is unknown.[1]

In 2012 the U.S. Food and Drug Administration approved phentermine/topiramate ER as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial BMI of: ≥30 kg/m2, or over ≥27 kg/m2 (overweight) in the presence of at least one weight-related comorbidity such as hypertension, type 2 diabetes mellitus, or dyslipidemia.[1][3] Phentermine/topiramate ER is available in certified retail pharmacies nationwide and also available through a certified mail-order pharmacy network.[4] Approval was denied by European regulatory authorities, who cited potential risk to the heart and blood vessels, psychiatric side effects, and cognitive side effects in explaining their decision.[5]

Available doses[edit]

The following doses of phentermine IR (immediate-release) and topiramate ER were used in Phase 3 testing:[1]

  • 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

Efficacy[edit]

In clinical trials, people treated with the highest dose of phentermine/topiramate ER in combination with a program of diet and exercise lost 10% to 11% of their body weight compared to 1% to 2% for those who received placebo.[1] In addition, 62% to 70% of subjects receiving the recommended dose or top dose of phentermine/topiramate ER achieved ≥5% weight by week 56 (ITT-LOCF) compared to 17% to 21% of those receiving a sugar pill.[1]

Pregnancy[edit]

Phentermine/topiramate ER can cause fetal harm. Data from pregnancy registries and epidemiology studies indicate that a fetus exposed to topiramate in the first trimester of pregnancy has an increased risk of oral clefts (cleft lip with or without cleft palate).[1] If a patient becomes pregnant while taking phentermine/topiramate ER, 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 phentermine/topiramate ER and monthly thereafter during phentermine/topiramate ER therapy. Females of reproductive potential should use effective contraception during phentermine/topiramate ER therapy.[1]

Adverse effects[edit]

In clinical trials, the most common adverse events which occurred at a rate ≥5% and ≥1.5 times placebo included paraesthesia (tingling in fingers/toes), dizziness, dysgeusia (altered taste), insomnia, constipation, and dry mouth.[1]

In the U.S., the drug label contains warnings for increased heart rate, suicidal behavior and ideation, glaucoma, mood and sleep disorders, creatine elevation, and metabolic acidosis. Some of these warnings are based on historical observations in epilepsy patients taking topiramate. The FDA is requiring the company to perform a post-approval cardiovascular outcomes trial, due in part to the observation of increased heart rate in some people taking the drug in clinical trials.

Contraindications[edit]

Phentermine/topiramate ER 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. Phentermine/topiramate ER can cause an increase in resting heart rate.[1]

Research[edit]

As cited in the FDA approval letter, VIVUS, Inc. is required to do 10 post marketing studies. Five of these are related to potential use in pediatric patients in the future per PREA (Pediatric Research Equity Act).[6]

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 transporter 2 (OCT2) and OCT3; organic anion transporter3 (OAT3) and OAT4; multidrug and toxin extrusion protein 1 (MATE1) and MATE2-K.

2. A prospective cohort study to a) determine the frequency of pregnancy in women of child-bearing age prescribed phentermine/topiramate ER and b) compare the risk of oral clefts, major congenital malformations, and low birth weight in offspring of women exposed to phentermine/topiramate ER 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 phentermine/topiramate ER 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 phentermine/topiramate ER 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 phentermine/topiramate ER (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 phentermine/topiramate ER 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 phentermine/topiramate ER 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.

Phentermine/topiramate ER 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 phentermine/topiramate ER in patients with OSA showed that patients who took phentermine/topiramate ER had improvements in sleep apnea events (apnea-hypopnea events) and lost more weight than those who took placebo.[7]

Risk Evaluation and Mitigation Strategy (REMS)[edit]

Phentermine/topiramate ER was approved with a REMS program to ensure that benefits of treatment outweigh the risks.[8] Because of the teratogenic risk associated with phentermine/topiramate ER therapy, phentermine/topiramate ER is distributed via certified pharmacies.

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.[9]

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.[10]

SEQUEL A 52-week extension of CONQUER, collecting long-term data over 108 weeks.[11]

Approval history[edit]

In December 2009 VIVUS, Inc. submitted a new drug application (NDA) to the FDA and on March 1, 2010, VIVUS, Inc. announced that the FDA accepted the NDA for review.[12]

In October 2010, the FDA announced its decision to not approve phentermine/topiramate ER 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.[13]

The FDA expressed concerns about the potential for phentermine/topiramate ER 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).[14]

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.[15][16]

On September 18, 2012, Qsymia became available on the US market.[17]

References[edit]

  1. ^ a b c d e f g h i j k l m https://www.qsymia.com/pdf/prescribing-information.pdf
  2. ^ "Welcome". Vivus. Retrieved 2014-06-19. 
  3. ^ "VIVUS, Inc. - Vivus Announces FDA Approval of Once Daily Qsymia™ (Phentermine and Topiramate Extended-release) Capsules CIV". Ir.vivus.com. Retrieved 2014-06-19. 
  4. ^ "VIVUS, Inc. - VIVUS Announces Initial Availability of Qsymia(R) Through Certified Retail Pharmacies". Ir.vivus.com. Retrieved 2014-06-19. 
  5. ^ "www.ema.europa.eu". 
  6. ^ http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/022580Origs000ltr.pdf
  7. ^ "SLEEP - A Randomized, Double-Blind, Placebo-Controlled Study of an Oral, Extended-Release Formulation of Phentermine/Topiramate ER for the Treatment of Obstructive Sleep Apnea in Obese Adults". Journalsleep.org. doi:10.5665/sleep.2204. Retrieved 2014-06-19. 
  8. ^ "VIVUS, Inc. - Vivus Announces FDA Approval of Once Daily Qsymia™ (Phentermine and Topiramate Extended-release) Capsules CIV". Ir.vivus.com. Retrieved 2014-06-19. 
  9. ^ [Allison DB, et al. Obesity (Silver Spring). 2012;20(2):330-342.]
  10. ^ [Gadde KM, et al. Lancet. 2011;377(9774):1341-1352.]
  11. ^ [Garvey WT, et al. Am J Clin Nutr. 201;95(2):297-308.]
  12. ^ http://ir.vivus.com/releasedetail.cfm?ReleaseID=447799
  13. ^ "VIVUS, Inc. - FDA Issues Complete Response Letter to VIVUS Regarding New Drug Application for QNEXA(R)". Ir.vivus.com. Retrieved 2014-06-19. 
  14. ^ "Vivus says FDA asks about Qnexa birth defect link". BusinessWeek. 2011-01-21. Retrieved 2014-06-19. 
  15. ^ "VIVUS, Inc. - VIVUS Resubmits Qnexa NDA to the FDA". Ir.vivus.com. Retrieved 2014-06-19. 
  16. ^ "VIVUS, Inc. - FDA Accepts New Drug Application Filing for Qnexa". Ir.vivus.com. Retrieved 2014-06-19. 
  17. ^ "VIVUS, Inc. - VIVUS Announces Availability Of Once Daily Qsymia™ (Phentermine And Topiramate Extended-Release) Capsules CIV". Ir.vivus.com. Retrieved 2014-06-19. 

External links[edit]