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David J. Lonneman, Jr., is a doctoral candidate in pharmacy at Nova Southeastern college in fort Lauderdale, Florida. Dr. Rey is director of the Psychopharmacology Residency Program and also Associate Professor in the department of Pharmaceutical scientific researches at the university. Dr. McKee is a Clinical Pharmacy specialist in mental health and wellness at the Atlanta Veterans Aff airs medical Center. Drug forecast is a regular column combination by Alan Caspi, PhD, PharmD, MBA, president of Caspi & Associates in brand-new York, brand-new York.

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This write-up has to be cited through other write-ups in PMC.

INTRODUCTION

Obesity is a rapidly cultivation medical condition in the U.S. In 2010, around 35% that American adults were classified together obese.1 The high prevalence of obesity has affected health care expenditures, with much more than $99 billion spent in 1999, attributed to symptom of the disease.1 excessive weight is connected with a greater incidence that and greater morbidity rates of several an illness states (Table 1); it also has adverse impacts on women’s health, consisting of complications during pregnancy and menstrual irregularities. Colon, breast, and endometrial cancer are found at greater incidence prices in obese patients, and also overall mortality prices are boosted by 50% to 100%.2


Table 1


Disease states With High Morbidity rates in Obese Patients


Hypertension

Dyslipidemia

Type-2 diabetes mellitus

Coronary love disease

Stroke

Gallbladder disease

Osteoarthritis

Sleep apnea


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The most generally used medications approved for weight loss include phentermine resin (Ionamin, UCB Pharma); phentermine HCl (Adipex-P, Gate), diethylpropion (Tenuate, formerly Sanofi-Aventis), and orlistat (Xenical, Roche/Genentech; nonprescription Alli, Glaxo-SmithKline). Amphetamines, methylphenidate (Ritalin, CIBA/Novartis), sertraline (Zoloft, Pfizer), fluoxetine (Prozac, Eli Lilly), zonisamide (Zonegran, Elan/Eisai), and also topiramate (Topamax, Janssen) have additionally been supplied in an off-label fashion for load loss.2–5

In 2010, Abbott’s sibutramine (Meridia), an previously adjunctive FDA-approved treatment, brought about weight reductions of 3.62 to 5.29 kg, yet this medicine was eliminated from the U.S. Market since of connected cardiovascular events.2–4 A meta-analysis confirmed that orlistat led to a weight loss that 2.2 come 3.31 kg, yet diarrhea and flatulence were among the most usual adverse effects.5 Phentermine monotherapy at sheep of 15 come 30 mg has actually been associated with a weight loss that 0.6 come 6.0 kg.

Another adjunctive agent, lorcaserin (Belviq, ADP-356, Arena/Eisai), authorized in June 2012, brought about a load loss of 4.5 come 5.8 kg during clinical trials.5 (Lorcaserin’s launch was delayed till June 2013 in bespeak to settle its category as a Schedule IV substance.)

On July 17, 2012, the FDA authorized a tablet combining phentermine to add extended-release topiramate (Qsymia, Vivus) for load loss. Phentermine has actually been provided for weight loss, and topiramate is an antiepileptic certified dealer that has actually been commonly associated with weight loss together a side effect. The doses authorized for weight reduction are reduced than either agent when supplied for its present indications.


INDICATION

Qsymia (previously dubbed Qnexa) is intended to be offered as an adjunct to a reduced-calorie diet together with increased physical task in patients through a body mass index (BMI) greater than 30 kg/m2 or a BMI of 27 kg/m2 or greater and who have actually at the very least one weight-related comorbidity (e.g., hypertension, dyslipidemia, diabetes or prediabetes, or abdominal muscle obesity).6,7


CHEMICAL and also PHYSICAL PROPERTIES

Phentermine, a centrally acting appetite suppressant, is designated chemically as α,α-dimethylphenethylamine HCl. Topiramate, one antiepileptic agent, is designated chemically as 2,3:4,5-di-O-isopropylidene-β-d-fructopyranose sulfa-mate. The tough gelatin capsule consists of immediate-release phentermine and also extended-release topiramate beads.6,7 due to the fact that earlier studies offered the designation phen/tpm cr (controlled release), CR is supplied for the generic medicine name in this article.


Clinical Pharmacology and also Mechanism that Action

The exact mechanism of weight loss v phentermine is not elucidated in the FDA briefing, but from the package insert, it deserve to be assumed that it acts together a sympathomimetic agent, which may suppress appetite as well as increase metabolism.6–8 The mechanism by which topiramate exerts its weight loss effects is unknown. Proposed instrument of weight loss connected with topiramate incorporate neurotransmitter-mediated appetite suppression and also enhancement that satiety.6,7,9


Pharmacokinetics

Qsymia is well absorbed orally, through or without food. Optimal concentrations (Cmax) are got to in 6 hours for phentermine and 10 hrs for topiramate. The half-life is 20 hrs for phentermine and also 65 hrs for topiramate. There is a huge volume that distribution.6,7 elimination is mostly via the urine.

Phentermine has minimal hepatic metabolism through the cytochrome P450 (CYP) 3A4 isoenzyme.6,7


CLINICAL EFFICACY


The EQUIP psychological (OB-302)10

A 56-week randomized, double-blind, parallel-group, placebo-controlled attempt was conducted to to compare placebo through phentermine/topiramate CR in ~ 3.75/23 mg and also 15/92 mg (Table 2). The trial had a 4-week post-randomization titration period, followed by 52 weeks in ~ the randomized therapy dose. A full of 1,267 patients to be enrolled in 91 web page in the U.S. Consists of clinical exercise sites, clinical psychological sites, and scholastic centers. Patients in between 18 and 70 years of age were included in the attempt if they had actually a BMI the 35 kg/m2 or greater, triglyceride levels of 200 mg/dL or below, blood pressure (BP) that 140/90 mm Hg or below, and a fasting plasma glucose level of 110 mg/dL or less.


Table 2


Percentage of load Loss through Dose and also Clinical Trial*


DoseEQUIP (OB-302)CONQUER (OB-303)SEQUEL (OB-305)
Placebo1.6%1.2%1.8%
P/T 3.75/23 mg5.1%
P/T 7.5/46 mg7.8%9.3%
P/T 15/92 mg10.9%9.8%10.5%

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Patients to be randomly assigned and stratified through sex in one allocation ratio of 2:1:2. This design was supplied to increase power that the safety analysis by having an ext patients obtain placebo and also a treatment team consisting of patients utilizing the highest doses that phentermine/topiramate CR. Every personnel to be blinded come the treatment and placebo groups. Patient in each team were recommend to reduce full daily caloric intake by 500 kilocalories (kcal) per day, rise water intake, and increase physics activity.

Primary outcomes were the percentage of adjust in human body weight and the proportion of patient achieving at the very least a 5% load reduction. A calibrated digital scale was supplied to measure transforms in weight. Secondary outcomes measured included waist circumference, BP, blood glucose, triglycerides, complete cholesterol, low-density lipoprotein-cholesterol (LDL-C) and high-density lipoproteincholesterol (HDL-C). All measurements were carry out by trained individuals and were analyzed in a single reference laboratory. Statistics analyses had an intention-to-treat and a amendment intention-to-treat method with the last observation lugged forward (mITT/LOCF), and also per protocol.

There to be no far-ranging differences in ~ baseline between groups. Many of the patients were ladies (83%), and African-American patients stood for 16% come 18% of those included. Patients in the treatment group lost significantly an ext weight 보다 those receiving placebo regardless of the statistical evaluation measurement used (all comparisons, P < 0.0001).

The percent of load loss in the high-dose team was substantially greater compared with low-dose phentermine/topiramate CR—1.6% for placebo, 5.1% because that phentermine/topiramate 3.75/23 mg, and also 10.9% because that phentermine/topiramate CR 15/92 mg (mITT/LOCF). Patient achieving to reduce of 5%, 10%, and also 15% or more in weight were, respectively, 25.5%, 13.0%, and 5.9% for placebo; 59.1%, 27.7%, and 12.4% for 3.75/23 mg; and 83.5%, 67.7%, and 48.1% for 15/92 mg amongst those perfect the psychological (all comparisons, P < 0.001).

The high-dose treatment group experienced far-ranging reductions in all second endpoint measurements compared with those receiving placebo. Low-dose therapy demonstrated decreases in all an additional measurements contrasted with placebo, although no all reductions were significant.

Doses the 3.75/23 mg and 15/92 mg were an ext effective 보다 placebo over the course of 52 weeks. The authors suggest that the percentage of body weight shed was higher with the study drug 보다 with at this time marketed weight-loss medications, yet they provided the require for head-to-head trials prior to this finding have the right to be validated.


The conquer Trial (OB-303)11

CONQUER was a 56-week randomized, double-blind, placebo-controlled psychological that compared phentermine/topiramate CR 7.5/46 mg and 15/92 mg v placebo (see Table 2). A full of 2,487 patients were enrolled in 93 centers in the U.S. Patient were consisted of if castle were between 18 and 70 years of age, had actually a BMI in between 27 and 45 kg/m2, and also had two or an ext weight-related comorbidities such as hypertension, dyslipidemia, diabetes or prediabetes, or ab obesity (Table 4). Exemption criteria because that the trial are presented in Table 5.


Table 4


Comorbidities in the overcome Trial


Hypertension

Systolic blood pressure, 140–160 mm Hg

Systolic blood pressure, 130–140 mm Hg in diabetes

Diastolic blood pressure, 90–100 mm Hg

Diastolic blood push 85–100 mm Hg in diabetes

Or patient is acquisition at the very least two antihypertensive drugs

Hyperlipidemia

Triglycerides, 2.26–4.52 mmol/L

Or patient is acquisition at least two lipid-lowering drugs

Glucose intolerance

Fasting blood glucose > 5.55 mmol/L

Oral glucose tolerance test > 7.77 mmol/L

Type-2 diabetes with only lifestyle transforms or metformin (Glucophage) monotherapy

Waist circumference

102 centimeter for men

88 centimeter for women


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Patients to be randomly assigned, in a 2:1:2 ratio, to get placebo, phentermine/topiramate CR 7.5/46 mg, or phentermine/topiramate CR 15/92 mg. Patients were stratified by sex and also diabetic status. All patients were advised come implement way of life changes and adhere come a total daily caloric intake reduction of 500 kcal/day. Doses were began at 3.75/23 mg and titrated to the target dose over a period of 4 weeks.

Primary outcomes were percentage of adjust in body weight and the proportion of patient achieving at the very least a 5% reduction in weight. An additional outcomes contained absolute weight loss; the relationship of patients through a load loss of more than 10%; transforms in belt circumference; and changes in BMI, BP, lipids, fasting blood glucose levels, glycosylated hemoglobin (HbA1c) and fasting insulin. Statistical evaluation was completed via mITT/LOCF. Analysis of covariance (ANCOVA) was used to test for significance.

There to be no far-ranging differences in the groups at baseline. Women consisted of 70% the the patients, and also 86% the patients were Caucasian. Treated patients lost significantly more weight than those receiving placebo. The median percentages the body weight loss were 7.8% through phentermine/topiramate CR 7.5/46 mg and 9.8% v 15/92 mg. The percentages the patients with a load loss of 5% or an ext were 21% for placebo, 62% for the 7.5/46-mg dose and also 70% for the 15/92-mg dose. The treatment teams showed far-reaching improvements in all an additional outcome measures other than reductions in diastolic BP and LDL-C levels.

Phentermine/topiramate CR 7.5/46 mg and also 15/92 mg carried about more weight loss contrasted with placebo in patients through two or much more weight-related comorbidities. However, the exclusion criteria (see Table 5) could limit stratification of the results to the general population.


The SEQUEL psychological (OB-305)12

A randomized, double-blind, placebo-controlled, 52-week extension of the conquer trial was carried out to identify the long-term efficacy and also safety of phentermine/topiramate CR (see Table 2, web page 449). Eligible patients from conquer continued through their treatment. Patients from overcome were excluded from the SEQUEL extension if your BMI was 22 kg/m2 or listed below at the completion of the dominate trial; if they had actually not take away the study drug for an ext than 4 main at perfect of the conquer trial; if they emerged a problem that would interfere with compliance or attainment of examine measures; or if they began participating in a officially weight-loss program.

A complete of 676 of 866 patients from 36 the the 93 website were had in this extension trial. Major outcomes were continued from CONQUER and included mean percentage weight loss and percentage of subjects achieving load loss the 5% or more. An additional outcomes had systolic and diastolic BP; triglycerides; HDL-C, LDL-C, and also non–HDL-C levels; and HbA1c in patients through type-2 diabetes mellitus. The mITT/LOCF strategy was used to analyze the data. There to be no far-reaching differences in baseline demographics amongst participants. The baseline groups were usually representative that the larger dominate trial.

Throughout the 52-week extension, treated patients confirmed a considerably greater portion of weight loss compared with placebo patients. In ~ week 108, prices of load loss were 1.8% for placebo, 9.3% because that 7.5/46 mg, and also 10.7% because that 15/92 mg. Significantly more treated patients lost 5%, 10%, 15%, and also 20% or more weight contrasted with those receiving placebo.

Secondary outcomes did not differ significantly between placebo and also treatment groups. However, the 15/92-mg sheep led to considerably decreased triglyceride, HDL-C, and also LDL-C levels compared with placebo, conversely, the 7.5/46-mg dose considerably decreased just LDL-C levels contrasted with placebo. Much more patients required antihypertensive and antihyperlipidemic medicines in the placebo group than in the therapy groups, back no statistical analyses were completed for this observation.

Overall, phentermine/topiramate CR 7.5/46 mg and also 15/92 mg produced far-reaching weight loss that was preserved throughout 108 weeks of treatment.


ADVERSE EFFECTS

The most common adverse drug occasions (ADEs) (in 10% of patients or more) that arisen significantly much more often with any type of dose of phentermine/topiramate CR than through placebo were constipation, paresthesia, and dry mouth. Dysgeusia, insomnia, and also dizziness arisen in an ext than 10% of patient who got the 15/92-mg dose.6,7,10,11

SEQUEL showed lessened rates that these common ADEs, but the trial contained only patients who had actually taken phenter-mine/topiramate CR for the coming before 52 weeks. It is possible that patient who had experienced an ext ADEs walk not proceed to the SEQUEL extension; therefore, the evaluate or report of ADEs would appear lower.10,11 Other fairly common ADEs (affecting an ext than 5% that patients) in the low-dose treatment groups (7.5/46 mg) to be dysgeusia and dizziness. Ago pain and also blurred vision were reasonably common (affecting more than 5% that patients) with high-dose therapy (15/92 mg). 10–12

Therapy discontinuation rates attributable to ADEs were similar between study groups in the SEQUEL trial; however, EQUIP and also CONQUER proved dose-dependent discontinuation rates, as follows: 10–12

EQUIP: 8.4% because that placebo, 11.3% for 3.75/23 mg, and 16% for 15/92 mg10

CONQUER: 9%, because that placebo, 12% because that 7.5/46 mg, and also 19% for 15/92 mg11

Adverse events leading come the discontinuation of therapy were comparable in all three trials and included insomnia, irritability, anxiety, headache, attention disturbances, depression, dry mouth, and nephrolithiasis.10–12 In the dominate trial, three instances of significant nephrolithiasis arisen in the 15/92-mg therapy group. One patient in the EQUIP attempt who obtained phentermine/topiramate CR 3.75/23 mg knowledgeable cholelithiasis, which resolved 1 week after treatment was interrupted.10

Substantial reduce in serum bicarbonate levels were observed in the conquer trial, influence one placebo patient, one patient receiving 7.5/46 mg, and also seven patient receiving 15/92 mg.11 Overall, an extensive serum bicarbonate reductions represented an incidence rate of much less than 1% because that each treatment group.7,10–12

In CONQUER, hypokalemia additionally occurred in three patients receiving placebo (fewer than 1%), in 7 patients receiving 7.5/46 mg (1%), and also in 30 patient receiving 15/92 mg (3%).11 other serious ADEs reported in EQUIP to be chest pain, pulmonary embolism, and myelogenous leukemia.10 only myelogenous leukemia occurred in the treatment group receiving 15/92 mg and was figured out after 6 month of therapy.

No increased risks of major cardiovascular serious ADEs to be noted,7,10–12 and also no significant effects on the repair QT interval were observed.7 No significant psychomotor results were documented. The incidence that cognitive dysfunction was low and also dose-related. Of these instances, attention and also memory deficits to be the most generally reported.7 There was an association v an boosted incidence that mild-to-moderate psychiatric ADEs, however serious depression and anxiety were not reported. No suicidal make the efforts or ideation to be observed.6,7


DRUG INTERACTIONS

Topiramate is a mild inducer the CYP 3A4 isoenzymes and a weak inhibitor of organic anion/cation transporters. This interactions are taken into consideration minimal, and also dosage adjustments need to not be necessary. The performance of dental contraception can be diminished during phenter-mine/topiramate CR therapy. Metformin (Glucophage, Bristol-Myers Squibb) levels may be increased, but dosage adjustments space not thought about necessary. The antiseizure agents carbamazepine (Carbatrol, Shire) and also phenytoin (Dilantin, Pfizer) might reduce plasma levels of topiramate by about 40% come 48%.7 Overall, phentermine/topiramate CR has actually a minimal drug-interaction profile.6,7


CONTRAINDICATIONS

Phentermine/topiramate CR (Qsymia) is contraindicated in pregnancy and is designated together a Pregnancy category X drug.7 However, topiramate is thought about Pregnancy category D together a single agent for migraines or epilepsy and also phenter-mine is classified as Pregnancy group C medicine when offered alone.8,9 as soon as used throughout the an initial trimester of pregnancy for epilepsy, topiramate brought about an enhanced risk of dental cleft formation.

The potential threat for teratogenic harm to the fetus has generated the production of a danger Evaluation and Mitigation Strategy (REMS) system for Qsymia. Health treatment professionals must finish a maintain program, and also only certain pharmacies might dispense this agent. Ladies of child-bearing age must use contraception and must it is in assessed for pregnancy standing on a continual basis. If pregnancy occurs, the medication must be discontinued and also the patient should be counseled regarding risks to the fetus.7

Because the reports of acute myopia and second angle-closure glaucoma with phentermine, phentermine/topiramate CR is contraindicated in glaucoma. Extr contraindications encompass hyperthyroidism and the concomitant usage of monoamine oxidase (MAO) inhibitors or their usage within 14 days.7–9


WARNINGS

Phentermine/topiramate CR dead a warning for raised heart rate, an especially in patients with known cardiac disease. Warnings generally associated with antiepileptic drugs, such together topiramate, incorporate an raised risk that suicidal thoughts and behaviors.9 alters in mood and increased stress and anxiety have developed with the combination, and the danger is higher in patients through a background of depression.7 These changes usually settle spontaneously or top top discontinuation of the product.

Because metabolic acidosis may take place with treatment,7 it is recommended that serum electrolytes, including bicarbonate, it is in monitored routinely. Elevated serum creatinine levels might occur during treatment, top at around 4 to 8 weeks, and then gradually decline; however, the elevation persists contrasted with baseline levels.

Dose-related cognitive impairment is associated with the use of phentermine/topiramate CR, especially with rapid dose titrations. Patients through diabetes who lose weight while taking antidiabetic medications have an enhanced risk the hypoglycemia.7


DOSAGE and ADMINISTRATION

The initial dose of phentermine/topiramate CR for adults is 3.75/23 mg daily for 14 days. The dose need to then be increased to 7.5/46 mg everyday for 90 days. If a greater dose is needed after 90 days, the dose have the right to be boosted to 11.25/69 mg daily for 14 days, followed by 15/92 mg day-to-day thereafter.7

The best recommended dose in patients through renal impairment is 7.5/46 mg daily. Although phentermine level are increased in those with mild-to-moderate hepatic impairment, doses above 7.5/46 mg/day might be considered. The FDA has actually designated Qsymia as a Schedule IV drug since phentermine is a Schedule IV agent v abuse potential regarded amphetamines.7,8 Topiramate is not thought about to have actually abuse potential.9 Both agents could produce an adverse withdrawal reactions if they are discontinued suddenly. Rapid tapering or discontinuation must be monitored to protect against complications.7


CONCLUSION

Phentermine/topiramate CR (Qsymia) to be the very first weight-loss drug to be introduced in the U.S. In 13 years. The capsules combine a formerly FDA-approved weight-loss medication with an approved antiepileptic agent well-known for load loss as a next effect. This mix works synergistically to reason weight ns at lower doses compared with the individual products used alone, thereby reducing disadvantage effects. The varieties of adverse effects demonstrated in clinical trials were comparable to those of the single products. The most notable adverse reactions of the individual commodities include cardiovascular and cognitive dysfunction. There were no significant cardiovascular events during the trials, and discontinuation of treatment attributable to cognitive dysfunction rarely occurred. Due to the fact that of the danger of teratogenicity, the patient, prescriber, and certified pharmacy need to all comply v the FDA-mandated REMS program for this medication.

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Trials have demonstrated the clinical efficacy of phentermine/topiramate CR in all recommended doses. The expected price is around $130 to $210 per month. Because that those with insurance coverage, the average co-pay is $50 or $60.13

Currently, no studies have compared the efficacy and safety that this combination product through either active ingredient alone as monotherapy or with other available weight-loss agents. Qsymia might represent an additional safe and also effective adjunctive treatment to be taken into consideration in the monitoring of obese and overweight patients with comorbid medical problems who would benefit from weight loss.