Qsymia: Combination Oral Therapy a New Weight-Loss Option for Obese or Overweight Patients

Value-Based Care in Cardiometabolic Health Dec 2012, Vol 1, No 3 - Drug Updates
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Obesity has reached epidemic proportions in the United States.1 Obesity, which is defined as a body mass index (BMI) of ≥30 kg/m2, affects an estimated 78.1 million Americans—more than 35% of all men and women.2,3 Moreover, more than 34% of adults aged ≥20 years are overweight, which is defined as a BMI of ≥25 kg/m2.3

Clinical and Economic Implications of Obesity
Obesity is associated with clinically serious and costly consequences, including an increased risk for developing type 2 diabetes, cardiovascular (CV) disease, hypertension, sleep apnea, stroke, dyslipidemia, osteoporosis, and some types of cancer (ie, breast, colon, and endometrial).1,3 Furthermore, obesity is associated with social stigma, discrimination, reduced life expectancy, and a reduced quality of life.1,3

The costs associated with obesity and overweight are staggering. The annual medical burden of obesity has climbed to nearly 10% of all medical spending in the United States, with an annual total of $147 billion.4,5 Moreover, medical costs per person are $1429 higher for obese individuals compared with normal-weight individuals, according to the Centers for Disease Control and Prevention.4

Weight loss achieved by medically recommended approaches is associated with reduced comorbidities in patients with obesity.6 A weight loss of 5% to <10% of an overweight or obese person’s initial body weight can lead to significant improvements in cardio­metabolic health at 1 year, including improved glycemic control, reduced blood pressure (BP), and improved high-density lipoprotein cholesterol and triglyceride levels in those with type 2 diabetes.7 These benefits can be even greater with a weight loss of 10% to 15% of body weight.7

Lifestyle changes may be particularly challenging for patients with physical restrictions that limit their activity, or for those whom the benefit of a multidisciplinary healthcare team is not available.8 Effective, long-term pharmacologic therapies—in conjunction with lifestyle modifications—may provide appropriate patients with a viable option for weight management and improved outcomes.8

Qsymia Receives FDA Approval
On July 17, 2012, the US Food and Drug Administration (FDA) approved the combination of phentermine/topir­amate extended-release (ER; Qsymia; Vivus) as an adjunct to a reduced-calorie diet and physical activity for chronic weight management in adults with an initial BMI of ≥30 kg/m2 (ie, obese) or ≥27 kg/m2 (ie, overweight) in the presence of at least 1 weight-related comorbidity, such as hypertension, type 2 diabetes, or dyslipidemia.9 Phentermine and topiramate are each approved by the FDA as a monotherapy, with different indications.

The FDA has required a Risk Evaluation and Mitigation Strategy (REMS) program for phentermine/topiramate ER to manage the known or potential serious risks that are associated with this new combination therapy. The purpose of this REMS is to inform prescribers and females of reproductive potential about several factors, including the increased risk of congenital malformation, specifically orofacial clefts, in infants exposed to the drug during the first trimester of pregnancy; the importance of pregnancy prevention for women of reproductive potential who are receiving the drug; and the need to discontinue use if pregnancy occurs.10,11

Dosing
Phentermine/topiramate ER is dosed orally once daily in the morning, with or without food. Evening dosing should be avoided, because of the possibility of insomnia. The recommended starting dose is phentermine/topiramate ER 3.75 mg/23 mg daily for 14 days; after 14 days, it is recommended that the dose be increased to phentermine/topiramate ER 7.5 mg/46 mg once daily.10

If a patient has not lost at least 3% of baseline body weight after 12 weeks of treatment with phentermine/topiramate ER 7.5 mg/46 mg, this dose should be discontinued or escalated. If a patient has not lost at least 5% of baseline body weight after an additional 12 weeks of treatment at the escalated dose of phentermine/topiramate ER 15 mg/92 mg, the patient should discontinue use gradually by taking a dose every other day for at least 1 week before stopping treatment altogether to reduce the possibility of precipitating a seizure.10

Phentermine/topiramate ER capsules are available in 3.75-mg/23-mg, 7.5-mg/46-mg, 11.25-mg/69-mg, and 15-mg/92-mg dosage strengths. The 3.75-mg/23-mg and the 11.25-mg/69-mg dosages are used for titration purposes only.10

Clinical Pharmacology
Mechanism of Action

Phentermine is a sympathomimetic amine with pharmacologic activity similar to the prototype drugs of this class that are used to treat obesity, amphetamines (dextroamphetamine and dextroamphetamine/levoamphetamine), which are known as “anorectics” or “anorexigenics.” Although the exact mechanism of action is not known, the effect of phentermine on chronic weight management is likely mediated by the release of catecholamines in the hypothalamus, resulting in reduced appetite and decreased food consumption; other meta­bolic effects may also be involved.10

The precise mechanism of action of topiramate on chronic weight management is not known. The effect of topir­amate on chronic weight management may be a result of its effects on both appetite suppression and on satiety enhancement, which are induced by a combination of pharmacologic effects, including the augmentation of the activity of the neurotransmitter gamma-aminobutyrate, the modulation of voltage-gated ion channels, the inhibition of AMPA/kainite excitatory glutamate receptors, or the inhibition of carbonic anhydrase.10

Pharmacodynamics
Typical actions of amphetamines include central nervous system stimulation and the elevation of BP. Tachyphylaxis and tolerance have been demonstrated with all drugs of this class in which these phenomena have been assessed.10

Cardiac electrophysiology. The effect of phentermine/topiramate ER on the corrected QT (QTc) interval was evaluated in a randomized, double-blind, placebo- and active (400 mg moxifloxacin)-controlled, parallel-group, crossover study. A total of 54 healthy subjects were administered phentermine/topiramate ER 7.5 mg/46 mg at steady state and then titrated to phentermine/topiramate ER 22.5 mg/138 mg at steady state.

Phentermine/topira­mate ER 22.5 mg/138 mg—a supra­thera­peutic dose resulting in phentermine/ topiramate ER maximum concentrations (Cmax) of 4 times and 3 times higher than those at the phentermine/ topiramate ER 7.5-mg/46-mg dose, respectively—did not affect cardiac repolarization, as measured by the change from baseline in QTc.10

Pharmacokinetics
Phentermine. On oral administration of a single phentermine/topiramate ER 15 mg/92 mg, the resulting mean plasma phentermine Cmax, time to Cmax (Tmax), area under the concentration curve (AUC) from time zero to the last time with measurable concentration (AUC0-t), and AUC from time zero to infinity (AUC0-∞) are 49.1 ng/mL, 6 hr, 1990 ng.hr/mL, and 2000 ng.hr/mL, respectively. A high-fat meal does not affect phentermine’s pharmacokinetics for phentermine/ topiramate ER 15 mg/92 mg.10

Topiramate. On oral administration of a single phentermine/topiramate ER 15 mg/92 mg, the resulting mean plasma topiramate Cmax, Tmax, AUC0-t, and AUC0-∞ are 1020 ng/mL, 9 hr, 61,600 ng.hr/mL, and 68,000 ng.hr/mL, respectively. A high-fat meal does not affect topiramate’s pharmacokinetics for phentermine/topiramate ER 15 mg/92 mg.10

Clinical Trials
The FDA approval of phentermine/ topiramate ER was based on 2 randomized, double-blind, placebo-controlled studies—EQUIP and CONQUER—that evaluated its effect on weight loss in conjunction with reduced caloric intake and increased physical activity in obese patients (the EQUIP trial) and in obese and overweight patients with ≥2 significant comorbidities (the CONQUER trial).6,10,12 Both studies had a 4-week titration period, followed by 52 weeks of treatment.

In addition, both studies measured 2 coprimary efficacy outcomes after 1 year of treatment (week 56), including the percent weight loss from baseline and treatment response, which was defined as achieving at least 5% weight loss from baseline.10

EQUIP
In the EQUIP trial, obese patients (BMI ≥35 kg/m2) were randomized to receive 1 year of treatment with placebo, phentermine/topiramate ER 3.75 mg/23 mg, or phentermine/to­piramate ER 15 mg/92 mg, in a 2:1:2 ratio.6 Patients with type 2 diabetes were excluded from this study. A well-balanced, reduced-calorie diet (approximate 500-kcal daily decrease in caloric intake) was recommended to all patients, and they were offered nutritional and lifestyle modification counseling.6,10

Table 1
EQUIP Trial: Weight Loss at 1 Year in Obese Patients (ITT-LOCF Population)

After 1 year of treatment with phentermine/topiramate ER, all dose levels resulted in a significant weight loss compared with placebo (Table 1).6,10

Before week 56, 40% of randomized patients withdrew from the study. The most common adverse events (AEs) were paresthesia, dry mouth, constipation, dysgeusia, and insomnia.6,10

CONQUER
In the CONQUER trial, overweight and obese patients were randomized to receive 1 year of treatment with placebo, phentermine/topiramate ER 7.5 mg/46 mg, or phentermine/topiramate 15 mg/92 mg, in a 2:1:2 ratio.12 Eligible patients had to have a BMI ≥27 kg/m2 and ≤45 kg/m2 (no lower limit on BMI for patients with type 2 diabetes) and ≥2 obesity-related comorbidities, including elevated BP (≥140/90 mm Hg, or ≥130/85 mm Hg for diabetic patients) or a requirement for ≥2 antihypertensive medications; triglycerides ≥200-400 mg/dL or receiving treatment with ≥2 lipid-lowering agents; elevated fasting blood glucose (>100 mg/dL) or diabetes; and/or a waist circumference of ≥102 cm for men and ≥88 cm for women.10,12

At the start of the study, 53% of the patients had hypertension and 16% had type 2 diabetes. Patients were advised to maintain a well-balanced, reduced-calorie diet (500-kcal daily decrease in caloric intake), and all were offered nutritional and lifestyle modification counseling.10,12

Table 2
CONQUER Trial: Weight Loss at 1 Year in Overweight and Obese Patients with Comorbidities (ITT-LOCF Population)
Table 3
CONQUER Trial: Mean Changea from Baseline in Cardiometabolic Comorbidities in Overweight and Obese Patients with Phentermine/Topiramate ER versus Placebo, at 1 Year

Treatment with all doses of phentermine/topiramate ER after 1 year showed significant weight loss compared with placebo (Table 2).10,12 Moreover, 1 year of therapy with phen­termine/topiramate ER resulted in relative improvements compared with placebo in obesity-related cardiometabolic risk factors, with the exception of heart rate (Table 3).10

The most common AEs were dry mouth, paresthesia, constipation, insomnia, dizziness, and dysgeusia.12

A Recent Trial: SEQUEL
Results of a third trial were published in 2012.8 The SEQUEL trial was a double-blind, placebo-controlled extension of the CONQUER trial that assessed the longer-term safety and efficacy of 2 doses of phentermine/ topiramate ER, in conjunction with lifestyle modification, for an additional 52 weeks (total of 108 weeks’ treatment duration).8

At 108 weeks, phentermine/topiramate ER showed significant, sustained weight loss in the intent-to-treat/last- observation-carried-forward population compared with placebo (P <.001); and significantly more patients achieved ≥5%, ≥10%, ≥15%, and ≥20% weight loss compared with placebo (P <.001).8 Phentermine/topiramate ER was also associated with sustained improvements in the clinical manifestations of weight-related cardiometabolic comorbidities, including hyper­glycemia, dyslipidemia, and elevated BP.8

The most common AEs were upper respiratory tract infection, constipation, paresthesia, sinusitis, and dry mouth.8

Safety Profile and Metabolic Properties
The effect of phentermine/topiramate ER on CV morbidity and mortality has not been established. The safety and effectiveness of phentermine/to­piramate ER in combination with other products that are intended for weight loss, including prescription and over-the-counter drugs and herbal preparations, have not been established.10

The most common AEs associated with phentermine/topiramate ER (incidence ≥5% and at a rate of at least 1.5 times placebo) include paresthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth.10 There are no black box warnings associated with the use of phentermine/topiramate ER.

Contraindications
Phentermine/topiramate ER is contraindicated in pregnant women; in patients with glaucoma; in patients with hyperthyroidism; in those receiving treatment or within 14 days after treatment with monoamine oxidase inhibitors; and in patients with hypersensitivity to sympathomimetic amines, topiramate, or any of the inactive ingredients in phentermine/topiramate ER.10

Important Safety Information
Phentermine/topiramate ER can cause fetal harm. Women of reproductive potential should have a negative pregnancy test before treatment and monthly thereafter, and they should use effective contraception consistently during therapy with phentermine/ topiramate ER.

Phentermine/topiramate ER can cause an increase in resting heart rate. Regular measurement of resting heart rate is recommended for all patients taking phentermine/topiramate ER, particularly patients with cardiac or cerebrovascular disease or when initiating or increasing the dose.

Topiramate, a component of phentermine/topiramate ER, increases the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients should be monitored for the emergence or the worsening of depression, suicidal thoughts or behavior, and/or for any unusual changes in mood or behavior. Phentermine/topiramate ER should be discontinued in patients who experience suicidal thoughts or behaviors; it is not recommended in patients with a history of suicidal attempts or active suicidal ideation.

Acute angle closure glaucoma has been reported in patients who are treated with topiramate, a component of phentermine/topiramate ER. Symptoms include acute onset of decreased visual acuity and/or eye pain. Symptoms typically occur within 1 month of the initiation of topiramate, but they may occur at any time during therapy. The primary treatment to reverse symptoms is immediate discontinuation of phentermine/topiramate ER.

Mood disorders, including depression and anxiety, as well as insomnia, can occur with phentermine/topiramate ER. In addition, phentermine/ topiramate ER has the potential to impair cognitive function, including impairment of concentration/attention, difficulty with memory, and speech or language problems. Patients should be cautioned about operating hazardous machinery, including automobiles.

Hyperchloremic, nonanion gap, metabolic acidosis has been reported in patients being treated with phentermine/topiramate ER. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing the use of the drug.

Phentermine/topiramate ER can cause an increase in serum creatinine. If persistent elevations in creatinine occur while taking phentermine/topir­amate ER, the dose should be reduced or the drug should be discontinued.

Weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus who are being treated with insulin and/or insulin secretagogues (eg, sulfonylureas). Phen­­ter­mine/topiramate has not been studied in combination with insulin. A reduction in the dose of antidiabetes medications that are non–glucose dependent should be considered to mitigate the risk of hypoglycemia.10

Specific Populations
Nursing mothers. Phentermine/topir­amate ER may be present in human milk, because topiramate and amphetamines (phentermine has pharmacologic activity and a chemical structure similar to amphetamines) are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into consideration the importance of the drug to the mother.10

Pediatric use. The safety and effectiveness of phentermine/topiramate ER in pediatric patients aged <18 years have not been established, and the use of phentermine/topiramate ER is not recommended in pediatric patients.10

Geriatric use. Clinical studies of phentermine/topiramate ER did not include sufficient numbers of subjects aged ≥65 years 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 of other drug therapies.10

Renal impairment. No dose adjustments are necessary in patients with mild renal impairment. In patients with moderate (creatinine clearance [CrCl] ≥30-<50 mL/min) and severe (CrCl <30 mL/min) renal impairments, the dose should not exceed phentermine/topiramate ER 7.5 mg/ 46 mg once daily.10

Hepatic impairment. No dose adjustments are necessary in patients with mild hepatic impairment. In patients with moderate hepatic impairment, the dose should not exceed phentermine/topiramate ER 7.5 mg/46 mg once daily.

Phentermine/topiramate ER has not been studied in patients with severe hepatic impairment (Child-Pugh score 10-15). Use in this patient population should be avoided.10

Potential for Abuse and Dependence
Phentermine/topiramate ER is a Schedule IV controlled substance because it contains phentermine, a Schedule IV drug. Topiramate is not a controlled substance. Phentermine, a component of phentermine/topiramate ER, is related chemically and pharmacologically to amphetamines, and it has a known potential for abuse. The possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including phentermine/topiramate ER as part of a weight-reduction program.10

Phentermine/topiramate ER has not been systematically studied for its potential to produce physical depen­dence. Limited information on the potential for physical dependence for the individual components of phentermine/topiramate ER is available.

Abrupt discontinuation of topiramate has been associated with seizures in patients without a history of seizures or epilepsy.

The abrupt cessation of phentermine after prolonged high-dosage administration may result in extreme fatigue, mental depression, and changes on a sleep electroencephalogram. In situations where rapid withdrawal of phentermine/ topiramate ER is required, appropriate medical monitoring is recommended.10

Conclusion
Clinical evidence has established the significant effect of phentermine/to­piramate ER on weight loss, in conjunction with lifestyle modification, in obese patients and overweight patients with significant cardiometabolic comorbidities, such as diabetes type 2, dyslipidemia, and hypertension. Reducing weight in this patient population has been shown to improve overall health, specifically cardiometabolic health. This new combination therapy is another option to help patients reduce and maintain weight loss, in combination with diet and exercise, as a way to improve overall health.

References

  1. National Institutes of Health, Department of Health and Human Services. About NIH obesity research. Background. http://obesityresearch.nih.gov/about/. Accessed December 4, 2012.
  2. Centers for Disease Control and Prevention. Obesity and overweight for professionals. Causes and consequences. www.cdc.gov/obesity/adult/causes/index.html. Accessed December 4, 2012.
  3. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity in the United States, 2009-2010. NCHS Data Brief. 2012;82:1-8.
  4. Centers for Disease Control and Prevention. Overweight and obesity. Adult obesity facts.
    www.cdc.gov/obesity/data/adult.html. Accessed December 4, 2012.
  5. Finkelstein EA, Trogdon JG, Cohen JW, Dietz W. Annual medical spending attributable to obesity: Payer- and service-specific estimates. Health Aff (Millwood). 2009;28:w822-w831.
  6. Allison DB, Gadde KM, Garvey WT, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring). 2012;20:330-342.
  7. Wing RR, Lang W, Wadden TA, et al. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care. 2011;34:1481-1486.
  8. Garvey WT, Ryan DH, Look M, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. 2012;95:297-308.
  9. Fitzgerald K. Qsymia for weight management approved by FDA [press release]. July 22, 2012. Med News Today. MediLexicon, Intl. www.medicalnewstoday.com/articles/248134.php. Accessed November 29, 2012.
  10. Qsymia (phentermine and topiramate extended-release) capsules [prescribing information]. Mountain View, CA: VIVUS; 2012.
  11. Qsymia (phentermine and topiramate extended-release) capsules. Risk Evaluation and Mitigation Strategy (REMS). www.qsymiarems.com/. Accessed November 29, 2012.
  12. Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomized, placebo-controlled, phase 3 trial. Lancet. 2011;377:1341-1352; correction, Lancet. 2011;377:1494.
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