Obesity:

Indications for: QSYMIA

As an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in: adults with an initial BMI of ≥30kg/m2 or ≥27kg/m2 in the presence of at least one weight related co-morbidity (eg, hypertension, type 2 diabetes, or dyslipidemia); or pediatric patients aged ≥12yrs with BMI in the 95th percentile or greater standardized for age and sex.

Limitations of Use:

Effects on cardiovascular morbidity/mortality not established. Safety, effectiveness in combination with other weight loss products not established.

Clinical Trials:

Clinical Studies in Adults  

The effect of Qsymia on weight loss in conjunction with reduced caloric intake and increased physical activity was studied in 2 randomized, double-blind, placebo-controlled studies in patients with obesity (Study 1) and patients with obesity or overweight with 2 or more significant co-morbidities (Study 2). Both studies had a 4-week titration period, followed by 52 weeks of treatment.

There were 2 co-primary efficacy outcomes measured after 1 year of treatment (Week 56):

  • the percent weight loss from baseline;
  • treatment response defined as achieving at least 5% weight loss from baseline.

In Study 1, patients with obesity (BMI ≥35 kg/m2) were randomized to receive 1 year of treatment with placebo (n=514), Qsymia 3.75 mg/23 mg (n=241), or Qsymia 15 mg/92 mg (n=512) in a 2:1:2 ratio. At the beginning of the study the average weight and BMI of patients was 116 kg and 42 kg/m2, respectively. Patients with type 2 diabetes were excluded from participating in Study 1. During the study, a well-balanced, reduced-calorie diet to result in an approximate 500 kcal/day decrease in caloric intake was recommended to all patients and patients were offered nutritional and lifestyle modification counseling.

In Study 2, patients with overweight or obesity were randomized to receive 1 year of treatment with placebo (n=994), Qsymia 7.5 mg/46 mg (n=498), or Qsymia 15 mg/92 mg (n=995) in a 2:1:2 ratio. Eligible patients had to have a BMI ≥27 kg/m2 and ≤45 kg/m2 (there was no lower limit on BMI for patients with type 2 diabetes) and two or more of the following obesity-related comorbid conditions:

  • Elevated blood pressure (≥140/90 mmHg, or ≥130/85 mmHg for diabetics) or requirement for ≥2 antihypertensive medications;
  • Triglycerides greater than 200-400 mg/dL or were receiving treatment with 2 or more lipid-lowering agents;
  • Elevated fasting blood glucose (greater than 100 mg/dL) or diabetes; and/or
  • Waist circumference greater than or equal to 102 cm for men or greater than or equal to 88 cm for women.

The average weight and BMI of patients at the start of the study was 103 kg and 36.6 kg/m2, respectively. Approximately half (53%) of patients had hypertension at the start of the study. There were 388 (16%) patients with type 2 diabetes at the start of the study. During the study, a well-balanced, reduced-calorie diet to result in an approximate 500 kcal/day decrease in caloric intake was recommended to all patients and patients were offered nutritional and lifestyle modification counseling. 

After 1 year of treatment with Qsymia, all dose levels resulted in statistically significant weight loss compared to placebo. A statistically significant greater proportion of the patients randomized to Qsymia than placebo achieved 5% and 10% weight loss. The following are the results observed for weight loss at 1 year in Studies 1 and 2 of patients treated with Qsymia doses compared to placebo:

Study 1 (Obesity)
Qsymia 3.75 mg/23 mg and Qsymia 15 mg/92 mg vs Placebo, respectively:

  • Weight % mean change from baseline:  -5.1 and -10.9 vs -1.6; difference from placebo:  3.5 (95% CI, 2.4-4.7; P <.0001) and 9.4 (95% CI, 8.4-10.3; P <.0001)
  • Percentage of patients losing ≥5% body weight:  45% and 67% vs 17%; risk difference vs placebo:  27.6 (95% CI, 20.4-34.8; P <.0001) and 49.4 (95% CI, 44.1-54.7; P <.0001)
  • Percentage of patients losing ≥10% body weight:  19% and 47% vs 7%; risk difference vs placebo:  11.4 (95% CI, 5.9-16.9; P <.0001) and 39.8 (95% CI, 34.8-44.7; P <.0001)

Study 2 (Obesity or overweight with comorbidities)
Qsymia 7.5 mg/46 mg and Qsymia 15 mg/92 mg vs Placebo, respectively:

  • Weight % mean change from baseline:  -7.8 and -9.8 vs -1.2; difference from placebo:  6.6 (95% CI, 5.8-7.4; P <.0001) and 8.6 (95% CI, 8.0-9.3; P <.0001)
  • Percentage of patients losing ≥5% body weight:  62% and 70% vs 21%; risk difference vs placebo:  41.3 (95% CI, 36.3-46.3; P <.0001) and 49.2 (95% CI, 45.4-53.0; P <.0001)
  • Percentage of patients losing ≥10% body weight:  37% and 48% vs 7%; risk difference vs placebo:  29.9 (95% CI, 25.3-34.5; P <.0001) and 40.3 (95% CI, 36.7-43.8; P <.0001)

 

Clinical Studies in Pediatric Patients Aged 12 Years and Older 

The effect of Qsymia on BMI in conjunction with reduced caloric intake and increased physical activity was evaluated in Study 3 (NCT 03922945), a 56-week, randomized, double-blind, placebo-controlled study in pediatric patients (12-17 years of age) with BMI ≥ 95th percentile standardized by age and sex. Patients were randomized to receive treatment with placebo (n=56), Qsymia 7.5 mg/46 mg (n=54), or Qsymia 15 mg/92 mg (n=113) in a 1:1:2 ratio. During the study, a well-balanced, reduced-calorie diet to result in an approximate 500 kcal/day decrease in caloric intake was recommended to all patients and patients were offered a family-based lifestyle modification program for adolescents.

At the beginning of the study, the average weight and BMI of patients was 106 kg and 38 kg/m2, respectively, with approximately 81% considered severely obese (120% of the 95th percentile or greater for BMI standardized by age and sex). Thirty-eight (38%) of randomized patients withdrew from the study prior to week 56. 

The primary efficacy parameter was mean percent change in BMI. After 56 weeks of treatment with Qsymia, all dose levels resulted in statistically significant reduction in BMI compared to placebo. A greater proportion of patients randomized to Qsymia than placebo achieved 5%, 10%, and 15% BMI reduction. The following are the results observed for BMI reduction at week 56 in Study 3:

Study 3 (Obesity)
Qsymia 7.5 mg/46 mg and Qsymia 15 mg/92 mg vs Placebo, respectively:

  • BMI (primary endpoint) % mean change from baseline:  -4.8 and -7.1 vs +3.3; difference from placebo:  -8.1 (95% CI, -11.9, -4.3) and -10.4 (95% CI, -13.9, -7.0)
  • Percentage of patients with a reduction of ≥5% BMI:  44% and 52.2% vs 13.6%; difference vs placebo:  29.7% (95% CI, 11.2-48.3) and 38.6% (95% CI, 23.1-54.1)
  • Percentage of patients with a reduction of ≥10% BMI:  33.5% and 44.4% vs 4.5%; difference vs placebo:  28.8% (95% CI, 13.6-44.0) and 40.5% (95% CI, 28.4-52.6)
  • Percentage of patients with a reduction of ≥15% BMI:  13.6% and 28.9% vs 2.9%; difference vs placebo:  11.7% (95% CI, 1.3-22.2) and 27.4% (95% CI, 17.7-37.1)

For more clinical trial data, see full labeling.

Adults and Children:

<12yrs: not established. Take once daily in the AM. ≥12yrs: Initially 3.75mg/23mg for 14 days; then increase to 7.5mg/46mg and evaluate weight loss after 12 weeks on this dose. If patient has not lost ≥3% baseline body wt. or BMI, increase to 11.25mg/69mg for 14 days; followed by an increase to 15mg/92mg and evaluate weight loss after 12 weeks on this dose. If patient has not lost ≥5% baseline body wt. or BMI, discontinue by taking 15mg/92mg every other day for at least 1 week prior to stopping altogether. Consider dose reduction if weight loss exceeds 2lbs (0.9kg) per week. Renal (moderate or severe), hepatic (moderate) impairment: max 7.5mg/46mg once daily.

QSYMIA Contraindications:

Pregnancy. Glaucoma. Hyperthyroidism. During or within 14 days of MAOIs.

QSYMIA Warnings/Precautions:

Embryo-fetal toxicity: obtain a negative pregnancy test before initiating and monthly during therapy; advise females of reproductive potential to use effective contraception. Recent or unstable cardiac or cerebrovascular disease: not recommended. Measure resting heart rate regularly. History of suicidal attempts or active suicidal ideation: avoid. Monitor for worsening of depression, suicidal thoughts, unusual behaviors; discontinue if occurs. History of depression. Sleep disorders. Discontinue if acute myopia and secondary angle-closure glaucoma syndrome occur. Consider discontinuing if visual field defects occur. Kidney stones. Maintain adequate hydration; avoid ketogenic diets. Measure electrolytes including serum bicarbonate, potassium, creatinine, blood glucose (in diabetics), BP (in patients on antihypertensives) prior to starting and during therapy. Monitor height velocity in children. Monitor for decreased sweating and increased body temperature during physical activity. Discontinue at the 1st sign of a rash. Avoid abrupt withdrawal (seizure risk). ESRD on dialysis, severe hepatic impairment: avoid. Elderly. Nursing mothers: not recommended.

QSYMIA Classification:

Sympathomimetic amine + antiepileptic.

QSYMIA Interactions:

See Contraindications. May potentiate CNS depression with concomitant alcohol or other CNS depressants (eg, barbiturates, benzodiazepines, hypnotics). Avoid excessive alcohol intake. Increased risk of hypokalemia with concomitant non-K+-sparing diuretics (eg, furosemide, HCTZ). Avoid other carbonic anhydrase inhibitors (eg, zonisamide, acetazolamide, methazolamide). Hyperammonemia (w/ or w/o encephalopathy) and/or hypothermia possible with valproic acid. May be antagonized by phenytoin, carbamazepine. May antagonize pioglitazone (monitor glucose control). May affect oral contraceptives (spotting may occur). May potentiate amitriptyline.

Adverse Reactions:

Paraesthesia, dizziness, dysgeusia, insomnia, constipation, dry mouth; also in children: depression, arthralgia, pyrexia, influenza, ligament sprain; cognitive impairment, metabolic acidosis, increased serum creatinine, oligohidrosis, hyperthermia, serious skin reactions (eg, SJS, TEN).

Note:

Only available through certified pharmacies enrolled in the Qsymia REMS program. For more information call (888) 998-4887.

Metabolism:

Phentermine has two metabolic pathways, namely p-hydroxylation on the aromatic ring and N-oxidation on the aliphatic side chain. Cytochrome P450 (CYP) 3A4 primarily metabolizes phentermine but does not show extensive metabolism. 

Topiramate does not show extensive metabolism. Six topiramate metabolites (via hydroxylation, hydrolysis, and glucuronidation) exist, none of which constitutes more than 5% of an administered dose.

Drug Elimination:

Seventy to 80% of a dose exists as unchanged phentermine in urine when administered alone. The mean phentermine terminal half-life is about 20 hours.

About 70% of a dose exists as unchanged topiramate in urine when administered alone. The mean topiramate terminal half-life is about 65 hours.

REMS:

YES

Generic Drug Availability:

NO

How Supplied:

Caps 3.75mg/23mg—14, 30; 7.5mg/46mg, 11.25mg/69mg, 15mg/92mg—30; Starter Pack (3.75mg/23mg + 7.5mg/46mg)—28; Dose Escalation Pack (11.25mg/69mg + 15mg/92mg)—28