Introduction
Qsymia (phentermine and topiramate extended-release) is a combination medication approved by the FDA in 2012 for chronic weight management in adults. It represents one of the first pharmacologic approaches to combine two established medications with complementary mechanisms of action to address the multifactorial nature of obesity.
Mechanism of Action
Qsymia employs a dual-mechanism approach to weight management:
- Phentermine: A sympathomimetic amine that promotes norepinephrine release, acting as an appetite suppressant through central nervous system stimulation
- Topiramate: An anticonvulsant that enhances GABA activity, modulates voltage-gated sodium channels, and inhibits carbonic anhydrase. Its weight loss effects are attributed to multiple mechanisms including appetite suppression, enhanced satiety, and potentially altered taste perception
The combination produces synergistic effects on weight reduction through complementary neurochemical pathways affecting hunger, satiety, and energy expenditure.
Indications
- Chronic weight management in adults with:
- Body mass index (BMI) ≥30 kg/m² (obese) - BMI ≥27 kg/m² (overweight) with at least one weight-related comorbidity (hypertension, type 2 diabetes, or dyslipidemia)
- Must be used in conjunction with reduced-calorie diet and increased physical activity
Dosage and Administration
Initial dose: 3.75 mg phentermine/23 mg topiramate extended-release daily for 14 days Maintenance dosing:- Increase to 7.5 mg/46 mg daily after 14 days
- After 12 weeks, evaluate weight loss:
- If <3% weight loss: discontinue or escalate to 11.25 mg/69 mg daily for 14 days, then 15 mg/92 mg daily - If ≥3% weight loss: continue current dose
- Maximum recommended dose: 15 mg/92 mg daily
- Renal impairment: Avoid use in patients with eGFR <30 mL/min; use caution in moderate impairment
- Hepatic impairment: Contraindicated in cirrhosis
- Geriatric patients: Use caution due to increased sensitivity
- Pregnancy: Contraindicated (Category X)
Pharmacokinetics
Absorption:- Phentermine: Rapidly absorbed, Tmax 6 hours
- Topiramate: More gradual absorption, Tmax 9 hours
- Food does not significantly affect absorption
- Phentermine: Protein binding ~96%, Vd ~1000 L
- Topiramate: Protein binding 9-17%, Vd 0.6-0.8 L/kg
- Phentermine: Hepatic metabolism via CYP3A4
- Topiramate: Minimal hepatic metabolism (20-30%)
- Phentermine: Renal elimination (80% unchanged), half-life ~20 hours
- Topiramate: Primarily renal elimination (70% unchanged), half-life ~65 hours
Contraindications
- Pregnancy or planning pregnancy
- Glaucoma
- Hyperthyroidism
- During or within 14 days of MAO inhibitor therapy
- Known hypersensitivity to sympathomimetic amines or topiramate
- Cirrhosis
Warnings and Precautions
Boxed Warning: Risk of teratogenicity (oral clefts)- Pregnancy testing required before initiation and monthly during therapy
- Effective contraception mandatory
- Increased heart rate: Monitor regularly
- Suicidal ideation and behavior: Monitor for emergence or worsening
- Cognitive impairment: May affect concentration, attention, memory
- Metabolic acidosis: Monitor serum bicarbonate
- Hypokalemia: Monitor potassium levels
- Acute myopia and secondary angle closure glaucoma
- Kidney stones: Increased risk due to carbonic anhydrase inhibition
Drug Interactions
Significant interactions:- MAO inhibitors: Contraindicated (risk of hypertensive crisis)
- Oral contraceptives: Topiramate may decrease efficacy (consider alternative contraception)
- CNS depressants: Additive sedation
- Carbonic anhydrase inhibitors: Increased risk of metabolic acidosis
- Alcohol: Enhanced cognitive effects
- CYP3A4 inducers/inhibitors: May affect phentermine levels
- Antiepileptic drugs: Altered topiramate concentrations
Adverse Effects
Most common (>5%):- Paresthesia
- Dizziness
- Dysgeusia (altered taste)
- Insomnia
- Constipation
- Dry mouth
- Teratogenicity (oral clefts)
- Increased heart rate
- Suicidal ideation
- Metabolic acidosis
- Acute angle-closure glaucoma
- Kidney stones
- Cognitive impairment
Monitoring Parameters
Baseline assessment:- Pregnancy test
- Comprehensive metabolic panel
- Serum bicarbonate
- ECG (if cardiac risk factors present)
- Blood pressure and heart rate
- BMI and waist circumference
- Weight loss response at 12-week intervals
- Heart rate and blood pressure monthly for first 3 months, then quarterly
- Serum bicarbonate annually or if symptoms suggest acidosis
- Mental health assessment regularly
- Pregnancy testing monthly
Patient Education
Key counseling points:- Take medication in morning to avoid insomnia
- Swallow capsule whole; do not crush or chew
- Importance of consistent contraception
- Report any pregnancy immediately
- Monitor for mood changes, depression, or suicidal thoughts
- Maintain adequate hydration to reduce kidney stone risk
- Be aware of potential cognitive effects (avoid driving if impaired)
- Do not discontinue abruptly (topiramate component requires taper)
- Continue lifestyle modifications (diet and exercise)
- Regular follow-up with healthcare provider essential
References
1. FDA Prescribing Information: Qsymia (phentermine and topiramate extended-release). 2022 2. Allison DB, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial. Obesity. 2012;20(2):330-342 3. Garvey WT, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults. Int J Obes. 2014;38(5):678-687 4. Shin JH, Gadde KM. Clinical utility of phentermine/topiramate combination in the treatment of obesity. Diabetes Metab Syndr Obes. 2013;6:209-216 5. Smith SR, et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med. 2010;363(3):245-256