What is the recommended titration schedule for phentermine/topiramate (Qsymia) in an adult eligible for weight‑loss therapy (BMI ≥ 30 kg/m² or ≥ 27 kg/m² with a weight‑related comorbidity)?

Phentermine/Topiramate (Qsymia) Titration Schedule

Start phentermine/topiramate ER at 3.75 mg/23 mg once daily for 14 days, then increase to 7.5 mg/46 mg daily; if weight loss is less than 3% after 12 weeks, escalate to 11.25 mg/69 mg for 14 days followed by 15 mg/92 mg daily, and discontinue if weight loss remains below 5% after an additional 12 weeks at maximum dose. 1

Initial Titration Phase

• Week 1–2: Begin with the starter dose of 3.75 mg/23 mg taken once daily in the morning. 1
• Week 3 onward: Advance to the standard maintenance dose of 7.5 mg/46 mg once daily. 1

This two-week lead-in minimizes adverse effects—particularly paresthesia, dizziness, and cognitive symptoms—that are common with topiramate initiation. 2

12-Week Efficacy Assessment

• Measure body weight at Week 12 to determine whether the patient has achieved at least 3% total body weight loss from baseline. 1
• If ≥3% weight loss: Continue 7.5 mg/46 mg daily as the maintenance dose. 1
• If <3% weight loss: Proceed to dose escalation (see below) or discontinue therapy, depending on tolerability and patient preference. 1

The 3% threshold at 12 weeks is a validated predictor of long-term response; patients who fail to meet this benchmark are unlikely to achieve clinically meaningful weight reduction with continued therapy at the standard dose. 1

Dose Escalation to Maximum Strength

• Week 13–14 (if escalating): Increase to 11.25 mg/69 mg once daily for 14 days. 1
• Week 15 onward: Advance to the maximum dose of 15 mg/92 mg once daily. 1

The 15 mg/92 mg dose produces superior weight loss compared with 7.5 mg/46 mg (mean ~10% vs. ~6–8% total body weight reduction) and should be the target dose whenever the benefit-to-risk balance remains favorable. 1, 2

Second Efficacy Checkpoint at Maximum Dose

• Reassess body weight 12 weeks after reaching 15 mg/92 mg (approximately Week 27 from initiation). 1
• If ≥5% total weight loss from baseline: Continue 15 mg/92 mg indefinitely as long as the medication is tolerated and no contraindications emerge. 1
• If <5% total weight loss: Discontinue phentermine/topiramate ER using a taper schedule (see below). 1

The 5% weight-loss threshold at maximum dose is the minimum clinically significant reduction required to improve cardiometabolic outcomes such as blood pressure, lipids, and glycemic control. 1

Discontinuation and Taper Protocol

Never stop phentermine/topiramate ER abruptly—the topiramate component requires gradual withdrawal to prevent seizure precipitation, even in patients without epilepsy. 1

• Taper schedule: Take one capsule every other day for at least 1 week before complete cessation. 1

This taper is mandatory regardless of the dose being discontinued (7.5 mg/46 mg or 15 mg/92 mg). 1

Available Formulations

Phentermine/topiramate ER is supplied in four fixed-dose combinations: 1

• 3.75 mg/23 mg (starter dose)
• 7.5 mg/46 mg (standard maintenance)
• 11.25 mg/69 mg (escalation intermediate)
• 15 mg/92 mg (maximum dose)

Monitoring Requirements Throughout Therapy

Cardiovascular Parameters

• Measure blood pressure and heart rate at every clinical visit. 1, 3
• Although phentermine is a sympathomimetic agent, pivotal trials demonstrated that blood pressure generally declined during phentermine/topiramate ER therapy (mean reductions of approximately –7 mmHg systolic and –5 mmHg diastolic), likely secondary to weight loss. 1, 3
• Heart rate increases are modest at the 7.5 mg/46 mg dose and slightly more pronounced at 15 mg/92 mg, but serious cardiovascular adverse events remain rare. 1

Pregnancy Prevention

• All women of reproductive potential require pregnancy counseling and reliable contraception before and throughout treatment. 1, 3
• Topiramate is a known teratogen (cleft lip/palate risk) and carries an FDA pregnancy category X designation. 1
• Consider monthly pregnancy testing in sexually active women who are not surgically sterile. 3

Metabolic and Renal Monitoring

• Baseline and periodic serum creatinine, electrolytes (particularly bicarbonate), and glucose are prudent, because topiramate can cause metabolic acidosis and nephrolithiasis. 1
• Patients with pre-existing kidney disease or those taking other carbonic anhydrase inhibitors require closer surveillance. 1

Common Pitfalls and Caveats

Confusing Phentermine Monotherapy with Phentermine/Topiramate ER

• The maximum phentermine dose in Qsymia is only 15 mg, which is lower than the 37.5 mg typically prescribed as phentermine monotherapy. 1
• Do not extrapolate cardiovascular safety concerns from older phentermine monotherapy data to the fixed-dose combination, which has distinct pharmacokinetics and a more favorable blood-pressure profile. 1

Misattributing "Fen-Phen" Risks to Phentermine

• Valvular heart disease and pulmonary hypertension associated with the discontinued fenfluramine-phentermine ("fen-phen") combination were caused by fenfluramine, not phentermine. 3
• Phentermine/topiramate ER does not carry these risks. 1

Failing to Taper Before Discontinuation

• Abrupt cessation of topiramate can precipitate seizures, even in individuals without epilepsy. 1
• Always use the every-other-day taper for at least 1 week. 1

Inadequate Contraception Counseling

• Topiramate reduces the efficacy of oral contraceptives containing estrogen. 1
• Women using hormonal contraception should add a barrier method or switch to a non-hormonal option (e.g., intrauterine device). 1

Special Clinical Considerations

Patients with Migraine Headaches

• Phentermine/topiramate ER should be strongly considered in patients with obesity and comorbid migraines, because topiramate is FDA-approved for migraine prophylaxis at doses up to 100 mg daily. 1
• The 92 mg topiramate dose in Qsymia provides dual benefit for weight reduction and headache prevention. 1

Patients with Type 2 Diabetes

• Phentermine/topiramate ER improves glycemic control and may necessitate downward adjustment of antidiabetic medications (particularly insulin and sulfonylureas) to prevent hypoglycemia. 2
• Monitor blood glucose closely during the first 12 weeks of therapy. 2

Patients with Controlled Hypertension

• Individuals whose blood pressure is well-controlled (systolic <140 mmHg, diastolic <90 mmHg) on antihypertensive therapy may receive phentermine/topiramate ER with intensive monitoring. 1, 3
• Blood pressure often decreases during treatment despite the sympathomimetic component. 1

Absolute Contraindications

• History of cardiovascular disease (coronary artery disease, stroke, arrhythmias, congestive heart failure). 1, 4
• Uncontrolled hypertension (systolic ≥160 mmHg or diastolic ≥100 mmHg). 1
• Pregnancy or inadequate contraception in women of childbearing potential. 1, 3
• Glaucoma (sympathomimetic effects can increase intraocular pressure). 3
• Hyperthyroidism (risk of arrhythmias and seizures). 3, 4
• Current or recent (within 14 days) use of monoamine oxidase inhibitors (risk of hypertensive crisis). 3, 4