QSYMIA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for QSYMIA (QSYMIA).
Phentermine is a sympathomimetic amine that stimulates release of norepinephrine in the hypothalamus, reducing appetite. Topiramate enhances GABA activity and inhibits glutamate receptors, contributing to weight loss and seizure control.
| Metabolism | Phentermine: primarily metabolized by cytochrome P450 (CYP) enzymes; topiramate: metabolized by CYP3A4 and excreted unchanged in urine. |
| Excretion | Phentermine: primarily renal excretion (~90% unchanged), with minor fecal elimination (1-5%). Topiramate: ~70% renal excretion as unchanged drug, ~30% metabolized with metabolites excreted renally; total renal elimination ~85-90%, fecal ~10-15%. |
| Half-life | Phentermine: terminal half-life ~19-24 hours. Topiramate: terminal half-life ~19-25 hours (normal renal function); may be prolonged in renal impairment (up to 50 hours). Clinical context: once-daily dosing maintains therapeutic concentrations. |
| Protein binding | Phentermine: ~17-20% bound to plasma proteins (primarily albumin). Topiramate: ~13-17% bound to plasma proteins (albumin). |
| Volume of Distribution | Phentermine: Vd ~3-4 L/kg, indicating extensive tissue distribution. Topiramate: Vd ~0.6-0.9 L/kg, reflecting moderate distribution into tissues (e.g., brain, fat). Clinical meaning: large Vd of phentermine suggests accumulation in tissues; topiramate penetrates CNS readily. |
| Bioavailability | Oral: phentermine ~90-95%; topiramate ~80-100% (linear, not affected by food). |
| Onset of Action | Oral: weight loss effect typically observed within 2-4 weeks of initiation; maximal effect may take 12 weeks. Time to peak plasma concentration: phentermine ~3-4.4 hours; topiramate ~1.5-3 hours. |
| Duration of Action | Oral: duration of weight loss effect persists with continued daily dosing; discontinuation may lead to regain within 6-12 months. Plasma levels sustain for ~24 hours, supporting once-daily dosing. |
Oral: Initial dose of 3.75 mg phentermine/23 mg topiramate extended-release once daily for 14 days, then increase to 7.5 mg phentermine/46 mg topiramate extended-release once daily. If at least 3% weight loss is not achieved after 12 weeks at the 7.5 mg/46 mg dose, may escalate to 11.25 mg phentermine/69 mg topiramate extended-release for 14 days, then 15 mg phentermine/92 mg topiramate extended-release once daily. Discontinue if <5% weight loss after 12 weeks at the maximal dose.
| Dosage form | CAPSULE, EXTENDED RELEASE |
| Renal impairment | Contraindicated in GFR <30 mL/min/1.73 m2. For moderate renal impairment (eGFR 30-60 mL/min/1.73 m2): maximum dose is 7.5 mg phentermine/46 mg topiramate extended-release once daily. No adjustment for mild impairment (eGFR >60 mL/min/1.73 m2). |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh class C). For moderate hepatic impairment (Child-Pugh class B): maximum dose is 7.5 mg phentermine/46 mg topiramate extended-release once daily. No dose adjustment for mild hepatic impairment (Child-Pugh class A). |
| Pediatric use | Not approved for use in pediatric patients. Safety and efficacy have not been established. |
| Geriatric use | Due to age-related decline in renal function, use with caution. Maximum dose 7.5 mg phentermine/46 mg topiramate extended-release once daily if eGFR 30-60 mL/min/1.73 m2. Avoid if eGFR <30 mL/min/1.73 m2. Monitor for cognitive impairment and electrolyte disturbances. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for QSYMIA (QSYMIA).
| Breastfeeding | Contraindicated in breastfeeding. Excreted in milk: topiramate M/P ratio ~0.86, phentermine M/P unknown. Potential for infant sedation, poor feeding, growth impairment. Use alternative therapy if breastfeeding. |
| Teratogenic Risk | Pregnancy Category X. Contraindicated in pregnancy due to known teratogenicity of topiramate. First-trimester exposure increases risk of oral clefts (cleft lip/palate) by 20-fold. Second/third trimester: risk of fetal growth restriction, oligohydramnios, and potential neurodevelopmental effects. Phentermine component: limited data but avoid due to maternal hypertension risks. |
■ FDA Black Box Warning
Topiramate component increases the risk of cleft lip and/or palate in infants exposed during pregnancy. Females of reproductive potential must use effective contraception, have a negative pregnancy test before starting, and monthly pregnancy tests while on therapy.
| Serious Effects |
["Pregnancy (due to topiramate teratogenicity).","Glaucoma (topiramate associated with acute angle-closure glaucoma).","Hyperthyroidism (phentermine may exacerbate).","Use of MAO inhibitors or within 14 days of stopping MAOIs (hypertensive crisis).","Known hypersensitivity to sympathomimetic amines or topiramate."]
| Precautions | ["Acute myopia and secondary angle closure glaucoma; discontinue if symptoms occur.","Mood disorders: increased risk of suicidal thoughts/behavior; monitor for depression or mood changes.","Cognitive impairment: may cause confusion, psychomotor slowing, or word-finding difficulties; caution when operating machinery.","Metabolic acidosis: topiramate can cause hyperchloremic, non-anion gap metabolic acidosis; monitor serum bicarbonate.","Hypokalemia: monitor potassium levels in patients on concomitant diuretics or potassium-losing drugs.","Kidney stones: increased risk due to topiramate; ensure adequate hydration.","Fetal toxicity: see black box warning."] |
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| Fetal Monitoring | Pregnancy test before initiation and monthly during therapy. If pregnancy occurs, immediate discontinuation and referral to obstetrics. Monitor fetal growth via ultrasound, amniotic fluid index (oligohydramnios risk), and screen for orofacial clefts if first-trimester exposure. |
| Fertility Effects | No direct evidence of impaired fertility. Topiramate may reduce oral contraceptive efficacy due to CYP3A4 induction; recommend non-hormonal contraception. Reversible menstrual irregularities possible. Contraception counseling mandatory. |