QSYMIA® (PHENTERMINE + TOPIRAMATE)

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• Qsymia
• Qsymia contains immediate-release phentermine, an appetite suppressant, and extended-release topiramate, a seizure medication that suppresses appetite in some people

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• Phentermine
• Phentermine is a sympathomimetic amine, a class of drugs that stimulates the sympathetic nervous system by mimicking the action of endogenous catecholamines (e.g. epinephrine, norepinephrine, dopamine). Its hunger-suppressing effects are believed to occur through increased norepinephrine activity in the hypothalamus. [1,3]


• Topiramate
• Topiramate is an anticonvulsant that inhibits seizure activity by augmenting GABA activity, blocking voltage-dependent sodium channels, antagonizing the AMPA/kainate subtype of the glutamate receptor, and inhibiting carbonic anhydrase. The mechanism by which topiramate promotes weight loss is not completely understood. [2]

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• Weight loss (adults)
• As an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with BMI ≥ 30 or ≥ 27 in the presence of at least one weight-related comorbidity such as hypertension, type 2 diabetes mellitus, or dyslipidemia [CONQUER trial]
• Adult BMI calculator


• Weight loss (children ≥ 12 years old)
• Pediatric patients aged 12 years and older with an initial BMI in the 95th percentile or greater standardized for age and sex [Adolescent weight-loss trial]
• Child and teen BMI calculator

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• Overview
• The two trials detailed below evaluated the effects of Qsymia® on weight loss; the CONQUER trial compared Qsymia® to placebo in obese adults, and the other study looked at its efficacy in adolescents.

• Summary
• In the CONQUER trial, Qsymia 15/92 mg caused about 10% weight loss over a year, an effect similar to that seen in a 12-week phentermine monotherapy trial (phentermine trial). In the one-year extension study, patients who continued Qsymia were able to maintain their weight loss for up to 2 years with no apparent safety issues. The EQUATE trial comparing Qsymia to phentermine and topiramate monotherapy found that Qsymia was superior to each individual drug; however, the highest phentermine dose was 15 mg/day, less than half the standard 37.5 mg/day.
• In the adolescent trial, Qsymia produced impressive weight loss, with the 15/92 mg dose achieving a 34 lb weight difference compared to placebo. The study was marred by a high dropout rate, which may have been due to the COVID-19 pandemic.
• Topiramate and phentermine are available generically as individual drugs, with GoodRX® pricing for each drug being less than $20/month. To compete with the generics, the Qsymia manufacturer has a mail-order pharmacy that offers the medication for $98 a month (Qsymia mail-order website).

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• Common side effects
• The table below shows the most commonly reported side effects in adult Qsymia trials

• Reference [4]

Side effect	Qsymia 15/92 mg	Placebo
Paresthesia	20%	2%
Dry mouth	19%	3%
Constipation	16%	6%
Upper respiratory infection	14%	13%
Headache	11%	9%
Taste perversion	9%	1%
Insomnia	9%	5%
Nasopharyngitis	9%	8%
Dizziness	9%	3%

• Metabolic acidosis
• Topiramate may cause a non-anion gap metabolic acidosis secondary to renal bicarbonate loss caused by topiramate's inhibition of carbonic anhydrase. In one-year adult trials, the incidence of bicarbonate levels < 21 mEq/L at 2 consecutive visits was 6.4% for Qsymia 7.5/46 mg, 12.8% for 15/92 mg, and 2.1% for placebo. For levels < 17 mEq/L, the incidences were 0.2%, 0.7%, and 0.1%, respectively. In adolescent trials, 60 - 70% of Qsymia-treated patients had bicarbonate levels < 21 mEg/L compared to 43% of placebo-treated patients.
• Symptoms of metabolic acidosis include hyperventilation, fatigue, decreased appetite, and in severe cases, heart arrhythmias and mental status changes. Chronic sequelae include nephrolithiasis, nephrocalcinosis, and osteomalacia, including reduced growth rates in adolescents.
• Factors that increase the risk of metabolic acidosis include renal disease, severe respiratory disorders, status epilepticus, diarrhea, surgery, ketogenic diet, and concomitant carbonic anhydrase inhibitors (e.g. acetazolamide)
• Measure electrolytes, including serum bicarbonate, before and during therapy. In trials, peak reductions in bicarbonate typically occurred within 4 weeks of titration to the assigned dose, and most levels returned to normal by 56 weeks. If persistent reductions occur, consider discontinuing Qsymia or reducing the dose.

• Increase in heart rate
• Qsymia increases the heart rate in some patients. In adult trials lasting up to one year, heart rate increases of greater than 15 bpm at any time occurred in 37.3% of Qsymia-treated patients (15/92 mg) and 26.3% of placebo-treated patients. In adolescent trials, the incidences were 42.5% and 30.4%, respectively. An 8-week adult trial showed that Qsymia increased average heart rate by 3.6 bpm compared to placebo.
• Monitor heart rate during therapy, including symptoms of tachycardia and palpitations. Use caution in patients with cardiovascular disease (e.g. arrhythmia, heart failure, coronary artery disease, stroke).

• Suicidal thoughts and behaviors
• In trials, seizure medications, including topiramate, have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
• In adolescent Qsymia trials, 1 patient (0.6%) reported suicidal thoughts that required hospitalization. Use caution in susceptible patients.

• Acute myopia and secondary angle closure glaucoma
• Topiramate has been associated with a syndrome of acute myopia with secondary angle closure glaucoma. Onset typically occurs within the first month of therapy, and cases have been reported in adults and children. Patients who complain of decreased visual acuity and/or ocular pain should be evaluated immediately. The primary treatment is discontinuation of topiramate as rapidly as possible.

• Visual field defects
• Visual field defects independent of elevated intraocular pressure have been reported in patients treated with topiramate. In trials, most defects resolved after discontinuation of topiramate. Consider discontinuing topiramate if vision problems occur at any time during therapy.

• Mood and sleep disorders
• Qsymia can cause mood and sleep disorders, including depression, anxiety, and insomnia. Use caution in susceptible patients, and consider discontinuation or dose reductions if symptoms occur.

• Cognitive impairment
• Qsymia may cause cognitive impairment, including concentration difficulties, memory issues, speech and language problems, and somnolence. Use caution when operating heavy machinery, including automobiles, especially during initiation and dose increases when adverse effects are unknown.

• Slowing of linear growth (adolescents)
• In a 56-week adolescent trial, height velocity (centimeters of height gained per year) was 1.3 - 1.4 cm/year slower in Qsymia-treated patients compared to placebo-treated patients. Monitor growth in adolescents and consider discontinuation or dose reductions in those not meeting goals.

• Increase in serum creatinine
• Topiramate may cause an increase in serum creatinine levels, with peak levels typically occurring 4 - 8 weeks after therapy initiation. In trials, serum creatinine increases ≥ 0.3 mg/dl were seen in 8.4% of Qsymia-treated patients (15/92 mg dose) and 2% of placebo-treated patients. Increases in creatinine ≥ 50% over baseline occurred in 2.8% and 0.6%, respectively. In 4-week studies, serum creatinine increases were reversible upon discontinuation. The effects of long-term use are unknown.
• Check serum creatinine levels before and during therapy, and discontinue Qsymia if persistent elevations occur

• Seizures with abrupt withdrawal
• Abrupt withdrawal of topiramate has been associated with seizures, even in individuals with no history of seizures or epilepsy. For patients receiving Qsymia 15/92 mg, it's recommended that the dose be tapered when discontinuing.

• Kidney stones
• Topiramate is a carbonic anhydrase inhibitor, which can promote kidney stone formation by reducing urinary citrate excretion and increasing urinary pH. Patients on a ketogenic diet may be at increased risk. Increasing fluid intake may help to prevent stone formation.

• Oligohidrosis (decreased sweating) and hyperthermia
• Topiramate may cause decreased sweating, leading to hyperthermia. Pediatric patients are at the greatest risk. Use caution in patients exposed to excessive heat and those taking certain medications (e.g. other carbonic anhydrase inhibitors, anticholinergics).

• Hypokalemia
• Topiramate may cause hypokalemia through the inhibition of carbonic anhydrase. In one-year adult trials, hypokalemia, defined as potassium < 3.5 mEq/L on 2 consecutive visits, occurred at the following incidences: 3.6% for Qsymia 7.5/46 mg, 4.9% for Qsymia 15/ 92 mg, and 1.1% for placebo. 88% of patients with persistent hypokalemia were receiving non-potassium-sparing diuretics.
• Monitor potassium levels during therapy, especially in those receiving diuretics

• Serious skin reactions
• Serious skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in patients receiving topiramate. Stop Qsymia for rashes that do not have an obvious alternative cause. If symptoms of SJS or TEN occur (e.g. fever, rash, lymphadenopathy, and/or facial swelling in association with other organ system involvement), Qsymia should be permanently discontinued.

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• Pregnancy
• Glaucoma
• Hyperthyroidism
• Within 14 days of a monoamine oxidase inhibitor
• Hypersensitivity to phentermine or topiramate

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• Kidney disease
• CrCl ≥ 50 ml/min: no dose adjustment necessary
• CrCl < 50 ml/min: maximum dose is 7.5/46 mg once daily
• Dialysis: DO NOT USE

• Liver disease
• Child-Pugh A: no dose adjustment necessary
• Child-Pugh B: maximum dose is 7.5/46 mg once daily
• Child-Pugh C: DO NOT USE

• Pregnancy
• DO NOT USE. Fetuses exposed to topiramate in the first trimester have an increased risk of major congenital malformations, including cleft lip, cleft palate (oral clefts), and being small for gestational age.

• Diabetes
• Qsymia-induced weight loss may lower blood sugars and increase the risk of hypoglycemia in diabetics, particularly those taking insulin and/or insulin secretagogues (e.g. sulfonylureas). Diabetics should monitor blood sugars closely when taking Qsymia.

• Hypertension
• Qsymia-induced weight loss may lower blood pressure and increase the risk of hypotension in patients receiving antihypertensives. Monitor blood pressure during Qsymia therapy and adjust medications if needed.

• FD&C Yellow No. 5 (tartrazine)
• Qsymia contains FD&C Yellow No. 5 (tartrazine), which can induce allergic reactions in certain individuals, particularly those with aspirin hypersensitivity.

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• NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).


• MAO inhibitors - concomitant use of MAO inhibitors and phentermine increases the risk of hypertensive crisis; therefore, they should not be taken within 14 days of each other.
• Oral contraceptives - in a study where Qsymia was taken with a combined oral contraceptive (ethinyl estradiol 35 mcg + norethindrone 1 mg), Qsymia 15/92 mg reduced the exposure of ethinyl estradiol by 16% and increased the exposure of norethindrone by 22%. These effects are not expected to reduce efficacy, but breakthrough bleeding may occur. Patients should notify their providers about changes in menstrual bleeding.
• CNS depressants including alcohol - Qsymia may potentiate the depressive effects of other CNS depressants, including alcohol, barbiturates, benzodiazepines, and sleep medications. Patients should use caution when combining and avoid activities that require full mental alertness (e.g. driving).
• Thiazide and loop diuretics - topiramate can enhance potassium loss from thiazide and loop diuretics, increasing the risk of hypokalemia (see hypokalemia above). Monitor potassium levels regularly when combining.
• Phenytoin - in studies, concomitant phenytoin decreased topiramate levels by 48%, while phenytoin concentrations increased by 25% in some patients.
• Carbamazepine - in studies, concomitant carbamazepine decreased topiramate levels by 40%
• Valproic acid - concomitant valproic acid increases the risk of hyperammonemia, encephalopathy, and hypothermia
• Carbonic anhydrase inhibitors - topiramate is a carbonic anhydrase inhibitor, and taking it with other carbonic anhydrase inhibitors (e.g. zonisamide, acetazolamide, and dichlorphenamide) increases the risk of metabolic acidosis, hyperammonemia, and kidney stones.
• Pioglitazone (Actos®) - in studies, topiramate decreased pioglitazone exposure. The clinical relevance of this effect is unknown, so patients should increase blood glucose monitoring when combining.
• Amitriptyline - topiramate may cause large increases in amitriptyline levels in some patients. Amitriptyline dose adjustments should be based on the patient's clinical response, not serum levels.

• Metabolism and clearance
• Phentermine
• Phentermine is metabolized by p-hydroxylation on the aromatic ring and N-oxidation on the aliphatic side chain. CYP3A4 primarily metabolizes phentermine but does not show extensive metabolism.
• Topiramate
• Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (70% of dose)

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• Dosage form (capsule)
• Immediate-release phentermine : Extended-release topiramate
• 3.75 : 23 mg
• 7.5 : 46 mg
• 11.25 : 69 mg
• 15 : 92 mg

• Dosing (adults and children ≥ 12 years old)
• Starting: 3.75/23 mg once daily for 14 days then 7.5/46 mg once daily. Take in the morning with or without food.
• Maintenance: 7.5/46 - 15/92 mg once daily
• Max: 15/92 mg once daily
• Evaluate weight loss after 12 weeks on 7.5/46 mg dose. If the patient has not lost ≥ 3% of baseline body weight (or 3% of baseline BMI for children), discontinue or increase to the next highest dose by giving 11.25/69 mg for 14 days, then 15/92 mg once daily.
• After 12 weeks on 15/92 mg, if the patient has not lost ≥ 5% of baseline body weight (or 5% of baseline BMI for children) dose, discontinue Qsymia
• If weight loss exceeds 2 lbs (0.9 kg)/week in children, consider dosage reduction
• Discontinuing 15/92 mg dose: When discontinuing the 15/92 mg dose, take every other day for 1 week to avoid precipitating seizures
• The 3.75/23 mg dose is for titration purposes only
• Qsymia is a Schedule IV (CIV) controlled substance


• Kidney disease
• CrCl ≥ 50 ml/min: no dose adjustment necessary
• CrCl < 50 ml/min: maximum dose is 7.5/46 mg once daily
• Dialysis: DO NOT USE


• Liver disease
• Child-Pugh A: no dose adjustment necessary
• Child-Pugh B: maximum dose is 7.5/46 mg once daily
• Child-Pugh C: DO NOT USE

• Cost
• Topiramate and phentermine are available generically as individual drugs, with GoodRX® pricing for each drug being less than $20/month. To compete with the generics, the Qsymia manufacturer has a mail-order pharmacy that offers the medication for $98 a month (Qsymia mail-order website).

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• OBS
  Safety and Effectiveness of Longer-Term Phentermine Use: Clinical Outcomes from an Electronic Health Record Cohort, Obesity (2019) [PubMed abstract]
• Design: Cohort registry study (N=13,972) in adults with first phentermine fill between 2010 and 2015
• Exposure: Phentermine for < 3 months (referent) vs Longer use
• Primary outcomes: 1. Percent weight loss 2. CVD or death
• Results:
• In multivariable models, longer-term users of phentermine experienced more weight loss; patients using continuously for > 12 months lost 7.4% more than the referent group at 24 months (P < 0.001). The composite CVD or death outcome was rare (0.3%, 41 events), with no significant difference in hazard ratios between groups.
• Findings: Greater weight loss without increased risk of incident CVD or death was observed in patients using phentermine monotherapy for longer than 3 months. Despite the limitations of the observational design, this study supports the effectiveness and safety of longer-term phentermine use for low-risk individuals.

• OBS
  Cardiovascular Safety During and After Use of Phentermine and Topiramate, J Clin Endocrinol Metab (2019) [PubMed abstract]
• Design: Retrospective cohort study in patients 18 and older prescribed phentermine (PHEN) and/or topiramate (TPM)
• Exposure: Periods on the medication vs Periods off
• Primary outcome: MACE, a composite of hospitalization for acute myocardial infarction and stroke and in-hospital CV death
• Results:
• Because the outcomes are rare and the duration of medication use was brief, few events occurred. The MACE rates among current users of PHEN/TPM, fixed-dose PHEN/TPM, and PHEN were lower than those among unexposed former users. In contrast, the rate of MACE among current users of TPM was greater than among unexposed former users [incidence rate ratio: PHEN/TPM, 0.57; 95% CI, 0.19 to 1.78; fixed-PHEN/TPM, 0.24; 95% CI, 0.03 to 1.70; PHEN, 0.56; 95% CI, 0.34 to 0.91; TPM, 1.58; 95% CI, 1.33 to 1.87).
• Findings: Overall, the data indicated no increased risk of MACE for current PHEN/TPM users; however, the 95% CIs for the PHEN/TPM groups were broad, indicating that the data were compatible with a wide range of possible values.

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• Phentermine was FDA-approved in the 1950s, and topiramate was approved in 1998. Both drugs have been proven safe when prescribed appropriately.

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• 1 - Phentermine PI
• 2 - Topamax PI
• 3 - PMID 24621808 - Cardiovascular effects of phentermine and topiramate: a new drug combination for the treatment of obesity, J Hypertens (2014)
• Qsymia PI