AHFS Class:

• Anorexigenic Agents 28:20.08

Generic Name(s):

• Phentermine

• Topiramate

Phentermine hydrochloride and topiramate (phentermine/topiramate) is a fixed-combination anorexigenic agent; phentermine is a sympathomimetic amine and topiramate is an anticonvulsant agent.1

Chronic Weight Management

The fixed combination of phentermine hydrochloride and extended-release topiramate (phentermine/topiramate; Qsymia^®) is used as an adjunct to caloric restriction and increased physical activity for chronic weight management.1 Appropriate candidates for therapy include adults with pretreatment body mass index (BMI) of 30 kg/m² or greater (obese) or adults with pretreatment BMI of 27 kg/m² or greater (overweight) who have at least one weight-related comorbidity such as hypertension, type 2 diabetes mellitus, or dyslipidemia.1 In clinical studies, treatment with phentermine/topiramate resulted in substantial weight loss compared with placebo and improved some metabolic risk factors in such patients.2 However, the effects of the drug on cardiovascular morbidity and mortality have not been established.1 In addition, safety and efficacy of phentermine/topiramate in combination with other products used to promote weight loss, including prescription drugs, nonprescription (over-the-counter [OTC]) drugs, and herbal preparations, have not been established.1

Clinical practice guidelines recommend treatment for obesity in patients with excess body weight and associated health risks.5,6 A comprehensive lifestyle intervention is an essential component of therapy and should be provided to all patients; pharmacologic therapy may be considered as an adjunct to behavioral modification in patients who fail to achieve or sustain clinically meaningful weight loss (generally defined as a loss of more than 4-5% of total body weight).5,6 Response to drug therapy should be evaluated after 3-4 months of treatment; if clinically meaningful weight loss is not achieved, it is generally recommended that a new treatment plan be considered because the patient is likely not responding to the drug.5,6

The current indication for phentermine/topiramate is based principally on the results of 2 randomized, double-blind, 56-week studies (EQUIP and CONQUER) that evaluated efficacy and safety of the fixed-combination preparation in conjunction with decreased caloric intake and lifestyle modifications.1,2,3,4 The EQUIP study included obese patients with a BMI of 35 kg/m² or greater (baseline mean weight of 115-119 kg).1,3 Patients were randomized to receive phentermine 3.75 mg/topiramate 23 mg, phentermine 15 mg/topiramate 92 mg, or placebo.1,3 The CONQUER study included a broader population of obese or overweight adults (BMI of 27-45 kg/m² with the exception of diabetic patients who had no lower BMI limit) who had at least 2 weight-related comorbid conditions such as hypertension, dyslipidemia, diabetes mellitus, prediabetes, or abdominal obesity; at baseline, patients had a mean weight of about 103 kg, and approximately 50% had hypertension and 16% had type 2 diabetes mellitus.1,2,4 In this study, patients were randomized to receive phentermine 7.5 mg/topiramate 46 mg, phentermine 15 mg/topiramate 92 mg, or placebo.1 Both studies included a 4-week titration period followed by a 52-week maintenance period; the primary measure of efficacy was weight loss at 1 year, as assessed by the proportion of patients achieving a reduction in body weight of at least 5% from baseline and the mean change in weight from baseline.1

In both studies, weight loss with phentermine/topiramate therapy at 1 year was substantially greater than with placebo at all dosages evaluated.1 In addition, a substantially greater proportion of patients who received phentermine/topiramate achieved a 5% and 10% weight loss from baseline compared with those who received placebo.1 The mean reduction in weight from baseline ranged from 5.1-10.9% across both studies in a dose-dependent manner.1,3,4 In these studies, improvements in several metabolic risk factors associated with obesity also were observed with phentermine/topiramate therapy compared with placebo, including decreased blood pressure, decreased waist circumference, improved lipid concentrations, and improved glycemic control.1,3,4 The most pronounced metabolic changes occurred in patients with preexisting comorbid conditions at baseline.1,2,4 Weight loss and metabolic improvements were sustained for up to 2 years in a placebo-controlled, double-blind, 52-week extension of the CONQUER study (SEQUEL).8 A limitation of these studies was a high drop-out rate (40% in EQUIP and 31% in CONQUER); however, this was generally consistent with the drop-out rates observed in other obesity studies.1,2,3,4,7 Another limitation was a lack of diversity in the overall study population, which consisted mostly of females (approximately 70-83%) and Caucasian patients (approximately 80-86%).1,2,3,4

Compared with other pharmacologic weight-reducing agents, phentermine/topiramate appears to be associated with greater weight loss, but a higher rate of weight regain.5,7 Additional studies are needed to evaluate the long-term safety and efficacy of the fixed-combination preparation.2,5

General

Restricted Distribution

Because of the teratogenic risk associated with phentermine/topiramate therapy, the fixed-combination preparation is available through a limited distribution program under the Qsymia REMS.1 Only certified pharmacies may distribute the drug.1 Additional information is available at www.qsymiaREMS.com or 1-888-998-4887.1

Administration

Phentermine/topiramate is administered orally as capsules once daily in the morning with or without food.1 (See Description.) Administration in the evening is not recommended to avoid insomnia.1

Patients receiving phentermine/topiramate should be monitored for possible worsening of depression, suicidality, or unusual changes in behavior during therapy.1 (See Suicidality Risk under Cautions: Warnings/Precautions.)

Dosage

Phentermine/topiramate is commercially available as capsules containing immediate-release phentermine hydrochloride and extended-release topiramate in various fixed-dose combinations.1 Dosage is expressed in terms of the dose of phentermine (as the free base) and dose of topiramate.1

Chronic Weight Management

The recommended initial adult dosage of phentermine/topiramate as an adjunct to diet and physical activity for chronic weight management is 1 capsule (phentermine 3.75 mg/topiramate 23 mg) once daily in the morning for 14 days; dosage should then be increased to the recommended dosage of 1 capsule (phentermine 7.5 mg/topiramate 46 mg) once daily.1 Response should be evaluated after 12 weeks of treatment at a dosage of phentermine 7.5 mg/topiramate 46 mg once daily; if a 3% weight loss has not been achieved, the drug should be discontinued or dosage should be increased.1 If a decision is made to escalate the dosage, the manufacturer recommends an increase to 1 capsule (phentermine 11.25 mg/topiramate 69 mg) once daily for 14 days, followed by an increase to 1 capsule (phentermine 15 mg/topiramate 92 mg) once daily.1 Response should be evaluated after 12 weeks of treatment at a dosage of phentermine 15 mg/topiramate 92 mg once daily; if a 5% weight loss has not been achieved, the drug should be discontinued as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.1 The maximum recommended dosage is phentermine 15 mg/topiramate 92 mg once daily.1

Discontinuance of therapy should be done gradually to prevent precipitation of seizures.1 In patients receiving a dosage of phentermine 15 mg/topiramate 92 mg, treatment should be discontinued by taking 1 dose every other day for at least 1 week prior to withdrawing therapy.1

Special Populations

In patients with moderate hepatic impairment, dosage should not exceed 7.5 mg of phentermine and 46 mg of extended-release topiramate once daily.1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

No dosage adjustment is necessary in patients with mild renal impairment.1 In patients with moderate (creatinine clearance 30-50 mL/minute) or severe (creatinine clearance less than 30 mL/minute) renal impairment, dosage should not exceed 7.5 mg of phentermine and 46 mg of extended-release topiramate once daily.1 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Contraindications

Phentermine/topiramate is contraindicated in patients with glaucoma, hyperthyroidism, or known hypersensitivity or idiosyncrasy to sympathomimetic amines.1

Use of phentermine/topiramate also is contraindicated during pregnancy and also during or within 14 days after administration of a monoamine oxidase (MAO) inhibitor.1 (See Drug Interactions: Monoamine Oxidase Inhibitors.)

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

Phentermine/topiramate can cause fetal harm.1 Data from pregnancy registries and epidemiology studies indicate that infants exposed to topiramate in utero (during first trimester of pregnancy) have an increased risk of oral cleft birth defects compared with infants with no such exposure.1 Topiramate also has demonstrated developmental toxicity, including teratogenicity and embryotoxicity, in multiple species of animals.1 Structural malformations, including craniofacial defects and reduced fetal weights, have occurred in the offspring of pregnant animals administered topiramate at clinically relevant dosages.1 (See Pregnancy under Cautions, in Topiramate 28:12.92.) Animal reproduction studies have not been conducted with phentermine.1 In pregnant animals exposed to the combination phentermine/topiramate preparation, reduced fetal body weight and reduced maternal weight gain were observed; there was also evidence of structural malformations consistent with those observed with topiramate alone.1

If phentermine/topiramate is used during pregnancy or if a patient becomes pregnant while taking the drug, treatment should be discontinued immediately and the patient should be apprised of the potential fetal hazard.1 Females of reproductive potential should have a negative pregnancy test prior to initiating phentermine/topiramate and monthly thereafter while taking the fixed-combination preparation.1 Females of reproductive potential also should use effective contraception during phentermine/topiramate therapy.1

Increased Heart Rate

Phentermine/topiramate can cause an increase in resting heart rate.1 In clinical studies, a higher frequency of patients receiving phentermine/topiramate experienced heart rate elevations from baseline of more than 5, 10, 15, and 20 beats per minute (bpm) compared with those receiving placebo.1 The clinical importance of this heart rate elevation is unclear, particularly for patients with cardiovascular and cerebrovascular disease (e.g., those with a history of myocardial infarction [MI] or stroke in the previous 6 months, life-threatening arrhythmias, or congestive heart failure).1

Regular measurement of resting heart rate is recommended in all patients taking phentermine/topiramate, especially those with cardiovascular or cerebrovascular disease or when initiating therapy or increasing dosage.1 (See Advice to Patients.) In patients who experience a sustained increase in resting heart rate during phentermine/topiramate therapy, the dosage should be reduced or fixed-combination preparation should be discontinued.1 Phentermine/topiramate has not been studied in patients with recent or unstable cardiovascular or cerebrovascular disease and therefore is not recommended in such patients.1

Suicidality Risk

The risk of suicidal thoughts or behavior is increased in patients receiving anticonvulsants, including topiramate, a component of phentermine/topiramate.1 An analysis of 199 placebo-controlled studies involving 11 different anticonvulsants in patients with epilepsy, psychiatric disorders, or other conditions found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%).1 This increased suicidality risk was observed as early as 1 week after beginning therapy.1 Because most of these studies did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior with anticonvulsant treatment beyond 24 weeks is not known.1 Although patients treated with an anticonvulsant for epilepsy, psychiatric disorders, and other conditions were all found to have an increased suicidality risk compared with those receiving placebo, the relative risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.1

Patients receiving phentermine/topiramate should be closely monitored for the emergence or worsening of suicidal thoughts and behavior.1 If any such symptoms emerge during therapy, the fixed-combination preparation should be discontinued.1 Phentermine/topiramate should be avoided in patients with a history of suicide attempts or active suicidal ideation.1 (See Advice to Patients.)

Acute Myopia and Secondary Angle Closure Glaucoma

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate.1 This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma.1 Symptoms include acute onset of decreased visual acuity and/or ocular pain and typically occur within 1 month of initiating topiramate therapy.1 Ophthalmologic findings may include myopia, anterior chamber shallowing, ocular hyperemia (redness), and increased intraocular pressure; mydriasis may or may not be present.1 Phentermine/topiramate should be immediately discontinued if any such symptoms develop.1 Elevated intraocular pressure of any etiology, if left untreated, can lead to serious adverse events including permanent loss of vision.1

Mood and Sleep Disorders

Phentermine/topiramate can cause mood disorders, including depression, anxiety, and insomnia.1 Patients with a history of depression may be at increased risk of recurrent depression or other mood disorders while receiving the drug.1 In most cases, symptoms resolved spontaneously or following discontinuance of the fixed-combination preparation.1

If clinically important or persistent mood or sleep disorders occur, dosage reduction or discontinuance of phentermine/topiramate should be considered.1 If patients exhibit symptoms of suicidal ideation or behavior, the fixed-combination preparation should be discontinued.1

CNS Effects

Phentermine/topiramate can cause cognitive dysfunction (e.g., impairment of concentration, attention, memory, speech, or language, particularly word-finding difficulties).1 Rapid titration or high initial dosages may be associated with higher rates of adverse cognitive events.1

Because of the potential for impaired cognitive function, patients should be cautioned about operating hazardous machinery, including driving a car, until they are reasonably certain that phentermine/topiramate does not affect them adversely.1 If cognitive dysfunction persists, dosage reduction or withdrawal of phentermine/topiramate should be considered.1

Concomitant use of phentermine/topiramate with alcohol or CNS depressant drugs (e.g., barbiturates, benzodiazepines, hypnotics) may potentiate CNS depression or other centrally mediated effects of these agents such as dizziness, adverse cognitive reactions, drowsiness, lightheadedness, impaired coordination, and somnolence.1 The manufacturer recommends that concomitant use of alcohol and phentermine/topiramate be avoided.1

Metabolic Acidosis

Hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate concentrations below the normal reference range in the absence of chronic respiratory alkalosis) has been reported in patients receiving phentermine/topiramate and is a known adverse effect of topiramate.1 The bicarbonate lowering effects of topiramate may be increased in patients with predisposing factors for acidosis (e.g., renal disease, severe respiratory disorders, status epilepticus, diarrhea, surgery, ketogenic diet).1 Manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor.1 Concomitant use of phentermine/topiramate and a carbonic anhydrase inhibitor (e.g., zonisamide, acetazolamide, dichlorphenamide) may increase the severity of metabolic acidosis and should be avoided.1 (See Drug Interactions: Carbonic Anhydrase Inhibitors.)

Because chronic, untreated metabolic acidosis may have potentially serious consequences (e.g., increased risk of nephrolithiasis or nephrocalcinosis, development of osteomalacia and/or osteoporosis with an increased risk for fractures), serum bicarbonate concentrations should be measured at baseline and during phentermine/topiramate therapy.1 In clinical studies, peak reductions in serum bicarbonate concentrations were observed at 4 weeks and normalized by 56 weeks without any change in therapy.1 If persistent metabolic acidosis occurs during phentermine/topiramate therapy, the manufacturer states that dosage should be reduced or therapy should be discontinued.1

Renal Effects

Phentermine/topiramate can increase serum creatinine concentrations, reflecting a decrease in renal function.1 In clinical studies, peak increases in serum creatinine concentrations were observed after 4-8 weeks of treatment and generally declined over time but remained elevated over baseline values.1 Although these changes appeared to be reversible with treatment discontinuance, the effect of chronic phentermine/topiramate therapy on renal function is not known.1

Serum creatinine concentrations should be measured at baseline and during phentermine/topiramate therapy.1 If persistent elevations in serum creatinine concentrations occur, dosage should be reduced or the drug should be discontinued. 1

Hypoglycemia in Patients with Type 2 Diabetes Mellitus

Weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus receiving treatment with insulin and/or sulfonylureas.1 Phentermine/topiramate has not been studied in combination with insulin.1 If phentermine/topiramate is used in patients with type 2 diabetes mellitus, blood glucose concentration should be measured at baseline and during treatment.1

To minimize risk of hypoglycemia, dosage reduction of non-glucose-dependent antidiabetic agents should be considered.1 If hypoglycemia develops during phentermine/topiramate therapy, the patient's antidiabetic regimen should be adjusted accordingly.1

Hypotension in Patients Receiving Antihypertensive Agents

Weight loss may increase the risk of hypotension in patients receiving antihypertensive therapy.1 In such patients, blood pressure should be measured prior to initiating phentermine/topiramate and during therapy.1 If symptoms of hypotension (e.g., dizziness, lightheadedness, syncope) occur, the patient's antihypertensive regimen should be adjusted accordingly.1

Discontinuance of Therapy

Abrupt withdrawal of topiramate has precipitated seizures in individuals without a history of seizures or epilepsy.1 If immediate discontinuance of phentermine/topiramate is medically necessary, appropriate monitoring is recommended.1 In patients discontinuing therapy from the maximum dosage of phentermine 15 mg/topiramate 92 mg, the dosage should be gradually tapered as recommended to reduce the risk of seizures.1 (See Dosage and Administration: Dosage.)

Kidney Stones

Formation of kidney stones has been reported in patients receiving phentermine/topiramate in clinical trials.1 Because topiramate is a carbonic anhydrase inhibitor, the drug may promote kidney stone formation by reducing urinary citrate excretion and increasing urinary pH.1 Risk of kidney stones may be increased in patients on a ketogenic diet or receiving concomitant therapy with carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide, methazolamide).1 (See Drug Interactions: Carbonic Anhydrase Inhibitors.)

To minimize the risk of kidney stone formation, patients receiving phentermine/topiramate should be instructed to increase fluid intake, which can increase urinary output and reduce the concentration of substances involved in stone formation.1

Oligohidrosis and Hyperthermia

Oligohidrosis has been reported in association with topiramate, a component of phentermine/topiramate, and has rarely resulted in hospitalization.1 Manifestations included decreased sweating and elevated body temperatures.1 Some of the cases occurred with use of topiramate after exposure to elevated environmental temperatures.1

Patients receiving phentermine/topiramate should be advised to monitor for decreased sweating and increased body temperature during physical activity, especially in hot weather.1 Caution is advised when phentermine/topiramate is used with other drugs that can also predispose patients to heat-related disorders (e.g., other carbonic anhydrase inhibitors, drugs with anticholinergic activity).1

Hypokalemia

Phentermine/topiramate can cause hypokalemia because of the potential for topiramate to inhibit carbonic anhydrase activity.1 Concomitant use with non-potassium sparing diuretics may further potentiate the potassium-wasting effects of these drugs and increase the risk of hypokalemia.1 (See Drug Interactions: Diuretics.) Patients receiving phentermine/topiramate should be monitored for hypokalemia.1

Laboratory Monitoring

Phentermine/topiramate was associated with changes in several laboratory parameters in clinical studies.1 The manufacturer recommends that a blood chemistry panel, including bicarbonate, creatinine, potassium, and glucose concentrations, be obtained at baseline and periodically during treatment.1

Abuse Potential and Dependence

Phentermine/topiramate is subject to control as a schedule IV (C-IV) drug.1 The phentermine component is chemically and pharmacologically similar to amphetamines, which have been extensively abused for their CNS stimulant effects.1 The potential for abuse of phentermine should be considered when determining whether to use phentermine/topiramate as part of a weight reduction program.1

The potential for phentermine/topiramate to cause physical dependence has not been systematically evaluated.1 However, limited information is available regarding the dependence potential of the individual components.1 Abrupt discontinuance of topiramate has been associated with seizures in patients without a history of seizures or epilepsy.1 Abrupt discontinuance of phentermine following prolonged administration of high dosages has resulted in extreme fatigue, depression, and sleep EEG changes.1 In situations where rapid withdrawal of phentermine/topiramate is required, appropriate medical monitoring is recommended.1

Specific Populations

Pregnancy

Phentermine/topiramate is contraindicated in pregnant women.1 Use of the drug can cause fetal harm and weight loss, and offers no potential benefit to a pregnant woman.1 If a patient becomes pregnant while taking phentermine/topiramate, the drug should be discontinued immediately and the patient should be apprised of the potential fetal hazard.1

Topiramate can cause metabolic acidosis.1 The effect of topiramate-induced metabolic acidosis has not been specifically studied during pregnancy; however, metabolic acidosis from other causes during pregnancy can result in decreased fetal growth, decreased fetal oxygenation, and fetal death, and also may affect the ability of the fetus to tolerate labor.1

A pregnancy test should be performed in women of childbearing potential prior to initiating phentermine/topiramate therapy and monthly thereafter to confirm that the patient is not pregnant.1 Women of childbearing potential should use effective contraception during phentermine/topiramate therapy.1

A Qsymia Pregnancy Surveillance Program has been established to monitor the maternal-fetal outcomes of pregnancies that occur during phentermine/topiramate therapy.1 Women who become pregnant while receiving phentermine/topiramate should be encouraged to report their pregnancy to the surveillance program by calling 888-998-4887.1

Lactation

Topiramate is distributed into human milk.1 Phentermine also may be present in human milk because the drug is pharmacologically and structurally similar to amphetamines, which can distribute into human milk.1 Because of the potential for serious adverse reactions from phentermine/topiramate in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother.1

Pediatric Use

Safety and efficacy of phentermine/topiramate in pediatric patients younger than 18 years of age have not been established; use of the drug is not recommended in such patients.1 Serious adverse reactions reported in pediatric patients receiving topiramate, a component of phentermine/topiramate, include acute angle glaucoma, oligohidrosis and hyperthermia, metabolic acidosis, cognitive and neuropsychiatric reactions, hyperammonemia and encephalopathy, and kidney stones.1

Geriatric Use

In clinical trials of phentermine/topiramate, 254 (7%) of the patients were 65 years of age and older.1 No overall differences in safety or effectiveness were observed between these patients and younger adults, but greater sensitivity of some older individuals cannot be ruled out.1

Clinical studies of phentermine/topiramate did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adults.1 In general, dosage selection in geriatric patients should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.1

Hepatic Impairment

In patients with mild (Child-Pugh score 5-6) or moderate (Child-Pugh score 7-9) hepatic impairment, exposure to phentermine was higher compared with healthy individuals.1 Dosage adjustment of phentermine/topiramate is recommended in patients with moderate hepatic impairment.1 (See Dosage and Administration: Special Populations.)

Phentermine/topiramate has not been studied in patients with severe hepatic impairment (Child-Pugh score 10-15); use of the drug should be avoided in such patients.1

Renal Impairment

Both phentermine and topiramate are eliminated by renal excretion.1 Therefore, exposure to the drugs may be higher in patients with moderate (creatinine clearance of 30 to less than 50 mL/minute) or severe (creatinine clearance less than 30 mL/minute) renal impairment.1 Dosage adjustment of phentermine/topiramate is recommended in such patients.1 (See Dosage and Administration: Special Populations.)

Phentermine/topiramate has not been studied in patients with end-stage renal disease on dialysis; use of the drug should be avoided in such patients.1

Common Adverse Effects

The most common adverse effects of phentermine/topiramate (reported at an incidence of at least 5%) in clinical studies include paresthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth.1

Phentermine does not inhibit cytochrome P-450 (CYP) 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 and does not induce CYP1A2, 2B6, or 3A4.1 Phentermine is not a substrate of P-glycoprotein (P-gp).

Topiramate is a mild inhibitor of CYP2C19, but does not inhibit CYP1A2, 2A6, 2B6, 2C9, 2D6, 2E1, or 3A4/5.1 Topiramate is a mild inducer of CYP3A4.1 Topiramate is not a substrate of P-gp.1

Amitriptyline

In healthy individuals, concomitant administration of topiramate and amitriptyline increased both peak plasma concentrations and area under the plasma concentration-time curve (AUC) of amitriptyline by 12%.1 Because some patients may experience a large increase in amitriptyline concentrations in the presence of topiramate, any adjustments in amitriptyline dosage should be made according to the patient's clinical response and not on the basis of plasma concentrations.1

Anticholinergic Agents

When phentermine/topiramate is used concomitantly with anticholinergic agents, there is a potential for additive risk of hyperthermia.1 (See Oligohidrosis and Hyperthermia under Cautions: Warnings/Precautions.)

Anticonvulsant Agents

Clinically important decreases in plasma concentrations of topiramate have been observed in patients receiving concomitant therapy with phenytoin or carbamazepine.1 Plasma concentrations of topiramate were reduced by 48% when administered concomitantly with phenytoin; plasma concentrations of phenytoin increased by 25% in some patients (generally in those receiving a twice-daily dosage regimen of phenytoin) and did not change substantially in others who received these drugs in combination.1 Concomitant administration of carbamazepine and topiramate decreased plasma concentrations of topiramate by 40%, but did not substantially alter plasma concentrations of carbamazepine or its active metabolite, carbamazepine-10,11-epoxide.1

Concomitant administration of topiramate and valproic acid decreased topiramate plasma concentrations by 14% and valproic acid plasma concentrations by 11%.1 Concomitant use of topiramate and valproic acid also has been associated with hyperammonemia with and without encephalopathy, and also with hypothermia (with and without hyperammonemia).1 (See Hyperammonemia and Encephalopathy (without and with Concomitant Valproic Acid), under Cautions in Topiramate 28:12.92.) The manufacturer states that it may be prudent to measure blood ammonia concentrations in patients who develop hypothermia or encephalopathy during concomitant therapy.1

Concomitant administration of topiramate and phenobarbital or primidone altered plasma concentrations of the concomitantly administered anticonvulsant by less than 10%; the effects of phenobarbital or primidone on the pharmacokinetics of topiramate were not evaluated.1

Plasma concentrations of lamotrigine were altered by less than 10% and plasma topiramate concentrations were decreased by 13% when the drugs were administered concomitantly.1

Antidiabetic Agents

Glyburide

Concomitant administration of topiramate and glyburide in patients with type 2 diabetes mellitus decreased steady-state peak plasma concentrations and AUC of glyburide by 22 and 25%, respectively.1 Systemic exposure of the active metabolites, 4- trans -hydroxyglyburide and 3- cis -hydroxyglyburide, also were reduced by 13 and 15%, respectively.1 Steady-state pharmacokinetics of topiramate were not affected by concomitant glyburide administration.1

Metformin

Concomitant administration of phentermine/topiramate and metformin increased peak plasma concentrations and AUC of metformin by 16 and 23%, respectively; pharmacokinetics of phentermine/topiramate were altered to only a slight extent.1

Pioglitazone

Decreased systemic exposure to pioglitazone and its active metabolites has been observed when the drug was used concomitantly with topiramate; however, the clinical importance is not known.1 Patients should be monitored for adequate glycemic control when pioglitazone is added to phentermine/topiramate therapy or vice versa.1

Sitagliptin

Concomitant administration of phentermine/topiramate and sitagliptin did not substantially alter pharmacokinetics of either drug.1

Carbonic Anhydrase Inhibitors

Concomitant use of phentermine/topiramate and carbonic anhydrase inhibitors (e.g., acetazolamide, dichlorphenamide, zonisamide) may increase the severity of metabolic acidosis and also may increase the risk of kidney stone formation and hyperthermia.1 (See Metabolic Acidosis, Kidney Stones, and also see Oligohidrosis and Hyperthermia under Cautions: Warnings/Precautions.) Such concomitant therapy should be avoided.1 If phentermine/topiramate is administered concomitantly with a carbonic anhydrase inhibitor in patients with a predisposing condition for metabolic acidosis, the patient should be monitored for the appearance or worsening of metabolic acidosis.1

CNS Depressants

Concomitant use of phentermine/topiramate with CNS depressants (e.g., alcohol, barbiturates, benzodiazepines, hypnotics) may potentiate CNS depression or other CNS effects (e.g., dizziness, drowsiness, impaired coordination, somnolence) of the drugs.1 Patients receiving such concomitant therapy should be advised of the potential for additive CNS effects.1 Patients should be advised not to consume alcohol while taking phentermine/topiramate.1

Digoxin

Serum digoxin AUC was decreased by 12% with concomitant use of topiramate in a single-dose study; however, the clinical importance of this interaction is unknown.1

Dihydroergotamine

Concomitant administration of topiramate and a single dose of dihydroergotamine (1 mg subcutaneously) in healthy individuals did not affect the pharmacokinetics of either drug.1

Diltiazem

Concomitant administration of topiramate and diltiazem decreased peak plasma concentrations and AUC of diltiazem by 10 and 25%, respectively.1 Systemic exposure to desacetyl diltiazem also was decreased, but there was no effect on N -desmethyl diltiazem.1 Diltiazem increased peak plasma concentrations and AUC of topiramate by 16 and 19%, respectively.1

Diuretics

Concomitant use of phentermine/topiramate with non-potassium sparing diuretics (e.g., loop diuretics, hydrochlorothiazide) may potentiate the potassium-wasting effects of these diuretics.1 Patients should be monitored for hypokalemia; potassium concentrations should be measured prior to and during treatment.1

In healthy individuals, peak plasma concentrations and AUC of topiramate increased by 27 and 29%, respectively, following concomitant administration of hydrochlorothiazide.1 Steady-state pharmacokinetics of hydrochlorothiazide were not substantially altered by topiramate.1

Haloperidol

Pharmacokinetics of haloperidol were not affected by topiramate in healthy individuals.1

Lithium

Although the pharmacokinetics of lithium were not affected during concurrent administration of topiramate at a dosage of 200 mg daily, peak plasma concentrations and AUC of lithium increased by 27 and 26%, respectively, during concurrent administration of topiramate dosages up to 600 mg daily.1 Serum lithium concentrations should be monitored in patients receiving concurrent lithium and high-dose topiramate therapy.1

Monoamine Oxidase Inhibitors

Concomitant use of phentermine during and within 14 days following administration of a monoamine oxidase (MAO) inhibitor is contraindicated because of the risk of hypertensive crisis.1

Oral Contraceptives

When phentermine/topiramate was administered concomitantly with an oral contraceptive containing 35 mcg of ethinyl estradiol and 1 mg of norethindrone, systemic exposure of ethinyl estradiol decreased by 16% and exposure of norethindrone increased by 16%.1 Although the effect of the pharmacokinetic interaction on contraceptive efficacy was not evaluated, an increased risk of pregnancy is not anticipated.1 However, irregular bleeding may occur as a result of altered concentrations of the estrogen and progestin components.1 Patients receiving phentermine/topiramate should be advised not to discontinue oral contraceptives if spotting occurs, but to notify their clinician if the spotting is troublesome.1

Propranolol

Concomitant administration of topiramate and propranolol in healthy individuals did not affect the pharmacokinetics of either drug.1

Risperidone

Risperidone systemic exposure was decreased by 16 and 33% during concomitant topiramate therapy at dosages of 250 and 400 mg daily, respectively; no alterations of 9-hydroxyrisperidone (active metabolite) concentrations were observed.1 Concurrent administration resulted in increased peak plasma concentrations and AUC of topiramate by 14 and 12%, respectively.1 There were no clinically important changes in the systemic exposure of risperidone plus 9-hydroxyrisperidone or of topiramate; therefore, this interaction is unlikely to be clinically important.1

Sumatriptan

In healthy individuals, topiramate did not affect the pharmacokinetics of single-dose sumatriptan.1

Venlafaxine

Concomitant administration of topiramate and venlafaxine in healthy individuals did not affect the pharmacokinetics of venlafaxine, O-desmethylvenlafaxine, or topiramate.1

Description

Phentermine hydrochloride and topiramate (phentermine/topiramate; Qsymia^®) is a fixed-combination preparation containing immediate-release phentermine hydrochloride and extended-release topiramate.1,2 Phentermine is a sympathomimetic amine that is structurally and pharmacologically related to amphetamine, and topiramate is an anticonvulsant agent.1 The fixed-combination preparation is an anorexigenic agent.1,2

The exact mechanism of action of phentermine/topiramate in chronic weight management is not known.1 The effects of phentermine are likely mediated by the release of catecholamines in the hypothalamus, resulting in reduced appetite and decreased food consumption, but other metabolic effects also may be involved.1,2 The mechanism of topiramate may be due to its effects on both appetite suppression and satiety enhancement induced by a combination of pharmacologic effects, including augmentation of gamma-aminobutyrate (GABA) neurotransmitter activity, modulation of voltage-gated ion channels, inhibition of the AMPA/kainite subtype of excitatory glutamate receptors, and inhibition of carbonic anhydrase.1,2 Several neuronal and peripheral pathways are involved in the regulation of food intake, satiety, and energy homeostasis; therefore, the combination of phentermine and topiramate may produce additive or synergistic effects.3,4 The fixed-combination preparation contains lower doses of both drugs than usually prescribed when the drugs are used alone; such dose combinations are intended to provide the greatest level of efficacy while improving tolerability.3,5

Following single-dose, oral administration of phentermine 15 mg (immediate-release)/topiramate 92 mg (extended-release) as the fixed-combination capsule, peak plasma concentrations of phentermine and topiramate were achieved in 6 and 9 hours, respectively.1 Both the phentermine and topiramate components exhibited approximately dose-proportional pharmacokinetics over the fixed-combination dose range of phentermine 3.75 mg/topiramate 23 mg to phentermine 15 mg/topiramate 100 mg, and the pharmacokinetics of the drugs were not altered when administered with a high-fat meal.1 Protein-binding capacity is 17.5% for phentermine and 15-41% for topiramate.1 Phentermine is minimally metabolized by cytochrome P-450 (CYP) 3A4; approximately 70-80% of an administered dose is eliminated in urine as unchanged drug.1 The mean terminal half-life of phentermine is about 20 hours.1 Topiramate also is not extensively metabolized; approximately 70% of an administered dose is found in urine as unchanged drug.1 The mean terminal half-life of topiramate is about 65 hours.1

For additional information on the chemistry, pharmacology, and pharmacokinetics of phentermine or topiramate, see Phentermine 28:20.08.04 or Topiramate 28:12.92.

Advice to Patients

Importance of advising patients that phentermine/topiramate is indicated for chronic weight management in conjunction with a reduced-calorie diet and increased physical activity.1

Importance of advising patients that phentermine/topiramate is only available through a network of certified pharmacies.1 Instruct patients on how to access the fixed-combination preparation through these pharmacies.1 Additional information may be obtained at www.QsymiaREMS.com or at 1-888-998-4887.1

Importance of advising patients to take phentermine/topiramate as prescribed.1

Risk of fetal harm.1 Advise patients to avoid getting pregnant while taking phentermine/topiramate; pregnancy testing is recommended prior to initiating the fixed combination and monthly thereafter during therapy.1,1 Advise patients about effective methods of contraception, as well as the importance of using effective contraception consistently during phentermine/topiramate therapy.1 Advise females who become pregnant during phentermine/topiramate therapy to immediately discontinue the fixed combination and inform their clinician.1

Risk of increased heart rate; importance of advising patients to inform their clinician if they experience sustained periods of heart pounding or racing while at rest.1

Anticonvulsants, including topiramate, may increase the risk of suicidal thoughts or behavior.1 Importance of patients, caregivers, and family members being alert to and immediately reporting emergence or worsening of depression, any unusual changes in mood or behavior, or emergence of suicidal thoughts, behavior, or thoughts of self harm.1

Risk of acute myopia and secondary angle closure glaucoma.1 Advise patients to report symptoms of severe and persistent eye pain or significant changes in vision to their clinician.1

Risk of CNS/cognitive effects such as dizziness, confusion, visual changes, and impaired concentration.1 Advise patients to inform their clinician if they experience any changes in attention, concentration, memory, and/or difficulty finding words.1 Advise patients not to drive or operate machinery until they have gained sufficient experience with the drug.1

Risk of metabolic acidosis.1 Advise patients to inform their clinician about any factors that can increase the risk of acidosis (e.g., prolonged diarrhea, surgery, high protein/low carbohydrate diet, and/or concomitant medications such as carbonic anhydrase inhibitors).1

Importance of informing patients that weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus who are being treated with insulin and/or insulin secretagogues (e.g., sulfonylureas).1 Advise patients with type 2 diabetes mellitus on antidiabetic therapy to monitor their blood glucose levels and report symptoms of hypoglycemia to their clinician.1

Importance of advising patients that concomitant use of alcohol or CNS depressants (e.g., barbiturates, benzodiazepines, sleep medications) with phentermine/topiramate may potentiate CNS depression or other centrally-mediated effects of these agents such as dizziness, cognitive adverse reactions, drowsiness, lightheadedness, impaired coordination, and somnolence.1 Advise patients not to drink alcohol while taking phentermine/topiramate.1

Importance of advising patients not to discontinue phentermine/topiramate therapy without consulting with their clinician.1 Abrupt withdrawal has been associated with seizures in patients without a history of seizures or epilepsy.1

Risk of kidney stone formation.1 Advise patients to increase fluid intake to increase urinary output, which can decrease the concentration of substances involved in kidney stone formation.1 Advise patients to report symptoms of severe side or back pain and/or blood in their urine to their clinician.1

Importance of informing patients that oligohidrosis (decreased sweating) and elevations in body temperature above normal have been reported in association with the use of topiramate.1 Advise patients to monitor for decreased sweating and increased body temperature during physical activity, especially in hot weather.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs or herbal supplements, as well as any concomitant illnesses.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It isessential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Vivus. Qsymia^® (phentermine and topiramate extended-release) capsules prescribing information. Campbell, CA; 2018 Mar. [Web]

2. Smith SM, Meyer M, Trinkley KE. Phentermine/topiramate for the treatment of obesity. Ann Pharmacother . 2013; 47:340-9. [PubMed 23482732]

3. Allison DB, Gadde KM, Garvey WT et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring) . 2012; 20:330-42. [PubMed 22051941][PubMedCentral]

4. Gadde KM, Allison DB, Ryan DH et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet . 2011; 377:1341-52. [PubMed 21481449]

5. Bray GA, Frühbeck G, Ryan DH et al. Management of obesity. Lancet . 2016; 387:1947-56. [PubMed 26868660]

6. Ryan DH, Kahan S. Guideline Recommendations for Obesity Management. Med Clin North Am . 2018; 102:49-63. [PubMed 29156187]

7. Dong Z, Xu L, Liu H et al. Comparative efficacy of five long-term weight loss drugs: quantitative information for medication guidelines. Obes Rev . 2017; 18:1377-1385. [PubMed 29024559]

8. Garvey WT, Ryan DH, Look M et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr . 2012; 95:297-308. [PubMed 22158731][PubMedCentral]