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Phentermine and Topiramate (Monograph)

Drug class: Anorexigenic Agents

Medically reviewed by Drugs.com on Jun 10, 2024. Written by ASHP.

Warning

Risk Evaluation and Mitigation Strategy (REMS):

FDA approved a REMS for the fixed combination of phentermine and topiramate (phentermine/topiramate; Qsymia) to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of phentermine/topiramate and consists of the following: elements to assure safe use and implementation system. See https://www.accessdata.fda.gov/scripts/cder/rems/.

Introduction

Anorexigenic agent; fixed combination containing phentermine (sympathomimetic amine) and topiramate (anticonvulsant agent).

Uses for Phentermine and Topiramate

Chronic Weight Management

Adjunct to caloric restriction and increased physical activity for chronic weight management; appropriate candidates for therapy include obese adults with pretreatment BMI ≥30 kg/m2 or overweight adults with pretreatment BMI ≥27 kg/m2 who have at least one weight-related comorbidity such as hypertension, type 2 diabetes mellitus, or dyslipidemia.

Effects on cardiovascular morbidity and mortality not established.

Safety and efficacy in combination with other products used to promote weight loss, including prescription drugs, nonprescription (OTC) drugs, and herbal preparations, not established.

Clinical practice guidelines recommend treatment for obesity in patients with excess body weight and associated health risks. Initiate comprehensive lifestyle intervention; may consider adjunctive pharmacologic therapy in patients who fail to achieve or sustain clinically meaningful weight loss (generally defined as loss of >4–5% of total body weight) with behavioral modification alone. Evaluate response to drug therapy after 3–4 months; if clinically meaningful weight loss not achieved, consider new treatment plan.

Phentermine and Topiramate Dosage and Administration

General

Restricted Distribution

Available only through a limited distribution program under the Qsymia REMS. Only certified pharmacies may distribute the drug. Additional information is available at www.qsymiaREMS.com or 1-888-998-4887.

Administration

Oral Administration

Administer orally as extended-release capsules once daily in the morning with or without food. (See Food under Pharmacokinetics.) Do not administer in the evening to avoid insomnia.

Dosage

Available as extended-release capsules containing immediate-release phentermine hydrochloride and extended-release topiramate in various fixed-dose combinations. Dosage is expressed in terms of dose of phentermine and dose of topiramate.

Adults

Chronic Weight Management
Oral

Initially, 1 capsule (phentermine 3.75 mg/topiramate 23 mg) once daily for 14 days, then increase to recommended dosage of phentermine 7.5 mg/topiramate 46 mg once daily.

Evaluate response after 12 weeks of treatment at a dosage of phentermine 7.5 mg/topiramate 46 mg once daily; if a ≥3% weight loss not achieved, discontinue drug or increase dosage. If a decision is made to escalate dosage, increase to phentermine 11.25 mg/topiramate 69 mg once daily for 14 days, and then to phentermine 15 mg/topiramate 92 mg once daily.

Evaluate response after 12 weeks of treatment at a dosage of phentermine 15 mg/topiramate 92 mg once daily; if a ≥5% weight loss not achieved, discontinue drug as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.

Discontinue therapy gradually to prevent precipitation of seizures. In patients receiving a dosage of phentermine 15 mg/topiramate 92 mg once daily, discontinue treatment by taking 1 dose every other day for at least 1 week prior to withdrawing therapy.

Prescribing Limits

Adults

Chronic Weight Management
Oral

Maximum recommended dosage is phentermine 15 mg/topiramate 92 mg once daily.

Special Populations

Hepatic Impairment

In patients with moderate hepatic impairment, do not exceed dosage of phentermine 7.5 mg/topiramate 46 mg once daily. Avoid use in patients with severe hepatic impairment. (See Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustment necessary in patients with mild renal impairment.

In patients with moderate (Clcr 30–50 mL/minute) or severe (Clcr <30 mL/minute) renal impairment, do not exceed dosage of phentermine 7.5 mg/topiramate 46 mg once daily. (See Renal Impairment under Cautions.)

Geriatric Patients

In general, select dosage cautiously, usually starting at the low end of the dosing range.

Cautions for Phentermine and Topiramate

Contraindications

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

Risk of fetal harm. In utero exposure to topiramate (during first trimester of pregnancy) associated with increased risk of oral cleft birth defects. Developmental toxicity (e.g., teratogenicity, embryotoxicity) demonstrated with topiramate in multiple species of animals. In animal reproduction studies using phentermine/topiramate, reduced fetal body weight, reduced maternal weight gain, and structural malformations consistent with those observed with topiramate alone reported.

If phentermine/topiramate is used during pregnancy or if a patient becomes pregnant while taking the fixed combination, discontinue treatment immediately and apprise patient of the potential fetal hazard.

In females of reproductive potential, obtain a negative pregnancy test prior to initiating therapy and monthly thereafter while receiving the fixed combination; such patients should use effective contraception during therapy.

Increased Heart Rate

Potential for increased heart rate. In clinical studies, increased heart rate reported in more patients receiving phentermine/topiramate than placebo; however, clinical importance not known, particularly in patients with cardiovascular or cerebrovascular disease (e.g., those with history of MI or stroke in previous 6 months, life-threatening arrhythmias, or CHF).

Measure resting heart rate on a regular basis, especially in patients with cardiovascular or cerebrovascular disease or when initiating therapy or increasing dosage. (See Advice to Patients.)

In patients who experience a sustained increase in resting heart rate during phentermine/topiramate therapy, reduce dosage or discontinue drug.

Not studied in patients with recent or unstable cardiovascular or cerebrovascular disease; therefore, not recommended in such patients.

Suicidality Risk

Increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants, including topiramate; risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%). Increased suicidality risk was observed as early as 1 week after initiation of anticonvulsant therapy; because most studies were ≤24 weeks' duration, risk of treatment beyond 24 weeks not known. Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.

Monitor closely for emergence or worsening of suicidal thoughts and behavior. If any such symptoms develop, discontinue therapy. Avoid use in patients with a history of suicide attempts or active suicidal ideation. (See Advice to Patients.)

Acute Myopia and Secondary Angle Closure Glaucoma

Acute myopia associated with secondary angle closure glaucoma reported in patients receiving topiramate. Typically occurs within 1 month of initiating topiramate therapy. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings may include myopia, anterior chamber shallowing, ocular hyperemia (redness), and increased intraocular pressure; mydriasis may or may not be present.

If any such symptoms occur, immediately discontinue drug. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious adverse events including permanent loss of vision.

Mood and Sleep Disorders

Mood disorders (e.g., depression, anxiety, insomnia) reported. Patients with a history of depression may be at increased risk of recurrent depression or other mood disorders while receiving the drug. In most cases, symptoms resolved spontaneously or following drug discontinuance.

If clinically important or persistent symptoms occur, consider dosage reduction or discontinuance of therapy. Discontinue therapy in patients who exhibit symptoms of suicidal ideation or behavior.

CNS/Cognitive Effects

Cognitive dysfunction (e.g., impairment of concentration, attention, memory, speech, or language) may occur. Risk is increased with rapid titration or use of high initial dosages.

If cognitive dysfunction persists, consider dosage reduction or discontinuance of therapy.

Concomitant use with alcohol or CNS depressant drugs (e.g., barbiturates, benzodiazepines, hypnotic agents) may potentiate CNS depression or other centrally mediated effects of these agents (e.g., dizziness, adverse cognitive reactions, drowsiness, lightheadedness, impaired coordination, somnolence). Avoid concomitant use of alcohol.

Metabolic Acidosis

Hyperchloremic, non-anion gap metabolic acidosis reported. Risk may be increased in patients with predisposing factors (e.g., renal disease, severe respiratory disorders, status epilepticus, diarrhea, surgery, ketogenic diet).

Manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe complications including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may result in potentially serious sequelae (e.g., nephrolithiasis or nephrocalcinosis, osteomalacia and/or osteoporosis with risk of fractures).

Concomitant use of carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide, dichlorphenamide) may increase severity of metabolic acidosis. (See Specific Drugs under Interactions.)

Measure serum bicarbonate concentrations prior to and during therapy. In clinical studies, serum bicarbonate concentrations were maximally reduced at 4 weeks and normalized by 56 weeks without any change in therapy. If persistent metabolic acidosis develops, manufacturer states to reduce dosage or discontinue phentermine/topiramate.

Renal Effects

Increased serum creatinine concentrations reported. In clinical studies, peak increases were observed after 4–8 weeks of treatment and generally declined over time. However, effect of chronic treatment on renal function not known.

Measure serum creatinine concentrations prior to and during therapy. If persistent elevations in serum creatinine concentrations occur, reduce dosage or discontinue phentermine/topiramate.

Hypoglycemia in Patients with Type 2 Diabetes Mellitus

Weight loss may increase risk of hypoglycemia in patients with type 2 diabetes mellitus receiving treatment with insulin and/or insulin secretagogues (e.g., sulfonylureas). Phentermine/topiramate has not been studied in combination with insulin.

Measure blood glucose concentrations prior to and during therapy in patients with type 2 diabetes mellitus. To minimize risk of hypoglycemia, consider reducing dosages of non-glucose-dependent antidiabetic agents. If hypoglycemia develops after initiating phentermine/topiramate, adjust patient's antidiabetic regimen accordingly.

Hypotension in Patients Receiving Antihypertensive Agents

Weight loss may increase risk of hypotension in patients receiving antihypertensive agents.

Measure BP prior to and during therapy in such patients. If symptoms of hypotension (e.g., dizziness, lightheadedness, syncope) occur, adjust patient's antihypertensive regimen appropriately.

Discontinuance of Therapy

Abrupt withdrawal of topiramate may precipitate seizures. If immediate discontinuance of phentermine/topiramate is medically necessary, monitor patient.

In patients discontinuing therapy from maximum dosage of phentermine 15 mg/topiramate 92 mg, gradually taper dosage as recommended to reduce risk of seizures. (See Dosage under Dosage and Administration.)

Kidney Stones

Risk of kidney stone formation. Topiramate is a carbonic anhydrase inhibitor; may promote stone formation by reducing urinary citrate excretion and increasing urinary pH. Ketogenic diet or concomitant use of carbonic anhydrase inhibitors may increase risk. (See Specific Drugs under Interactions.)

Instruct patients to increase fluid intake. (See Advice to Patients.)

Oligohidrosis and Hyperthermia

Oligohidrosis, sometimes resulting in hospitalization, reported with topiramate. Manifestations included decreased sweating and elevated body temperature. Some cases occurred with use of topiramate after exposure to elevated environmental temperatures.

Advise patients to monitor for decreased sweating and increased body temperature during physical activity, especially in hot weather. Use caution when phentermine/topiramate is administered with other drugs that can also predispose patients to heat-related disorders (e.g., other carbonic anhydrase inhibitors, drugs with anticholinergic activity).

Hypokalemia

Risk of hypokalemia because of potential for topiramate to inhibit carbonic anhydrase. Concomitant use with non-potassium sparing diuretics may increase risk. (See Specific Drugs under Interactions.)

Monitor patients for hypokalemia.

Laboratory Monitoring

Changes in several laboratory parameters reported in clinical studies. Obtain a blood chemistry profile, including bicarbonate, creatinine, potassium, and glucose concentrations, at baseline and periodically during treatment.

Abuse Potential and Dependence

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

Potential for phentermine/topiramate to cause physical dependence not systematically evaluated. Limited information available on dependence potential of the individual components. Abrupt discontinuance of topiramate associated with seizures in patients without a history of seizures or epilepsy. Abrupt discontinuance of phentermine following prolonged high-dosage administration resulted in extreme fatigue, depression, and sleep EEG changes. If rapid withdrawal of phentermine/topiramate is required, appropriately monitor patient.

Specific Populations

Pregnancy

Contraindicated in pregnancy. May cause fetal harm and offers no potential benefit to a pregnant woman. If a patient becomes pregnant, discontinue drug immediately and apprise patient of the potential fetal hazard.

In women of childbearing potential, perform pregnancy test prior to initiating therapy and monthly thereafter. Advise such women to use effective contraception during therapy.

A Pregnancy Surveillance Program has been established. Encourage women who become pregnant while receiving the drug to call the program at 888-998-4887.

Effect of topiramate-induced metabolic acidosis not specifically studied during pregnancy; however, metabolic acidosis during pregnancy is known to cause decreased fetal growth, decreased fetal oxygenation, and fetal death.

Lactation

Phentermine/topiramate may be distributed into human milk. Discontinue nursing or drug.

Pediatric Use

Safety and efficacy not established; use not recommended. Serious adverse reactions including acute angle glaucoma, oligohidrosis and hyperthermia, metabolic acidosis, cognitive and neuropsychiatric reactions, hyperammonemia and encephalopathy, and kidney stones, reported in pediatric patients receiving topiramate.

Geriatric Use

In clinical trials, only a limited number (7%) of patients were ≥65 years of age; no overall differences in safety or effectiveness observed between these patients and younger adults, but greater sensitivity of some older individuals cannot be ruled out.

Insufficient experience in patients ≥65 years of age to determine whether they respond differently from younger patients. In general, select dosage carefully in geriatric patients, 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.

Hepatic Impairment

In patients with mild (Child-Pugh score 5–6) or moderate (Child-Pugh score 7–9) hepatic impairment, exposure of phentermine may be increased. Adjust dosage of phentermine/topiramate in patients with moderate hepatic impairment. (See Hepatic Impairment under Dosage and Administration.)

Not studied in patients with severe hepatic impairment (Child-Pugh score 10–15); avoid use.

Renal Impairment

Both phentermine and topiramate are eliminated by renal excretion. Therefore, exposure to the drugs may be increased in patients with renal impairment. Adjust dosage in patients with moderate or severe renal impairment. (See Renal Impairment under Dosage and Administration.)

Not studied in patients with end-stage renal disease on dialysis; avoid use.

Common Adverse Effects

Paresthesia, dizziness, dysgeusia, insomnia, constipation, dry mouth.

Drug Interactions

Phentermine does not inhibit CYP1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 and does not induce CYP1A2, 2B6, or 3A4. 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. Topiramate is a mild inducer of CYP3A4. Topiramate is not a substrate of P-gp.

Specific Drugs

Drug

Interaction

Comments

Amitriptyline

Increased plasma amitriptyline concentrations

Adjust amitriptyline dosage based on clinical response

Anticholinergic agents

Possible increased risk of hyperthermia

Use concomitantly with caution

Carbamazepine

Clinically important decreases in plasma concentrations of topiramate observed; plasma concentrations of carbamazepine or its active metabolite not substantially altered

Carbonic anhydrase inhibitors (e.g., acetazolamide, dichlorphenamide, zonisamide)

Possible increased risk or severity of metabolic acidosis and kidney stone formation; possible increased risk of hyperthermia

Avoid concomitant use

If used concomitantly in patients with predisposing risk factors for metabolic acidosis, monitor for onset or worsening of this condition

CNS depressants (alcohol, barbiturates, benzodiazepines, hypnotics)

May potentiate CNS depression or other CNS effects (e.g., dizziness, drowsiness, impaired coordination, somnolence)

Avoid concomitant use of alcohol

Digoxin

Serum digoxin AUC was decreased by 12% in one study; however, clinical importance not known

Dihydroergotamine

Pharmacokinetics of both drugs not affected

Diltiazem

Decreased peak plasma concentrations and AUC of diltiazem by 10 and 25%, respectively; systemic exposure to desacetyl diltiazem also decreased, but no effect on N-desmethyl diltiazem

Increased peak plasma concentrations and AUC of topiramate by 16 and 19%, respectively

Glyburide

Concomitant administration in patients with type 2 diabetes mellitus decreased peak plasma concentrations and AUC of glyburide by 22 and 25%, respectively; systemic exposure of the active metabolites, 4-trans-hydroxyglyburide and 3-cis-hydroxyglyburide, also were reduced

Pharmacokinetics of topiramate not affected

Haloperidol

Pharmacokinetics of haloperidol not affected

Hydrochlorothiazide

Peak plasma concentrations and AUC of topiramate increased by 27 and 29%, respectively; pharmacokinetics of hydrochlorothiazide not substantially altered

Non-potassium sparing diuretics such as hydrochlorothiazide may potentiate hypokalemia

Monitor patients for hypokalemia; measure potassium concentrations prior to and during treatment

Lamotrigine

Plasma concentrations of lamotrigine were altered by <10% and plasma topiramate concentrations were decreased by 13%

Lithium

Pharmacokinetics of lithium not affected during concurrent administration of topiramate 200 mg daily, but peak plasma concentrations and AUC of lithium increased by 27 and 26%, respectively, during concurrent administration of topiramate dosages up to 600 mg daily

Monitor serum lithium concentrations in patients receiving concurrent high-dose topiramate therapy

Loop diuretics (e.g., furosemide)

Non-potassium sparing diuretics such as loop diuretics may potentiate hypokalemia

Monitor patients for hypokalemia; measure potassium concentrations prior to and during treatment

MAO inhibitors

Risk of hypertensive crisis

Concomitant use during and within 14 days following administration of MAO inhibitor contraindicated

Metformin

Increased peak plasma concentrations and AUC of metformin by 16 and 23%, respectively; pharmacokinetics of phentermine/topiramate altered to only a slight extent

Oral contraceptives

Systemic exposure of ethinyl estradiol decreased by 16% and exposure of norethindrone increased by 16%

Effect on contraceptive efficacy not evaluated

Increased risk of pregnancy not anticipated; however, irregular bleeding may occur as a result of altered concentrations of the estrogen and progestin components

Advise patients to not discontinue oral contraceptives if spotting occurs, but to notify clinician if spotting is troublesome

Phenobarbital

Altered plasma concentrations of phenobarbital by <10%

Phenytoin

Clinically important decreases in plasma topiramate concentrations observed; possible increase in serum phenytoin concentrations (generally in those receiving twice-daily phenytoin regimen)

Pioglitazone

Decreased systemic exposure to pioglitazone and its active metabolites observed; however, clinical importance not known

Monitor patients for adequate glycemic control when pioglitazone is added to phentermine/topiramate therapy or vice versa

Primidone

Altered plasma concentrations of primidone by <10%

Propranolol

Pharmacokinetics of either drug not affected

Risperidone

No clinically important changes in systemic exposure of risperidone plus 9-hydroxyrisperidone or topiramate; therefore, interaction not likely to be clinically important

Sitagliptin

Pharmacokinetics of both drugs unaffected

Sumatriptan

No effects on pharmacokinetics of sumatriptan

Valproic acid

Decreased topiramate plasma concentrations by 14% and valproic acid plasma concentrations by 11%

Concomitant use also associated with hyperammonemia with and without encephalopathy, and also with hypothermia (with and without hyperammonemia)

May be prudent to measure blood ammonia concentrations in patients who develop hypothermia or encephalopathy during concomitant therapy

Venlafaxine

Pharmacokinetics of venlafaxine, O-desmethylvenlafaxine, and topiramate not affected

Phentermine and Topiramate Pharmacokinetics

Absorption

Bioavailability

Following oral administration of fixed combination, peak plasma concentrations of phentermine and topiramate achieved in 6 and 9 hours, respectively.

Food

Pharmacokinetics of both phentermine and topiramate were not altered when administered with a high-fat meal.

Special Populations

In patients with mild (Child-Pugh score 5–6) or moderate (Child-Pugh score 7–9) hepatic impairment, exposure of phentermine may be increased.

Exposure to both phentermine and topiramate may be increased in patients with moderate (Clcr 30 to <50 mL/minute) or severe (Clcr <30 mL/minute) renal impairment.

Distribution

Plasma Protein Binding

Phentermine: 17.5%.

Topiramate: 15–41%.

Elimination

Metabolism

Phentermine: Minimally metabolized by CYP3A4.

Topiramate: Not extensively metabolized.

Elimination Route

Phentermine: Approximately 70–80% of an administered dose is eliminated in urine as unchanged drug.

Topiramate: Approximately 70% of an administered dose is found in urine as unchanged drug.

Half-life

Phentermine: Mean terminal half-life is about 20 hours.

Topiramate: Mean terminal half-life is about 65 hours.

Stability

Storage

Oral

Fixed-combination Capsules

15–25°C; keep container tightly closed and protect from moisture.

Actions

Advice to Patients

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Phentermine hydrochloride/topiramate is subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.

The fixed combination of phentermine and topiramate (phentermine/topiramate; Qsymia) is available only through a REMS program, the Qsymia REMS program, because of the teratogenic risk associated with phentermine/topiramate therapy. (See Restricted Distribution under Dosage and Administration.)

Phentermine Hydrochloride and Topiramate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

Phentermine Hydrochloride 3.75 mg (of phentermine; immediate-release) and Topiramate 23 mg (extended-release)

Qsymia (C-IV)

Vivus

Phentermine Hydrochloride 7.5 mg (of phentermine; immediate-release) and Topiramate 46 mg (extended-release)

Qsymia (C-IV)

Vivus

Phentermine Hydrochloride 11.25 mg (of phentermine; immediate-release) and Topiramate 69 mg (extended-release)

Qsymia (C-IV)

Vivus

Phentermine Hydrochloride 15 mg (of phentermine; immediate-release) and Topiramate 92 mg (extended-release)

Qsymia (C-IV)

Vivus

AHFS DI Essentials™. © Copyright 2024, Selected Revisions June 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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