Continuing Education Activity

Phentermine and extended-release (ER) topiramate have been used separately in various ways. Phentermine was first introduced in 1959 as part of an anti-obesity combination drug. Topiramate was released for commercial use in 1996. Phentermine on its own has been used for short-term treatment of obesity in combination with exercise and caloric restriction. In addition, Topiramate has been used to treat partial-onset or primary generalized tonic-clonic seizures, Lennox-Gastaut syndrome, and as a prophylactic treatment of migraine headaches. The United States Food and Drug Administration approved the combination of these two drugs in 2012 to treat obesity. The drugs are to be used in combination with a reduced-calorie diet and exercise program in individuals with an initial body mass index (BMI) over 30 kg/m2 or those with a BMI of over 27 in combination with at least one obesity-related comorbidity. This activity outlines the indications, mechanism of action, methods of administration, important adverse effects, contraindications, toxicity, and monitoring, of topiramate/phentermine so providers can direct patient therapy where they are indicated as part of the interprofessional team.

Objectives:

• Describe the mechanisms of action of topiramate and phentermine.
• Outline the indications for initiating topiramate/phentermine therapy in a weight loss regimen.
• Review the adverse events profile for topiramate/phentermine combination therapy.
• Summarize interprofessional team strategies for improving care coordination and communication to properly use topiramate/phentermine combination therapy to improve patient outcomes as part of a weight-loss regimen.

Indications

Phentermine and extended-release (ER) topiramate have been used separately in various ways. Phentermine was first introduced in 1959 as part of an anti-obesity combination drug. Topiramate was discovered in 1979 but was not released for commercial use until 1996. Phentermine on its own has been used for short-term treatment of obesity in combination with exercise and caloric restriction. Topiramate on its own has been used to treat partial-onset or primary generalized tonic-clonic seizures, Lennox-Gastaut syndrome, and as a prophylactic treatment of migraine headaches.[1] Non-FDA-approved indications for topiramate are sleep-related eating disorder, nightmares - post-traumatic stress disorder associated, and alcohol dependence.[2]

The United States Food and Drug Administration approved the combination of phentermine and topiramate drugs in 2012 to treat obesity. The drugs are to be used in combination with a reduced-calorie diet and exercise program in individuals with an initial body mass index (BMI) over 30 kg/m or in those with a BMI of over 27 kg/m in combination with at least one obesity-related comorbidity.[3]

Mechanism of Action

Phentermine is a sympathomimetic amine anorectic. It has a similar mechanism of action as amphetamine in that it is an agonist at the trace amine-associated (TAAR1) receptor site, stimulating the release of norepinephrine and epinephrine. It is a central nervous system stimulant.[4]

Topiramate is an anticonvulsant lowering the seizure threshold stabilizing membrane by acting on high-voltage-activated calcium channels and voltage-gated sodium channels and its augmenting effect on GABA-A receptors. Topiramate is also a weak carbonic anhydrase inhibitor, and it also antagonizes glutamate receptors. Topiramate augments appetite suppression and satiety enhancement based on the combination of the mechanisms above. 

Pharmacokinetics

According to product labelling, phentermine/topiramate pharmacokinetics is approximately dose-dependent from 3.75 mg/23 mg to 15 mg/ 100 mg.

Distribution

Phentermine is 17.5% plasma protein-bound, while topiramate is 15 - 41% plasma protein-bound when the blood concentration range is 0.5 to 250 µg/mL. The plasma protein binding decreases as blood topiramate increases. 

Metabolism

Phentermine has two metabolic pathways; hydroxylation and oxidation. Cytochrome P450 (CYP) 3A4 primarily metabolizes phentermine. Topiramate does not show extensive metabolism. Topiramate is primarily metabolized by hydroxylation, hydrolysis, and glucuronidation. Topiramate inhibits CYP2C19 enzymes and induces the CYP3A4 enzymes.[5]

Excretion

70 to 80% of a dose is excreted as unchanged phentermine in urine. The phentermine terminal half-life is about 20 hours. Similarly, about 70% of an administered topiramate dose is excreted unchanged in urine when given independently. The mean topiramate half-life is about 65 hours.

Administration

Phentermine/topiramate is available as oral capsules in various strength combinations (i.e., 3.75 mg/23 mg, 7.5 mg/46 mg, 11.25 mg/69 mg, and 15 mg/92 mg of phentermine mg/topiramate mg ER). It is recommended to take this medication in the morning to prevent insomnia.[6]

• The medication's initiation begins with the lowest dose of 3.75 mg/23 mg phentermine mg/topiramate mg ER. Continue on the lowest dose for 14 days, then increase to the 7.5 mg/46 mg phentermine mg/topiramate mg ER dosage. Reevaluate in 12 weeks.
• If 3% weight loss is not achieved after 12 weeks on the 7.5 mg/46 mg phentermine mg/topiramate mg ER dosage, discontinue or escalate the dose to 11.25 mg/69 mg every morning for 14 days. Reevaluate again in 12 weeks.
• If 5% weight loss is not achieved after 12 weeks on the maximum dose of 15 mg/92 mg phentermine mg/topiramate mg ER, discontinue by gradually tapering the dose to prevent possible seizures.

Renal Impairment: For patients with severe renal impairment, it is recommended that the clinician should not prescribe more than 7.5 mg/46 mg phentermine mg/topiramate mg ER per day.[7]

Hepatic Impairment: No dosage adjustment is essential for patients with mild hepatic impairment. The maximum recommended daily dose for patients with moderate hepatic impairment is phentermine 7.5 mg/topiramate 46 mg per day. Phentermine/topiramate has not been studied in patients with severe hepatic impairment (Child-Pugh score 10 - 15)

Pregnancy Considerations: Phentermine/topiramate is teratogenic with a category X classification. Data has indicated that users who become pregnant have an increased risk of oral clefts due to exposure to topiramate in the first trimester. Topiramate has been shown to cause metabolic acidosis, leading to fetal growth restriction and hypoxic events.[8]

Breastfeeding Considerations: Phentermine/topiramate has been found distributed in breast milk. There is a potential for adverse effects like hypertension and weight loss in breastfeeding; therefore, breastfeeding is contraindicated on phentermine/topiramate.[9]

Adverse Effects

The most common adverse events reported in clinical trials are dry mouth, constipation, and paresthesia.[6] Topiramate may cause severe hypohidrosis and hyperthermia. Avoid combination with anticholinergics which can increase the risk of hyperthermia.[10]

Phentermine/topiramate may cause an increased resting heart rate of up to 20 bpm. Any patient with a history of the cardiac or cerebrovascular disease should use caution. Therefore, it is important to monitor heart rate in all patients taking phentermine/topiramate.[4] Appetite suppressants drugs such as phentermine are associated with valvular heart disease.[11]

Phentermine/topiramate can lead to psychiatric and cognitive disturbances. Mood disorders, including anxiety, depression, or insomnia, may occur with use. Clinicians should monitor patients for suicidal ideations and behaviors, depressed mood, and increased anxiety. It has also been associated with insomnia. Any history of a mood disorder may increase the risk of recurrence with the use of this drug. Phentermine/topiramate has been associated with cognitive impairment causing lapses in memory and judgment. In addition, the patient's ability to concentrate may also be affected.[12]

Acute myopia associated with secondary angle-closure glaucoma may occur with use. Monitoring for increased intraocular pressure will help prevent permanent vision loss if an event occurs.[13]

Elevated serum creatinine may occur. As a result, there is an increased risk of hypokalemia. Obtain periodic blood chemistry panels to monitor for changes. Topiramate is a weak carbonic anhydrase inhibitor; therefore, it can lead to metabolic acidosis, hypokalemia and may lead to the development of nephrolithiasis.[14]

Due to decreased appetite, hypoglycemia may occur, especially in patients with type-2 diabetes mellitus.

Central nervous system (CNS) depression has been noted, and it is advised to avoid other CNS depressants such as alcohol to avoid adverse effects such as dizziness and impaired coordination. Abrupt withdrawal of phentermine/topiramate combination may trigger seizures. Therefore, therapy should be withdrawn gradually to minimize the potential of increased seizure frequency.[15]

Clinically apparent liver injury due to this combination has not been reported, but several instances of acute liver injury have been linked to topiramate monotherapy of other conditions. Case reports of liver injury attributed to topiramate have occurred largely in patients with seizure disorders receiving other anticonvulsants with known hepatotoxic potential.[16]

Contraindications

Use of phentermine/topiramate is contraindicated in individuals who are suffering from glaucoma, those who have shown hypersensitivity to any part of the combination drugs, those with a history of hyperthyroidism, women who are pregnant, and those who have recently used a monoamine oxidase inhibitor as it may lead to hypertensive crisis.[17]

The inhaled anesthetics such as isoflurane, desflurane, and sevoflurane are to be used cautiously in patients taking phentermine/topiramate as the risk for ventricular tachycardia increases.

The use of phentermine/topiramate is contraindicated when patients are on a current regimen of isocarboxazid, linezolid, phenelzine, procarbazine, or transdermal selegiline due to the risk of hypertensive episodes.

Phentermine-topiramate can cause dangerous interactions with drugs. For example, selective serotonin reuptake inhibitors (SSRI) can cause serotonin syndrome when combined with phentermine/topiramate. This can lead to high body temperature, agitation, sweating, tremors, dilated pupils, hyperreflexia, and diarrhea. In severe cases, this could be life-threatening, especially with seizures, high fever, irregular heartbeat, and unconsciousness.[18]

Monitoring

Renal impairment: Clinicians need to consider the glomerular filtration rate(GFR) for patients with renal impairment. No dose adjustment is indicated if an individual has a GFR or CrCl greater or equal to 50 mL/min. For individuals with a GFR less than 50 mL/min, it is recommended that dosing should not exceed 7.5 mg/46 mg (phentermine/topiramate) per day.[19]

Hepatic impairment: It is important to consider the Child-Pugh score for individuals with hepatic impairment. A Child-Pugh score of 5 or 6 indicates that no adjustment needs to be made. If the Child-Pugh score is 7 to 9, then it is recommended that dosing should not exceed 7.5 mg/46 mg (phentermine/topiramate) per day. If the Child-Pugh score is 10 to 15, indicating severe impairment, it is advised to avoid using phentermine/topiramate.[7]

Monitor for weight reduction and changes in heart rate. Clinicians should periodically monitor a comprehensive metabolic panel, arterial blood gas analysis, and serum electrolytes to check for non-anion gap hyperchloremic metabolic acidosis.

Monitor for flank pain and hematuria as long-term treatment with topiramate can increase the risk of nephrolithiasis.[20]

Toxicity

In acute topiramate overdose, the most frequent clinical features reported are drowsiness, vertigo, agitation, and mydriasis. In severe overdose, secondarily generalized tonic-clonic seizures followed by deep coma, somnolence, bradykinesia have been reported. Mild to moderate metabolic acidosis has been observed with topiramate overdose. Therefore it is important to assess arterial blood gas(ABG) status in any patient presenting an acute topiramate overdose.[21] In acute overdose from phentermine, clinical manifestations of sympathetic hyperactivity are prominent such as tachycardia, mydriasis, fever, diaphoresis, hyperventilation, and combativeness.[22]

Management

Treatment of acute phentermine intoxication is largely symptomatic and includes lavage and sedation with a barbiturate. Acidification of the urine increases phentermine excretion. Intravenous phentolamine has been suggested for severe hypertension. Activated charcoal has been shown to adsorb topiramate. Hemodialysis is an efficacious means of removing topiramate from the body. Currently, there is no specific antidote for phentermine-topiramate overdose. Therefore, treatment for overdose is largely supportive, focusing on the airway, breathing, and circulation. It is important to note that current AHA guidelines of cardiopulmonary resuscitation (CPR) recommend following order CAB (circulation-airway-breathing).[23]

Enhancing Healthcare Team Outcomes

Obesity is a global issue, and almost every country faces this serious public health problem. Obesity is not a benign disorder, and its management usually requires an interprofessional group of healthcare team members. The answer to obesity is not only prescribing the latest weight loss medication or referring the patient for the most advanced bariatric procedure- but also educating the patient on its complications and the need to change lifestyle. The recommended course of action is as follows. 

Clinicians prescribe phentermine-topiramate for the appropriate indication. The patient should be encouraged to exercise and become physically active. As phentermine-topiramate is teratogenic, clinicians should counsel women of childbearing age to avoid taking phentermine-topiramate. The pharmacist should counsel the patient about the potential side effects and report back to clinicians for significant drug interactions. Constipation is also a real issue with this drug combination, and the patient should be told to increase fiber in the diet, drink more water, and use stool softeners or laxatives as needed. Clinical dieticians should prescribe individual diet plans for the patient and educate the patient that a change in diet is necessary for any intervention to work. 

Emergency department triage nurses and physicians should recognize the signs of acute overdose and ensure a patent airway, breathing, and circulation. In addition, the critical care physician consultation is necessary if the patient requires MICU level of care requiring intubation and mechanical ventilation. In the cases of severe acute overdose, medical toxicologist consultation is required. Finally, a psychiatrist consult is required if the overdose is intentional. 

Clinicians can refer the patient to the bariatric surgeon if there is a failure to achieve desired weight despite maximal exercise, dietary, and pharmacological interventions. Weight loss with phentermine-topiramate can take many months, and thus, compliance with therapy is necessary. Therefore clinicians should counsel the patient regarding weight-loss expectations.[24][25]

Outcomes

Based on clinical trial data, about 70% of patients did lose 5-10% of their body weight over 56 weeks.[26][27] As depicted above, prescribing phentermine-topiramate demands an interprofessional team strategy among clinicians (MDs, DOs, NPs, PAs), specialists, nurses, and pharmacists. An interprofessional approach is necessary to maximize efficacy and minimize adverse drug reactions, enhancing patient outcomes. [Level 5]