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Topiramate And Phentermine

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Last Update: July 29, 2021.

Continuing Education Activity

Phentermine and extended-release (ER) topiramate have been used separately in a variety of 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 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. The United States Food and Drug Administration approved the combination of these 2 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 in 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.
Access free multiple choice questions on this topic.

Indications

Phentermine and extended-release (ER) topiramate have been used separately in a variety of 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. Non-FDA-approved indications for topiramate are sleep-related eating disorder, nightmares - post-traumatic stress disorder associated, and alcohol dependence.[1][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/m2 or in those with a BMI of over 27 in combination with at least one obesity-related comorbidity.[3][4][5]

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.[6][7]

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 mechanisms mentioned above. Topiramate has an inhibitory effect on the CYP2C19 enzymes, and it induces the CYP3A4 enzymes.[8][9]

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.[10]

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 then 15 mg/92 mg every morning. 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 dose to one dose every other day for at least 1 week to prevent possible seizure. For patients with severe renal impairment or moderate hepatic impairment, it is recommended that the clinician should not prescribe more than 7.5 mg/46 mg phentermine mg/topiramate mg ER per day.[11][12][13]

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.[14]

Phentermine/topiramate has been found distributed in breast milk. There is a potential for adverse effects like hypertension and weight loss in the breastfeeding infant; therefore, breastfeeding is contraindicated while on phentermine/topiramate.[15][16][17]

Adverse Effects

  • The most common adverse events reported in clinical trials are dry mouth, constipation, and paresthesia.[10][18]
  • Phentermine/topiramate may cause an increased resting heart rate of up to 20 bpm. Any patient with a history of cardiac or cerebrovascular disease should use caution. Therefore, it is important to monitor heart rate in all patients taking phentermine/topiramate.[7]
  • 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.[19]
  • Acute myopia associated with secondary angle-closure glaucoma may occur with use. Monitoring for increased intraocular pressure will help prevent permanent loss of vision if an event occurs.[20]
  • Elevated serum creatinine may occur. As a result, there is an increased risk of hypokalemia. Obtain periodic blood chemistry panels to monitor for changes.
  • 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.[21]
  • Topiramate is a weak carbonic anhydrase inhibitor; therefore, it can lead to metabolic acidosis, hypokalemia and may lead to the development of nephrolithiasis.[22]
  • Topiramate may cause severe hypohidrosis and hyperthermia. Avoid combination with anticholinergics which can increase the risk of hyperthermia.[23]
  • Appetite suppressants drugs such as phentermine are associated with valvular heart disease.[24]

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 in those who have recently used a monoamine oxidase inhibitor as it may lead to hypertensive crisis.[25]
  • 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 is increased.
  • 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.[26]

Monitoring

  • Renal impairment - For patients with renal impairment, clinicians need to consider the glomerular filtration rate(GFR). 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.[27]
  • Hepatic impairment - For individuals with hepatic impairment, it is important to consider the Child-Pugh score. 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 the use of phentermine/topiramate.[13]

Toxicity

In acute overdose of topiramate, the most frequent clinical features reported are somnolence, 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 with an acute overdose of topiramate.[28] In acute overdose from phentermine, clinical manifestations of sympathetic hyperactivity are prominent such as tachycardia, mydriasis, fever, diaphoresis, hyperventilation, and combativeness.[29]

Currently, there is no specific antidote for phentermine-topiramate. Therefore, treatment in toxicity remains largely supportive, focusing on airway, breathing, and circulation. It is important to note that current AHA guidelines of cardiopulmonary resuscitation (CPR) recommend following order CAB (circulation-airway-breathing).[30]

Enhancing Healthcare Team Outcomes

Obesity is a global issue, and almost every country is facing 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 educate 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 must 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. 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. The 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.[31][32]

Outcomes

Based on clinical trial data, about 70% of patients did lose 5-10% of their body weight over 56 weeks.[33][34] 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, therefore enhancing patient outcomes. [Level 5]

Review Questions

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