Topiramate And Phentermine

Article Author:
Donavon Johnson
Article Editor:
Judy Quick
Updated:
11/23/2018 11:08:03 AM
PubMed Link:
Topiramate And Phentermine

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 include: sleep related eating disorder, nightmares - PTSD associated, and alcohol dependence. 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.[1][2][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 TAAR1 receptor site stimulating the release of norepinephrine and epinephrine. It is a stimulant.[4][5]

Topiramate is an anticonvulsant lowering the seizure threshold stabilizing membrane by acting on high-voltage-activated calcium channels and voltage-gated sodium channels, and by its augmenting effect on GABA-A receptors. It has inhibitory effects on the carbonic anhydrase enzyme group that can lead to serious side effects such as metabolic acidosis, hypokalemia, and may lead to the development of nephrolithiasis. It antagonizes glutamate receptors. Topiramate has an inhibitory effect on the CYP 2C19 enzymes, and it induces the CYP 3A4 enzymes.

Administration

Phentermine/topiramate is taken orally with capsules in dosage forms 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. Initiation of the medication is begun 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. 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 dose to 11.25 mg/69 mg every morning for 14 days, then 15 mg/92 mg every morning. 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 1 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 a dose of only 7.5 mg/46 mg phentermine mg/topiramate mg ER per day should be prescribed.[6][7]

Adverse Effects

Phentermine/topiramate is teratogenic with a category X classification. Data has indicated that users who become pregnant have a 9.6% increased risk of oral clefts due to exposure to topiramate in the first trimester. Topiramate has shown to cause metabolic acidosis which might lead to fetal growth restriction and hypoxic events, but has not been studied in pregnancy. Phentermine/topiramate has also been found distributed in breast milk. There is a potential for adverse effects due to this distribution.  Breastfeeding should be avoided while on phentermine/topiramate or the drug should be discontinued for the duration of breastfeeding.[8][9]

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 with caution. It is important to monitor heart rate in all patients taking phentermine/topiramate.

Phentermine/topiramate has been mood altering. Suicidal ideations and behaviors, depressed mood and increased anxiety should be monitored.  It has also been associated with insomnia. Any history of mood disorder may increase the risk of recurrence with use of this drug.

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.

It has been reported that phentermine/topiramate has been associated with cognitive impairment causing lapses in memory and judgment. Patient's ability to concentrate may also be affected.

Elevated serum creatinine may occur. 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 medication may trigger seizures. Dosage must be tapered to prevent any major shifts in serum electrolyte concentrations.

Kidney stones are a possible side effect due to carbonic anhydrase inhibition.

Oligohydrosis, decreased production and secretion of sweat, is a possible side effect and may lead to hyperthermia.

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.

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.

There have been serious, dangerous interactions with various pharmaceuticals. Antidepressants in the class selective serotonin reuptake inhibitors (SSRI) can cause serotonin syndrome when used in combination with phentermine/topiramate which results in 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. 

Use of phentermine/topiramate has been found to decrease the effect of statin drugs such as simvastatin and lovastatin.

The use of inhaled anesthetics such as isoflurane, desflurane, and sevoflurane are to be used with caution in patients taking phentermine/topiramate as the risk for ventricular tachycardia is increased.

Monitoring

For individuals with renal impairment, it is important to take glomerular filtration rate (GFR) into consideration. If an individual has a GFR or CrCl greater or equal to 50 mL/min, then no dose adjustment is indicated. 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.

For individuals with hepatic impairment, it is important to take into account 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.

Enhancing Healthcare Team Outcomes

Obesity is a global problem, and almost every country is facing this serious public health problem. Obesity is not a benign disorder, and its management usually requires a multidisciplinary group of healthcare professionals. The answer to obesity is not prescribing the latest weight loss medication or to refer the patient for the most advanced bariatric procedure- but to educate the patient on its complications and the need to change lifestyle. The nurse, physician, therapist and pharmacist have a great opportunity to educate the public about the dangers of untreated obesity. First, these patients need a dietary consult as a change in diet is necessary for any intervention to work. The patient will need to maintain the consistent lifestyle diet. The patient should be encouraged to exercise and become physically active. If  phentermine-topiramate is prescribed, the pharmacist should inform the patient about the potential side effects. Women of child-bearing age should be told to avoid this combination because of possible teratogenic effects. 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. Finally, the patient should be told to be realistic about expectations- the weight loss with the use of phentermine-topiramate can take many months and thus, compliance with therapy is necessary.[10][11]

Outcomes

Based on clinical trial data, about 70% of patients did lose 5-10% of the body weight over 56 weeks. The results were not consistent or predictable. The most difficult part is that no long-term studies are available and it is not known if the weight loss persists and how many people relapse back into obesity.[12][13] (Level V)