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[Claude]

TheFood and Drug Administration recently approved the combination of phentermine and extended-release topiramate (PHN/TPM) for weight loss. This is one of only two weight-loss agents to arrive on the US market in the last decade. This product combines the anorexigenic agent, phentermine, which is approved for the short-term treatment of weight loss, with a carbonic anhydrase inhibitor, topiramate, which is approved for non-weight loss indications, including seizure disorders and migraine headache. Although the combination is believed to be synergistic, no clinical trial data currently address this. The PHN/TPM combination is a once-daily formulation. Mean weight loss among participants who completed 1 year of PHN/TPM treatment in research trials, in combination with lifestyle modification, has ranged from approximately 7% (lower doses) to over 14% (higher doses), relative to approximately 2% with placebo. In addition to weight loss, PHN/TPM resulted in improved comorbidities and quality of life, although it has not been shown to improve mental/psychosocial issues. Among the common adverse events observed in clinical trials are paresthesia, dry mouth, constipation, and headache. Other noteworthy adverse events that occurred more commonly with PHN/TPM versus placebo included dysgeusia, insomnia, irritability, and alopecia. Laboratory abnormalities in serum bicarbonate and potassium were also observed in a subset of patients. Due to the teratogenic potential of topiramate, women of child-bearing potential are required to have a negative pregnancy test at baseline and are instructed to take monthly pregnancy tests. As part of a risk-management approach, only pharmacies certified by the manufacturer will be allowed to dispense PHN/TPM and will be required to provide information on birth defects. Like phentermine, the combination drug will be designated as a schedule IV medication. In comparison with other agents currently on the market, the combination of PHN/TPM appears to provide significant advantages for weight loss, while improving comorbid conditions and quality of life. Monitoring for laboratory abnormalities, adverse events, and changes in psychiatric status should occur during therapy.

A minority of patients is extremely successful in attaining and maintaining significant weight loss through lifestyle modification alone [9]. For the majority, however, lifestyle modification in the absence of a behavioral weight-loss program, pharmacotherapy regimen, or weight-loss surgery is inadequate. Pharmacotherapy is a much needed intermediate intervention for those who are unsuccessful with lifestyle intervention alone and for whom weight-loss surgery is not indicated or desired. Currently, the pharmacotherapeutic options for obesity management are extremely limited. Although several drugs are in the obesity pipeline, the process for getting such drugs to market has recently proven difficult.

Studies were found using PubMed. No limits on dates were set. Major keywords included phentermine and topiramate, phentermine, topiramate, pharmacotherapy for weight loss, lorcaserin, orlistat, and others.

Perhaps the most memorable pitfall in obesity pharmacotherapy involved fenfluraminephentermine (fen-phen) in 1997. Although this combination was efficacious and widely prescribed, fenfluramine was withdrawn following FDA concerns about cardiac valve damage [16, 17].

Although never available in the US market, cannabinoid 1 receptor (CB1) antagonists, such as rimonabant, were in late-stage development by several pharmaceutical companies before being aborted due to the increased risk of depression/suicide. Rimonabant was also removed from the European market.

PHN/TPM is a combination of an immediate-release formulation of the anorexigenic agent, phentermine, and an extended-release formulation of the anticonvulsant medication, topiramate. Phentermine, with a history of use spanning 52 years, is currently the most widely prescribed drug for weight loss in the US with over 6.5 million prescriptions written in 2011 [22]. Topiramate has a 15-year history of use. The drug combination is formulated to produce peak exposure to phentermine in the morning and peak concentrations of topiramate in the evening [22].

The drug was approved in four dosage strengths of PHN/TPM: 3.75/23 mg, 7.5/46 mg, 11.25/69 mg, and 15/92 mg. The scientific rationale for the specific doses included in the combination is not clear, for example, 92 mg topiramate instead of the commercially available 100 mg dosage form of topiramate. The doses of topiramate used for weight loss are somewhat lower than for the other indications of the drug. The recommended migraine headache prophylaxis dose is 100 mg/day given in two divided doses [23]. The dose for partial-onset seizure and primary generalized tonic-clonic seizure is up to a maximum of 400 mg/day given in two divided doses, and similar doses are used for adjunctive therapy in these seizure disorders [24]. Topiramate doses up to 1,600 mg/day have been studied in epilepsy [23].

It has been suggested that topiramate and phentermine may have synergistic effects toward weight loss [26], although this theory has not been tested in clinical trials. Until the combination of PHN/TPM is compared against each of the agents individually, claims of synergy cannot be addressed. Topiramate is currently FDA-approved for the treatment of seizure disorders and prophylaxis of migraine headaches [23]. The mechanism of action that contributes to weight loss is currently unclear. The pharmacology of topiramate is complex. It is known to block neuronal voltage-dependent sodium channels, antagonize 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid/kainite glutamate receptors, enhance gammaaminobutyric acid activity, and weakly inhibit carbonic anhydrase [23].

A recent 3-month study of 40 patients treated with topiramate 100 mg/day for migraine prophylaxis found no change in resting metabolic rate [36]. There were, however, statistically significant reductions in mean BMI, body fat ratio, and abdominal skin-fold measurements. The findings of this study led the authors to conclude that the anorexigenic activity of topiramate may occur through hypothalamic activity. It has been suggested that topiramate may also lead to weight loss through increased satiety due to decreased gastrointestinal motility, increased taste aversion, increased energy expenditure, and decreased caloric intake [22]. The propensity of topiramate to contribute to neuropsychiatric and cognitive events at higher dosages has hindered its development as a monotherapy for weight loss [37].

Phentermine was approved by the FDA in 1959. Appetite reduction associated with phentermine is thought to be centrally mediated, including hypothalamic stimulation that results in norepinephrine release [23]. Phentermine is indicated for short-term use for weight reduction, in combination with a reduced calorie diet and exercise [23]. The utility of phentermine when used short-term according to its labeling is questionable.

Phentermine is generally well-tolerated. Common side effects are characteristic of sympathomimetic amines, including dry mouth, headache, insomnia, nervousness, irritability, and constipation. More serious side effects include palpitations, tachycardia, and hypertension [38]. Phentermine should be avoided in patients with hyperthyroidism, glaucoma, agitated states, advanced arteriosclerosis, symptomatic cardiovascular disease, moderate-severe hypertension, a history of substance abuse, or those who would have a drug interaction (e.g., monoamine oxidase inhibitors).

Three large RCTs address the efficacy of PHN/TPM for weight loss. A fourth trial has been completed but not yet published (EQUATE). These trials provide efficacy and tolerability information regarding the effect of this drug combination on comorbid conditions. All trials were funded by Vivus, the manufacturer of the PHN/TPM combination. The published trials include: CONQUER [37], EQUIP [39], and SEQUEL [40]. The results of each of these trials will be discussed in detail and a summary of each is presented in Table 1 [37, 39, 40].

The SEQUEL study [40] assessed the efficacy and safety of PHN/TPM for longer-term use in overweight/obese individuals with existing cardiometabolic disease. This was a 52-week, placebo-controlled, double-blind, extension study following CONQUER. Participants who completed and complied with the CONQUER trial were eligible for SEQUEL. Patients continued the product to which they were originally randomized, in conjunction with lifestyle modification. Interestingly, more participants met criteria for type 2 diabetes mellitus at baseline in the SEQUEL extension study compared with the CONQUER cohort (21.5% vs. 15.8%). Percentage rates of participation were as follows: 15/92 mg (85.5%), 7.5/46 mg (79.4%), placebo (69.4%).

It is thought that the inhibition in carbonic anhydrase that occurs with topiramate contributes to changes in bicarbonate, potassium, and risk of nephrolithiasis. When looking at laboratory results overall, there were no differences between the medication and placebo groups regarding the incidence of serious laboratory-related adverse events or drug discontinuations due to laboratory adverse events [22]. There were, however, some notable laboratory findings reported in the major trials. All cases of hypokalemia associated with a potassium value 0.5 mmol/L from baseline reportedly occurred in patients taking non-potassium-sparing diuretics [22]. More information on laboratory abnormalities that occurred during clinical trials can be found in Table 2.

In EQUIP, psychiatric side effects were assessed with the Patient Health Questionnaire-9 (PHQ-9) [44] and the Columbia Suicide Severity Rating Scale (C-SSRS) [45]. Mean PHQ-9 scores indicated improvements in depressive symptoms over time in all treatment groups, with no between group differences observed. No increases in suicidal ideation or behavior were identified on the C-SSRS for any participants. It should be noted that participants had minimal depressive symptoms at baseline (mean PHQ-9 = 2.8) due to exclusionary criteria (PHQ-9 >10). Data presented in study appendices reflect that there may be a small number of patients whose psychiatric function worsens while on the drug. Psychiatric and neurocognitive effects have not been specifically and thoroughly assessed in patients with clinical depression or other significant mental health disorders. Therefore, clinicians should monitor for any potential worsening of these conditions if PHN/TPM is started.

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