©1998 by Candice Silversides and Sara Cherkerzian. All rights reserved
Introduction
Obesity and the complications of obesity have been called "the number one public health problem in America". In the US, 20 - 34% of Americans are obese. Obesity is a problem of such serious concern because excess weight is a major risk factor for serious and even potentially fatal complications, the most common being cardiovascular disease. The population risk of coronary heart disease (CHD) mortality attributable to obesity in the United States has been estimated to be 32% (2) and the total societal cost of obesity in terms of medical services and lost productivity, as high as 39.3 billion dollars annually (1). While obesity is of health concern in the US, weight also co-exists as a cosmetic obsession. It is for both of these reasons that 30 - 40 billion dollars are spent each year in the US on weight loss treatment (2). Medical treatment for weight loss involves diet, exercise, behavior modification, and drug therapy. Drug therapy alone or in combination has shown to be particularly successful in short and long term weight loss.
While the FDA regulates what drugs are on the market, there is difficulty in regulating combinations of FDA-approved individual drugs. One such combination was that of phentermine and fenfluramine (Phen-Fen) which had been widely used for the treatment of exogenous obesity until it was found to have serious effects on cardiac valves (3). Soon after fenfluramine was withdrawn many commercial diet clinics such as Nutri/System began promoting an alternative drug therapy - the combination of phentermine and fluoxetine hydrochloride (Prozacä ). ABC News reported the Nutri/System claim that "No other diet will help you lose weight faster without the risk" (4). Dr. M Anchors, who first suggested the combination, has recently published the book Safer than Phen-Fen! (5) in which he proposes that the combination is a "safe, and effective alternative". Like Phen-Fen, Phen-Pro is an "off-label’ combination. There have been no studies demonstrating either the effectiveness or safety of the two drugs taken together or for longer periods of time.
The requirements for clinically acceptable anorectic drugs include: acceptable safety profiles; low potential for abuse; reduction of hunger and food intake in normal subjects; and efficacy over placebo in enabling obese patients to adhere to a dietary regime and weight loss. The purpose of this paper is to review the evidence that would suggest that phentermine-fluoxetine hydrochloride is an acceptable anorectic combination.
Anorectic Agents
The classes of currently available FDA-approved anorectic agents are the phenethylamine agents (diethylpropion, phentermine), a nonphenethylamine agent (mazindol), and until recently, the serotonergic agent (fenfluramine). Serotonergic drugs that are thought to be useful for the treatment for obesity, but are not currently approved for such treatment, are fluoxetine hydrochloride and sertraline. Because of the addictive potential of amphetamines, the phenethylamine and nonphenethylamine agents are also classified according to the Drug Enforcement Administration (DEA) schedules of the Controlled Substances Act. Phentermine is considered a schedule IV drug - very low addictive potential (6). Fluoxetine does not have addictive potential.
Phentermine: Mechanisms of Action and Pharmacokinetics
Phentermine (Ionaminä or Fastinä ) is a sympathomimetic amine with pharmacologic activity similar to a weak amphetamine, the prototypic drugs used to treat obesity. Amphetamines are able to bind to peripheral a- and b-adrenergic receptors and affect the CNS by releasing biogenic amines (norepinephrine and dopamine) from the nerve terminals. Phentermine decreases food consumption through an inhibitory effect on the appetite control center in the lateral hypothalamus. There is little evidence, by any of the drug classes, that the metabolic rate in the users of these drugs is increased. The primary problems in using amphetamines, and even weak amphetamines such as phentermine, as treatment for obesity is that there is an early loss of effect, potential for withdrawal, and addictive potential. Amphetamines have little effect on CNS serotonin levels. At high doses, amphetamines can lead to disturbances in perception and locomotion due to the release of dopamine in the mesolimbic system (7).
At present, the only indication for phentermine is as an adjunct to supervised regimes of weight reduction with a recommended dose of 30 mg / day. Contraindications to the use of phentermine include advanced atherosclerosis and other cardiovascular disease, severe hypertension, hyperthyroidism, and hypersensitivity to sympathomimetics (8). Because of potential drug – drug interactions, it is important to be aware of concomitant medications used by the individual before beginning therapy with phentermine. Phentermine is metabolized by the hepatic P450 enzyme system and can interact with other drugs metabolized by the P450 enzyme system.
Fluoxetine: Mechanisms of Action and Pharmacokinetics
Fluoxetine hydrochloride (Prozacä ) is a member of the selective serotonin reuptake inhibitor (SSRI) drug class. These drugs inhibit CNS neuronal uptake of serotonin into the presynaptic neurons. In rats, this mechanism causes an increase of serotonin concentrations within the synapses in the brain. The serotonin is believed to exhibit an inhibitory effect on the appetite control center in the lateral hypothalamus (9). Peripherally fluoxetine inhibits the uptake of serotonin into rat and human platelets, an action which has been shown to results in higher levels of serum serotonin in rats (13). While the SSRIs increase CNS serotonin, they have no effect on the catecholamines. These drugs may interact with the dopaminergic system since there have been case reports of akathesia, dystonic reactions, and Parkinson-like syndromes. Fluoxetine has no affinity for the opioid, GABA-benzopine, cholinergic, histaminergic, or a- or b-receptors (7).
The FDA has approved of fluoxetine for use in the treatment of depression and of obsessive compulsive disorder. The recommended initial dose is 20 mg / day. Fluoxetine inhibits the hepatic cytochrome P450 system and concomitant therapy with drugs also metabolized by this enzyme system, including phentermine, may lead to deleterious drug interactions. Due to the relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 - 6 days after chronic administration) and its metabolite norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration) drugs prescribed following discontinuation of fluoxetine may nonetheless interact with fluoxetine or norfluoxetine (8).
Phentermine-Fluoxetine Combination Therapy in Obesity-Mechanisms of Action and Pharmacokinetics
The combination of anorectic agents that work by different mechanisms of action is thought to be more useful than single agents alone by allowing for lower doses of single agents with potentially less side effects. It was also believed that the short term effect of phentermine could be prolonged when combined with a serotonergic agent such as fenfluramine. Weintraub et al. (10) reported that combination therapy with 30 mg / day fenfluramine and 15 mg / day phentermine was as effective as therapy with the individual agents, but the side effects occurred with much less frequency than when the drugs were taken individually. Although the study was small (20 patients in each arm) and suffered high drop out rates (approximately 40%), it was the basis for using the combined regime.
Fenfluramine was withdrawn from the market due to its association with valvular heart disease (3). The histopathologic features of the valve lesions are similar to those of patients with high serotonin levels, suggesting that fenfluramine’s serotonergic effects may be a cause. It is interesting to note that 5/24 patients with the valve lesions had been taking SSRIs (fluoxetine and sertraline). The release of serotonin by fenfluramine, the inhibition of the potassium current in pulmonary artery muscle by fenfluramine, and the interference in pulmonary clearance of serotonin by phentermine are possible mechanisms that may contribute to the drugs’ association with primary pulmonary hypertension, PPH (11).
The market demand for easy weight-loss solutions prompted the industry to develop newer, more effective, and safer drug therapy. One solution proposed was to replace fenfluramine with fluoxetine. The suggested dosage is phentermine at 30 mg / day and fluoxetine at 10 mg / day (5). The main argument justifying the untested use of phentermine and fluoxetine in combination is that fluoxetine is thought to be a safer drug than fenfluramine. Fluoxetine acts upon the central nervous system and, unlike fenfluramine, is not believed to act peripherally. Fluoxetine is known to have a safe drug profile, a reason for which the drug is so widely prescribed. In clinical trials the use of fluoxetine alone has not been shown to be associated with either primary pulmonary hypertension or cardiac valve lesions (12).
Despite the relative safety profiles of fluoxetine hydrochloride and phentermine alone the potential adverse effects of the combination are unknown. There are four possible mechanisms by which these drugs may act synergistically to produce adverse effects. First, fluoxetine, like fenfluramine, affects the serotonergic system. Fluoxetine decreases the uptake of 5-hydroxy tryptamine (5-HT) in rat and human platelets and can initially increase the serum serotonin levels in the rat (13). Its effect on serum levels in humans is unreported. Monoamine oxidase (MAO), the enzyme system that catalyses the conversion of norepinephrine and 5-HT to their deaminated products can potentially be blocked by amphetamines also increasing the levels of serotonin. Because serotonin can potentiate the vasoconstriction produced by noradrenaline, angiotensin II, and histamine (14) these mechanisms could produce acute serotonergic hyperstimulation (such as the serotonin syndrome) or effects due to chronic elevated serotonin exposure (such as hypertension or cardiac valve disease). Second, fluoxetine inhibits the cytochrome P450 enzyme system (15). Because phentermine is cleared by this system, its decreased clearance may lead to higher levels and possibly toxic sympathomimetic effects. Third, amphetamines can increase the uptake and the release of dopamine in vitro. The stereotyped behaviors induced by amphetamines are thought to be due to the release of dopamine (7). There have been multiple case reports of patients on fluoxetine who have developed movement disorders possibly due to the drug’s interaction with the dopaminergic system (16). Finally, and probably most importantly, because the exact etiology of the valvular heart disease and pulmonary hypertension remains unknown, it may be that the combination of amphetamines and serotonergic agents can produce harmful effects by other unknown mechanisms.
Anorectics-Drug Safety
There are no randomized clinical trials examining the safety of the phentermine - fluoxetine combination. Information regarding this combination is limited to one case report and one case series.
The most frequently reported side-effects of phentermine are dry mouth, insomnia, and constipation. In addition to its central nervous system effects (over-stimulation, dizziness, euphoria, tremor, rarely psychotic episodes) the main potential serious adverse side effects involve the cardiovascular system (palpitations, tachycardia, and hypertension). Other side effects include diarrhea, impotence, and changes in libido. Overdoses cause restlessness, tachypnea, hyperreflexia, hallucinations, nausea, vomiting, abdominal cramps, hyper- or hypotension, arrythmias, and circulatory collapse. Fatal overdoses often terminate in convulsions and coma (7).
In the four randomized placebo-controlled clinical trials of obese patients taking phentermine the most common side-effects noted were dry mouth, headaches, and nervousness. No potentially serious or life-threatening were reported during these short-term trials (table 1/references 10, 17-22).
TABLE 1:
Clinical Trials Side Effect Profiles: Phentermine
| STUDY AUTHORS | NUMBER PATIENTS | FIVE MOST COMMON SIDE EFFECTS (%) | NUMBER POTENTIALLY SERIOUS OR LIFE THREATENING EVENTS | |
| PHENTERMINE | PLACEBO | |||
| Truant et al (1972) |
|
|
|
0 |
| Langlois et al. (1974) |
|
|
|
0 |
| Wise et al. (1975) |
|
|
|
0 |
| Weintraub et al. (1984) |
|
|
|
0 |
The most frequently reported side effects of fluoxetine are headache, insomnia, nausea, and nervousness. Potential side effects of fluoxetine involve the central nervous system (seizures, anxiety, nervousness, insomnia, tremor, dizziness, akathesia, dystonic reactions, and Parkinsonlike syndrome), the gastrointestinal system (anorexia, nausea, diarrhea), and the endocrine system (syndrome of inappropriate anti-diuretic hormone). The drug has minimal cardiotoxicity. There have been case reports of angina pectoris, atrial arrhythmias, hypertension, and hypotension and it is difficult to know whether these are nothing more than chance events. Fatal overdose produces nausea, vomiting, tremor and the "serotonin syndrome" (7).
Obese subjects, compared to depressed subjects, are more likely to develop nausea, anxiety, and fatigue. Through the end of March 1986 (12) there has been eight serious and potentially serious adverse events reported in over 1000 obese patients taking fluoxetine as an anorectant. One was a case of an undiagnosed "sense of choking", two were secondary to elevated liver enzymes, and five were cases of skin rashes (none of which were severe enough to require hospitalization). No deaths thought to be due to fluoxetine have been reported in this population. Fatal overdoses are rare, but as of December 1987 two deaths due to overdose had been reported in obese patients taking fluoxetine (8). Both of these deaths were in combination with other drugs (maprotiline, norfluoxetine hydrochloride, codeine, and temazepam).
In the four randomized placebo-controlled clinical trials of obese patients taking fluoxetine hydrochloride the most common side-effects noted in the population were nausea, headache, and asthenia. No potentially serious or life-threatening were reported (table 2/references 23-30).
TABLE 2:
Clinical Trials Side Effect Profiles: Fluoxetine hydrochloride
| STUDY AUTHORS | NUMBER PATIENTS | FIVE MOST COMMON SIDE EFFECTS (%) | NUMBER OF POTENTIALLY SERIOUS OR LIFE THREATENING EVENTS | |
| FLUOXETINE | PLACEBO | |||
| Levine et al. (1987) |
|
|
|
0 |
| Levine et al. (1989) |
|
|
|
0 |
| Marcus et al. (1990) |
|
|
|
0 |
| Daubresse et al. (1996) |
|
|
|
0 |
| Wise et al. (1989) |
|
|
N / A | N / A |
Fewer data are available for the phentermine-fluoxetine hydrochloride combination. There are just one case report (31) and one case series (5, 32) in the MEDLINE database from 1966 through 1997. Eight days after stopping fluoxetine hydrochloride the patient restarted phentermine and developed restlessness, altered mentation, tremor, hyperreflexia, and gastrointestinal symptoms. The authors speculated that the symptoms may have been due to the P450 inhibition by fluoxetine or due to the serotonin syndrome. The case series (letter to the editor) consisted of 557 patients treated with the phentermine-fluoxetine hydrochloride. Three cases of insomnia, 2 cases of palpitations, 1 case of nausea, and 2 cases of hyperglycemia in type II diabetics were reported. No serious side effects were reported.
From the book Safer than Phen-Fen! (5) the side effect profile of the combination drug use in 535 patients treated with phentermine-fluoxetine hydrochloride for obesity (same subjects as in the above published case series) is shown below (table 3). Unfortunately no detailed information was provided regarding the episodes of tachycardia or partial amnesia.
TABLE 3:
Side Effect Profile of Phen-Pro As Seen In 535 Patients
| SIDE EFFECTS: |
FREQUENT (MORE THAN 30 PERCENT OF PATIENTS)
|
MODERATELY FREQUENT (10 - 30 PERCENT OF
PATIENTS)
|
RARE (FEWER THAN 10 PERCENT OF PATIENTS)
|
Multiple studies have shown that obesity drugs, either alone or in combination, produce both short-term (weeks) and long-term (several months to years) weight loss. An early meta-analysis (33) examined 200 placebo-controlled trials using anorectic agents. The analysis included results from 10,000 patients. A larger portion of subjects treated with anorectics lost weight compared to subjects treated with placebo and dietary intervention. Subjects treated with anorectic agents lost 0.23 kg/week more than the placebo-treated subjects. No efficacy differences were shown between different classes of anorectic drugs.
We examined all the randomized double-blind placebo-controlled clinical trials in obese patients being treated with either phentermine or fluoxetine hydrochloride available in the MEDLINE database 1966-1998 (table 4/references 10, 17-22 and table 5/references 23-30).
The most effective dose of phentermine is 30 mg/day. These studies suggest that on average, fluoxetine-treated patients continue to lose weight for duration of treatment. Rebound weight gain is reported once the phentermine is stopped.
TABLE 4:
Double - Blind Placebo Controlled Clinical Trials: Phentermine
| DOSE
|
|
|
|
DIFFERENCE IN WEIGHT LOSS | DIET RESTRICTION | REFERENCE | ||
|
|
|
|
|
|||||
| 30 mg / day |
|
|
|
|
|
|
9 kcal / lb | Traunt et al. (1972) |
| 30 mg / day |
|
|
|
|
|
|
1000 kcal / day | Langlois et al. (1974) |
| 30 mg / day |
|
|
|
|
|
|
1000 kcal / day | Wise et al. (1975) |
| 30 mg / day |
|
|
|
|
|
|
none | Campbell et al. (1977) |
| 30 mg / day |
|
|
|
|
|
|
20 kcal / lb of ideal body wt. | Weintraub et al. (1984) |
|
|
|
|
|
|
|
|
hypocaloric diet | Tuominen et al. (1990) |
The most effective dose of fluoxetine is 60 mg/ day. These studies suggest that on average, fluoxetine-treated patients lose weight for 20 - 28 weeks, but fail to lose additional weight thereafter. These studies suggest that once the fluoxetine treatment is terminated that the patient rapidly regains the weight.
TABLE 5:
Double - Blind Placebo Controlled Clinical Trials: Fluoxetine
hydrochloride
| DOSE
|
|
|
|
DIFFERENCE IN WEIGHT LOSS | DIET RESTRICTION | REFERENCE | ||
|
|
|
|
|
|||||
| begin with 20 mg / day & increase to 40 - 80 mg / day |
|
|
|
|
|
|
reduce calorie consumption by 20% | Levine et al. (1987) |
| 10, 20, 40 or 60 mg / day |
|
|
|
|
|
|
none | Levine et al. (1989) |
| 60 mg / day |
|
|
|
|
|
|
based on individual | Marcus et al. (1990) |
| 60 mg / day |
|
|
|
|
|
|
1200 - 1600 kcal / day | Daubresse et al. (1996) |
| 65 mg / day (mean dose) |
|
|
|
|
|
|
decrease food intake by 20% | Ferguson et al. (1987) |
| N / A |
|
|
|
|
|
|
N / A | Wise et al. (1989) |
| 60 mg / day |
|
|
|
|
|
|
1400 kcal / day | Daubresse et al. (1990) |
| 60 mg / day |
|
|
|
|
|
|
N / A | McGuirk et al. (1990) |
While both treatments appear to be effective, difficulties arise in comparing the trials because of the heterogeneity of the study population, the duration of treatment, and the variability in other treatment interventions.
Most trials have been short-term trials. The only published long-term trial used the fenfluramine-phentermine combination and demonstrated continued weight loss in patients maintained on the drug regime for four years (33, 34). Because weight gain occurs once drug treatment is stopped and maintenance on treatment prevents rebound weight gain long-term therapy is suggested by most experts in the field. Intermittent therapy was associated with weight-cycling and more reported side effects of the medications.
In the one case series (32) in the medical literature regarding the efficacy of Phen-Pro in obese patients, the author reports that a total weight loss of 3645 kg in 557 patients over two years. No other data are available and thus the information is uninformative.
No clinical trial data is available in the medical literature regarding the efficacy of the phentermine-fluoxetine combination.
Cost Effectiveness
Based on retail prices (35) the cost to treat subjects with phentermine is $0.08/day, fluoxetine hydrochloride is $6.75/day, and phentermine-fluoxetine hydrochloride combination is $2.26/day. Despite being less costly than using fluoxetine hydrochloride alone, the decision to use the combination therapy ultimately needs to be based on clinical trials to assess the efficacy and safety profile of this drug regime.
Summary
At the suggested doses of fluoxetine 60 mg / day and phentermine 30 mg / day, no serious side effects were reported during relatively short-term clinical trials; however many patients suffered from unwanted side effects at these dosages. Phentermine commonly caused dry mouth, headaches, and nervousness whereas fluoxetine caused nausea, headaches and asthenia. It seems reasonable that lower doses (phentermine 15 md / day combined with fluoxetine 10 mg / day) would produce fewer side effects. This is a sensible argument for using low dose combined therapy. There remain theoretical reasons that the combination may have harmful long-term sequlae. This is of particular importance since anorectic therapy is suggested for use in lifelong therapy as weight tends to be regained after termination of drug therapy. Only one trial examined the long-term use of fluoxetine (52 weeks). For these reasons it would be useful to have animal studies which are able to demonstrate the safety of the drug combination before this combination is used by obese patients.
The efficacy of phentermine and fluoxetine indicate their usefulness in the short-term treatment of obesity. By using two drugs working through different mechanisms of action it may be that combination therapy is more effective. In the trial by Weintraub et al. (10), no significant differences in efficacy were found when patients were treated with combination therapy compared to single agent therapy. If the drug combination of phentermine and fluoxitine were safe, it would be useful to have clinical studies which demonstrate its efficacy over single agents. Currently fluoxetine is not FDA-approved for treatment of obesity; however, after review of the clinical trials in obese patients treated with fluoxetine, it appears that the drug is a safe alternative treatment for obese patients.
In conclusion, many questions remain unanswered. There are theoretical reasons that the combination may be potentially useful and also potentially harmful. Until adequate animal studies and clinical trials demonstrate that the combination does not produce adverse effects, single agent therapy alone is probably the safest drug choice for the treatment of obesity.
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35.Correspondence Corrbett Drugs March 2,1998.