Prescribing and managing the side effects of Duromine (phentermine)

Phentermine (Duromine) is one of the oldest discovered anorectic agents. In 1968 the first randomised controlled trial with the agent resulted in a mean significant weight loss in the active compound group of 12.6 kg over a period of 36 weeks for both continuous and intermittent use compared to 4.8 kg in the placebo group.1

Professor Joseph Proietto of the Endocrine Specialist Centre in Heidelberg, Victoria, said "phentermine works fairly quickly, in maybe one or two weeks."

Phentermine – the safe half of phen-fen

There has been a cloud of uncertainty surrounding phentermine since the discovery of significant associations between valvular heart disease and the potent phentermine and fenfluramine combination (phen-fen) used to treat obesity.² In 1997 fenfluramine was withdrawn from the market, leaving the safe half of the combination, phentermine, to treat obesity alone.³ 

As phentermine was developed around 50 years ago, recent safety and efficacy studies are lacking, leaving a large gap in the literature for the past 20 years.

Professor Proietto said, "Phentermine is a very old drug. It’s off patent now, so you’re not going to have any pharmaceutical companies doing major studies because they cost billions."

Studies during this time instead have been focused on orlistat, sibutramine and the research and development of around 150 new anti-obesity compounds. That said, the multitude of review papers and meta-analyses available suggest that phentermine is safe, well-tolerated and efficacious in treating obesity.³ Moreover phentermine is no longer under patent, making it a more cost effective option than other weight loss medications.⁴

Side effects and medical monitoring

The most serious and common adverse effects associated with phentermine include tachycardia and hypertension. These side effects carry with them strict medical monitoring requirements and contraindications.⁴

Patients taking phentermine need to be monitored regularly for heart rate and blood pressure, even more so for patients predisposed to the cardiovascular side effects of the drug, such as patients with mild hypertension. Close monitoring should occur in all patients for the first month and at any time the dose is titrated.⁴ Patients that will continue the treatment for longer than 3 months must also be monitored closely as there have been no long term efficacy and safety data for the drug beyond the 36 week mark.^1,3

Phentermine use is contraindicated in patients with a history of psychiatric illness such as depression, a history of pulmonary artery hypertension, existing heart valve abnormalities or heart murmurs, moderate to severe arterial hypertension, cerebro-vascular disease or severe cardiac disease, including arrhythmias and advanced arteriosclerosis, monoamine oxidase inhibitors (MAOIs) (or within 14 days following their administration), and hyperthyroidism. The concurrent use of thyroid hormones with phentermine may increase CNS stimulation.⁶

Less risky but common side effects associated with phentermine use include restlessness, dizziness, insomnia, nausea, dry mouth, headache, irritability, nervousness and constipation.^3,6 These effects, if experienced, can last approximately 12–14 hours post dose,^3,6 which is why it is suggested that in order to reduce restlessness and insomnia that the drug is taken in the morning or, in the case of shift workers, at a corresponding time when they have just woken. If the dose is forgotten in the morning it can be taken before lunch, but any time after this will cause sleep disturbances and hence patients should be advised to skip the dose.⁵

Do patients become tolerant to the effects of phentermine?

A patient on phentermine needs to have a medical review after three months;⁶ however, use can be extended if the patient is responding well to the drug at the three month mark. A good basis for this decision is the weight lost; patients responding well will have lost approximately 1.8 kg per month. If patients have not lost at least 1.5 kg in the first six weeks, or 5% of their body weight within six months, pharmacotherapy with phentermine should be reconsidered.⁷

The development of tolerance to phentermine is controversial. While earlier studies report no tolerance to the medication⁸ newer studies have conceded that the effects of phentermine do subside over time and accordingly the weight loss effects of the drug cease after around 6 months.⁴

Interestingly, findings from recent rat studies suggest that there is a degree of cross-tolerance between phentermine and sibutramine; rats pretreated with phentermine were less responsive to the anoretic effects of sibutramine compared to those that were not.⁹ This finding has not been replicated in humans.

Without a long-term randomised controlled trial of phentermine the issue of tolerance cannot be determined. A trial of this nature is highly unlikely now as the drug is no longer under patent. What is known is that after 3–6 months, phentermine’s anorectic effects, and subsequent weight loss, do subside; however, continuation of the drug can be efficacious in preventing weight regain.⁴

Professor Proietto said, "It could be perfectly safe long term but we just don’t know. There was a study in America when they did the phen/fen, where they took it for four years and kept the weight off for four years. Then as soon as they stopped the drug, they regained the weight."

Individual responses to phentermine

Individual side effect profiles and weight loss response to phentermine are variable and seem to be unrelated to the plasma concentration of the drug.¹⁰ The recommended starting dose is 30 mg. This should be titrated to a maintenance dose of 15–40 mg depending on the individual response to the drug.⁶ For some, phentermine may affect their work or lifestyle; for example dizziness may cause work safety issues for those who work with heavy machinery.⁵

References

1. Munro JF, MacCuish AC, Wilson EM, Duncan LJ. Comparison of continuous and intermittent anorectic therapy in obesity. BMJ. 1968; 1: 352-4.
2. Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med. 1997; 337(9): 581-8.
3. Schnee DM, Zaiken K, McCloskey WW. An update on the pharmacological treatment of obesity. Curr Med Res Opin. 2006; 22(8): 1463-74.
4. Kaplan LM. Pharmacological therapies for obesity. Gasteroenterol Clin North Am. 2005; 34(1): 91-104.
5. Duromine (Phentermine) Consumer Product Information. Thornleigh NSW: 3M Pharmaceuticals Pty Ltd, 2000 Dec.
6. Duromine (Phentermine) Product Information. Thornleigh NSW: iNova Pharmaceuticals (Australia) Pty Limited, 2007 May 18.
7. Caterson ID, Finer N. Emerging pharmacotherapy for treating obesity and associated cardiometabolic risk. Asia Pac J Clin Nutr. 2006; 15(Suppl): 55-62.
8. Langlois KJ, Forbes JA, Bell GW, Grant GF. A double-blind clinical evaluation of the safety and efficacy of phentermine hydrochloride (Fastin) in the treatment of exogenous obesity. Curr Ther Res Clin Exp. 1974; 16(4): 289-96.
9. Wellman PJ, Jones SL, Miller DK. Effects of preexposure to dexfenfluramine, phentermine, dexfenfluramine-phentermine, or fluoxetine on sibutramine-induced hypophagia in the adult rat. Pharmacol Biochem Behav. 2003; 75(1): 103-14.
10. Douglas A, Douglas JG, Robertson CE, Munro JF. Plasma phentermine levels, weight loss and side-effects. Int J Obes. 1983; 7(6): 591-5.