Weighing the Benefits of Reformulated Medications

I sometimes get depressed myself (just a little!) when I see the latest offerings from pharmaceutical manufacturers. There are many new medications, but almost all are re-workings of familiar molecules-typically launched just before patent life is about to expire on the original formulation.

Because I serve as a member of the pharmacy and therapeutics committees of several health insurers in addition to caring for patients as a psychiatrist, I need to keep up on all new pharmacological offerings in the behavioral health area from both a clinical and a cost perspective. My initial position is always that new formulations may or may not offer significant advantages, and may or may not be worth a price differential. If the new formulation does not offer much of an improvement in efficacy or safety, or fewer adverse effects for most patients, unfavorable drug formulary tiering and/or restrictive preauthorization requirements may be implemented.

Here I discuss 2 recent launches of reformulated products offered to patients, prescribers, and third-party payers. My purpose is not to evaluate these new medications fully or set myself up as an expert and final arbiter on either formulation. Rather, it is to share the perspectives in play when new drugs come along that are based on existing products.

Pristiq (desvenlafaxine) is a new antidepressant whose active ingredient is the main metabolite of Effexor XR (venlafaxine extended release). Effexor XR recently lost patent protection after generating $3.8 billion in sales in 2007. However, if there are advantages to using the metabolite, why not recognize the brand manufacturer for having a better product? Let us first consider the issue of efficacy. Because desvenlafaxine is the major active metabolite of venlafaxine, it is no surprise that studies show that it works better than placebo for major depression. However, there are no published head-to-head studies of desvenlafaxine versus venlafaxine extended release. Thus, one preparation has extensive clinical use and will be available at less cost than the new brand-name medication, and there are no data about relative efficacy. But because desvenlafaxine is the major active metabolite, aren’t patients already getting it when they take venlafaxine?

The manufacturer maintains that patients can improve by taking the initial daily dose of 50 mg and do not need to have their dose titrated upward, as often needs to be done with patients taking venlafaxine extended release. That may be an important consideration for busy prescribers. However, patients receiving a starting dose of 75 mg of venlafaxine extended release in the original venlafaxine trials also did better than those receiving placebo, comparable to 50 mg of desvenlafaxine versus placebo, so we are left wondering about any advantage for the new preparation. A psychiatrist considers in his blog whether efficacy of the 2 preparations would be found to be similar if measured or if the new preparation might be shown to be less effective.¹ This is because dosages greater than 50 mg daily of desvenlafaxine seem to result in diminished efficacy in clinical trials whereas venlafaxine extended release shows improved efficacy at higher dosages.

In any event, there may be other advantages for Pristiq because it does not have to be metabolized through complicated enzyme systems in the liver. Certain patients, because of genetic variation, may not have the requisite enzymes to break down venlafaxine and might benefit only from desvenlafaxine. Also, it is theoretically possible that the metabolite will have the same efficacy as the parent compound but with fewer adverse effects. If, for example, desvenlafaxine turns out to have fewer adverse effects on sexual function or to result in less long-term weight gain, then it might have an important place in clinical use.

Invega (paliperidone) has been approved by the FDA for the treatment of adults with schizophrenia. Paliperidone was found to be better than placebo at reducing the symptoms of schizophrenia based on a sample size of 1420 patients in 4 studies. It was also found to improve social functioning based on trials involving 884 patients, again in 4 studies. Those data would be impressive, except that they are totally expected because paliperidone is the active metabolite of risperidone.

Cochrane Reviews recently published a literature review of paliperidone.² The authors’ conclusions were that in short-term studies, oral paliperidone is more efficacious as an antipsychotic than placebo. Adverse effects were similar to those seen with its parent compound, risperidone, including greater risk of movement disorders, weight gain, and substantial increases in serum prolactin levels (and probably related adverse effects on sexual function). At dosages greater than 3 mg/d, oral paliperidone appears to be comparable in efficacy to oral olanzapine at 10 mg/d. The key comparison, of course, is to risperidone, and the Cochrane authors complained that they could find no information and were thus “unable to determine if paliperidone has any advantages or disadvantages compared with its well-known parent compound.”

Conclusion
I recognize that it is extremely difficult to come up with genuinely new medications that work better than existing ones. Often, progress is incremental. I certainly prefer the newer SSRI and serotonin-norepinephrine reuptake inhibitor antidepressants to the older tricyclics or monoamine oxidase inhibitors, even though much of the advance has been in tolerability and safety rather than in efficacy. However, I do hope that pharmaceutical companies spend the requisite research effort to bring us something that really is an improvement rather than just tweaking a molecule here or there for the main purpose of sustaining patent exclusivity and revenue stream.

The way to convince me (and others) that these reformulated new medications offer benefits over existing therapies is to conduct head-to-head comparison studies between any new medication and the related compound it seeks to replace in clinical use. Failing that, we will continue to see much pharmaceutical marketing, but also much “push back” from third-party payers.

References:

References

1. Carlat D. Top 5 reasons to forget about Pristiq. The Carlat Psychiatry Blog. March 1, 2008.

http://carlatpsychiatry.blogspot. com/2008_03_01_ archive. html

. Accessed December 9, 2008.
2. Nussbaum AM, Stroup TS. Paliperidone for the treatment of adults with schizophrenia.

Cochrane Database Syst Rev.

2008;(2):CD006369.

http:// www. cochrane.org/reviews/en/ab006369.html

. Accessed December 9, 2008.