Addiction Medicine Practice

 

Alma Saravia
Flaster, Greenberg, Wallenstein, Roderick, Spirgel,
Zuckerman, Skinner & Kirchner, P.C.
Commerce Center
1810 Chapel Avenue West, Third Floor
Cherry Hill, New Jersey 08002-4609

Re: Naltrexone

Dear Ms. Saravia:

You have asked us to review the black box warning which appears in the Revia (naltrexone hydrochloride) package insert (PI), the data supporting that warning and the warning's current clinical relevance. Based on our review, it appears that the black box warning for Revia is based on evidence from a small trial in a population for which the drug is not labeled and in which no clinically-relevant adverse events were noted. The original studies in the within-label patients -- opiate dependent addicts -- do not support the warning. Clinical experience and literature published subsequent to Revia's approval have apparently led the addiction treatment medical community to largely consider these warnings to be unnecessary. Our analysis is provided below.

Revia is an oral tablet dosage form of naltrexone which is FDA approved for both the treatment of alcohol dependence and the effects of exogenously administered opioids. The PI for Revia notes that the black box warning is primarily based on results of a single, small (50 patient), placebo-controlled study in an off-label patient population (obesity patients) using six times the recommended dose. In that study a substantial portion of the Revia patients developed serum transaminase elevations of three to nineteen times baseline within eight weeks of beginning treatment. The clinical relevance of this data is not apparent. The patients demonstrated no clinical signs of liver malfunction, and their transaminase levels returned to or approached baseline values within weeks of discontinuing treatment.

In addition to the PI, we reviewed the FDA Medical Officer's Summary Basis of Approval (SBA) for Revia to search for any additional evidence on the hepatotoxic potential of the drug and FDA's basis for requiring the black box warning. The SBA is an internal FDA document which sets out the reviewer's analysis of the data. The SBA does include a safety review of the obesity trials, and a conclusion based on that data that, at doses four to seven times the recommended dose, Revia "has the potential to cause apparently reversible hepatocellular injury in a substantial proportion of patients to whom it is administered for several weeks" (emphasis added). The dose range referred to by the medical officer would be 200-350 mg per day. The Medical Officer goes on to minimize the relevance of that study to the treatment of opioid addiction and concludes, "Clinical experience using [Revia] in detoxified, formerly opioid dependent individuals at the dose recommended in the [Revia] labeling fails to provide a basis for substantive concern about [Revia's] safety."

Results of the only placebo-controlled study in detoxified opioid dependent patients do not implicate Revia as a hepatotoxin. In that study no new laboratory abnormalities developed and there were no differences detected between the placebo and naltrexone groups. In fact, in summarizing the safety evidence from studies in this population the medical officer stated that "the enumeration of treatment emergent signs, symptoms, and abnormal laboratory findings that occurred in the clinical trials of [Revia] in detoxified opioid-dependent populations did not display a sequence or pattern that implicated [Revia] treatment as the cause of the abnormalities detected." The Medical Officer specifically emphasized that "this statement applies to the occurrence of elevated serum transminase levels."

While FDA did not clearly articulate why a black box warning was included in the Revia PI, such a warning is typically reserved for drugs with a greater quantity and quality of clinical data in the NDA indicating that the drug may be hepatotoxic. The clinical data submitted in the NDA did not show that naltrexone was hepatatoxic in the patients who would actually be administered the drug at the recommended dose.

In 1988, Brahen confirmed the lack of effect of naltrexone on hepatic enzymes of opioid dependent patients. His research involved a within-label group of patients receiving the recommended dose for a period longer than the obesity group submitted in the NDA.

benefit of admitting patients with the sole problem of elevated hepatic enzymes generally exceeds the risk." (J Clin Pharmacol, 28(l)68-70 1988 Jan.)

Moreover, according to Dr. Charles O'Brien, Professor and Chief of Psychiatry at the University of Pennsylvania Veterans Medical Center, Revia is routinely prescribed to detoxified opioid dependent patients without the subsequent liver function monitoring recommended in the black box warning. In fact, Dr. O'Brien noted that notwithstanding the fact that patients in this population often have underlying liver disease due to years of illicit drug use, Revia is routinely prescribed.

It appears from our review that the black box warning for Revia was supported by very tenuous data and has not been found warranted by subsequent research or clinical experience.

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Please let us know if we can provide you with any further information.