FDA Panel Debates CV Safety of Opioid Constipation Drugs

Pauline Anderson

June 13, 2014

The Food and Drug Administration (FDA) should not require randomized controlled cardiovascular outcomes trials for peripherally active mu opioid receptor antagonists (PAMORAs) that are being developed for the treatment of opioid-induced constipation (OIC) in patients with chronic noncancer pain, according to a recommendation by members of the FDA's Anesthetic and Analgesic Drug Products Advisory Committee.

During a day and a half–long meeting, committee members agreed that the issue of cardiovascular safety that was raised earlier with alvimopan (Entereg, Cubist Pharmaceuticals Inc) was not class specific and that the safety of other related drugs could be assessed during postmarket observational studies.

"It is the sense of this committee that there is insufficient information to determine the presence or absence of a class effect," commented committee chair, Randall P. Flick, MD, director, Hospital Operations and Quality, and associate professor, anesthesiology, Mayo Clinic Children's Center, Rochester, Minnesota. "The absence of a class effect would tend to favor a sense that the effect is limited to one study."

Myocardial Infarction Imbalance

That 52-week study of more than 800 patients (GSK014) found that more patients taking alvimopan than placebo experienced a myocardial infarction (MI), with 7 events on treatment vs 0 with placebo. It is because of this imbalance that alvimopan was approved with a risk evaluation and mitigation strategy (REMS) label and is only used short term in the hospital after surgeries that include partial bowel resection with primary anastomosis.

In light of this cardiac signal, the committee was asked to consider how extensive cardiovascular safety assessments for opioid antagonists should be, including the necessity, timing, design, and size of cardiovascular outcome trials.

The FDA had asked committee members to discuss whether data suggest a cardiovascular safety signal associated with the use of PAMORAs, the strength of such a signal and whether it's related to just 1 drug, and where there the signal has a plausible biological explanation.

Most opioids are relatively selective for the mu receptors (as opposed to delta or kappa receptors), which are expressed in the central and peripheral nervous system, with multiple lines of evidence indicating that these receptors are expressed in cardiac and vascular tissues.

Activation of mu receptors leads to analgesia but also such adverse effects as sedation, respiratory depression, dependence, and bowel dysfunction. PAMORAs target peripheral receptors in the gastrointestinal tract.

An estimated 116 million adult Americans have a common chronic pain condition that is increasingly being treated with an opioid. OIC is one of the most common adverse effects of opioid therapy; according to 1 study cited in the FDA briefing document made available to committee members, OIC affected an average of 41% of patients taking an opioid for up to 8 weeks.

Symptoms Persist

In his presentation to the committee, Bill McCarberg, MD, president, Western Pain Society, and president elect, American Academy of Pain Medicine, said constipation and related symptoms persist in many patients despite laxative use. Available options are inadequate for a good deal of these patients, he told the committee.

Other than alvimopan, the only FDA-approved peripherally selective opioid receptor antagonist is methylnaltrexone (Relistor, Salix Pharmaceuticals Inc), which is used to treat OIC in patients with advanced illness receiving palliative care. That drug and others are being developed for OIC in patients with chronic pain that is not associated with advanced illness.

During the meeting, the committee heard from 5 sponsors: Cubist and Salix as well as AstraZeneca (naloxegol [Movantik]), Theravance Inc (axelopran, formerly TD-1211), and Develco Pharma Schweiz AG (naloxone, approved for the treatment of opioid overdose). Over and over, presenters stressed that no definitive conclusions can be drawn with regard to an association between the long-term use of their drug and the risk for cardiovascular adverse events.

Speakers also stressed that randomized controlled studies on cardiovascular outcomes would be expensive, time-consuming, and difficult to interpret because of the low cardiovascular incidence rate in this population and the high study dropout rate.

No Undue Risk

Addressing the committee on behalf of the sponsors, William Mezzanotte, MD, vice president, Global Medicines Development, AstraZeneca, said that given the totality of the safety data, their position is that "PAMORA use over and above that of chronic opioid use alone does not represent an undue excess risk to the intended treatment population."

Therefore, he added, "PAMORAs that demonstrate a favorable benefit-risk profile in phase 3 studies can be safely approved for the treatment of chronic opioid-induced constipation in patients with no cancer pain, without the need for cardiovascular outcome trials."

In their vote on this issue, most committee members agreed that such outcome trials aren't warranted. They felt that with the exception of alvimopan, cardiovascular safety going forward can be assessed postmarket, but that these trials should be at least 1 year in length to assess long-term outcomes.

John Teerlink, MD, director, Heart Failure Program, and director, Clinical Echocardiography, San Francisco Veterans Affairs Medical Center, California, called alvimopan "the canary in the coal mine." Many members commented that the committee would not be assembled at all if not for the 1 alvimopan study.

Safety Signal

Although there were mixed opinions, slightly more committee members agreed that a cardiac safety signal does exist, although almost all felt it was weak and possibly ambiguous. However, some thought that even a weak signal can't be ignored because, unlike something like nausea, it's a severe adverse effect.

"Given that the consequences could be life threatening, I think we have to err on the side of treating this as a signal and do further investigation," commented Mitchell S. Cappell, MD, PhD, chief, Division of Gastroenterology & Hepatology, William Beaumont Hospital School of Medicine, Royal Oak, Michigan.

On the other hand, some members, for example, Milton Packer, MD, Stoffel Distinguished Chair in Cardiology, and professor and chair, Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, felt strongly that there wasn't a signal at all. But if there was a signal, said Dr. Packer, "the only way it will go away is with a randomized clinical trial."

Many committee members repeatedly expressed a concern about the lack of cardiovascular data, at least 1 member calling this dearth "striking."

"I have a message for sponsors," said Dr. Teerlink. "From now on, do your trials with prospectively defined cardiovascular outcomes and aggressively follow up, even if people stop taking the study drug."

Biological Mechanisms

The committee members also discussed the biological mechanisms that might explain the imbalance in MI events in the GSK014 study. These included an opioid withdrawal-related increase in sympathetic autonomic activity, hemodynamic changes, and the effect of off-target receptor affinity for opioid receptors on the heart.

The debate also included the cardiac effect of the stressing and straining of constipated patients, many of whom go off their opioid just to have a bowel movement.

Most felt that there was insufficient evidence to implicate any of these possible mechanisms."The quality of the evidence is insufficient to definitively rule out these mechanisms or any other," said Dr. Flick.

The spike in MI events uncovered by the GSK014 study remains a mystery. Not only is there a lack of obvious biological mechanism, but, as committee members heard, there does not appear to be any real pattern related to patients at risk or to the timing of the cardiac event, and no cardiovascular surrogate markers of risk. Thus, unknown mechanisms and "play of chance" are still possible contributors.


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