Thank you for the opportunity to speak today. My name is Dr. Megan Polanin. I am a Senior Fellow at the National Center for Health Research. Our research center analyzes scientific and medical data and provides objective health information to patients, providers, and policymakers. We do not accept funding from the drug or medical device industry, and I have no conflicts of interest.
Opioid withdrawal symptoms affect functioning and quality-of-life for both patients with OUD and those who take opioids appropriately. Withdrawal symptoms deter patients with OUD from seeking treatment and contribute to their continued use of opioids.
We can all agree that there is an unmet need for non-opioid alternatives. FDA scientists stated that these alternatives must show substantial evidence of effectiveness that they facilitate completion of opioid withdrawal management.
If approved for both of the proposed indications, lofexidine would be the first non-opioid approved for treating opioid withdrawal and the only product approved to support completion of opioid discontinuation treatment. This drug would set a standard for future drugs to meet. Thus, it is important for this committee and the FDA to make decisions based on sound science and strong data.
We have concerns about the efficacy and safety of this drug:
The data provided offer limited information about lofexidine’s efficacy. For study 3002, treatment time was 5 days, and only half of patients who took the drug completed the treatment period. In the 3003-1 study, treatment time was 7 days, and only 41% of patients who took the drug completed this treatment period. Generally speaking, patients who took lofexidine reported lower severity of opioid withdrawal symptoms (at day 3 for study 3002; at day 7 for study 3003-1) and completed treatment at higher rates compared with placebo groups for up to 7 days.
What are the implications for the real world? Treatment took place in controlled, inpatient settings, so we don’t know how well this drug would work in other settings. Benefits were demonstrated only in patients discontinuing opioids abruptly, so we cannot assume that this drug works for gradual opioid tapering, which is a common practice. Finally, we don’t yet know whether lofexidine will continue to help reduce withdrawal symptoms or discontinue opioid treatment after one week.
Lofexidine use is associated with cardiac-related safety issues. The sponsor’s current data as well as data from the UK show that there are cardiac-related safety issues, particularly at the higher 32 milligram dose. They included low blood pressure, orthostatic hypotension, syncope, and bradycardia. Females taking lofexidine were at higher risk of developing hypotension and bradycardia and were twice as likely to experience syncope.
These cardiac events could have implications for severe cardiac events in the real world. In the current studies, these events were bothersome enough to make patients quit taking lofexidine. In many cases, cardiac events were sufficiently severe for doctors to stop administering the drug. Keep in mind that individuals who had cardiac issues, such as uncontrolled arrhythmia, high blood pressure, low heart rate, and symptomatic bradycardia were excluded from at least study 3002. Thus, we do not know how this drug would affect patients with existing cardiac problems.
Today the committee must decide whether the current data support lofexidine’s efficacy and whether the benefits of this drug outweigh its risks — and if so, for whom? Data show that this drug can provide symptomatic relief of opioid withdrawal symptoms for up to 7 days. Reducing opioid withdrawal symptoms for this long may be sufficient to help people get off opioids temporarily. However, this is only one element of addiction management: What is most important is helping individuals stop taking opioids completely.
The sponsor’s proposed second indication is that lofexidine facilitates completion of opioid discontinuation treatment. However, they have provided no long-term data to support that indication. Ideally, this drug should be used as part of long-term treatment for managing opioid use disorder after a patient stops taking opioids. We respectfully urge you to let the FDA know that they should require evidence that this drug helps patients complete opioid discontinuation treatment rather than approving this indication based on the current data.
In summary, patients undergoing opioid withdrawal need non-opioid effective treatment alternatives. In order to ensure the we are doing more good than harm, the FDA must ensure that treatments show substantial evidence of effectiveness. Current data indicate that lofexidine can successfully provide short-term relief of patients’ opioid withdrawal symptoms following abrupt discontinuation. However, due to cardiac safety risks, this drug should not be indicated for individuals with existing cardiac conditions, and if approved, there should be a clear warning on the drug’s label. Finally, the sponsor has not provided sufficient evidence that lofexidine increases the likelihood that individuals will complete withdrawal treatment and, ultimately, move toward ending their physical dependence on opioids. We believe they must do so in order to receive this indication.
Thank you for the opportunity to share our perspective.
The Psychopharmacologic Drugs Advisory Committee voted 12-0 that the data provided substantial evidence of effectiveness of lofexidine for the mitigation of symptoms associated with abrupt opioid withdrawal and 11-1 for approval of the drug application. For the second voting question, committee members expressed concern that, though current data indicated that lofexidine can successfully provide short-term relief of patients’ opioid withdrawal symptoms following abrupt discontinuation, there is a lack of evidence to show that lofexidine increases the likelihood that individuals will complete withdrawal treatment. Read more about the meeting here.