Tag Archives: Vivitrol

11/30/21

Not as a Stand-Alone Therapy

© lekcej | 123rf.com

The pharmaceutical company Alkermes began planning an alcohol dependency awareness campaign before the pandemic, but its launch in May of 2021 coincidently happened to overlap with the publicity of increasing of alcohol use and misuse during the pandemic. Fierce Pharma noted that while all drinking is not problematic, spikes in binge drinking particularly among women, are causes for concern. The Alkermes campaign emphasizes that alcohol dependence is a disease, not a moral failing. The VP and general manager of addiction marketing at Alkermes said, the disease model was useful for people to see problem drinking as a medical condition, “that there are medical criteria that you can assess and look at your own situation and make informed choices.”

The campaign initially centered on a new website that asks on the front page, “Is it time to rethink your relationship with alcohol?” There are personal stories of people’s “journey with alcohol dependence and recovery.” There is a link to a questionnaire developed by the National Institutes of Health (NIH) that was based on the criteria for alcohol dependence outlined in the DSM-IV. Finally, there is a link to “Learn more about a treatment option,” which leads you to a separate website for Alkermes’ addiction drug, Vivitrol. But there is more going on here than just following a breadcrumb trail from a public service campaign to a treatment option for alcohol dependence.

If you follow the link to the Vivitrol website, you are asked if you are ready for the next step in your recovery. What follows is largely a repeat of information that is contained in the medication guide for Vivitrol. Even though this Alkermes ad campaign is aimed to treat alcohol dependence, there is a significant amount of time spent there describing and discussing the risk of opioid overdose and sudden opioid withdrawal. What you won’t find on the website is information on exactly how Vivitrol treats alcohol dependence! Why would a marketing campaign for an alcohol dependence treatment spend so much effort cautioning against how Vivitrol could create safety issues with opioids?

Because Alkermes has been known to gloss over safety risks in its promotion of Vivitrol to treat opioid addiction. Not only is Vivitrol used to treat alcohol dependence, it is also approved as a medication-assisted treatment for opioid use disorder.

The FDA previously cited Alkermes in a warning letter for omitting safety risks in an ad for Vivitrol. “In the letter, the agency said it had contacted the company twice before issuing the warning.” The FDA was concerned enough with Alkermes’ apparent disregard of it previous letters that it also issued a press release that announced this action. The press release said Alkermes had omitted warnings about the most serious risks associated with the drug from promotional materials.

While the print advertisement contains claims and representations about the drug’s benefits, it fails to adequately communicate important warnings and precautions listed in the product labeling, including vulnerability to opioid overdose, a potentially fatal risk.

What you won’t find on the new Vivitrol website or in the Vivitrol medication guide is information on exactly how it treats alcohol dependence and what are the specific concerns in using Vivitrol to treat alcohol dependence. The active ingredient in Vivitrol is naltrexone, which has been used to treat alcohol use disorder for over twenty years. It works by suppressing cravings for alcohol and opioid drugs. It does this by binding to opioid receptors in the person’s brain, which also removes any opioid drugs binding with these receptors and can precipitate sudden opioid withdrawal. The medication guide for Vivitrol cautions that anyone receiving the drug should be opioid-free for at least 7 to 14 days before receiving Vivitrol, since the injection “may cause you to suddenly have symptoms of opioid withdrawal.”

The American Addiction Centers website said the following about naltrexone and naltrexone’s effectiveness:

Individuals with moderate to severe alcohol use disorders [i.e., alcohol dependence] who are using naltrexone may experience withdrawal symptoms if they stop drinking that can be potentially fatal due to the development of seizures. These individuals should consult with an addiction medicine physician or psychiatrist before discontinuing their use of alcohol. Research findings are mixed, but overall, they tend to support the notion that individuals who use naltrexone to treat alcohol abuse reduce the total amount of alcohol they consume and observe a reduction in the number of times they drink alcohol. In addition, heavy drinkers often notice significant reductions in alcohol use. However, the research does not indicate that the use of naltrexone is effective at assisting individuals in remaining totally abstinent, but it does most likely result in a significant reduction in cravings for alcohol and an overall reduction in the amount of alcohol consumed.

Counterintuitively, naltrexone products like Vivitrol are not effective in helping someone abstain from alcohol. But as the American Addiction Centers website noted, it is used in the Sinclair Method to help the individual reduce their alcohol intake. This “treatment” method actually encourages individuals to drink, but only after taking naltrexone before they start drinking. Naltrexone blocks endorphins from being released when alcohol is consumed. Endorphins are naturally occurring opiates in the brain. “When the endorphins are blocked, there is no ‘buzz’ or rewarding experience, and the alcohol doesn’t make you feel the pleasure that drives you to drink excessively.”

The Sinclair Method sees alcoholism as primarily a learned behavior that can be extinguished by naltrexone systematically closing off this reward circuit in the brain. But naltrexone (as ReVia or Vivitrol) does not close the door on how alcohol effects functional impairments, such as a loss of motor coordination, decreased response time, slowed rate of thinking and judgement. ReVia is a tablet or capsule of naltrexone that you take about an hour before you plan to drink and can be skipped if you plan on drinking and want to feel the euphoria from drinking. With Vivitrol, you have some level of naltrexone in your system for up to a month, meaning that the blocking effect when drinking is stronger the closer you are to when you received your Vivitrol shot.

Vivitrol may be effective in reducing your overall alcohol intake when drinking, but it does not seem to be effective in helping you remain totally abstinent. Moreover, if your alcohol intake is substantial enough, and Vivitrol successfully helps you reduce your craving for alcohol and the amount of alcohol you consume too rapidly, using it can result in seizures and other alcohol withdrawal symptoms. If you use or abuse opioids along with drinking alcohol, Vivitrol can also throw you into sudden opioid withdrawal. It also decreases your tolerance level for opioids and makes you vulnerable to opioid overdose, if you use opioids.

Above, I noted where the Alkermes campaign for Vivitrol as a treatment for alcohol dependence emphasized it was a medical condition with criteria that could be assessed by an individual as they make an informed choice on whether Vivitrol was right for them. Alcohol dependence is never just a medical condition. And recovery is not simply learning to abstain or drastically curtail your alcohol use. It is also about making radical changes in your feeling, thinking and behavior around alcohol. To its credit, Alkermes did emphasize that for Vivitrol to be effective, it must be used with other alcohol or drug recovery programs. So, Vivitrol may work in some cases with alcohol abuse, but not as a stand-alone therapy for alcohol dependence.

Remember the final advice Alkermes gives: “Vivitrol may not work for everyone.”

01/23/18

Opioid Epidemic Price Gouging

© Karen Roach | 123rf.com

The FDA recently approved Sublocade, the first once-monthly buprenorphine injection in its fight against the opioid epidemic. Indivior, the company which also sells Suboxone film, projected it would be available on the market sometime in the first quarter of 2018. Sublocade is a drug-device combination product. “It is injected by a healthcare professional (HCP) under the skin as a solution, and the delivery system form a solid deposit, or depot, containing buprenorphine.” The initial procedure will to be to start with daily stabilizing doses of Suboxone for at least seven days before the first injection of Sublocade.

After initial formation of the depot, buprenorphine is released by the breakdown (biodegradation) of the depot. In clinical trials, Sublocade provided sustained therapeutic plasma levels of buprenorphine over the one-month dosing interval.

Prescribing information for Sublocade said the recommended protocol was two monthly doses of 300 mg followed by 100 mg monthly maintenance doses. “Increasing the maintenance dose to 300 mg monthly may be considered for patients for whom the benefits outweigh the risks.” Sublocade will come in prefilled syringes of 100 mg and 300 mg. It will carry a boxed warning of the risk of serious harm or death if used intravenously.

The Indivior announcement of Sublocade’s approval indicated Sublocade will be distributed through a restricted distribution system, “which is intended to prevent the direct distribution to a patient.” This restricted release to only healthcare professionals is because of the risk of serious harm or death if someone were to attempt intravenous self-administration of Sublocade. Intriguingly, the boxed warning in the prescribing information wasn’t as clear on the intent of the restricted distribution system to prevent patients from having direct access to Sublocade. The harder it is to get a hold of Sublocade, the harder it will be to figure out a way to hack into the buprenorphine it contains.

The FDA is requiring postmarketing studies to assess four things. First, whether patients would benefit from a higher dose. Second, whether Sublocade can be safely started without a dose stabilization period of Suboxone. Third, to assess the feasibility of administering Sublocade at a longer inter-dose interval than once-monthly. Fourth, to determine a process for transitioning patients stabilized long term on Suboxone film to a monthly dose of Sublocade without the loaded dose in the first two months of treatment.

I assume the study to see if patients would benefit from a higher dose fits into the above prescribing information that maintenance doses could be increased up to 300 mg monthly. But I have this nagging question of whether Indivior felt unsure about the safety risk of maintenance doses above 100 mg. So they wanted to be safe rather than sorry, knowing there was always Suboxone film to supplement Sublocade in a pinch. And postmarketing studies could look at whether higher maintenance doses put people at risk in some way.

The procedure of having an initial “dose stabilization” period on Suboxone before injecting Sublocade helps ensure the individual has really stopped using opioids before their injection. The required postmarketing study will help evaluate whether that’s necessary. My initial thoughts are that given the significant amount of buprenorphine in the depot, clinically the dose stabilization period should remain, especially if this is done when the person is an outpatient. If the person’s pattern of use isn’t stable enough to reach a week of daily Suboxone use, they should probably try inpatient drug treatment to stabilize first before Sublocade.

Depots containing either 100 mg or 300 mg have a significant amount of buprenorphine. So I’m concerned about thoughts of assessing the feasibility of administering Sublocade at longer inter-dose intervals, which would require even higher doses. I guess the thinking behind the longer inter-dose interval study is anticipating of having/keeping Sublocade patients on the treatment for an indeterminate length of time, perhaps years.

Except for the supposed convenience of a once-monthly shot, why would someone who is stable on Suboxone film long term want to switch to Sublocade? If you have demonstrated the discipline, stability and willingness to successfully maintain opioid abstinence with Suboxone, why switch to Sublocade? I do know why Indivior would want you to switch. The average monthly cost for Suboxone is $132, while the average monthly cost for Sublocade is $1,580. The cost for Sublocade puts it in the ballpark for Vivitrol, which costs around  $1,687 per month.

STAT News quoted one addiction professional who said: “It’s potentially a game changer. . . . This could become first-line [medication] for opioid addiction.” But Sublocade is just the first injectable buprenorphine product to be approved. A similar medication, known as CAM 2038, is made by Braeburn Pharmaceuticals and it could be get FDA approval by January 19, 2018. The president and CEO of Braeburn said: “This new technology has the potential to greatly influence the way patients are treated today. . . [It can] free patients from the daily decision and reminder of the disease.” Did this guy ignore or just forget about the Warnings and Precautions on the Sublocade medication guide?

It says: “Buprenorphine can be abused in a manner similar to other opioids; Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with Sublocade.” Pain treatment should be with a non-opioid analgesic whenever possible. “If opioid therapy is required, monitor patients closely because higher doses may be required for analgesic effect.” Sublocade won’t free patients of the daily reminder of the disease, because it is the daily reminder.

STAT said long-acting buprenorphine could make future inroads within the criminal justice system. “In recent years judges, wardens, and health officials have warmed up to Vivitrol, citing fears that daily tablets of buprenorphine can be diverted or abused.” Additionally, the criminal justice system has been more receptive to Vivitrol because Alkermes has been doing targeted marketing with them to promote Vivitrol for a number of years. However, the approval of Sublocade adds a second monthly injectable alongside Vivitrol and potentially could diminish “one of the biggest competitive advantages held by Vivitrol.”

STAT also pointed to another likely financial incentive for Invidior to put Sublocade into the market. Medicaid spending on buprenorphine last year was five times higher than for Vivtrol. But those spending statistics could be partly due to the cost discrepancy between monthly Vivitrol and Suboxone and not the preference for buprenorphine. However, it is likely Invidior will be able to slice off a nice chunk of non-negotiated drug price income for Sublocade from Medicaid.

Another STAT article discussed a study published in The Lancet, Lee et al., that found both Vivitrol and Suboxone had comparable effectiveness outcomes during 24 weeks of outpatient treatment. STAT quoted Dr. Nora Volkow, director of NIDA as saying she hoped the study will change the widespread prejudice patients don’t do as well on naltrexone as they do on buprenorphine.  Apparently it didn’t. In the very same STAT article, two different doctors, not involved in the study, said the study showed buprenorphine was more effective than Vivitrol. However, the lead author of the study, Dr. Joshua Lee told STAT: “Both medications worked quite similarly and, therefore, both should be discussed as treatment options.”

The study findings pointed to by the two doctors included the following: its easier to initiate and patients stay with the treatment (buprenorphine) longer. Fewer participants successfully started Vivitrol treatment, as it required a three day period for detoxification, whereas Suboxone participants could begin as soon as the onset of withdrawal symptoms began. The differences in induction rates were 72% for Vivitrol and 94% for Suboxone.

Naltrexone (Vivitrol) is an antagonist, meaning if there were residual levels of opioids in a participant’s body they would immediately be thrown into acute withdrawal. The delay was medically necessary. Naltrexone is also not an opioid, while Suboxone (buprenorphine) is. The induction period with Vivitrol was expected by the study authors themselves to be more difficult. They didn’t get the easement of acute opioid withdrawal that the Suboxone group did—and yet, 72% were successfully inducted into the study.

Curiously one individual pointed to where many of the overdoses in the study occurred after detox, apparently indicating more occurred with Vivitrol. Yet she failed to comment on the fact that of the five fatal overdoses in the study, THREE were in the Suboxone group!

There were more relapse events (defined as 4 consecutive weeks of any non-study opioid use by urine toxicology or self-report, or 7 consecutive days of self-reported use.) for the Vivitrol group, but “most or all of this difference [was] accounted for by early relapse in nearly all (70 [89%] of 79) XR-NTX induction failures.” The more difficult time intiating patients into Vivitrol treatment effected the over relapse rates. “However, once initiated, both medications were equally safe and effective.”

The Lee et al. study was actually the second study to demonstrate that Vivitrol was as effective as Suboxone in maintaining short-term abstinence. The previous study was a smaller Norwegian study, Tanum et al., that followed its participants for 12 weeks. The bottom line is replicated results are more difficult to rationalize away.

Diversion and abuse of Suboxone has been evident from the time it was approved by the FDA. The approval of Sublocade would hopefully nullify the diversion and abuse problems experienced with Suboxone, if you have the money or insurance for it.

Bringing buprenorphine into the realm of “a restricted delivery system” to prevent direct distribution to patients also seems to be where some justification for the added cost factor comes in. But I wonder to what extent dispensing Vivitrol and Sublocade in a medical setting can justify the high cost. Is there price gouging going on? This is now the second time that technological innovation has extended patent exclusivity for Indivior’s buprenorphine products. Read more about how Reckitt Benckiser, the parent company to Indivior and Indivior itself accomplished this in “The Opioid Buzzard.”