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.”