"buprenorphine sublingual products have been
increasingly identified in the illicit drug market, and it is known that they are diverted,
abused, and misused. Additionally, they have been implicated in an increasing number of
cases of accidental poisonings of young children. Therefore, a depot injection or an
implantable product which would be difficult to divert or abuse, and would be less likely
to be accidentally ingested by young children, offers potential advantages. In addition,
patients could not periodically discontinue use in order to allow the blocking effect to
dissipate, so that they could experience the effects of their opioids of choice. Probuphine
was developed to address these issues."
"The Division agreed with
the Applicant that Probuphine had the potential to meet an important public health need
because implants would be more difficult to divert, and because young children are less
likely to be accidentally exposed to an implanted rod than to sublingual formulations.
This application has been accorded Priority Review status in recognition of this potential."
"In general, the common adverse events associated with Probuphine treatment were
similar to those seen with sublingual buprenorphine treatment. The hepatic effects and
effects on cardiac conduction were also consistent with buprenorphine’s expected effects.
The most notable adverse events for Probuphine were related to the implants themselves
and to the surgical procedures related to insertion and removal.
In a safety database comprising 262 patients treated with Probuphine, 6 (2%) experienced
expulsions or extrusions of implants. Five patients discontinued treatment due to implantsite
adverse events. No patients treated with placebo implants experienced expulsions,
extrusions, or AEs leading to discontinuation, suggesting that the irritancy of
buprenorphine could play a role in these implant site adverse events. More minor
implant-site AEs were reported in a significant number of study partic
Areas of concern:
"Ultimately, it is necessary to weigh the benefits against the risks, either known or not-yetcharacterized.
Does Probuphine work well enough to outweigh these concerns?
Probuphine-treated patients were more likely than patients treated with
placebo to complete the study and were less likely to require the frequency of
sublingual buprenorphine administration that met criteria for “treatment
However, only 32% of Probuphine-treated patients in Study PRO-805
and 27% in Study PRO-806 submitted opioid-negative samples for
even half of the urine tests.
On the other hand, 23% of the Probuphine-treated treated patients in
Study PRO-805 and 27% in Study PRO-806 had 5% opioid-negative
samples or fewer.
Even after for allowing for four months of “grace period,” only 29% of
Probuphine-treated patients in Study PRO-805 and 23% in Study
PRO-806 submitted opioid-negative samples for even half of the urine
tests during the last two months of treatment. Applying a stricter
definition of 75% opioid-negative samples after four months of
“grace,” 14% in PRO-805 and 16% in PRO-806 would be considered
The dose of buprenorphine delivered by 4 Probuphine implants is less than a
third of the dose delivered by 16 mg sublingual buprenorphine. It is possible
that the dose is sufficient to provide some agonist effects but not to block the
effects of exogenous opioids. Potentially, Probuphine could deliver just
enough buprenorphine to allow patients to continue to use illicit opioids
without experiencing withdrawal when they stop. Patients who do not
considerably modify their drug-taking behavior may not accrue significant
benefit from Probuphine treatment."