RMOC Buprenorphine Long-acting Injection Guidance

19 April 2021On behalf of the national Regional Medicines Optimisation Committee system, RMOC (South) has led development of “Buprenorphine long-acting injection: considerations for opioid substitution treatment use…

Safety in Lactation: Opioid dependence

27 October 2020An assessment of the risks associated with breastfeeding by an opioid-dependent mother, in terms of sustaining successful breastfeeding and possible exposure of the infant to…

Safety in Lactation: Opioid analgesics

21 October 2020The evidence relating to the safe use of opioid analgesics in breastfeeding mothers is very variable between individual drugs. This group of drugs presents a…

What naloxone doses should be used in adults to urgently reverse the effects of opioids?

19 December 2019The opioid antagonist, naloxone, is a highly effective antidote the use of which is potentially life-saving. The drug has a role in a wide range…

How can you minimise the risks of medication errors with buprenorphine patches?

15 April 2019Transdermal buprenorphine patches are widely prescribed and available from a variety of manufacturers. A number of patient safety incidents have occurred in the use of…
Search Articles

Medicine Compliance Aid Stability


Tablets sublingual 400 micrograms, 2mg, 8mg
R2 · Red 2Drug is not suitable for CAs due to theoretical reasons that cannot be mitigated.
Sublingual tablet, unsuitable for storage in MCA.
3 March 2015

TemgesicReckitt Benckiser Healthcare UK Ltd

Reckitt Benckiser Healthcare UK Ltd
Tablets sublingual 200 micrograms, 400 micrograms
R1 · Red 1Stability data indicates that the drug is not suitable for CAs.
Sublingual tablet, unsuitable for storage in MCA.
11 May 2015

SubutexReckitt Benckiser Healthcare UK Ltd

Reckitt Benckiser Healthcare UK Ltd
Tablets 400 micrograms, 2mg, 8mg
R2 · Red 2Drug is not suitable for CAs due to theoretical reasons that cannot be mitigated.
Sublingual tablet, unsuitable for storage in MCA.
3 March 2015

Lactation Safety Information

For pain

For pain
Small amounts in breast milk
Includes combinations with naloxone
Infant monitoring advised, especially in young infants (see summary)
23 September 2020

For opioid dependence

For opioid dependence
Considered safe for short-term use
Small amounts in breast milk
Infant monitoring advised, especially in young infants (see summary)
23 September 2020

New Medicines

Sixmo [EU]; Probuphine [US]Opioid dependence - six-monthly subdermal implant


Sixmo [EU]; Probuphine [US]
New formulation
Accord Healthcare Ltd

Development and Regulatory status

Licensed but not launched
Licensed but not launched
Jun 20Molteni Farmaceutici enters into an exclusive distribution agreement with Accord Healthcare Europe for distribution and commercialisation of Sixmo in the EU. Under the terms of agreement, Molteni is eligible to receive $US1.1 million in future milestone payments and royalty payments on net sales following commercialisation planned in H2 2021 [31].
Jun 20Titan Pharmaceuticals enters into a co-promotion partnership agreement with Indegene Inc. to establish multichannel digital marketing programs throughout the US and expand the capabilities for the engagement of health care providers, who are eligible to prescribe Probuphine implant [31].
Jun 19Molteni plans to progressively launch Sixmo across Europe, accomplishing one of the major milestones of its five-year European strategic plan of growth [30].
Jun 19Approved in EU [29].
Apr 19Recommended for EU approval by CHMP - the full indication is "for substitution treatment for opioid dependence in clinically stable adult patients who require no more than 8 mg/day of sublingual buprenorphine, within a framework of medical, social and psychological treatment.” It is proposed that the product be prescribed by physicians experienced in the treatment of opioid dependence [28].
Nov 17Filed in EU using the centralised procedure [27].
Mar 17EMA confirms that buprenorphine implant is eligible for review and approval under the centralized procedure for the treatment of opioid addiction [25].
Mar 17Titan is in the process of negotiating licensing agreements for development and marketing of the product outside the US [25].
Jun 16Launched in US [25].
May 16Approved in US [22].
Jan 16FDA Advisory Committee recommends approval: target agency action date has been set for February 27, 2016 [21].
Dec 15Meeting scheduled between company and US FDA on Jan 12th 2016 to review the New Drug Application (NDA) for Probuphine® for the maintenance treatment of opioid addiction [20].
Aug 15Following positive results of a final Phase III trial, a New Drug Application has been resubmitted to the US FDA for Probuphine®, an investigational subdermal implant designed to deliver buprenorphine continuously for six months, for the maintenance treatment of opioid addiction [19].
Jun 15Titan Pharmaceuticals to plan to resubmit an NDA to the US FDA late in 2015 and to potentially secure approval during in the first half of 2016 [18].
Mar 15Titan intends intended to obtain marketing approval of Probuphine for treatment of opioid dependence in the US and in Europe [17].
Nov 14Patient enrolment completed in the Braeburn PRO-814 (NCT02180659) study, with 178 patients randomised across 21 clinical research sites. Braeburn anticipates that the trial will be completed by mid-2015, which will be followed by a resubmission of the NDA later in 2015 [16].
May 13The FDA has issued a Complete Response Letter requesting additional data including: the ability of Probuphine to provide opioid blockade of relevant doses of agonists; the effect of higher doses of Probuphine, ideally doses more closely approximating the blood plasma levels associated with sublingual doses of buprenorphine of 12 to 16 mg/day; and human factors testing of the training associated with Probuphine´s insertion and removal [12].
Mar 13The FDA advisory committee voted 10-4 in favour of approval with one abstention. They also voted 10-5 in favour of the effectiveness of probuphine, 22-2 in support of safety and 5-4 with 6 abstentions in support of the Risk Evaluation and Mitigation Strategy (REMS) programme [11].
Mar 13Ahead of an FDA advisory committee meeting on 21 Mar, FDA staff question the efficacy data provided, the dose used in the pivotal study as well as its design, & the purported benefits & unanswered questions about the risks it presents to pts and their families [10].
Jan 13New Drug Application for Probuphine® accepted for review and granted Priority Review designation by the US FDA. Based upon the Prescription Drug User Fee Act (PDUFA), the FDA has set a target date of April 30, 2013 for FDA action on the NDA [9].
Oct 12Filed in the US for the maintenance treatment of opioid dependence in adults patients. The company has asked for a priority review [8].
Feb 12Plan to file in US 3Q 2012 [7].
Dec 11Hope to file in US mid-2012 [6].
Oct 06PIII studies started in Oct 2006 [1].


Probuphine is an implant designed to deliver six months of continuous, therapeutic levels of buprenorphine, an opioid receptor antagonist.
In 2015-16, 149,807 individuals presented with a dependency on opiates. There were 13,231 individuals aged 18-24 who commenced treatment in 2015-16, of these the majority cited problems with cannabis, alcohol or cocaine (7095, 54% 5,799, 44% and 3,137, 24% respectively). In total, 127,080 individuals exited the drug and alcohol treatment system in 2015-16, with 50% (64,166) having successfully completed their treatment free of dependence [26].
Opioid dependence - six-monthly subdermal implant

Trial or other data

Oct 18First-ever implantable option to support patients efforts to maintain treatment as part of their overall recovery program [23].
Jul 16Study NCT02180659 (n=177) found that implants were non-inferior to sublingual therapy with 96.4% receiving buprenorphine implants and 87.6% receiving sublingual buprenorphine, were classified as responders (8.8% difference p< .001 for non-inferiority) [24].
Jun 15Positive topline results from PIII double blind, double dummy clinical study of study of Probuphine for opioid addiction. This study met the pre-specified primary endpoint of non-inferiority (proportions of treatment responders in each group) as well as all secondary efficacy endpoints. The 177 pts were clinically stable and receiving maintenance treatment with sublingual buprenorphine/naloxone for at least 3 months prior to entering the trial. Pts were randomised to receive either the probuphine implants (4 implants + placebo tablets) or sublingual tablets (4 placebo implants plus daily sublingual buprenorphine/naloxone tablets) for 6 months. A responder was defined as a pt having >4/6 months free of illicit opioids based on urine testing and subject self-report. Response rates of 96.4% for the Probuphine arm and 87.6% for the sublingual buprenorphine/naloxone arm; 95% confidence interval 0.009 to 0.167. This was well within the pre-defined successful margin for non-inferiority. The overall safety and tolerability profiles for each treatment group were also comparable [18].
Jul 14Braeburn Pharmaceuticals initiated enrolment of the first patient with opioid addiction in a phase III clinical trial of the buprenorphine implant (Braeburn PRO-814; NCT02180659). The trial is aimed at addressing questions raised in the complete response letter to an NDA submitted by Titan and Braeburn and is based on guidance from the US FDA [14].
Feb 12Results reported from an open-label, six-month safety re-treatment study (PRO-811) in 85 patients with opioid dependence who previously completed a full six months of treatment in a confirmatory PIII study. 67 patients (79%) completed the retreatment study, with more than 90% of completers indicating that, if given the option, they would elect to receive further treatment with Probuphine. At the end of treatment, 80% of patients reported that they had not used illicit opioids within the last two weeks. 17 of 85 patients used supplemental rescue medication with a mean of 10 days and median of 7 days of use out of the possible 168 days of the study. 11% of treated patients received a dose increase to a total of five Probuphine implants during the study. Probuphine was well-tolerated, including the implant insertion and removal procedures; the most common adverse events were headache (12%), upper respiratory infection (8%), back pain (6%) and urinary tract infection (6%) [7].
Jul 11Results reported from a PIII confirmatory study. The randomized, placebo and active-controlled, multi-centre US study treated 287 patients (18 to 60 years) in 3 arms: Probuphine (n=114), the sublingual formulation of buprenorphine, Suboxone, (119) and placebo implants (54). The Probuphine and placebo arms were double-blinded, and Suboxone arm open-label. Probuphine was superior to placebo on
the Cumulative Distribution Function of the % of
opioid-negative urines over the 24-week treatment period and in the second, FDA requested primary efficacy analysis, of the % of opioid-negative urines
incorporating patient self reported opioid use (p < 0.0001). Probuphine was non-inferior to Suboxone in significantly reducing illicit opioid use
(proportion of negative urine samples 31% vs 33% respectively) with the same rates of trial
completion (64%) and a similar
safety profile [5].
Oct 10Findings of the NCT00447564 trial (n=163) published (JAMA 2010; 304: 1576-83). In the intention to treat analysis, more urine samples in the buprenorphine gp were free from illicit opioids vs. those from the placebo gp for weeks 1 to 16 (mean proportions 40.4% vs. 28.3%, p=0.04) and also for weeks 17 to 24 & overall (mean 36.6% vs. 22.4%, p=0.01). Secondary outcomes also favoured the buprenorphine group [4].
Aug 10Patient enrollment is more than 60% complete in the confirmatory PIII study and the study. It is expected to complete enrollment by early Q4 of this year, almost 3 months ahead of schedule and the results are now expected to be available by late 2Q 2011 [3].
Mar 10A confirmatory randomized, placebo and active controlled, multi-center PIII study of Probuphine in the treatment of opioid addiction, being conducted in 23 sites in the US, has started. The study is designed to confirm the safety and effectiveness of Probuphine vs placebo in reducing use of illicit opioids over a 24 week treatment period, and to perform a non-inferiority comparison of Probuphine vs Suboxone. Patients will be randomised into three arms: Probuphine (100 patients), Suboxone® (100 patients) and placebo (50 patients). The Probuphine and placebo arms will be double blinded, while the Suboxone arm will be open-label. Completion of patient enrollment is expected by the end of 2010 and study completion by Q3 2011. The study is part of a registration directed program intended to obtain marketing approval of Probuphine for the treatment of opioid addiction in the US and EU. The National Institutes of Health (NIH) has supported this confirmatory study by awarding the company a two year $7.6 million Research and Research Infrastructure Grand Opportunities grant [2].
Mar 10The safety and effectiveness of treatment with probuphine has been initially established in three PIII studies: a 163 patient placebo controlled study which demonstrated clinically meaningful and statistically significant treatment with Probuphine over a 24 week period (NCT00447564); an open label 24 week retreatment study in 62 patients who had successfully completed 6 months of treatment in the controlled study NCT00630201, PRO-807); and a relative bioavailability study in nine patients treated with Suboxone and then switched to Probuphine treatment for 60 days (NCT00768482, PRO-810) [1,2].

Evidence based evaluations

Buvidal (EU), Brixadi (US) Chronic low back pain in opioid dependent patients - once-weekly or once-monthly SC depot injection formulation


Buvidal (EU), Brixadi (US)
Licence extension / variation

Development and Regulatory status

Phase III Clinical Trials
Apr 21According to its latest annual report, filing has not yet taken place in the EU or Australia. Camurus has had a scientific advisory meeting with CHMP expert representatives ahead of a planned application for a marketing approval for CAM2038 for chronic pain in the EU. The outcome of the meeting was positive, and they are working on the commercial strategy and plan to submit an application for marketing approval for CAM2038 to the EMA later in 2021. UK plans not described [13].
Sep 20Camurus submits applications for a Buvidal licence extension in the EU and Australia in Q3 20 [12].
Apr 20In its latest annual report, Camurus states that it continues to prepare for market authorisation applications for CAM2038 for treatment of chronic pain. It completed a 12-month PIII study of long-term safety and efficacy. Results from the study met the overall endpoints of safety, tolerability and efficacy and complemented the previously reported positive results from the pivotal PIII efficacy study of CAM2038. Discussions are now ongoing with regulatory authorities before a planned submission during Q3 2020, with a possible approval during 2021 [10].
Nov 19During Q3 19, Camurus has been preparing for health authority meetings to discuss the planned regulatory submissions e.g. the EU during H1 2020 [8].
Nov 19CAM2038 still listed as PIII for chronic pain in Camurus pipeline [7].


Opioid mu receptor agonist and opioid kappa receptor antagonist. Once weekly and once monthly subcutaneous injection of either 50mg/mL or 356 mg/mL.
Back pain is extremely common. 60-80% of people in the UK report back pain at some time in their lives. A UK population-based cross-sectional study of people aged 25 years and older found the one-month period prevalence of low back pain to be around 30%, peaking at age 41-50 years. The one-year prevalence of chronic low back pain is about 1% [3].
Chronic low back pain in opioid dependent patients - once-weekly or once-monthly SC depot injection formulation

Trial or other data

Apr 20In the pivotal PIII study (NCT02946073), in 676 adults with chronic low-back pain, buprenorphine depot met its primary endpoint demonstrating significant relief of average and worst pain in patients compared to placebo. The treatment difference for buprenorphine depot versus placebo was 1.03 (p<0.001) for the average pain intensity and 1.11 (p<0.001) for the worst pain intensity [11].
Apr 20PIII extension study (NCT02672111) was an open-label multi-centre 48-week safety study, that completed in May 17. It was published in the journal, Addiction (2019 Aug;114(8):1416-1426). CAM2038, weekly or monthly, was well tolerated, with a systemic safety profile consistent with the known profile of sublingual buprenorphine. CAM2038 weekly and monthly was associated with high retention rates and low levels of illicit opioid use throughout this study [9].
Feb 20PIII trial (NCT02946073) is reported as completed in Feb 19; no results posted yet [9].
Nov 19No update posted for PIII trial (NCT02946073) on US trials register; status of trial uncertain [6].
Jul 18PIII trial (NCT02946073) is active but not recruiting. Estimated study completion date is Jan 19 [5].
Dec 17No update available on progress of PIII (NCT02946073) study [4].
Jan 17PIII (NCT02946073) study is recruiting patients. Collection of primary outcome data (difference of worst pain intensity scores from baseline to week 12) is expected to complete Dec 2017 [2].
Sep 16Braeburn Pharmaceuticals and Camurus initiate a PIII trial of once weekly and once monthly formulations of buprenorphine depot for treatment of moderate to severe chronic low back pain in opioid dependent patients (NCT02946073). The randomised, double-blind, placebo-controlled study will enrol approximately 340 patients in the US [1].

SublocadeOpioid dependence - maintenance treatment after induction on sublingual or buccal buprenorphine - once-monthly SC injection


New formulation

Development and Regulatory status

Approved (Licensed)
Jun 21Company has no immediate plans to launch in the UK [12].
Mar 21Sublocade is now licensed for use in the US, Israel, Sweden, Finland, New Zealand and Denmark. Indivior has also filed in the US for a label expansion to include changes related to long-term safety, the transition from transmucosal buprenorphine to Sublocade in clinically stable OUD patients, and the ability of high sustained buprenorphine plasma concentrations to reduce the respiratory depression caused by fentanyl in opioid-dependent patients. The FDA is currently the submissions with decisions expected throughout 2021 [11].
Jul 20Approved in Finland. Previously in May 20, Sublocade was approved in Sweden, marking the first approval in Europe [10].
Mar 20In its latest annual report, Indivior states that it anticipates receiving European approvals (in France, Germany, Italy and the UK) during 2020 and 2021, and at that time will determine the best path forward for commercialisation [9].
May 19Sublocade has been available in the US since Mar 18 [8].
Jan 19Currently pre-registration in EU [7].
Nov 17Suclocade once-monthly SC injection approved in US for treatment of moderate-to-severe opioid use disorder in adults who have initiated treatment with a transmucosal buprenorphine-containing product and have been on a stable dose of buprenorphine treatment for a minimum of seven days [5].
Nov 17Indivior plans to file to the MHRA [3].
Oct 17Psychopharmacologic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee of the US FDA recommended approval of the company´s buprenorphine depot for the treatment of adults with moderate-to-severe opioid abuse as part of a complete treatment plan to include counselling and psychosocial support [4].
Jul 17Filed in US. FDA grants priority review designation [2].


Buprenorphine is an opioid partial agonist at the mu-opioid receptor, an antagonist at the kappa and delta opioid receptors of the brain. Once-monthly subcutaneous injectable depot formulation using the ATRIGEL® delivery system. Requires fridge storage.
In 2015-16, 288,843 individuals were in contact with drug and alcohol services in 2015-16; a 2% reduction on last year. Individuals that presented with a dependency on opiates made up the largest proportion of total numbers in treatment (149,807; 52%). This is a fall of fall of 2% in the number since the previous year and substantial reduction (12%) since a peak in 2009-10 [1].
Opioid dependence - maintenance treatment after induction on sublingual or buccal buprenorphine - once-monthly SC injection

Trial or other data

Feb 19Results from PIII study NCT02357901 (n=504) are published; abstinence from opioid use was 41.3% for BUP-XR (RBP-6000) 300 mg/300 mg (six 300mg depot doses) and 42.7% for 300 mg/100 mg (two 300mg and four 100mg injections), compared with 5.0% for placebo (p<0.0001 for both BUP-XR regimens) [6].
Oct 18It is expected that RBP-6000, due to its monthly administration, will eliminate the need for daily supervision of administration. This will reduce burden on NHS including decreasing dispensing costs. Clinical trial (RBP-13-0001) has reported improvement on QoL for patients on RBP-6000. It is expected that increased treatment retention rates on RBP-6000 versus standard of care will be reflected in improvement in QoL of carers and a reduction in burden of disease on carers/family members. It is expected that risks of abuse and diversion of the treatment will be reduced with RBP-6000 [3].
Aug 17Indivior completes an extension PIII trial that provided ongoing treatment with buprenorphine depot and safety monitoring for patients who complete the RB-US-13-0003 study and for whom a new treatment venue has not been identified (NCT02896296; INDV6000-301). The open-label trial enrolled 208 patients in the US [2].
Jun 17Indivor present positive results from PIII study NCT02357901 (RB-US-13-0001) for once-monthly RBP-6000 in adults with moderate-to-severe opioid use disorder. In the 24-week study, RBP-6000 was associated with a higher mean percentage abstinence (opioid-free weeks) than placebo (41.3% for 6 once-monthly doses of 300mg; 42.7% for 2 once-monthly 300mg doses followed by 4 once-monthly 100mg doses; 5.0% placebo, p<0.0001) [2].
Jan 17PIII trial evaluating safety and tolerability of buprenorphine depot in patients seeking treatment for opioid abuse completes (RB-US-13-0003; NCT02510014). Suboxone sublingual film was used as an induction therapy. The non-randomised, single group assignment trial enrolled 672 patients in the US [2].

Evidence based evaluations

BelbucaModerate-to-severe pain including dental pain, postoperative pain and chronic pain due to osteoarthritis, lower back disorders and rheumatoid arthritis - transmucosal formulation


New formulation
BioDelivery Sciences International
BioDelivery Sciences International

Development and Regulatory status

Mar 20In its latest annual report, BDSI announces that it has no plans at the moment to market BELBUCA outside of the US [10].
Mar 19In its annual report, BDSI states that for commercialisation of Belbuca in other regions outside the U.S. and Canada, they are currently seeking partners with commercial reach and experience in pain management in their respective regions [10].
Dec 16BDSI plans to explore other options for longer-term growth for Belbuca within and ex-U.S [8].
Dec 16Endo announces it is returning Belbuca to BioDelivery Sciences International [7].
Feb 16Launched in US [6].
Oct 15The US FDA has approved Belbuca for use in pts with chronic pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate [5].
Mar 15The Medicines Company has a partnership with Endo Pharmaceuticals for Belbuca. Endo has an agreement with BioDelivery Science to commercialise transmucosal buprenorphine outside the US through its own efforts or through regional partnerships [1,2].
Feb 15US FDA accepts the NDA for review for treatment of moderate to severe chronic pain. The action date is expected to be Oct 15. The filing was supported by results from Study BUP-307 and BUP-308 [1,2].
Dec 14Filed in the US [1].


A long-acting, transmucosal formulation of buprenorphine using BEMA® (BioErodible MucoAdhesive) drug delivery technology.
Chronic pain is common within the community, but there are few substantial data. Approximately 18% of the population are currently affected by moderate to severe chronic pain. A systematic search of multiple databases found a one-month prevalence of moderate-to-severe non-cancer chronic pain in Europe of 19% [3].
Moderate-to-severe pain including dental pain, postoperative pain and chronic pain due to osteoarthritis, lower back disorders and rheumatoid arthritis - transmucosal formulation

Trial or other data

May 15Pivotal data from two PIII double-blind, randomized, studies for buprenorphine transmucosal demonstrated consistent, statistically significant improvement in patient-reported pain relief of chronic lower back pain. A total of 971 patients completed both trials: those who had received opioid therapy (study EN3409-307; abstract 437) or were opioid-naive at the start of the study (study EN3409-308; abstract 439). Overall, average pain scores increased more in the placebo arm versus BEMA® buprenorphine at week 12 from baseline, and the difference between the two groups was statistically significant: (EN3409-307/opioid experienced population) mean score change: 1.92, placebo versus 0.88, BEMA® buprenorphine; p<0.00001); (EN3409-308/opioid naive population) mean score change:1.59, placebo versus 0.94, BEMA® buprenorphine; p=0.0012). A statistically significant percentage of patients on BEMA® buprenorphine experienced pain reductions of greater than 30 percent compared to placebo (EN3409-307: 64.2 percent versus 30.6 percent; p<0.0001; EN3409-308: 62.7 percent versus 46.9 percent; p=0.0012). [4]
Nov 14Endo Pharmaceuticals in collaboration with BioDelivery Sciences complete an open-label PIII trial evaluating long-term tolerability, safety and analgesic efficacy of buprenorphine transmucosal in subjects with moderate to severe chronic pain requiring continuous around-the-clock opioid analgesia for an extended period of time (NCT01755546). The trial was initiated in December 2012 and enrolled 554 patients in the US with chronic pain, including lower back pain, osteoarthritis and neuropathic pain [1].
Aug 12BioDelivery Sciences completes a PIII, long-term safety study of buprenorphine transmucosal, in patients with moderate to severe chronic pain, including back, musculoskeletal (osteoarthritis) and neuropathic pain (BUP-305; NCT01298765). The open-label trial was initiated in March 2011, and enrolled 434 patients in the US [1].
Jul 11BioDelivery completes a PIII trial to assess efficacy and safety of buprenorphine transmucosal in patients with moderate-to-severe chronic lower back pain (BUP-301; NCT01256450). This randomised, double-blind, placebo-controlled withdrawal trial involved 334 patients in the US. Patients who titrated to an effective and tolerated dose were randomised to either continue on that dose of buprenorphine transmucosal, or be randomised to placebo, with treatment continuing for 12 weeks. In Sep 11, BioDelivery Sciences reported that the trial did not meet its primary endpoint of overall pain intensity difference between buprenorphine transmucosal and placebo in this mixed opioid-naive and opioid-experienced population [1].