Summary Basis of Decision for Probuphine

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Probuphine is located below.
Recent Activity for Probuphine

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Probuphine

Updated:  2024-11-18

The following table describes post-authorization activity for Probuphine, a product which contains the medicinal ingredient buprenorphine hydrochloride. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Drug Identification Number (DIN):

  • DIN 02474921 - 80 mg buprenorphine hydrochloride, implant, subcutaneous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
DIN 02474921 cancelled (post market) Not applicable Discontinuation date 2023-06-30 The manufacturer notified Health Canada that sale of the drug has been discontinued post market. Health Canada cancelled the DIN pursuant to section C.01.014.6(1)(a) of the Food and Drug Regulations.
Drug product (DIN 02474921) market notification Not applicable Date of first sale:
2018-11-22		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 204746 2017-04-20 Issued NOC
2018-04-18		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Probuphine

Date SBD issued: 2018-07-06

The following information relates to the New Drug Submission for Probuphine.

Buprenorphine hydrochloride
80 mg, implant, subcutaneous

Drug Identification Number (DIN):

  • 02474921

Knight Therapeutics Inc.

New Drug Submission Control Number: 204746

 

On April 18, 2018, Health Canada issued a Notice of Compliance to Knight Therapeutics Inc. for the drug/device combination product Probuphine.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit-harm-uncertainty profile of Probuphine is favourable for the management of opioid dependence in patients clinically stabilized on no more than 8 mg of sublingual buprenorphine in combination with counselling and psychosocial support.

 

1 What was approved?

 

Probuphine is an implant formulation of buprenorphine, a partial opioid agonist. It was authorized for the management of opioid dependence in patients clinically stabilized on no more than 8 mg of sublingual buprenorphine in combination with counselling and psychosocial support.

Probuphine is not indicated for use in the pediatric and geriatric populations.

Probuphine is contraindicated in:

  • patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container
  • patients who have severe respiratory insufficiency, acute respiratory depression, elevated carbon dioxide levels in the blood and cor pulmonale
  • patients with severe hepatic insufficiency
  • patients with severe central nervous system depression, increased cerebrospinal or intracranial pressure and head injury
  • patients with acute alcoholism or delirium tremens
  • opioid-naïve patients
  • patients with convulsive or seizure disorders
  • patients with known or suspected mechanical gastrointestinal obstruction (e.g., bowel obstruction or strictures) or any diseases/conditions that affect bowel transit (e.g., ileus of any type).
  • congenital long QT Syndrome or QTc prolongation at baseline
  • uncorrected hypokalemia, hypomagnesemia, or hypocalcemia

Probuphine was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Probuphine (80 mg buprenorphine hydrochloride, equivalent to 74.2 mg buprenorphine) is presented as a subdermal implant. In addition to the medicinal ingredient, the subdermal implant contains ethylene vinyl acetate. One Probuphine kit consists of four individually packaged sterile implants (for a total of 320 mg buprenorphine hydrochloride to be delivered over 6 months) and one individually packaged sterile disposable applicator.

Each Probuphine dose consists of four implants inserted subdermally in the inner side of the upper arm. Probuphine must be inserted and removed only by healthcare professionals who have successfully completed a live training program, the Probuphine Education Program.

For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Probuphine Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Probuphine approved?

 

Health Canada considers that the benefit-harm-uncertainty profile of Probuphine is favourable for the management of opioid dependence in patients clinically stabilized on no more than 8 mg of sublingual buprenorphine in combination with counselling and psychosocial support.

Opioid addiction/dependence (opioid use disorder as per the Diagnostic and Statistical Manual of Mental Disorders, fifth edition [DSM-5]) is a complex issue that often requires long-term management. How addiction develops and progresses is determined by biological, social and environmental factors that differ across individuals. Since addiction recovery differs among individuals, an effective program must be tailored to individual needs and preferences. For some individuals, abstinence-based programs and support provide a pathway of recovery. For others, harm reduction approaches, which involve steps to reduce harm instead of eliminating drug use altogether (e.g., substitution treatments) might provide a pathway of recovery. Probuphine, an implant formulation of buprenorphine, is a candidate for the latter option.

Buprenorphine is listed in Schedule I of the Controlled Drugs and Substances Act as well as in the Schedule of the Narcotic Control Regulations. Buprenorphine has been approved since 1994 as Buprenex (an injectable for pain, not marketed), Butrans (a transdermal patch for chronic pain), Belbuca (a buccal film for chronic pain), and Suboxone and its generic equivalents (sublingual buprenorphine/naloxone tablets for opioid drug dependence).

The efficacy of buprenorphine is thought to be mediated by high-affinity binding to, and very slow dissociation from, µ-opioid receptors in the central nervous system, which prolongs partial activity at the opioid receptors and alleviates opioid withdrawal symptoms. As a partial agonist, buprenorphine activity is limited by a ceiling effect and rarely triggers serious respiratory depressions. This ability of buprenorphine added to its strong affinity to opioid receptors is an advantage that also helps block severe (sometimes fatal) respiratory depressions triggered by high doses of full opioid agonists through competition for opioid receptors.

The market authorization of Probuphine was based on efficacy and safety data derived from three key studies (PRO-805, PRO-806 and PRO-814). The efficacy of the implant was measured by evaluating the incidence of patients who were resorting to illicit opioid consumption while under treatment with the implant. The main difference between studies was that patients in the pivotal study PRO-814 (a study of 24-week duration, involving 173 patients) had to be on a maintenance treatment of sublingual buprenorphine and tapered down to 8 mg of sublingual buprenorphine for three months prior to receiving the implant, while in the other two studies patients underwent and completed induction with 12 mg/day to 16 mg/day of sublingual buprenorphine within 10 days of screening.

In the pivotal study PRO-814, 79% of Probuphine-treated patients had urine samples free of illicit opioids compared to 64% of controls, treated with sublingual buprenorphine. However, for studies PRO-805 and PRO-806, no patients (0%) in the Probuphine group and the control groups had 100% negative urine samples for illicit opioids throughout the total study period of up to 24 weeks. Although other factors may have impacted the results, the difference in the results between the studies was thought to be largely driven by the study designs rather than a lack of efficacy of Probuphine. This difference in efficacy is likely due to the fact that patients were not clinically stabilized before implantation of Probuphine in studies PRO-805 and PRO-806. In light of these findings, Probuphine is recommended to be used after the patient is clinically stabilized on sublingual buprenorphine.

The safety profile of Probuphine was similar to other buprenorphine formulations used for the same purpose, except for the local adverse events expected with an implant. These were various (bleeding, bruising, edema, erythema, infection, itching and pain, etc.) and most were not of severe or serious nature. The risk of implant migration, protrusion, expulsion, and nerve damage that may result from the insertion and removal procedure is specifically addressed in the Serious Warnings and Precautions Box included in the Probuphine Product Monograph.

The electrocardiogram (ECG) data submitted for Probuphine were inconclusive because of limitations of clinical trial design and methodology. A QTc study is planned (a report is expected in 2019) to assess the risk of QT prolongation with Probuphine. Since concentration-dependent QTc prolongation has been reported with other buprenorphine-containing products, contraindications, serious warnings and precautions as well as potential drug interactions were added to the Probuphine Product Monograph to mitigate potential cardiovascular risks.

The abuse potential of buprenorphine and the need for monitoring patients for conditions indicative of diversion or progression of opioid dependence are highlighted in the Serious Warnings and Precautions Box of the Probuphine Product Monograph. Additionally, serious warnings and precautions address neonatal opioid withdrawal syndrome and neonatal respiratory depression that can result from prolonged maternal use of opioids during pregnancy.

The risks from concomitant use of opioids with benzodiazepines or other central nervous system depressants, including alcohol, which may result in profound sedation, respiratory depression, coma and death, are also highlighted in the Serious Drug Interactions box of the Probuphine Product Monograph.

Safety of the device component of Probuphine was supported by biocompatibility testing, toxicological assessment, risk assessment of measured impurities, sterilization validation, sterilant residual testing, pyrogen testing, packaging validation, bench testing of the implant and delivery system including characterization of excipient, physiochemical testing of the implant, stylet dimensional and pull testing, cannula dimensional, pull, and leakage testing, and swivel nut/hub testing. The manufacturer has demonstrated device-related effectiveness by human factors validation of the implant training program, animal studies that were able to assess the method of implantation, and clinical studies that assessed the safety and effectiveness of the device-related implant and delivery system components in the intended population.

Non-implant site and implant-site adverse drug reactions collected through post-marketing surveillance have been included in the Probuphine Product Monograph.

A Risk Management Plan (RMP) for Probuphine was submitted by Knight Therapeutics Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. The QTc study to assess the risk of QT prolongation with Probuphine is included in the planned additional pharmacovigilance activities of the RMP (the study report is expected in 2019).

The submitted inner and outer labels, package inserts and Patient Medication Information section of the Probuphine Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Probuphine was accepted.

Probuphine has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Probuphine Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

 

3 What steps led to the approval of Probuphine?

 

Submission Milestones: Probuphine

Submission Milestone Date
Pre-submission meeting: 2016-10-12
Submission filed: 2017-04-20
Screening  
Screening Acceptance Letter issued: 2017-06-08
Review  
Quality Evaluation complete: 2018-04-13
Clinical Evaluation complete: 2018-04-13
Medical Evaluation complete: 2018-02-09
Review of Risk Management Plan complete: 2018-01-17
Labelling Review complete, including Look-alike Sound-alike Probuphine assessment: 2018-03-13
Notice of Compliance issued by Director General, Therapeutic Products Directorate: 2018-04-18

 

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

 

4 What follow-up measures will the company take?

 

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

 

5 What post-authorization activity has taken place for Probuphine?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product's life cycle.

The PAAT for Probuphine is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

6 What other information is available about drugs?

 

Up to date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision

 

Clinical Pharmacology

The clinical pharmacological data support the use of Probuphine for the recommended indication.

Buprenorphine, the medicinal ingredient in Probuphine is a partial agonist at the µ-opioid receptor and the ORL-1 (nociceptin) receptor. Buprenorphine is also an antagonist at the κ and δ opioid receptors. Buprenorphine has a high affinity for µ-receptors, therefore reducing the binding ability, and thus the activity, of other opioids on these receptors. The activity of buprenorphine in opioid maintenance treatment is attributed to its slowly reversible link with the µ-opioid receptors in the brain, which prolongs activity at the receptor, leading to reduced opioid withdrawal symptoms.

Buprenorphine is a κ-receptor antagonist, but the clinical relevance of this finding has not been established. Like other opioid agonists, buprenorphine may produce increases in cerebrospinal fluid pressure, and cause altered mental status, mental clouding or amnesia following intravenous administration.

Comparison of buprenorphine with full opioid agonists such as methadone, suggests that buprenorphine produces typical opioid effects, which are limited by a ceiling effect in the case of buprenorphine.

Buprenorphine has been associated with concentration-dependent prolongation of the QTc interval in randomized, double-blind, placebo- and positive-controlled electrocardiogram (ECG) assessment studies in healthy subjects.

The nature of the Probuphine matrix formulation blends the active ingredient (buprenorphine) with the inactive ingredient (ethylene vinyl acetate) in a manner that limits the extraction and solubility of buprenorphine after breakage of the implant.

For further details, please refer to the Probuphine Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Probuphine in the management of opioid dependence was supported by data derived from three controlled Phase III clinical trials (PRO-805, PRO-806 and PRO-814).

The pivotal study PRO-814 was a randomized, double-blind, double-dummy, active-controlled multicentre Phase III clinical trial of 24-week duration. It involved a total of 173 adult outpatients with opioid dependence and who were clinically stabilized on ≤8 mg sublingual buprenorphine. The patients were randomized in a 1:1 ratio to receive daily doses of sublingual buprenorphine tablets (≤8 mg per day) plus 4 placebo implants (number of patients [n] = 89) or daily sublingual placebo tablets plus 4 Probuphine implants (n = 84).

The primary objective of the study was to demonstrate maintenance of treatment efficacy when transferring adult outpatients with opioid dependence, clinically stabilized on ≤8 mg sublingual buprenorphine, to 4 Probuphine implants compared to sublingual buprenorphine.

The supportive study PRO-805 was a randomized, double-blind, placebo-controlled, multicentre study of Probuphine in adult patients with opioid dependence. Its primary objective was to determine the efficacy of Probuphine versus placebo in the treatment of patients with opioid dependence over 16 weeks of treatment. Patients meeting inclusion and exclusion criteria underwent and completed induction with 12 mg/day to 16 mg/day of sublingual buprenorphine within 10 days of screening. A total of 108 patients were randomized to Probuphine implants and 55 patients randomized to placebo implants.

The second supportive study, PRO-806, was a randomized, placebo- and active-controlled, multicentre study of Probuphine in adult patients with opioid dependence. The primary objective of this study was to confirm the efficacy of Probuphine versus placebo in adult patients with opioid dependence over Weeks 1 through 24 of outpatient treatment through the assessment of thrice-weekly urine toxicology results (total of 72 samples) and patient self-reported illicit drug use data. As it was the case in study PRO-805 but contrary to the pivotal study PRO-814, patients were not stabilized before randomization in this study and only went through an induction period (with 12 mg/day to 16 mg/day) that could be as short as 3 days. There were 114 patients randomly assigned to Probuphine, 54 patients randomly assigned to placebo implant, and 119 patients randomly assigned to sublingual buprenorphine.

The efficacy of the implant was measured by evaluating the incidence of patients who were resorting to illicit opioid consumption while under treatment with the implant.

In the pivotal study PRO-814, 79% of patients on Probuphine had 100% of their urine samples free of illicit opioids.

In studies PRO-805 and PRO-806, no patients (0%) in the Probuphine group and the control groups had 100% negative urine samples for illicit opioids throughout the duration of the studies.

Although other factors may have impacted the results, the difference in the results between the studies was thought to be largely driven by the study designs rather than a lack of efficacy of Probuphine. Study PRO-814 followed a protocol where patients were already on maintenance treatment and were tapered down and stabilized on ≤8 mg sublingual buprenorphine for three months prior to Probuphine implantation. Patients in studies PRO-805 and PRO-806 underwent induction with 12 mg/day to 16 mg/day of sublingual buprenorphine for a maximum of 10 days before randomization. Absence of stabilization prior to randomization was considered an important difference between these two studies and study PRO-814. This difference was thought to impact the seemingly better efficacy results of Probuphine in study PRO-814.

As an implant, Probuphine may be more efficacious at decreasing the risks of withdrawal symptoms compared to other buprenorphine formulations because of the slow and constant release of buprenorphine with minimal peaks and troughs. Moreover, as Probuphine dosing happens only once during 6 months of opioid dependence management, dosing errors are eliminated and patients' quality of life as well as treatment compliance should be improved.

Indication

The New Drug Submission for Probuphine was filed by the sponsor with the following indication:

  • Probuphine (buprenorphine hydrochloride subdermal implant) is indicated for the treatment in adults with opioid drug dependence after initiation with transmucosal buprenorphine-containing product. Probuphine should be used as part of a complete treatment program to include counselling and psychosocial support.

The proposed indication was modified to reflect the conditions of use in the pivotal clinical study (PRO-814) in order to increase the chance of success in a real-world setting. Accordingly, Health Canada approved the following indication:

  • Probuphine (buprenorphine hydrochloride subdermal implant) is indicated in the management of opioid dependence in patients clinically stabilized on no more than 8 mg of sublingual buprenorphine in combination with counselling and psychosocial support.

For more information, refer to the Probuphine Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

A total of 258 subjects were exposed to Probuphine for at least 24 weeks and 82 subjects were exposed for 48 weeks during Probuphine clinical development.

The overall safety profile of Probuphine was similar to other buprenorphine formulations used for the same purpose.

As Probuphine is an implant, there were local adverse events specific to its formulation (bleeding, bruising, edema, erythema, infection, itching and pain, etc.) but most were not severe or serious in nature.

The most common (>1%) treatment emergent adverse events reported with the opioid pharmacological class (to which buprenorphine belongs) include constipation, headache, insomnia, asthenia, drowsiness, nausea and vomiting, fainting and dizziness, orthostatic hypotension, and sweating.

In the double-blind double-dummy pivotal study PRO-814, comparing Probuphine to 8 mg sublingual buprenorphine, the most common treatment emergent adverse events in the Probuphine group were nasopharyngitis (6.3%), headache (5.1%), implant site pain (4.5%), and depression (4.5%). Twelve (6.8%) patients, 3 (3.4%) in the Probuphine group and 9 (10.1%) in the sublingual buprenorphine group, had at least 1 severe treatment emergent adverse event. All severe treatment emergent adverse events were non-implant site events. None of the patients died during the study.

 

 

The electrocardiogram (ECG) data provided for Probuphine were inconclusive because of limitations of clinical trial design and methodology. A QTc study is planned (a study report is expected in 2019) to assess the risk of QT prolongation with Probuphine. Since concentration-dependent QTc prolongation has been reported with other buprenorphine-containing products, contraindications, serious warnings and precautions as well as potential drug interactions were added to the Probuphine Product Monograph to mitigate potential cardiovascular risks.

A Serious Warnings and Precautions Box in the Probuphine Product Monograph also includes the risk of implant migration, protrusion, expulsion, and nerve damage that may result from the insertion and removal procedure. In addition, the abuse potential of buprenorphine is highlighted in the Serious Warnings and Precautions Box of the Probuphine Product Monograph. Furthermore, serious warnings and precautions address the risks of neonatal opioid withdrawal syndrome and neonatal respiratory depression that can result from prolonged maternal use of opioids during pregnancy.

Non-implant site and implant-site adverse drug reactions collected through post-marketing surveillance have been included in the Probuphine Product Monograph.

Probuphine is available only through a controlled distribution process (i.e., directly from a pharmacy to the healthcare professionals), which decreases the probability of diversion or tampering with the implants.

Overall, the benefit-harm-uncertainty profile of Probuphine is considered acceptable when Probuphine is used as described in the approved Product Monograph. Appropriate warnings and precautions are in place in the Probuphine Product Monograph to address the identified safety concerns.

For more information, refer to the Probuphine Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

7.2 Non-Clinical Basis for Decision

 

The safety profile of buprenorphine, the medicinal ingredient in Probuphine, has been well established in non-clinical studies. Given that no changes were anticipated with the subcutaneous implantation of this drug, a significant portion of the non-clinical data relied on previous studies. Review of the new studies conducted with Probuphine, which included a chronic toxicity study in beagles, did not identify any significant safety signals at exposure-based safety margins approximately 13 and 15 times the estimated 24-week clinical exposure for a dosage of five Probuphine implants.

Implants were generally well tolerated in all Probuphine studies, with the exception of a few minor issues. These included significant (30%-40%) breakage of rods occurring exclusively in the Probuphine-treated dogs while none of the rods were broken in the ethylene vinyl acetate placebo control animals in the chronic toxicity study. The rod breakage did not appear to significantly affect buprenorphine pharmacokinetic parameters in these animals. In addition, implants were classified as slight irritants in studies conducted in beagles and rabbits. Some limited inflammation/infection around the implant site was also observed, and was resolved with antibiotic treatment.

Results of carcinogenicity, reproductive and developmental toxicity bridging studies in rats, mice and rabbits with oral or subcutaneous administration showed no significant concerns.

A few abnormalities of the pelage and skin were noted in the chronic toxicity study in beagles, as well as in non-gravid rats, gravid rats and rabbits when buprenorphine was administered orally or subcutaneously. In addition, some swelling of the face and limbs was also observed in the beagle and rat studies. The significance of these findings could not be established given the low number of animals examined in each instance.

Probuphine extracts did not induce dermal contact sensitization in guinea pigs, or intracutaneous reactivity or pyrogenicity in rabbits and were not cytotoxic in an in vitro assay. In addition, they were non-mutagenic, non-clastogenic and did not damage the mitotic apparatus, under the given conditions of each respective study.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Probuphine Product Monograph. In view of the intended use of Probuphine, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Probuphine Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

7.3 Quality Basis for Decision

 

The Chemistry and Manufacturing information submitted for Probuphine has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. The drug product is stored at room temperature (15ºC to 30ºC).

All sites involved in production are compliant with Good Manufacturing Practices.

The non-medicinal ingredient (described earlier) found in the drug product is acceptable for use in drugs according to the Food and Drug Regulations.

 

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