Important Safety Information on SUBOXONE (buprenorphine and naloxone) and the Risk of Overdose or Underdose when Switching Between Dosage Forms or Routes of Administration

Starting date:
January 7, 2021
Posting date:
January 7, 2021
Type of communication:
Dear Healthcare Professional Letter
Subcategory:
Drugs
Source of recall:
Health Canada
Issue:
Important Safety Information
Audience:
Healthcare Professionals, Hospitals
Identification number:
RA-74719

Last updated:

Audience

Healthcare professionals including family physicians, emergency room physicians, psychiatrists, addiction specialists, nurse practitioners, registered nurses and pharmacists.

Key messages

  • Switching between SUBOXONE (buprenorphine and naloxone) Soluble Film and SUBOXONE Sublingual Tablet, or switching between different routes of administration using the film, could lead to inadvertent overdosing or underdosing. The film and tablet dosage forms are not bioequivalent at all doses and routes of administration.
  • When switching between sublingual tablet and soluble film, healthcare professionals are advised that:
    • patients should be started on the same dosage of the previously administered product.
    • given the greater bioavailability of the film compared to the tablet at certain strengths, patients switching from tablet to film should be monitored for symptoms of overdose. The film should initially be administered sublingually.
    • patients should be monitored for symptoms of underdose, including opioid withdrawal, when switching from film to tablet.
    • combining or alternating between film and tablet dosage forms is not advised.
  • When switching between sublingual and buccal sites of administration (film only), healthcare professionals are advised that:
    • for induction, the film should only be administered sublingually, including when switching from tablet to film.
    • once induction is complete, patients can be switched between sublingual and buccal administration without significant risk of overdosing or underdosing.
    • patients should be monitored when switching between the 2 routes of administration.

   

Issue

Health Canada has authorized 2 dosage forms of SUBOXONE (buprenorphine and naloxone), a sublingual tablet and soluble film, that are not bioequivalent at all doses and routes of administration. Switching between dosage forms or routes of administration could result in variations in buprenorphine or naloxone blood plasma concentrations, which could lead to inadvertent overdosing or underdosing, including opioid withdrawal.

Products affected

Product Route(s) of Administration Medicinal Ingredients Strength Drug Identification Number (DIN)
SUBOXONE Soluble Film Sublingual,
Buccal
Buprenorphine/ Naloxone 2 mg / 0.5 mg 02502313
4 mg / 1 mg 02502321
8 mg / 2 mg 02502348
12 mg / 3 mg 02502356
SUBOXONE Sublingual Tablet Sublingual Buprenorphine/
Naloxone
2 mg / 0.5 mg 02295695
8 mg / 2 mg 02295709
12 mg / 3 mg 02468085
16 mg / 4 mg 02468093

Background Information

SUBOXONE will be available in 2 dosage forms: SUBOXONE Soluble Film and SUBOXONE Sublingual Tablet. Both dosage forms are used for substitution treatment in adults with problematic opioid drug dependence.

SUBOXONE Soluble Film may be administered sublingually (for both induction and maintenance therapy) or buccally (for maintenance therapy). SUBOXONE Sublingual Tablet can only be administered sublingually.

SUBOXONE Soluble Film and Sublingual Tablet are not bioequivalent at all doses and routes of administration.

In several pharmacokinetic studies following the administration of different dosages, a dose of one or two 2 mg / 0.5 mg SUBOXONE films administered sublingually or buccally showed comparable buprenorphine and naloxone bioavailability to the same total dose of SUBOXONE tablets.

In contrast, one 8 mg / 2 mg and one 12 mg / 3 mg SUBOXONE film administered sublingually or buccally showed higher relative bioavailability for both buprenorphine and naloxone compared to the same total dose of SUBOXONE tablets.

A combination of one 8 mg / 2 mg and two 2 mg / 0.5 mg SUBOXONE films (total dose of 12 mg / 3 mg) administered sublingually showed comparable buprenorphine and naloxone bioavailability to the same total dose of SUBOXONE tablets, while buccally administered SUBOXONE film showed higher relative bioavailability.

For more information regarding the relative increase in exposure to buprenorphine and naloxone associated with SUBOXONE Soluble Film compared to SUBOXONE Sublingual Tablet, including the effect of route of administration, healthcare professionals should refer to Table 6 of the SUBOXONE Canadian Product Monograph, which can be found on Health Canada's Drug Product Database.

Who is affected

Information for consumers

SUBOXONE (also known as buprenorphine and naloxone) will be available in 2 dosage forms: a soluble film (placed under the tongue or inside the cheek) and a sublingual tablet (placed under the tongue). Both dosage forms are used as part of a medical, social and psychological treatment program for adults undergoing substitution treatment for problematic opioid drug dependence.

Switching between SUBOXONE film and tablet, or switching the location of where the film is placed inside the mouth, may affect how much medicine is absorbed into the body. Patients should not switch between the tablet and the film unless directed by their doctor. Patients should not change their treatment in any way, or stop their treatment, without first consulting their doctor. Doctors may change the dose of SUBOXONE after seeing how it affects patients.

When beginning treatment with SUBOXONE film, patients should only take it under the tongue. After a few days, patients can choose (after consulting their doctor) whether they will take the film under the tongue or on the inside of their cheek.

Patients should monitor for any signs and symptoms of overdose or underdose when changes to their treatment are made.

Signs of overdose may include unusually slow or weak breathing, dizziness, confusion or extreme drowsiness.

Signs of underdose include withdrawal symptoms such as body aches, diarrhea, goosebumps, loss of appetite, nausea, feeling nervous or restless, runny nose, sneezing, tremors or shivering, stomach cramps, rapid heart rate, trouble sleeping, an unusual increase in sweating, heart palpitations, an unexplained fever, weakness or yawning.

Patients should discuss any questions or concerns about this information with their healthcare professional.

Information for healthcare professionals

Healthcare professionals should be aware of the following when switching patients between SUBOXONE Soluble Film and SUBOXONE Sublingual Tablet:

  • Patients being switched between the tablet and the film should be started on the same dosage of the previously administered product. When switching between the tablet and film, patients should be monitored in case there is a need to adjust the dose.
  • When switching from tablet to film, the film should initially be administered sublingually. Patients who are stabilized on sublingually-administered film can be switched to buccally-administered film.
  • Due to the greater bioavailability of the film compared to the tablet at certain strengths, patients switching from tablet to film should be monitored for symptoms of overdose. Those switching from film to tablet should be monitored for symptoms of underdose, including opioid withdrawal.
  • Combining or alternating between film and tablet dosage forms is not advised.

Healthcare professionals should be aware of the following when switching patients between sublingual and buccal sites of administration with SUBOXONE Soluble Film:

  • For induction, the film should only be administered sublingually.
  • Once induction with the film is complete (typically within 2 days), patients can be switched between sublingual to buccal administration without significant risk of overdosing or underdosing. This is because the systemic exposure of buprenorphine between buccal and sublingual administration of the film is similar.
  • Patients should be monitored when switching between the two routes of administration.

Action taken by Health Canada

The Canadian Product Monograph (CPM) for SUBOXONE contains the recommendations outlined in this communication. The SUBOXONE CPM can be found on Health Canada’s Drug Product Database.

Health Canada is communicating this important safety information to healthcare professionals and Canadians via the Recalls and Safety Alerts Database on the Healthy Canadians Web Site. This communication will be further distributed through the MedEffect™ e-Notice email notification system as well as through social media channels, including LinkedIn and Twitter.

Report health or safety concerns

Managing marketed health product-related side effects depends on healthcare professionals and consumers reporting them. Any case related to overdosing or underdosing when switching between different SUBOXONE dosage forms or routes of administration, or other serious or unexpected side effects in patients receiving SUBOXONE Soluble Film or SUBOXONE Sublingual Tablet, should be reported to Indivior UK Limited or Health Canada.

Indivior UK Ltd.
Pharmacovigilance, Adverse Event Reporting and Questions related to the product
Phone: 1-877-782-6966
Email:  PatientSafetyNA@indivior.com

To correct your mailing address or fax number, contact Indivior UK Limited.

You can report any suspected adverse reactions associated with the use of health products to Health Canada by:

  • Calling toll-free at 1-866-234-2345; or
  • Visiting MedEffect Canada's Web page on Adverse Reaction Reporting for information on how to report online, by mail or by fax.

For other health product inquiries related to this communication, contact Health Canada at:

Marketed Health Products Directorate
E-mail: mhpd_dpsc@hc-sc.gc.ca
Telephone: 613-954-6522
Fax: 613-952-7738

Sincerely,

Original signed by

Christine Mormont,
Head, Medical Affairs
Indivior Canada Ltd.