Usual Adult Dose for Opiate Dependence - Maintenance

SUBLINGUAL Tablets: Following a 2-day induction:

• Adjust dose in 2 to 4 mg increments/decrements to a level that holds patient in treatment and suppresses opioid withdrawal signs and symptoms
• Target dose: 16 mg sublingually once a day; range 4 to 24 mg/day
• Maximum dose: 24 mg/day; higher doses have not shown a clinical advantage

Comments:

• Buprenorphine with naloxone is the preferred drug for maintenance treatment; unsupervised maintenance treatment with buprenorphine should be limited to those who cannot tolerate buprenorphine-naloxone.
• When determining prescription quantity for unsupervised administration, consider the patient's level of stability, the security of his or her home situation, and other factors likely to affect the ability to manage supplies of take-home medications.

EXTENDED-RELEASE SUBCUTANEOUS Injection (Sublocade): Following a minimum of 7-days of treatment with a transmucosal product delivering the equivalent of 8 to 24 mg buprenorphine per day:

• Initial dose: 300 mg subcutaneously once a month for 2 months
• Maintenance dose: 100 mg subcutaneously once a month
• Maintenance dose may be increased to 300 mg monthly for those tolerating lower dose and demonstrating a less than satisfactory clinical response, e.g. self-reported illicit opioid use or positive urine drug screens

Comments:

• Initiating therapy with subcutaneous injections has not been studied; subcutaneous injections should only be initiated following induction and dose-adjustment with a transmucosal buprenorphine-containing product.
• Monthly doses should allow for a minimum of 26 days between doses; occasional delays in dosing of up to 2 weeks are not expected to have a clinically significant impact on treatment effect.

SUBDERMAL IMPLANT (Probuphine): For use in opioid-tolerant patients who meet ALL of the following criteria:

• Achieved and sustained prolonged clinical stability on transmucosal buprenorphine as evidenced by a stable dose for 3 months or longer without any need for supplemental dosing or dose adjustments.
• Currently receiving buprenorphine maintenance (with or without naloxone) at doses of 8 mg/day or less, or equivalent transmucosal product (e.g. Bunavail[R] buprenorphine 4.2 mg/naloxone 0.7 mg per day or less; or Zubsolv[R] buprenorphine 5.7 mg/naloxone 1.4 mg per day or less)
• Patients should not be tapered to a lower dose for the sole purpose of transitioning to the implant.

Insert 1 dose subdermally in the inner side of the upper arm

• Remove at the end of the sixth month

Comments:

• Implant insertions and removals should be performed by certified healthcare providers.
• Each dose consists of 4 implants; each implant contains 74.2 mg of buprenorphine
• After 1 insertion in each arm, most patients should be transitioned back to transmucosal products for continued treatment as there is no experience with inserting additional implants into other sites in the arm or into a previously-used site.

Uses: For the treatment of opioid dependence as part of a complete treatment plan to include counseling and psychosocial support. There is no maximum recommended duration for maintenance therapy as indefinite treatment may be required; when the decision is made to discontinue, doses should be tapered.

Usual Adult Dose for Pain

Initial dose: 0.3 mg deep IM or slow IV (over at least 2 minutes); may repeat this dose once after 30 to 60 minutes if needed; then, 0.3 mg IV/IM every 6 hours as needed

• A single 0.6 mg IM dose may be given to patients who are not in a high risk category (see Warnings)

Maximum single dose: 0.3 mg (IV) or 0.6 mg (IM)

Comments:

• Use extra caution with IV administration, especially the first dose.
• Monitor closely for respiratory depression, especially within the first 24 to 72 hours.
• Use the lowest effective dose for the shortest duration consistent with the individual patient's treatment goals.

Use: For the management of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate.

Usual Adult Dose for Chronic Pain

BUCCAL Film:
Opioid-Naive and Opioid Non-Tolerant:
As Initial Opioid Analgesic: 75 mcg buccally once a day, or if tolerated every 12 hours for at least 4 days; then increase to 150 mcg every 12 hours

• Titrate individually in increments of up to 150 mcg every 12 hours no more frequently than every 4 days to a dose that provides adequate analgesia and minimizes adverse reactions

Maximum dose: 900 mcg every 12 hours due to potential for QTc interval prolongation
CONVERSION from Other Opioids to BUCCAL Film: To reduce the risk of opioid withdrawal, taper patients to no more than 30 mg/day oral morphine mg equivalents (MME) before beginning therapy
Discontinue all around-the-clock opioid drugs when initiating buccal film
For opioid dose of less than 30 MME/day prior to taper:

• Initial dose: 75 mcg buccally once a day, or every 12 hours

For opioid dose between 30 and 89 MME/day prior to taper:

• Initial dose: 150 mcg buccally every 12 hours

For opioid dose between 90 and 160 MME/day prior to taper:

• Initial dose: 300 mcg buccally every 12 hours
• Following initiation, titrate as above

Buccal Film NOTES:

• For opioid doses greater than 160 MME/day: Consider alternate analgesics as buccal film may not provide adequate analgesia.
• Film strengths of 600 mcg, 750 mcg, and 900 mcg are only for use following titration from lower doses.

TRANSDERMAL System:
Opioid-Naive and Opioid Non-Tolerant:
As Initial Opioid Analgesic: Apply 5 mcg/hr patch transdermally; change every 7 days

• Individually titrate to a dose that provides adequate analgesia and minimizes adverse reactions; minimal titration interval is 72 hours

Maximum dose: 20 mcg/hr
CONVERSION from Other Opioids to TRANSDERMAL System:
Discontinue all other around-the-clock opioid drugs when initiating therapy

• For prior opioid dose of less than 30 oral morphine mg equivalents (MME) per day: Initiate with 5 mcg/hr patch applied transdermally at next dosing interval
• For prior opioid dose between 30 and 80 MME/day: Taper around-the-clock opioids for up to 7 days to no more than 30 MME/day; then, initiate with 10 mcg/hr patch applied transdermally at next dosing interval; may use short-acting analgesics as needed until analgesic efficacy is attained
• Following initiation, titrate as above

Transdermal NOTES:

• For prior opioid dose greater than 80 MME/day: Consider an alternate analgesic as transdermal therapy may not provide adequate analgesia
• Transdermal patches of 7.5, 10, 15, and 20 mcg/hour are only for use in patients who are opioid-tolerant

Comments:

• Conversion from Methadone: Close monitoring will be of particular importance as methadone has a long half-life and accumulates in the plasma; no specific conversion is provided with an understanding that there is wide interpatient variability.
• The buccal film and transdermal system should be prescribed by healthcare providers knowledgeable in the use of potent opioids for chronic pain; these products are not for use as as-needed analgesics.
• Monitor patients closely for respiratory depression, especially within 24 to 72 hours after initiating therapy and with dose increases.
• If pain level increases after dose stabilization, attempt to identify source of increased pain before increasing dose; rescue medication with an immediate-release analgesic may be needed.
• Because of the risks of opioid addiction, abuse, and misuse, this drug should be reserved for patients for whom alternative treatment options have not or are not expected to be tolerated; or have not or are not expected to provide adequate analgesia.
• Upon discontinuation, use a gradual downward titration; for patients on transdermal system, may need to switch to an immediate-release opioid.

Use: For the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment for which alternative treatment options are inadequate.

Usual Adult Dose for Opiate Dependence - Induction

Treatment should be initiated when objective and clear signs of moderate opioid withdrawal appear, and

• at least 4 hours have elapsed since last use of heroin or other short-acting opioids
• at least 24 hours have elapsed since last use of methadone or other long-acting opioids

INDUCTION:
Day 1: 8 mg sublingually once a day (may give in 2 to 4 mg increments, if preferred)
Day 2: 16 mg sublingually once a day

Comments:

• This drug should be used as part of a complete treatment plan to include counseling and psychosocial support.
• Buprenorphine (without naloxone) is the preferred drug for induction; following induction, unsupervised administration should be limited to those patients who cannot tolerate buprenorphine/naloxone.
• Adequate treatment doses should be given as soon as possible as gradual induction over several days has led to higher dropout rates.

Uses: For the treatment of opioid dependence and is preferred for induction.

Usual Pediatric Dose for Pain

2 to 12 years:
Initial dose: 2 to 6 mcg/kg IM or slow IV every 4 to 6 hours

• Some patients may not need to be remedicated for 6 to 8 hours; fixed interval or round the clock dosing should not be used until the proper inter-dose interval has been established

Over 12 years:
Initial dose: 0.3 mg deep IM or slow IV (over at least 2 minutes); may repeat this dose once after 30 to 60 minutes if needed; then, 0.3 mg IV/IM every 6 hours as needed
Maximum single dose: 0.3 mg

Comments:

• Use extra caution with IV administration, especially the first dose.
• Monitor closely for respiratory depression, especially within the first 24 to 72 hours.
• Use the lowest effective dose for the shortest duration consistent with the individual patient's treatment goals.

Use: For the management of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate.

Renal Dose Adjustments

No adjustment recommended

Liver Dose Adjustments

Transdermal:

• Severe hepatic impairment: Consider analgesics that permit more flexibility in dosing

Buccal Film:

• Severe hepatic impairment: Reduce starting dose and titration dose by one-half (i.e. from 150 mcg to 75 mcg)

Sublingual Tablets:

• Mild hepatic impairment: No adjustment recommended
• Moderate hepatic impairment: Use with caution and close monitoring
• Severe hepatic impairment: Consider reducing the starting and titration dose by one-half; monitor closely for signs and symptoms of toxicity

Extended-release subcutaneous injection:

• Moderate to severe hepatic impairment: Not recommended
• For patients developing moderate to severe hepatic impairment while on treatment, monitor for signs and symptoms of toxicity or overdose for several months.

Implant:

• Moderate to severe hepatic impairment: Not recommended
• For patients developing moderate to severe hepatic impairment while on treatment, monitor for signs and symptoms of toxicity or overdose, if signs and symptoms of toxicity or overdose are observed, the implant should be removed.

Dose Adjustments

Elderly: Initiate therapy at the low end of the dosing range and titrate slowly to account for increased sensitivity to drug

Oral Mucositis (buccal film): Reduce starting dose and dose titration by one-half in patients with known or suspected oral mucositis

Parenteral:

• Reduce dose by one-half in patients at high risk for respiratory depression, including, but not limited to patients with respiratory diseases, patients in the immediate postoperative period, the elderly, debilitated patients, and those concomitantly receiving CNS depressants.

CYP450 Inhibitors or Inducers:

• Monitor patients starting or stopping CYP450 3A4 inhibitors or inducers for potential over or under dosing

Unstable Patients undergoing Treatment for Opioid Dependence:

• Some patients may need more intensive behavioral treatment environment; decisions should be based on a treatment plan established and agreed upon with the patient at the beginning of treatment.

DISCONTINUATION:

• Abrupt discontinuation is not recommended; when therapy is ending, taper gradually while monitoring for signs and symptoms of withdrawal; if signs and symptoms of withdrawal develop, raise dose to previous level and taper more slowly.
• Patients undergoing treatment for opioid dependence should be advised of the potential to relapse.
• Patients receiving extended-release subcutaneous injection should be monitored for several months following discontinuation for signs and symptoms of withdrawal due to characteristics of the formulation; after steady-state has been achieved (4 to 6 months), detectable levels of buprenorphine may be present for 12 months or longer.

Precautions

The US FDA requires Risk Evaluation and Mitigation Strategy (REMS) for buprenorphine:

• Buprenorphine Transmucosal Products for Opioid Dependence (BTOD) Shared System REMS which includes a medication guide, elements to assure safe use, and implementation system (buprenorphine sublingual tablets)
• Opioids intended for outpatient use; the new FDA Opioid Analgesic REMS is a designed to assist in communicating the serious risks of opioid pain medications to patients and health care professionals. It includes a medication guide and elements to assure safe use.
• Probuphine (buprenorphine hydrochloride) implant which includes a medication guide, elements to assure safe use, and implementation system
• Sublocade (buprenorphine extended-release) injection which includes elements to assure safe use and implementation system
• Suboxone/Subutex which includes a medication guide, elements to assure safe use, and implementation system

For additional information: www.fda.gov/REMS

US BOXED WARNINGS: Transdermal Patch, Buccal Film, IV/IM Injection
ADDICTION, ABUSE, AND MISUSE:

• This drug exposes patients and other users to the risks of opioid addiction, abuse, or misuse which can lead to overdose and death. Assess each patient's risk before prescribing; regularly monitor for these behaviors or conditions.

RISK EVALUATION AND MITIGATION STRATEGY (REMS):

• To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, a REMS is required for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to complete a REMS-compliant education program; counsel patients and/or their caregivers, with every prescription on safe use, serious risks, storage, and disposal of these products; emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and consider other tools to improve patient, household, and community safety.

LIFE-THREATENING RESPIRATORY DEPRESSION:

• Serious, life-threatening, or fatal respiratory depression may occur. Monitor for respiratory depression, especially during initiation or following a dose increase. Misuse or abuse by chewing, swallowing, snorting, or injecting buprenorphine extracted from the buccal film or transdermal patch will result in uncontrolled delivery and pose a significant risk of overdose and death.

ACCIDENTAL EXPOSURE:

• Accidental exposure to even 1 dose of buccal film or transdermal patch, especially in children, can be fatal.

NEONATAL OPIOID WITHDRAWAL SYNDROME:

• Prolonged opioid use during a pregnancy can result in neonatal opioid withdrawal syndrome which can be life-threatening syndrome if not recognized and treated promptly. Treatment requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure appropriate treatment will be available.

RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS:

• Concomitant use with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Concomitant use should be reserved for patients for whom alternative treatment options are inadequate. If needed, limit dose and duration to the minimum required and follow patients for signs and symptoms of respiratory depression and sedation.

US BOXED WARNING: Extended-Release Injection for Subcutaneous Use:
RISK OF SERIOUS HARM OR DEATH WITH INTRAVENOUS ADMINISTRATION; SUBLOCADE(R) RISK EVALUATION AND MITIGATION STRATEGY:

• Serious harm or death could result if administered intravenously. This formulation forms a solid mass upon contact with body fluids and may cause occlusion, local tissue damage, and thrombo-embolic events, including life threatening pulmonary emboli, if administered intravenously.
• Because of the risk of serious harm or death that could result from intravenous self-administration, this formulation is available only through a restricted program called the SUBLOCADE REMS Program. Healthcare settings and pharmacies that order and dispense this formulation must be certified in this program and comply with the REMS requirements.

US BOXED WARNING: Implant for Subdermal Administration
IMPLANT MIGRATION, PROTRUSION, EXPULSION, and NERVE DAMAGE ASSOCIATED WITH INSERTION and REMOVAL:

• Risk Associated with Insertion and Removal: Insertion and removal of this formulation is associated with the risk of implant migration, protrusion, and expulsion resulting from the procedure. Rare but serious complications including nerve damage and migration resulting in embolism and death may result from improper insertion of drug implants inserted in the upper arm. Additional complications may include local migration, protrusion, and expulsion. Incomplete insertions or infections may lead to protrusion or expulsion.
• Because of the risks associated with insertion and removal, this formulation is only available through a restricted program called the PROBUPHINE REMS Program. All healthcare providers must successfully complete a live training program on the insertion and removal procedures and become certified, prior to performing insertions or prescribing implants. Patients must be monitored to ensure that the implant is removed by a healthcare provider certified to perform insertions.

Drug Addiction Treatment Act:
Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this product in the treatment of opioid dependence is limited to healthcare providers who meet qualifying requirements, and who have notified the Secretary of Health and Human Services (HHS) of their intent to prescribe or dispense this product for the treatment of opioid dependence and have been assigned a unique identification number that must be included on every prescription.

CONTRAINDICATIONS:
All Products:

• Hypersensitivity to the active substance or any of the product excipients

Additional US CONTRAINDICATIONS when buprenorphine is used for pain management:

• Severe respiratory insufficiency; significant respiratory depression; acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; known or suspected paralytic ileus

Safety and efficacy of the IM/IV parenteral product have not been established in patients younger than 2 years.

Safety and efficacy of implant for subdermal administration have not been established in patients younger than 16 years.

Safety and efficacy of buccal film, sublingual tablets, transdermal patch, or extended-release subcutaneous injection have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

US Controlled Substance: Schedule III

Dialysis

Data not available

Other Comments

Administration advice:
SUBLINGUAL TABLETS:

• Initiate treatment when objective and clear signs of moderate opioid withdrawal appear AND not less than 4 hours after last use of heroin or other short-acting opioid OR not less than 24 hours after last use of methadone or other long-acting opioid
• Allow tablets to dissolve under tongue; do not chew; do not swallow until tablets are dissolved
• If multiple tablets are necessary, place all tablets under tongue at once, OR if more than 2 tablets do not fit comfortably, place 2 tablets at a time under tongue and hold under tongue until dissolved
• Patients should be consistent in how tablets are taken to ensure consistent bioavailability; proper administration technique should be demonstrated

EXTENDED-RELEASE SUBCUTANEOUS INJECTION:

• For abdominal subcutaneous use only; do not administer IV or IM
• Only healthcare providers should prepare and administer injection (see REMS); use only the syringe and safety needle included with the product
• Administer once a month with a minimum of 26 days between doses
• Periodically exam the injection site for signs of infection or evidence of tampering or attempts to remove the depot.
• If the depot must be removed, it can be surgically excised under local anesthesia within 14 days of injection; only the most recently-injected depot can be removed
• Further information is available at www.SublocadeREMS.com or 1-866-258-3905

IMPLANT for subdermal administration:

• Implants must be inserted and removed by certified healthcare providers (see REMS); insertion site should be examined one week following insertion for signs of infection, problems with wound healing, and/or evidence of implant extrusion from the skin.
• If spontaneous expulsion occurs, patient should promptly notify healthcare provider as they will need to bring implant to provider to determine whether full implant was expelled; expelled implant should be placed in plastic bag and safely out of reach of children until returned to healthcare provider.
• Further information is available at www.PROBUPHINEREMS.com or 1-844-859-6341

BUCCAL FILM:

• Application site should be wet with tongue or rinsed with water; apply film (yellow side down) immediately after removal from package; do not use if pouch seal is broken or the film appears damaged in any way
• Hold film in place with clean, dry fingers for 5 seconds; then, allow to completely dissolve without any further manipulation with fingers or tongue; usually dissolves in 30 minutes
• Patients should not eat or drink until film has dissolved
• Proper administration technique should be demonstrated; film should not be chewed or swallowed

PARENTERAL:

• Administer by deep IM injection or slow IV injection (over at least 2 minutes)

TRANSDERMAL:

• Apply patch immediately after removal from sealed pouch; do not use if pouch seal is broken or the patch is damaged in any way.
• Apply to a hairless or nearly hairless skin site of upper outer arm, upper chest, upper back, or side of chest; if not hairless, hair should be clipped, not shaven; do not apply to irritated skin.
• If application site must be cleaned, clean with water only and allow to dry before applying patch.
• Rotate application sites: allow a minimum of 21 days before reapplying to the same skin site.
• If adhesion problems occur, first aid tape to the edges may be used; if problem persists, the patch may be covered with waterproof or semipermeable dressing suitable for 7 days of wear.
• If patch falls off, dispose of properly and place a new patch on a different skin site.
• A maximum of 2 patches may be used to obtain correct dose; for application of 2 patches at the same time, apply adjacent to one another.
• A patch-disposal unit is provided for disposal of the transdermal system, follow instructions on unit. Alternatively, dispose of patches by folding adhesive side to itself and flush down the toilet.

General:
Opiate dependence:

• This drug should be used as part of a complete treatment program to include counseling and psychosocial support; buprenorphine without naloxone is generally used for induction, while buprenorphine with naloxone is used for maintenance therapy; use of buprenorphine alone for maintenance therapy should be limited to those patients who cannot tolerate naloxone.
• Titration to adequate treatment doses should be done as rapidly as possible; gradual induction over several days may lead to higher drop-out rates during the induction period.
• There is no maximum recommended duration of maintenance treatment; for some patients treatment may continue indefinitely.
• Patients who continue to misuse, abuse, or divert this drug or other opioids should be referred to more intensive and structured treatment.

Pain:

• Maximum dose limits have been set due to the potential for QTC interval prolongation.
• Individualize dosing regimen for each patient taking into account patient's prior analgesic treatment experience and risk factors for respiratory depression, addiction, abuse, and misuse.
• Prescribing this drug for chronic pain management should be done by healthcare professionals knowledgeable in the use of potent opioids.
• Do not discontinue abruptly in physically dependent patients.

Monitoring:

• Monitor for respiratory depression, especially in the 24 to 72 hours after initiation and with each dose increase
• Monitor for hypotension, especially in ambulatory patients
• Obtain liver function tests at baseline and periodically during therapy for patients at increased risk of hepatotoxicity
• Periodically examine the abdominal subcutaneous injection site for signs of infection or evidence of tampering or attempts to remove the depot.
• Check implant insertion site 1 week following insertion for signs of infection, problems with wound healing, and/or evidence of implant extrusion from the skin
• Monitor for opioid dependence

Patient advice:

• Patients should be instructed to read the US FDA-approved Medication Guide each time this drug is dispensed; they should understand the safe use, serious risks, and proper storage and disposal of this drug.
• Patients should understand that this drug, even when taken as recommended can result in addiction, abuse, and misuse; instruct patients not to share their drug with others and protect drug from theft or misuse.
• Accidental ingestion, especially by children, can result in death; keep out of reach of children.
• Patients and caregivers should understand life-threatening respiratory depression may occur; they should understand when this risk is greatest, and seek medical attention if breathing difficulties develop.
• Women of child bearing potential should understand that prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome and that prompt recognition and treatment will be necessary.
• Patients should understand this drug has potentially serious side effects including adrenal insufficiency, severe constipation, and hypotension, as well as potentially significant drug interactions, especially with other CNS depressants, including alcohol; patients should be instructed to speak with a healthcare professional regarding any change in medications or if any new symptoms develop.
• This drug may cause drowsiness, dizziness, or impair thinking or motor skills; patients should avoid driving or operating machinery until adverse effects are determined.
• Patients should avoid heat exposure to transdermal application site or surroundings areas (e.g. hot water, prolonged direct sunlight).
• Patients electing treatment with the subdermal implant should understand the risks associated with insertion and removal of the implant, and be instructed on what to do if the implant protrudes or is expelled or if they develop bleeding or symptoms of infection at insertion site, numbness, weakness, or shortness of breath.

Frequently asked questions

• How long does opioid withdrawal last?
• How long does buprenorphine stay in your system?
• What are the different brands of buprenorphine?
• What is the difference between Sublocade and Brixadi?
• What are the different types of buprenorphine/naloxone?
• How long do you take buprenorphine for?
• Is Buprenex the same as buprenorphine?