buprenorphine buccal (Rx)

Brand and Other Names:Belbuca
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

buccal film: Schedule III

  • 75mcg
  • 150mcg
  • 300mcg
  • 450mcg
  • 600mcg
  • 750mcg
  • 900mcg

Chronic Severe Pain

Indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate

Buccal film for oral buccal use only; apply to buccal mucosa q12hr

Initiate the dosing regimen for each patient individually, taking into account the patient’s severity of pain, response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse

Opioid-naïve

  • Initiate with 75 mcg film qDay or, if tolerated, q12hr for at least 4 days, then increase dose to 150 mcg q12hr
  • Individual titration to a dose that provides adequate analgesia and minimizes adverse reactions should proceed in increments of 150 mcg q12hr, no more frequently than every 4 days
  • Doses up to 450 mcg q12hr were studied in opioid-naïve patients in the clinical trials

Conversion from other opioids

  • There is a potential for buprenorphine to precipitate withdrawal in patients who are already on opioids
  • To reduce the risk of opioid withdrawal, taper patients ≤30 mg oral morphine sulfate equivalents (MSE) daily before beginning buprenorphine buccal
  • May supplement with prompt-acting opioid and nonopioid analgesic for break-through pain during taper
  • Following analgesic taper, base the starting dose on the patient’s daily opioid dose prior to taper, as described
    • Oral morphine equivalent <30 mg/day: Initiate with 75 mcg qDay or q12hr
    • Oral morphine equivalent 30-89 mg/day: Initiate with 150 mcg q12hr
    • Oral morphine equivalent 90-160 mg/day: Initiate with 300 mcg q12hr
    • Oral morphine equivalent >160 mg/day: Consider alternate analgesic
    • Buprenorphine buccal doses of 600 mcg, 750 mcg, and 900 mcg are only for use following titration from lower doses of buprenorphine buccal
    • Individual titration should proceed in increments of 150 mcg q12h, no more frequently than every 4 days

Conversion from methadone

  • Close monitoring is of particular importance when converting from methadone to other opioid agonists, including buprenorphine buccal
  • The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure
  • Methadone has a long half-life and can accumulate in the plasma

Titration and maintenance dose

  • Individually titrate to a dose that provides adequate analgesia and minimizes adverse reactions
  • Continually reevaluate to assess the maintenance of pain control and the relative incidence of adverse reactions and monitor for the development of addiction, abuse, or misuse
  • Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration
  • During long-term therapy, periodically reassess the continued need for opioid analgesics
  • The minimum titration interval is 4 days, based on the pharmacokinetic profile and time to reach steady-state plasma levels
  • Individual titration should proceed in increments that do not exceed 150 mcg q12hr
  • Maximum dose: 900 mcg q12hr; do not exceed this dose because of potential for QTc interval prolongation
  • If pain is not adequately managed on buprenorphine buccal 900 mcg, consider an alternate analgesic
  • Patients who experience breakthrough pain may require dosage adjustment of buprenorphine or may need rescue medication with an appropriate dose of an immediate-release analgesic
  • If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the dose
  • If unacceptable opioid-related adverse reactions are observed, adjust the dose to obtain an appropriate balance between the management of pain and opioid-related adverse reactions

Dosage Modifications

Renal impairment: No dosage adjustment required for any level of renal impairment

Oral mucositis: In patients with known or suspected mucositis, reduce the starting dosage and titration incremental dosage by half compared with patients without mucositis

Hepatic impairment

  • Mild (Child-Pugh A): No dosage adjustment required
  • Moderate (Child-Pugh B): No dosage adjustment required; however, monitor these patients for signs and symptoms of toxicity or overdose
  • Severe (Child-Pugh C): Reduce the starting dose and reduce the titration dose by half that of patients with normal liver function, from 150 mcg to 75 mcg

Dosing Considerations

Limitations of use

  • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve for patients in whom alternative treatment options (eg, nonopioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain
  • Not indicated as a PRN analgesic

Safety and efficacy not established

Although specific dose adjustments on the basis of advanced age are not required for pharmacokinetic reasons, use caution in the elderly population to ensure safe use

Clinical trials observed that some adverse effects (ie, respiratory depression, constipation, urinary retention) occur more frequently in elderly patients

See adult dosing

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Interactions

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            Adverse Effects

            >10%

            Open-label titration phase

            • Nausea, opioid-naive (50%)
            • Nausea, both opioid-naïve and opioid-tolerant (33%)
            • Nausea, opioid-tolerant (17%)
            • Constipation, opioid-naïve (13%)
            • Constipation, opioid-naïve and opioid-tolerant (11%)

            1-10%

            Open-label titration phase

            • Constipation, opioid-tolerant (8%)
            • Headache (8%)
            • Vomiting (7%)
            • Dizziness (6%)
            • Somnolence (6%)
            • Drug withdrawal syndrome: (1%)

            Postmarketing Reports

            Adrenal insufficiency

            Hepatotoxicity

            Serotonin syndrome

            Anaphylaxis

            Androgen deficiency

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            Warnings

            Black Box Warnings

            Opioid analgesic risk evaluation and mitigation strategy (REMS)

            • To ensure that benefits of opioid analgesics outweigh risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products; under 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
              • Consider other tools to improve patient, household, and community safety

            Addiction, abuse, and misuse

            • Risk of opioid addiction, abuse, and misuse, which can lead to overdose and death
            • Assess each patient’s risk prior to prescribing and monitor all patients regularly for the development of these behaviors or conditions

            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

            Accidental exposure

            • Accidental exposure of even 1 dose, especially by children, can result in a fatal overdose

            Neonatal opioid withdrawal syndrome

            • Prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts
            • Syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight
            • Onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn
            • 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 that appropriate treatment will be available

            Concomitant use with benzodiazepines or other CNS depressants

            • Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death; reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to minimum required; and follow patients for signs and symptoms of respiratory depression and sedation

            Contraindications

            Significant respiratory depression

            Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment

            Known or suspected gastrointestinal obstruction, including paralytic ileus

            Hypersensitivity (eg, anaphylaxis) to buprenorphine

            Cautions

            Misuse, abuse, diversion: Partial agonist at the mu opioid receptor and a schedule III controlled opioid exposes users to the risks of addiction, abuse, and misuse; there is a greater risk for overdose and death with extended-release opioids owing to the larger amount of active opioid present; screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of risk for overdose and death associated with use of additional CNS depressants including alcohol and illicit drugs (see Black Box Warnings)

            Life-threatening respiratory depression more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients (even to moderate therapeutic doses) (see Black Box Warnings); because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and may be useful to monitor renal function

            Neonatal opioid withdrawal syndrome reported with long-term use during pregnancy (see Black Box Warnings)

            Accidental exposure reported, including fatalities (see Black Box Warnings)

            Interactions with CNS depressants (eg, alcohol, sedatives, anxiolytics, hypnotics, neuroleptics, other opioids) can cause additive effects and increase risk for respiratory depression, profound sedation, and hypotension

            Risk of apnea in patients with chronic pulmonary disease; closely monitor these patients, when initiating and titrating therapy; alternatively, consider the use of alternative non-opioid analgesics in these patients (see Black Box Warnings and Contraindications)

            QTc prolongation observed in healthy individuals at 40 mcg/hr; avoid in patients with history of long QT syndrome or coadministration with class IA (eg, quinidine, procainamide, disopyramide) or class III (eg, sotalol, amiodarone, dofetilide) antiarrhythmics

            Head injury: Respiratory depressant effects of opioids may include carbon dioxide retention and lead to elevated CSF pressure

            Hypotensive effects: Can cause severe hypotension; caution with depleted blood volume or coadministration of drugs that that affect vasomotor tone (eg, phenothiazines), vasodilators, or antihypertensives

            Hepatoxicity: Cases of cytolytic hepatitis and hepatitis with jaundice observed in individuals receiving buprenorphine SL for opioid dependence treatment; increased risk for overdose with moderate or severe hepatic impairment (see Dosage Modifications)

            Anaphylactic reactions reported

            May cause sphincter of Oddi spasm and aggravate abdominal conditions, including ileus (see Contraindications)

            Similar to other opioids, may aggravate seizure disorders by lowering seizure threshold

            Patients with cancer who have oral mucositis may absorb buprenorphine more rapidly than intended and have higher plasma levels of buprenorphine (see Dosage Modifications)

            Special risk groups may experience increased adverse reactions; caution with alcoholism, delirium tremens, adrenocortical insufficiency, CNS depression, debilitation, kyphoscoliosis associated with respiratory compromise, myxedema or hypothyroidism, prostatic hypertrophy or urethral stricture, severe impairment of hepatic, pulmonary or renal function, and toxic psychosis

            Profound sedation, respiratory depression, coma, and death may result from concomitant use with benzodiazepines or other CNS depressants (see BBW); prescribe lowest effective dosages and minimum durations of concomitant use

            Cases of adrenal insufficiency reported with opioid use, more often following greater than one month of use; symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure; if adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids; wean patient off of opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers; other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency

            Chronic use of opioids may cause reduced fertility in females and males of reproductive potential; unknown whether effects on fertility are reversible

            Opioid analgesic risk evaluation and mitigation strategy (REMS)

            • To ensure that benefits of opioid analgesics outweigh risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products
            • Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed; use the following link to obtain the Patient Counseling Guide (PCG): www.fda.gov/OpioidAnalgesicREMSPCG
            • Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them
            • Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities
            • To obtain further information on opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com; the FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint
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            Pregnancy & Lactation

            Pregnancy

            Opioids cross the placenta and may produce respiratory depression and psychophysiologic effects in neonates; not recommended for use in women immediately prior to and during labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate

            Neonates whose mothers have been taking opioids long term may also exhibit withdrawal signs, either at birth and/or in the nursery, because they have developed physical dependence; neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening and should be treated according to protocols developed by neonatology experts

            Lactation

            Caution should be exercised when therapy is administered to nursing women; the developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed child from drug or from underlying maternal condition

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Elicits partial agonistic effects at the mu opioid receptor in the CNS, and antagonistic effects at the kappa opioid receptor

            Absorption

            Absolute bioavailability: 46-65%

            75-mcg single dose

            • Peak plasma concentration: 0.17 ng/mL
            • Peak plasma time: 3 hr
            • AUC (0-4 hr): 0.46 h·ng/mL
            • AUC (1 - ∞): 0.63 h·ng/mL

            300-mcg single dose

            • Peak plasma concentration: 0.47 ng/mL
            • Peak plasma time: 2.5 hr
            • AUC (0-4 hr): 2 h·ng/mL
            • AUC (1 - ∞): 2.3 h·ng/mL

            1200-mcg single dose

            • Peak plasma concentration: 1.43 ng/mL
            • Peak plasma time: 3 hr
            • AUC (0-4 hr): 9.6 h·ng/mL
            • AUC (1 - ∞): 10.5 h·ng/mL

            Food and beverage decrease systemic exposure

            • Systemic exposure to buprenorphine was reduced by 23-27% by the ingestion of liquids (cold, hot, and room temperature water) during film administration
            • Systemic exposure also reduced if coadministration with low pH liquid (eg, decaffeinated cola) by ~37%
            • The consumption of food and liquids should be avoided until the buccal film has completely dissolved

            Distribution

            Protein bound 96%; primarily to alpha and beta globulin

            Metabolism

            Undergoes both N-dealkylation to norbuprenorphine and glucuronidation

            The N-dealkylation pathway is mediated primarily by CYP3A4

            Norbuprenorphine, the major metabolite, can further undergo glucuronidation

            Elimination

            Half-life: 27.6 hr

            Excretion: 30% urine; 69% feces

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            Administration

            Instructions

            Instruct patients not to use if the pouch seal is broken or the buccal film is cut, damaged, or changed in any way

            Buccal film for oral buccal use only; apply to buccal mucosa q12hr

            Do not apply to areas of the mouth with any open sores or lesions

            Monitor patients closely for respiratory depression, especially within the first 24-72 hr after initiating therapy and following dosage increases; adjust the dosage accordingly

            Also see Adult Dosing for titration and maintenance dosing

            Buccal Application

            First, the patient must use the tongue to wet the inside of the cheek or rinse the mouth with water to wet the area for placement of buprenorphine buccal

            Buprenorphine is then applied immediately after removal from the individually sealed package

            The yellow side of the Belbuca film is placed against the inside of the cheek; the entire film is held in place with clean, dry fingers for 5 seconds and then left in place on the inside of the cheek until fully dissolved

            The buccal film adheres to the moist buccal mucosa and will completely dissolve after application, usually within 30 minutes

            The film should not be manipulated with the tongue or finger(s)

            Avoid eating food and drinking liquids until the film has dissolved

            A buprenorphine buccal film that is chewed or swallowed may result in lower peak concentrations and lower bioavailability than when used as directed

            Discontinuation

            When a patient no longer requires therapy with buprenorphine buccal, use a gradual downward titration of the dose to prevent signs and symptoms of withdrawal in the physically dependent patient

            Do not abruptly discontinue

            Storage

            Store at controlled room temperature (25°C [77°F]); excursions permitted to 15-30°C (59-86ºF)

            Advise patients to store buprenorphine-containing medications safely and out of sight and reach of children

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            Formulary

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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