buprenorphine/naloxone (Rx)

Brand and Other Names:Suboxone, Zubsolv, more...Bunavail, Cassipa
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

buprenorphine/naloxone

film, sublingual: Schedule III

  • 2mg/0.5mg (Suboxone, generic)
  • 4mg/1mg (Suboxone, generic)
  • 8mg/2mg (Suboxone, generic)
  • 12mg/3mg (Suboxone, generic)
  • 16mg/4mg (Cassipa)

tablet, sublingual (Zubsolv): Schedule III

  • 0.7mg/0.18mg
  • 1.4mg/0.36mg
  • 2.9mg/0.71mg
  • 5.7mg/1.4mg
  • 8.6mg/2.1mg
  • 11.4mg/2.9mg

buccal film (Bunavail): Schedule III

  • 2.1mg/0.3mg
  • 4.2mg/0.7mg
  • 6.3mg/1mg

tablet, sublingual (generic): Schedule III

  • 2mg/0.5mg
  • 8mg/2mg
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Opioid Dependence

Induction (buprenorphine SL)

  • Day 1: 4 mg SL initially; may be repeated after 2 hours if withdrawal symptoms are not relieved; not to exceed 8 mg
  • Day 2: If no withdrawal symptoms are present, 4 mg SL; if withdrawal symptoms are present, dose is increased by 4 mg; if symptoms are not relieved after >2 hr, 4 mg is administered; not to exceed 16 mg SL
  • Switch to buprenorphine/naloxone for unsupervised maintenance

Induction (buprenorphine/naloxone [Suboxone])

  • Caution: buprenorphine/naloxone (Suboxone) induction is only for patients dependent on short-acting opioids (eg, heroin) and not for those dependent on long-acting opioids (eg, methadone); buprenorphine monotherapy is recommended for induction for long-acting opioids
  • Day 1: 2 mg/0.5 mg or 4 mg/1 mg SL initially; may titrate upwards in 2-4 mg increments at 2 hr intervals, under supervision; not to exceed 8 mg/2 mg
  • Day 2: Up to 16 mg/4 mg SL as a single daily dose

Induction (buprenorphine/naloxone [Zubsolv])

  • Caution: buprenorphine/naloxone (Zubsolv) induction is only for patients dependent on short-acting opioids (eg, heroin) and not for those dependent on long-acting opioids (eg, methadone); buprenorphine monotherapy is recommended for induction for long-acting opioids
  • Day 1
    • An induction dose of up to 5.7 mg/1.4 mg is recommended, given in divided doses; initiate with 1.4 mg/0.36 mg SL; give remainder of Day 1 dose of up to 4.2 mg/1.08 mg should be divided into doses of 1 to 2 tablets of 1.4 mg/0.36 mg at 1.5 to 2 hr intervals
    • Some patients (eg, those with recent exposure to buprenorphine) may tolerate up to 3 x 1.4 mg/0.36 mg SL as a single, second dose
  • Day 2
    • A single daily dose up to 11.4 mg/2.9 mg SL is recommended

Induction (buprenorphine/naloxone [Bunavail])

  • Caution: buprenorphine/naloxone (Bunavail) induction is only for patients dependent on short-acting opioids (eg, heroin) and not for those dependent on long-acting opioids (eg, methadone); buprenorphine monotherapy is recommended for induction for long-acting opioids
  • Day 1
    • The first dose should not be administered <6 hr after the patient last used an opioid
    • An induction dose of up to 4.2 mg/0.7 mg is recommended; initiate with 2.1 mg/0.3 mg and repeat at ~2-hr, under supervision, to a total dose of 4.2 mg/0.7 mg based on control of acute withdrawal symptoms
  • Day 2
    • A single daily dose up to 8.4 mg/1.4 mg buccal is recommended

Maintenance

  • Suboxone
    • Target dose: 12-16 mg/4 mg buprenorphine/naloxone SL as a single daily dose
    • Range: 16-24 mg buprenorphine component; not to exceed 32 mg/day
    • Progressively adjust buprenorphine/naloxone dose in increments or decrements of 2 mg/0.5 mg or 4 mg/1 mg to level that holds patient in treatment and suppresses opioid withdrawal signs and symptoms
  • Zubsolv
    • Target dose: 11.4/2.9 mg as a single daily dose
    • Range: 2.9/0.71 mg to 17.2/4.2 mg
    • Progressively adjust buprenorphine/naloxone dose in increments or decrements of 1.4/0.36 mg or 2.9/0.71 mg to level that holds patient in treatment and suppresses opioid withdrawal signs and symptoms
  • Bunavail
    • Target dose: 8.4/1.4 mg as a single daily dose
    • Range: 2.1/0.3 mg to 12.6/2.1 mg
    • Progressively adjust dose in increments or decrements of 2.1/0.3 mg to a level that holds patient in treatment and suppresses opioid withdrawal signs and symptoms
    • There is no maximum recommended duration of maintenance treatment; for some patients, treatment may continue indefinitely
  • Cassipa
    • Used after induction and stabilization of the patient, and after buprenorphine dose titrated to 16 mg using another marketed product
    • If dose needs adjustment in order to maintain treatment and suppress opioid withdrawal signs and symptoms, a different product will be needed; Cassipa comes in a single dose and cannot be adjusted (ie, SL film available only as 16 mg buprenorphine/4 mg naloxone)
    • There is no maximum recommended duration of maintenance treatment; for some patients, treatment may continue indefinitely

Dosage Modifications

Hepatic impairment

  • Mild: No dosage adjustment necessary
  • Moderate: May not be appropriate
  • Severe: Avoid use

Renal impairment

  • No differences in buprenorphine pharmacokinetics observed between 9 dialysis-dependent and 6 normal patients following IV administration of 0.3 mg buprenorphine
  • Renal failure: Unknown

Dosing Considerations

Prior to induction, consideration should be given to the type of opioid dependence (ie, long- or short-acting opioid products, the time since last opioid use, and the degree or level of opioid dependence

To avoid precipitating an opioid withdrawal syndrome, the first dose of buprenorphine/naloxone should be administered only when objective and clear signs of moderate withdrawal are evident, and divided doses should be used

It is recommended that an adequate treatment dose, titrated to clinical effectiveness, be achieved as rapidly as possible

Patients dependent on methadone or long-acting opioid products may be more susceptible to precipitated and prolonged withdrawal during induction than those on short-acting opioid products; buprenorphine monotherapy is recommended in patients taking long-acting opioids instead of buprenorphine/naloxone, which may worsen withdrawal symptoms

Patients dependent on heroin or other short-acting opioid products may be induced with buprenorphine/naloxone or with SL buprenorphine monotherapy

Equivalents

  • Zubsolv 5.7/1.4 mg SL provides equivalent buprenorphine exposure to Suboxone 8/2 mg SL
  • Bunavail 2.1/0.3 mg buccal provides equivalent buprenorphine exposure to Suboxone 4/1 mg SL
  • Bunavail 4.2/0.7 mg buccal provides equivalent buprenorphine exposure to Suboxone 8/2 mg SL
  • Bunavail 6.3/1 mg buccal provides equivalent buprenorphine exposure to Suboxone 12/3 mg SL

Safety and efficacy not established

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Interactions

Interaction Checker

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            Adverse Effects

            >10%

            Headache (28-36.4%)

            Withdrawal syndrome (24-25.2%)

            Insomnia (14-23%)

            Pain (22.4%)

            Nausea (7-15%)

            Hyperhidrosis (14%)

            Asthenia (6.5-14%)

            Constipation (5-12.1%)

            Abdominal pain (11.2%)

            1-10%

            Diarrhea (10%)

            Vasodilation or peripheral edema (9.3%)

            Chills (6-7.5%)

            Vomiting (4-7.5%)

            Postmarketing Reports

            Adrenal insufficiency

            Anaphylaxis

            Serotonin syndrome

            Hepatotoxicity

            Glossodynia

            Glossitis

            Oral mucosal erythema

            Oral hypoesthesia Stomatitis

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            Warnings

            Contraindications

            Hypersensitivity

            Cautions

            Significant respiratory depression may occur with therapeutic doses

            Use with caution in hypothyroidism, preexisting respiratory compromise, obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve and kyphoscoliosis, myxedema, adrenocortical insufficiency, alcohol intoxication, alcohol withdrawal syndrome, coma, severe renal impairment, geriatric or debilitated patients, delirium tremens, toxic psychoses, kyphoscoliosis, prostatic hypertrophy, urethral stricture, comatose patients, central nervous system (CNS) depression, biliary tract dysfunction, severe hepatic impairment, head injury, intracranial lesions, and intracranial hypertension or conditions in which intracranial pressure (ICP) may be increased

            Use caution with concurrent use of other CNS depressants

            Respiratory sedation is dose-dependent; usual doses may depress respiration to same degree as 10 mg of parenteral morphine

            Use caution in patients with history of ileus or bowel obstruction

            May cause orthostatic hypotension; use caution in patients with hypovolemia, cardiovascular disease, or drugs that may worsen hypertension

            Effects in CNS depression may impair ability to perform tasks that require mental alertness

            Life-threatening neonatal syndrome may occur in newborns following maternal exposure to opioids; treat according to protocols developed by neonatology experts; prescribers should discuss with patients importance and benefits of management of opioid addiction throughout pregnancy

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

            Use caution when switching between formulations; certain sublingual film strengths may have greater bioavailability compared to the same strength of sublingual tablet; monitor for overdosing or underdosing when switching formulations

            Buprenorphine may precipitate acute narcotic withdrawal in opioid-dependent patients upon rapid discontinuation or rapid taper; taper dose gradually when discontinuing therapy

            May obscure diagnosis or clinical course of patients with acute abdominal conditions

            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

            Advise pregnant women receiving opioid addiction treatment with sublingual film of risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available

            Drug can be abused in a manner similar to other opioids; consider this when prescribing or dispensing buprenorphine in situations when clinician is concerned about increased risk of misuse, abuse, or diversion

            Coadministration with benzodiazepines

            • Life-threating respiratory depression and death may occur; many, but not all, postmarketing reports regarding coma and death involved misuses by self-injection or were associated with concomitant use of benzodiazepines or other CNS depressants, including alcohol; warn patients of potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment
            • Concomitant use of buprenorphine and benzodiazepines or other CNS depressants increases risk of adverse reactions including overdose and death; medication-assisted treatment of opioid use disorder, however, should not be categorically denied to patients taking these drugs; prohibiting or creating barriers to treatment can pose an even greater risk of morbidity and mortality due to the opioid use disorder alone
            • Develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants at initiation of buprenorphine treatment, or if it emerges as a concern during treatment; adjustments to induction procedures and additional monitoring may be required; there is no evidence to support dose limitations or arbitrary caps of buprenorphine as a strategy to address benzodiazepine use in buprenorphine-treated patients; however, if a patient is sedated at the time of buprenorphine dosing, delay or omit the buprenorphine dose if appropriate
            • Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate
            • Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the patient’s buprenorphine treatment and coordinate care to minimize the risks associated with concomitant use
            • Confirm patients are taking their medications as prescribed and are not diverting or supplementing with illicit drugs; toxicology screening should test for prescribed and illicit benzodiazepines
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            Pregnancy & Lactation

            Pregnancy

            Data on use of buprenorphine, one of the active ingredients are limited; however, these data do not indicate an increased risk of major malformations specifically due to buprenorphine exposure; there are limited data from randomized clinical trials in women maintained on buprenorphine that were not designed appropriately to assess the risk of major malformations; the extremely limited data on sublingual naloxone exposure in pregnancy are not sufficient to evaluate a drug associated risk; dosage adjustments of buprenorphine may be required during pregnancy, even if patient was maintained on stable dose prior to pregnancy; withdrawal signs and symptoms should be monitored closely and dose adjusted as necessary  

            Neonates whose mothers have been taking opioids long term may 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; advise breastfeeding women taking buprenorphine products to monitor infant for increased drowsiness and breathing difficulties

            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

            Buprenorphine: Semisynthetic narcotic mixed agonist-antagonist analgesic; exerts agonistic effects at mu and delta opioid receptors in CNS, as well as antagonistic effects at kappa opioid receptor

            Naloxone: Potent antagonist at mu opioid receptors and produces opioid withdrawal signs and symptoms in individuals physically dependent on full opioid agonists when administered parenterally

            Absorption

            Suboxone

            • Peak plasma time: Buprenorphine, 1.53-1.72 hr; naloxone, 0.77-0.81 hr
            • Peak plasma concentration: Buprenorphine, 0.947-3.37 ng/mL; naloxone, 54.1-193 pg/mL

            Zubsolv

            • Bioavailability differs from that of Suboxone
            • Compared with Suboxone 8/2 mg, Zubsolv 5.7/1.4 mg provides equivalent buprenorphine exposure and 12% lower naloxone exposure

            Bunavail

            • Bioavailability differs from that of Suboxone
            • Compared with Suboxone 8/2 mg, Bunavail 4.2/0.7 mg provides equivalent buprenorphine exposure and 33% lower naloxone exposure
            • Coadministration of liquids reduced the systemic exposure up to 59% for buprenorphine and up to 76% for naloxone (depending on the pH of the liquid)

            Distribution

            Protein bound: Buprenorphine, 96% (primarily alpha and beta globulin); naloxone, 45% (primarily albumin)

            Metabolism

            Buprenorphine: Metabolized by N-dealkylation via CYP3A4 to norbuprenorphine (active metabolite) and by glucuronidation

            Naloxone: Metabolized by direct glucuronidation to naloxone-3-glucuronide, as well as by N-dealkylation and reduction of 6-oxo group

            Elimination

            Excretion: Buprenorphine, urine (30%) and feces (69%)

            Half-life

            • Suboxone, Zubsolv: 24-42 hr (buprenorphine); 2-12 hr (naloxone)
            • Cassipa: 35-37 hr (buprenorphine); 5.6-6.6 hr (naloxone)
            • Bunavail: 16.4-27.5 hr (buprenorphine); 1.9-2.4 hr (naloxone)
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            Administration

            Sublingual Administration

            Switching between SL tablet and SL film: Potential for greater bioavailability with SL film than with generic SL tablets (monitor for over- or underdosing)

            Instruct patient to rinse mouth with small volume of room-temperature water before placement of the SL film strip or tablet under their tongue

            High pH beverages should be avoided prior to dosing

            Place film/tablet under the tongue, close to the base on the left or right side; keep in place until completely dissolved

            Advise patients not to eat or drink anything until the film is completely dissolved

            Use entire tablet/film; do not chew, cut, or swallow SL or buccal preparations

            Bunavail Buccal Film Application

            Use the tongue to wet the inside of the cheek or rinse mouth with water to moisten the area immediately before placement

            Open package immediately prior to use

            Hold the buccal film with clean, dry fingers with the text (BN2, BN4, or BN6) facing up, THEN

            Place the side of the film with the text (BN2, BN4, or BN6) against the inside of the cheek

            Press and hold the film in place for 5 seconds

            Buccal film completely dissolves after applicationInstruct the patient to avoid manipulating the film(s) with the tongue or finger(s) and avoid drinking or eating food until the film(s) dissolve

            Multiple Bunavail films

            • If multiple films are needed, the patient should immediately apply the next film according to the steps above
            • When 2 films are required for one dose, the patient should place one film on the inside of one cheek and the other film on the inside of the other cheek
            • For doses requiring multiple films, no more than 2 films should be applied to the inside of one cheek at a time
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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
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            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            NC NOT COVERED – Drugs that are not covered by the plan.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.