Belbuca (buprenorphine HCl)

Dosage of buprenorphine and buprenorphine hydrochloride usually is expressed in terms of buprenorphine. Dosage of buprenorphine hydrochloride subdermal implants may be expressed as either the salt or the base.

Not all formulations, strengths, or dose combinations of oral transmucosal buprenorphine/naloxone preparations are bioequivalent.

Patients who currently are receiving generic buprenorphine or buprenorphine/naloxone sublingual tablets (i.e., generic equivalents of Subutex(R) or Suboxone(R) sublingual tablets) and are switching to buprenorphine/naloxone sublingually dissolving strips (Suboxone(R)), or vice versa, should continue to receive the same drug dosage. However, not all strengths and dose combinations of the strips and sublingual tablets are bioequivalent. Because of potentially greater bioavailability with the strips relative to the tablets, patients should be monitored for underdosage (e.g., manifestations of withdrawal) or overdosage when switching between sublingual dosage forms and the dosage should be adjusted when indicated.

The 4 strengths of Suboxone(R) sublingually dissolving strips differ in size and buprenorphine and naloxone concentrations (on a % (w/w) basis). Switching between various combinations of lower- and higher-strength strips to obtain the same total dose may result in changes in systemic exposure to buprenorphine and naloxone and require that the patient be monitored for underdosage or overdosage. Therefore, substitution of one or more strip strengths for another without the prescriber's approval is not recommended. Because systemic exposure to naloxone is somewhat higher after buccal compared with sublingual administration of the strips, sublingual administration is recommended during induction to minimize the risk of precipitated withdrawal. However, exposure to buprenorphine is similar following either buccal or sublingual administration, and once induction is complete, patients can switch between buccal and sublingual administration without substantial risk of underdosage or overdosage.

Bunavail(R) and Zubsolv(R) have different bioavailabilities than Suboxone(R) (or generic equivalent) sublingual tablets. Patients switching between these preparations should receive a different dosage strength (see Table 1 and Table 2) and should be monitored for underdosage or overdosage. Dosage adjustments may be necessary. Systemic buprenorphine exposure following administration of one Suboxone(R) sublingual tablet containing buprenorphine 8 mg and naloxone 2 mg is equivalent to that achieved following administration of one Bunavail(R) buccally dissolving strip containing buprenorphine 4.2 mg and naloxone 0.7 mg or one Zubsolv(R) sublingual tablet containing buprenorphine 5.7 mg and naloxone 1.4 mg.

Table 1. Corresponding Doses and Strengths of Suboxone(R) Sublingual Tablets and Bunavail(R) Buccally Dissolving Strips

Suboxone(R) Sublingual Dose or Corresponding Bunavail(R) Strip Tablet Strength Strength Buprenorphine 4 mg and naloxone 1 mg Buprenorphine 2.1 mg and naloxone 0.3 mg Buprenorphine 8 mg and naloxone 2 mg Buprenorphine 4.2 mg and naloxone 0.7 mg Buprenorphine 12 mg and naloxone 3 Buprenorphine 6.3 mg and naloxone 1 mg mg

Table 2. Corresponding Dosage Strengths of Suboxone(R) Sublingual Tablets (or Generic Equivalent) and Zubsolv(R) Sublingual Tablets

Suboxone(R) (or Generic Equivalent) Corresponding Zubsolv(R) Sublingual Sublingual Dose (Tablet Strength) Tablet Strength Buprenorphine 2 mg and naloxone 0.5 One 1.4-mg/0.36-mg tablet mg (as one 2-mg/0.5-mg tablet) Buprenorphine 4 mg and naloxone 1 mg One 2.9-mg/0.71-mg tablet (as two 2-mg/0.5-mg tablets) Buprenorphine 8 mg and naloxone 2 mg One 5.7-mg/1.4-mg tablet (as one 8-mg/2-mg tablet) Buprenorphine 12 mg and naloxone 3 One 8.6-mg/2.1-mg tablet mg (as one 8-mg/2-mg tablet and two 2-mg/0.5-mg tablets) Buprenorphine 16 mg and naloxone 4 One 11.4-mg/2.9-mg tablet mg (as two 8-mg/2-mg tablets)

Transdermal buprenorphine has not been studied in patients with severe hepatic impairment; use of an alternative analgesic regimen that allows for greater dosage flexibility should be considered in these patients.

When buprenorphine buccally dissolving strips (Belbuca(R)) are used for analgesia in patients with severe hepatic impairment (i.e., Child-Pugh class C), the usual initial dosage should be reduced and each incremental change in dosage during titration should be reduced by one-half (i.e., from 150 mcg to 75 mcg). No dosage adjustment is required in patients with moderate hepatic impairment, but patients with either moderate or severe hepatic impairment should be monitored for overdosage and toxicity.

When buprenorphine or buprenorphine/naloxone is used sublingually or buccally for the management of opiate dependence in patients with mild hepatic impairment, plasma concentrations and half-lives of the drugs are not substantially altered. However, in individuals with moderate or severe hepatic impairment, plasma concentrations of both buprenorphine and naloxone are increased and half-lives of the drugs are prolonged. Naloxone is affected to a greater degree than buprenorphine, and the magnitude of the difference in effect is greater in individuals with severe hepatic impairment than in those with moderate hepatic impairment. (See Pharmacokinetics: Elimination.) This may result in an increased risk of precipitated withdrawal during induction and interference with buprenorphine's efficacy throughout treatment. Buprenorphine/naloxone should be avoided in patients with severe hepatic impairment and may not be appropriate for those with moderate hepatic impairment. In patients with moderate hepatic impairment, buprenorphine/naloxone is not recommended for induction therapy but may be used with caution and careful monitoring for maintenance treatment following induction therapy with buprenorphine alone. The manufacturer states that the initial dose and titration increments of buprenorphine administered as the single-entity sublingual tablets should be reduced by one-half in patients with severe hepatic impairment and recommends that patients with either moderate or severe hepatic impairment be monitored for buprenorphine overdosage or toxicity.

Use of buprenorphine extended-release subcutaneous injection or buprenorphine subdermal implants is not recommended in patients with preexisting moderate to severe hepatic impairment since the extended-release injection does not allow for rapid adjustment of plasma buprenorphine concentrations and the implant dosage cannot be titrated.

When generic buprenorphine sublingual tablets (i.e., generic equivalents of Subutex(R) sublingual tablets), generic buprenorphine/naloxone sublingual tablets (i.e., generic equivalents of Suboxone(R) sublingual tablets), or buprenorphine/naloxone sublingually dissolving strips (Suboxone(R)) are used for induction therapy, the recommended induction dosage of buprenorphine on day 1 is up to 8 mg (alone or in fixed combination with up to 2 mg of naloxone). Induction should be initiated on day 1 with a buprenorphine dose of 2 or 4 mg (alone or in fixed combination with naloxone 0.5 or 1 mg, respectively), with additional doses of 2 or 4 mg administered at approximately 2-hour intervals if there are continued withdrawal symptoms and sedation is not observed. Use of an opiate withdrawal scale (e.g., COWS) during induction can be helpful in assessing the effects of administered doses. On day 2, a single dose of up to 16 mg of buprenorphine (alone or in fixed combination with up to 4 mg of naloxone) is given. Other induction dosages that also employ a low initial dose with rapid titration to an effective maintenance dosage have been used.

For oral transmucosal maintenance treatment, buprenorphine/naloxone is preferred over buprenorphine alone. (See initial paragraphs of Opiate Dependence under Dosage and Administration: Dosage.) From day 3 onward, buprenorphine/naloxone dosage should be adjusted in increments or decrements of 2 or 4 mg of buprenorphine in fixed combination with 0.5 or 1 mg, respectively, of naloxone daily to a dosage that suppresses opiate withdrawal symptoms and ensures that the patient continues buprenorphine treatment. The maintenance buprenorphine/naloxone dosage generally ranges from 4-24 mg of buprenorphine in fixed combination with 1-6 mg of naloxone daily. The recommended buprenorphine/naloxone target dosage during maintenance treatment is 16 mg of buprenorphine and 4 mg of naloxone as a single daily dose. Dosages exceeding 24 mg of buprenorphine in fixed combination with 6 mg of naloxone daily have not been shown to provide any additional clinical advantage.

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Drug interactions that reportedly occur with other opiate agonists may also potentially occur during administration of buprenorphine.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

Buprenorphine is contraindicated in patients with known hypersensitivity to the drug or any components of the formulation. In addition, buprenorphine/naloxone is contraindicated in patients with known hypersensitivity to naloxone. Buprenorphine formulations labeled for analgesic use are contraindicated in patients with known or suspected GI obstruction (including paralytic ileus), substantial respiratory depression, or acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment.

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

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There are no severe adverse reactions for this drug.

There are no less severe adverse reactions for this drug.

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Buprenorphine is distributed into milk in humans. In 2 studies that included 13 nursing women receiving maintenance treatment with sublingual buprenorphine (2.4-24 mg daily) for opiate dependence, buprenorphine and its metabolite norbuprenorphine were present in low concentrations in milk and in the breast-fed infant's urine; the infants were exposed to less than 1% of the maternal daily buprenorphine dosage. In the first study in 6 women receiving buprenorphine (median dosage of 0.29 mg/kg daily) at 5-8 days postpartum, breast milk provided a median infant dosage of 0.42 mcg/kg daily of buprenorphine and 0.33 mcg/kg daily of norbuprenorphine (0.2 and 0.12%, respectively, of the maternal weight-adjusted dosage). In the other study in 7 women receiving buprenorphine (median dosage of 7 mg daily) at an average of 1.12 months postpartum, mean milk concentrations of buprenorphine and norbuprenorphine were 3.65 and 1.94 mcg/L, respectively; based on the results of this study, an exclusively breast-fed infant consuming 150 mL/kg daily of milk would receive a mean estimated dosage of 0.55 mcg/kg daily of buprenorphine and 0.29 mcg/kg daily of norbuprenorphine (0.38 and 0.18%, respectively, of the maternal weight-adjusted dosage). Adverse reactions in nursing infants were not observed.

Experts recommend that women who are stable on buprenorphine or buprenorphine/naloxone treatment for opiate dependence, are not using other illicit drugs, and have no contraindications to nursing be encouraged to breast-feed their infants; to lower the risk of return to substance use, women receiving buprenorphine should be encouraged to continue treatment during the postpartum period. Breast-feeding has been associated with decreased severity of neonatal opiate withdrawal syndrome, decreased need for pharmacotherapy, and shorter hospital stays for the neonate. The manufacturers of buprenorphine-containing preparations used for treatment of opiate dependence state that developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for buprenorphine or buprenorphine/naloxone and any potential adverse effects on the breast-fed child from the drug or from the underlying maternal condition. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in nursing infants, the manufacturers of buprenorphine preparations labeled for use as analgesics state that women should be advised not to nurse an infant while receiving the drug. Infants who are exposed to buprenorphine through breast milk should be monitored for excess sedation and respiratory depression.

Symptoms of withdrawal can occur in opiate-dependent infants when maternal administration of opiates is discontinued or breast-feeding is stopped.

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