Suboxone (buprenorphine HCl/naloxone HCl)

Naloxone is commercially available as naloxone hydrochloride; dosage is expressed in terms of the salt.

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.

Naloxone may be administered by IV, subcutaneous, or IM injection; by IV infusion; or intranasally. The drug also has been administered via endotracheal tube+ and by intraosseous+ (IO) injection.

No dosing information is available for this tab.

No dosing information is available for this tab.

Naloxone is metabolized in the liver primarily by glucuronide conjugation.

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.

*Patients with known hypersensitivity to the drug or any ingredient in the formulation.

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.

Intranasal naloxone: Adverse effects reported in clinical trials of intranasally administered naloxone include abdominal pain, asthenia, dizziness, headache, increased blood pressure, constipation, toothache, muscle spasms, musculoskeletal pain, nasal congestion, nasal discomfort, nasal dryness, nasal edema, nasal inflammation, presyncope, rhinalgia, and xeroderma.

Parenteral naloxone: Adverse effects, including serious and fatal cases, reported in clinical trials of parenterally administered naloxone for postoperative patients include cardiac arrest, dyspnea, hypotension, hypertension, pulmonary edema, and ventricular tachycardia and fibrillation. Excessive doses of naloxone in postoperative patients may result in agitation caused by significant reversal of analgesia. Adverse effects reported in clinical trials of parenterally administered naloxone after abrupt reversal of dependence are related to acute withdrawal syndrome, which may include the following signs and symptoms: abdominal cramps, body aches, diarrhea, fever, increased blood pressure, nausea or vomiting, nervousness, runny nose, piloerection, restlessness or irritability, shivering or trembling, sneezing, sweating, tachycardia, weakness, yawning. Abrupt reversal of opioid depression may result in cardiac arrest, increased blood pressure, nausea, pulmonary edema, seizures, sweating, tachycardia, tremulousness, ventricular tachycardia and fibrillation, and vomiting. In the neonate, opioid withdrawal may also include convulsions, excessive crying, and hyperactive reflexes. Adverse effects reported in clinical trials of naloxone hydrochloride injection for IM or subcutaneous use (Zimhi(R)) included dizziness, elevated bilirubin, lightheadedness, and nausea.

There are no severe adverse reactions for this drug.

There are no less severe adverse reactions for this drug.

No enhanced messaging available.

Naloxone hydrochloride injection may be used to reverse the effects of opioids in pediatric patients, including neonates. In addition, safety and efficacy of naloxone hydrochloride prefilled syringes for IM or subcutaneous use (Zimhi(R)) or nasal spray (e.g., Narcan(R), Kloxxado(R)) have been established in pediatric patients of all ages for the emergency treatment of known or suspected opioid overdosage manifested by respiratory and/or CNS depression. Use of naloxone for reversal of opioid effects in pediatric patients is supported by adult bioequivalence studies and evidence from the safe and effective use of other naloxone hydrochloride products.

As in adults, naloxone may precipitate opiate withdrawal in pediatric patients who are physically dependent on opiates; however, unlike opiate withdrawal in adults, neonatal opiate withdrawal may be life-threatening and should be treated according to protocols developed by neonatology experts. To avoid abrupt precipitation of neonatal opiate withdrawal syndrome, use of a naloxone preparation that can be dosed based on weight and titrated to effect may be preferred over a preparation that delivers a fixed dose of the drug (e.g., auto-injector, nasal spray) in neonates with known or suspected exposure to maternally administered opiates.

Absorption of naloxone following intranasal administration or IM or subcutaneous injection in pediatric patients may be erratic or delayed. Pediatric patients who have responded to naloxone must be carefully monitored for at least 24 hours, since relapse may occur as the opioid antagonist is metabolized.

Safety and efficacy of naloxone hydrochloride injection in the management of hypotension associated with septic shock have not been established in pediatric patients. In a study of 2 neonates with septic shock, treatment with naloxone produced a positive pressor response; however, one patient subsequently died after intractable seizures.

There are limited data to date on use of naloxone in pregnant women. Naloxone should be used during pregnancy only when clearly needed. Reproduction studies in mice and rats using naloxone hydrochloride dosages of 4 and 8 times, respectively, a human dosage of 10 mg daily in a 50-kg individual demonstrated no embryotoxic or teratogenic effects. Furthermore, no adverse effects were reported in the offspring of rats receiving naloxone hydrochloride subcutaneously at dosages of 2 or 10 mg/kg (up to 12 times a human dosage of 8 mg daily) from gestation day 15 to postnatal day 21. No embryotoxic or teratogenic effects were observed in mice and rats during the period of organogenesis with the 8 mg/0.1 mL nasal spray at doses 3 and 6 times a human dose of 16 mg.

The risk-benefit ratio must be considered before naloxone is administered to a pregnant woman who is known or suspected to be dependent on opioids, since maternal dependence may often be accompanied by fetal dependence. Naloxone crosses the placenta and may precipitate withdrawal symptoms in both the fetus and the pregnant woman. Use of naloxone in opioid-dependent pregnant women should be accompanied by monitoring for fetal distress.

It is not known if naloxone affects the duration of labor and/or delivery. However, published reports indicate that administration of naloxone during labor did not adversely affect maternal or neonatal status. Carefully monitor patients with mild to moderate hypertension who receive naloxone during labor, as severe hypertension may occur.

It is not known whether naloxone is distributed into milk or has any effect on the breast-fed infant or on milk production; use naloxone with caution in nursing women. The drug does not affect prolactin or oxytocin concentrations in nursing women, and oral bioavailability of naloxone is minimal.

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.

The manufacturers recommend using caution when selecting a dose of naloxone for geriatric patients.

Clinical studies of naloxone did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients. While other clinical experience has not revealed age-related differences in response, drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.