buprenorphine/naloxone (Suboxone, Zubsolv, Bunavail)

Dosing and uses of Suboxone, Zubsolv (buprenorphine/naloxone)

• Adult
• Pediatric

 

Adult dosage forms and strengths

buprenorphine/naloxone

film, sublingual (Suboxone): Schedule III

• 2mg/0.5mg
• 4mg/1mg
• 8mg/2mg
• 12mg/3mg

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

 

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

Maintenance (buprenorphine/naloxone combo [Suboxone, generic])

• 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

Maintenance (buprenorphine/naloxone combo [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

Maintenance (buprenorphine/naloxone combo [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

 

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

 

Pediatric dosage forms and strengths

Safety and efficacy not established

 

Suboxone, Zubsolv (buprenorphine/naloxone) adverse (side) 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%)

 

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

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

 

Pregnancy and lactation

Pregnancy category: C

Lactation: Buprenorphine is excreted in breast milk; breastfeeding is not advised

 

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.

 

Pharmacology of Suboxone, Zubsolv (buprenorphine/naloxone)

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

Half-life: Buprenorphine, 24-42 hr; naloxone, 2-12 hr

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

 

Administration

Instructions

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

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