buprenorphine/naloxone (Rx)

>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

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

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia; opioid use increases risk of CSA in a dose-dependent fashion; in patients who present with CSA, consider decreasing opioid dosage using best practices for opioid taper

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

Because it contains naloxone, drug is highly likely to produce marked and intense withdrawal signs and symptoms if misused parenterally by individual dependent on full opioid agonists such as heroin, morphine, or methadone

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

Due to risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose

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
• If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response; follow patients closely for signs and symptoms of respiratory depression and sedation
• 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
• If concomitant use with benzodiazepine is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose
• 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

Patient access to naloxone for emergency treatment of opioid overdose

• Assess potential need for naloxone; consider prescribing for emergency treatment of opioid overdose
• Consult on availability and ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines
• Educate patients regarding the signs and symptoms of respiratory depression and to call 911 or seek immediate emergency medical help in the event of a known or suspected overdose

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.

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)

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