buprenorphine, long-acting injection (Rx)

>10%

Injection site reactions (5.3-11.6%)

1-10%

Headache (8.5-9.4%)

Constipation (8-9.4%)

Vomiting (5.5-9.4%)

Nausea (8-8.9%)

Fatigue (3.9-6%)

CPK increased (2.5-5.4%)

ALT increased (1-5%)

Somnolence (2-4.9%)

AST increased (3.4-4.5%)

GGT increased (3-4%)

Sedation (1.5-3.4%)

Dizziness (1.5-2.5%)

Postmarketing Reports

Serotonin syndrome during concomitant use of opioids with serotonergic drugs

Adrenal insufficiency with use >1 month

Anaphylaxis

Androgen deficiency with long-term opioid use

Contraindications

Documented hypersensitivity to buprenorphine or Atrigel delivery system components

Cautions

Risk of serious harm or death with IV administration (see Black Box Warnings)

Only available through a restricted access program called the Sublocade REMS program (see Black Box Warnings)

Buprenorphine is a schedule III controlled substance that can be abused in a manner similar to other opioids

Neonatal withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy, whether that use is medically authorized or illicit; unlike opioid withdrawal syndrome in adults, NOWS may be life-threatening if not recognized and treated in the neonate (also see Pregnancy)

Adrenal insufficiency reported with opioid use, more often with use exceeding 1 month; if diagnosed, treat with physiologic replacement doses of corticosteroids and wean patient off the opioid to allow adrenal recovery

Hypersensitivity reported and may include angioneurotic edema and anaphylactic shock; common signs and symptoms include rashes, hives, and pruritus (see Contraindications)

Because of the partial opioid agonist properties of buprenorphine, it may precipitate opioid withdrawal signs and symptoms in persons who are currently physically dependent on full opioid agonists (eg, heroin, morphine, methadone) before the effects of the full opioid agonist have subsided

Emergent acute pain should be treated with a nonopioid analgesic whenever possible; patients requiring opioid therapy for analgesia may be treated with a high–affinity full opioid analgesic under the supervision of a physician, with particular attention to respiratory function; higher doses may be required for analgesic effect

Deaths reported if used in opioid-naïve individuals who received a 2 mg-dose as a sublingual tablet

Prolonged QTc interval observed in some patients participating in clinical trials; consider these observations in clinical decisions when prescribing buprenorphine to patients with hypokalemia, hypomagnesemia, or clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, or active myocardial ischemia; avoid the use of buprenorphine in patients with a history of long QT syndrome or an immediate family member with this condition or those taking class IA antiarrhythmic medications

May impair mental or physical abilities; caution patients regarding driving or operating machinery

Orthostatic hypotension may occur

May elevate CSF pressure; caution with head injury, intracranial lesions, and other circumstances when CSF pressure may be increased; buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation

Opioids increase intracholedochal pressure; caution with biliary tract dysfunction

May obscure the diagnosis or clinical course of acute abdominal conditions

Can cause severe, possibly fatal, respiratory depression in children who are accidentally exposed

Patients who elect to discontinue treatment should be monitored for withdrawal signs and symptoms; consider transmucosal buprenorphine if needed to treat withdrawal after discontinuing long-acting injection

Serious injection site reactions reported; site reactions are most commonly manifested by pain, erythema, and pruritis; some reports have involved abscess, ulceration, and necrosis; some cases have resulted in surgical depot removal, debridement, antibiotic administration, and therapy discontinuation; likelihood of serious injection site reactions may be increased with inadvertent intramuscular or intradermal administration

QTc prolongation

• Thorough QT studies with buprenorphine products have demonstrated QT prolongation less than or equal to 15 msec; this QTc prolongation effect does not appear to be mediated by hERG channels; based on these two findings, buprenorphine is unlikely to be pro-arrhythmic when used alone in patients without risk factors; the risk of combining buprenorphine with other QT-prolonging agents is not known
• Consider these observations in clinical decisions when prescribing this medication to patients with risk factors such as hypokalemia, bradycardia, recent conversion from atrial fibrillation, congestive heart failure, digitalis therapy, baseline QT prolongation, subclinical long-QT syndrome, or severe hypomagnesemia

Risk of opioid withdrawal

• Buprenorphine is a partial agonist at the mu-opioid receptor and long-term administration produces physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation
• The withdrawal syndrome is milder than that seen with full agonists and may be delayed in onset
• Owing to the long half-life of buprenorphine long-acting SC injection, withdrawal signs and symptoms emerge after about 1 month following discontinuation

Hepatitis and hepatic events

• Cytolytic hepatitis and hepatitis with jaundice reported
• Abnormalities range from transient asymptomatic elevations in hepatic transaminases to case reports of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy
• Liver function tests, prior to initiation of treatment, are recommended to establish a baseline
• Monthly monitoring of liver function during treatment, particularly with the 300-mg maintenance dose, is also recommended
• In a pharmacokinetic study with transmucosal buprenorphine, buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment

Respiratory depression

• Associated with life-threatening respiratory depression and death; many, but not all, postmarketing reports regarding coma and death involved misuse by self–injection or were associated with the concomitant use of buprenorphine and benzodiazepines or other CNS depressants, including alcohol; if concomitant use with benzodiazepine is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose
• 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
• Caution with compromised respiratory function (eg, COPD, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, preexisting respiratory depression)
• Owing to its extended–release characteristics, if discontinued as a result of compromised respiratory function, monitor patients for ongoing buprenorphine effects for several months

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

Drug interaction overview

• Muscle relaxants: Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and increase risk of respiratory depression; 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
• Diuretics: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone
• Anticholinergics: Coadministration may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus
• Medications that prolong QT interval (eg, Class IA or Class III antiarrhythmic medications: Buprenorphine may enhance the effects of drugs that cause QT prolongation; coadministration may increase the effects

• Benzodiazepines or other CNS depressants

  • Concomitant use with benzodiazepines or other CNS depressants, including alcohol, increases the risk of adverse reactions including overdose, respiratory depression, profound sedation, and death
  • For patients in buprenorphine treatment, benzodiazepines are not the treatment of choice for anxiety or insomnia
  • 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 a benzodiazepine or other CNS depressant or decreasing to the lowest effect dose may be appropriate

• Coadministration with CYP3A4 inhibitors or inducers

  • Buprenorphine is metabolized to norbuprenorphine primarily by CYP3A4
  • CYP3A4 inhibitors (eg, azole antifungals, macrolide antibiotics, protease inhibitors [atazanavir, ritonavir], delavirdine) can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects
  • CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin, phenobarbital, efavirenz, nevirapine, etravirine) may induce the metabolism of buprenorphine and, therefore, may cause increased clearance of the drug, which could lead to a decrease in buprenorphine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome

• Coadministration with serotonergic drugs

  • MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (eg, respiratory depression, coma); do not use buprenorphine while taking MAOIs or within 14 days of stopping MAOIs (eg, phenelzine, tranylcypromine, linezolid)

Pregnancy

Data are limited regarding use in pregnancy; 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

Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes (eg, low birth weight, preterm birth, fetal death)

Additionally, untreated opioid addiction often results in continued or relapsing illicit opioid use

Fetal/neonatal adverse reactions

• Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with buprenorphine
• Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity, abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight
• Signs of neonatal withdrawal usually occur in the first days after birth
• The duration and severity of neonatal opioid withdrawal syndrome may vary
• Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly

Labor or delivery

• Opioid-dependent women on buprenorphine maintenance therapy may require additional analgesia during labor
• As with all opioids, use of buprenorphine prior to delivery may result in respiratory depression in the newborn; closely monitor neonates for signs of respiratory depression
• An opioid antagonist (eg, naloxone) should be available for reversal of opioid-induced respiratory depression in the neonate

Animal data

• In a pre-and postnatal development study in rats, this drug was administered subcutaneously to pregnant animals once during implantation (on GD 7) and once during weaning (on Lactation Day 7); there were no adverse effects on offspring survival, sexual maturation, behavioral assessment, or reproductive performance at up to 300 mg/kg (approximately 15 times the MRHD on an AUC basis)
• Reduced fetal body weights increased visceral malformations and skeletal malformations were also observed in rats and rabbits at buprenorphine doses equivalent to 38 and 15 times, respectively, MRHD; the skeletal and visceral malformations in rats appear at least partially attributable to buprenorphine; based on animal data, advise pregnant women of potential risk to fetus

Lactation

Based on two studies in 13 lactating women maintained on buprenorphine treatment, buprenorphine and its metabolite norbuprenorphine are present in low levels in human milk and infant urine

Available data have not shown adverse reactions in breastfed infants, although caution is 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.

Mechanism of Action

Partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor

Absorption

Peak plasma time: 24 hr

Steady-state plasma concentrations

• Steady-state is reached after 4 injections of 100 mg or 300 mg, or 2 injections of 300 mg
• Peak plasma concentration: 4.88 ng/mL (100 mg/dose); 10.12 ng/mL (300 mg/dose)
• Minimum plasma concentration: 2.48 ng/mL (100 mg/dose); 5.01 ng/mL (300 mg/dose)
• Average plasma concentration (steady-state): 3.21 ng/mL (100 mg/dose); 6.54 ng/mL (300 mg/dose)

Distribution

Protein bound: 96%, primarily to alpha and beta globulin

Metabolism

Metabolized to its major metabolite, norbuprenorphine, by CYP3A4

Norbuprenorphine can further undergo glucuronidation

Elimination

Half-life: 43-60 days

Excretion: 30% (<1% unchanged) urine; 69% (33% unchanged) feces

Drug addiction treatment act

Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this product in treatment of opioid dependence is limited to healthcare providers who meet certain qualifying requirements, and who have notified the Secretary of Health and Human Services (HHS) of their intent to prescribe this product for the treatment of opioid dependence and have been assigned a unique identification number that must be included on every prescription

SC Preparation

Only healthcare providers should prepare and administer

As a universal precaution, always wear gloves

Administer once monthly with a minimum of 26 days between doses

Initiating treatment with buprenorphine long-acting SC injection as the first buprenorphine product has not been studied

Initiate treatment only following induction and dose adjustment with a transmucosal buprenorphine–containing product (see Adult Dosing)

Remove buprenorphine long-acting SC injection from the refrigerator prior to administration; requires at least 15 minutes to reach room temperature

Do not open the foil pouch until the patient has arrived for his or her injection; do not attach needle until time of injection

Administer each injection only using the syringe and safety needle included with the product

SC Administration

For abdominal SC injection only; do not administer IV or IM

Subcutaneous tissue should be free of skin conditions (eg, nodules, lesions, excessive pigment); not for injection into an area where skin is irritated, reddened, bruised, infected or scarred in any way

Missed or delayed doses

• A patient who misses a dose should receive the next dose as soon as possible, with the following dose given no sooner than 26 days later
• Occasional delays in dosing up to 2 weeks are not expected to have a clinically significant impact on treatment effect

Storage

Refrigerate at 2-8°C (35.6-46.4°F)

Once outside the refrigerator, this product may be stored in its original packaging at room temperature at 15-30°C (59-86°F) for up to 7 days prior to administration

Discard if left at room temperature >7 days