buprenorphine

byoo-pre-NOR-feen

Therapeutic Classification: opioid analgesics

Pharmacologic Classification: opioid agonists antagonists

IM:

High Alert

IV: Moderate to severe acute pain.
Pain that is severe enough to require daily, around-the-clock long-term opioid treatment and for which alternative treatment options (e.g., nonopioid analgesics or immediate-release opioids) are inadequate.
Opioid use disorder (preferred for induction only); suppresses withdrawal symptoms in opioid detoxification.
SC: Moderate to severe opioid use disorder in patients who have initiated treatment with a buprenorphine-containing product for ≥7 days (Sublocade).
SC: Moderate to severe opioid use disorder in patients who have initiated treatment with a single dose of a transmucosal buprenorphine product or who are already being treated with buprenorphine (Brixadi).

Binds to opiate receptors in the CNS.
Alters the perception of and response to painful stimuli while producing generalized CNS depression.
Has partial antagonist properties that may result in opioid withdrawal in physically dependent patients when used as an analgesic.

Therapeutic effects:

IV: Decreased severity of pain.
Suppression of withdrawal symptoms during detoxification and maintenance from heroin or other opioids. Produces a relatively mild withdrawal compared to other agents.
SC: Continued cessation of opioid use.

Absorption: Well absorbed after IM and SL use; 46–65% absorbed with buccal use; 15% of transdermal dose absorbed through skin; IV administration results in complete bioavailability.

Distribution: Extensively distributed to tissues; CNS concentration is 15–25% of plasma.

Protein Binding: 96%.

Metabolism/Excretion: Mostly metabolized by the liver mostly via the CYP3A4 isoenzyme; one metabolite is active; 70% excreted in feces; 27% excreted in urine.

Half-Life: IV: 2–3 hr; Buccal: 27 hr; Transdermal: 26 hr; SL: 37 hr; Subdermal: 24–48 hr; SUBQ: 43–60 days.

(analgesia)

ROUTE	ONSET	PEAK	DURATION
IM	15 min	60 min	6 hr‡
IV	rapid	less than 60 min	6 hr‡
SL	unknown	unknown	unknown
Transdermal	unknown	unknown	7 days
Buccal	unknown	unknown	unknown
SUBQ	unknown	unknown	unknown

‡4–5 hr in children.

Contraindicated in:

Hypersensitivity;
Significant respiratory depression (transdermal, buccal);
Acute or severe bronchial asthma (transdermal, buccal);
Paralytic ileus (transdermal, buccal);
Acute, mild, intermittent, or postoperative pain (transdermal);
Long QT syndrome;
Concurrent use of class I or III antiarrhythmics;
Lactation: Lactation.

Use Cautiously in:

Personal or family history of substance use disorder or mental illness (for pain management);
↑intracranial pressure;
Compromised respiratory function including COPD, cor pulmonale, diminished respiratory reserve, hypoxia, hypercapnia, or respiratory depression of other causes;
Severe renal impairment;
Moderate or severe hepatic impairment (dose ↓ needed for severe impairment);
Hypothyroidism;
Seizure disorders;
Adrenal insufficiency;
Biliary tract disease;
Acute pancreatitis;
Debilitated patients (dose ↓ required);
Oral mucositis (dose ↓ required) (buccal);
Undiagnosed abdominal pain;
Hypokalemia, hypomagnesemia, unstable atrial fibrillation, symptomatic bradycardia, unstable HF, QT interval prolongation, or myocardial ischemia;
Prostatic hyperplasia;
OB: Safety not established in pregnancy; prolonged use of buccal, transdermal, or SL buprenorphine during pregnancy can result in neonatal opioid withdrawal syndrome;
Pedi: Safety and effectiveness not established in children 18 yr (SL and transdermal) or 2 yr (parenteral);
Geri: risk of respiratory depression in older adults (dose required).

CV: hypertension, hypotension, palpitations, QT interval prolongation

Derm: sweating, clammy feeling, erythema, pruritus, rash

EENT: blurred vision, diplopia, miosis (high doses)

Endo: adrenal insufficiency

GI: nausea, constipation, dry mouth, HEPATOTOXICITY, ileus, vomiting

GU: urinary retention

Local: injection site reactions

Neuro: confusion, dysphoria, hallucinations, sedation, dizziness, euphoria, floating feeling, headache, unusual dreams

Resp: RESPIRATORY DEPRESSION (INCLUDING CENTRAL SLEEP APNEA AND SLEEP-RELATED HYPOXEMIA)

Misc: allodynia, HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS, ANGIOEDEMA, AND BRONCHOSPASM), opioid-induced hyperalgesia, physical dependence, psychological dependence, tolerance

Drug-drug:

Concurrent use with class Ia antiarrhythmics, class III antiarrhythmics, or other QT interval prolonging medications may ↑ risk of QT interval prolongation; avoid concurrent use.
Use with benzodiazepines or other CNS depressants, including other opioids, nonbenzodiazepine sedative/hypnotics, anxiolytics, general anesthetics, muscle relaxants, antipsychotics, and alcohol, may cause profound sedation, respiratory depression, coma, and death; reserve concurrent use for when alternative treatment options are inadequate.
Use with extreme caution in patients receiving MAO inhibitors (↑ CNS and respiratory depression and hypotension—↓ buprenorphine dose by 50%; may need to ↓ MAO inhibitor dose; do not use transdermal formulation within 14 days of MAO inhibitor).
May ↓ effectiveness of other opioid analgesics.
CYP3A4 inhibitors, including itraconazole, ketoconazole, erythromycin, ritonavir, atazanavir, or fosamprenavir, may ↑ levels and risk of toxicity; may need to ↓ buprenorphine dose.
CYP3A4 inducers, including carbamazepine, rifampin, or phenytoin, may ↓ levels and effectiveness; buprenorphine dose modification may be necessary during concurrent use.
Concurrent abuse of buprenorphine and benzodiazepines may result in coma and death.
Drugs that affect serotonergic neurotransmitter systems, including tricyclic antidepressants, SSRIs, SNRIs, MAO inhibitors, TCAs, tramadol, trazodone, mirtazapine, 5-HT3 receptor antagonists, linezolid, methylene blue, and triptans, ↑ risk of serotonin syndrome.

Drug-Natural Products:

Concomitant use of kava-kava, valerian, chamomile, or hops can ↑ CNS depression.

Analgesia

IM IV (Adults ): 0.3 mg every 4–6 hr as needed. May repeat initial dose after 30 min (up to 0.3 mg every 4 hr or 0.6 mg every 6 hr); 0.6-mg doses should be given only IM.
IM IV (Children 2–12 yr): 2–6 mcg (0.002–0.006 mg)/kg every 4–6 hr.
Transdermal (Adults ): Opioid-naive: Transdermal system delivering 5–20 mcg/hr applied every 7 days. Initiate with 5 mcg/hr system; each dose titration may occur after 72 hr; do not exceed dose of 20 mcg/hr (due to ↑ risk of QT interval prolongation); Previously taking <30 mg/day of morphine or equivalent: Initiate with 5 mcg/hr system; each dose titration may occur after 72 hr; do not exceed dose of 20 mcg/hr (due to ↑ risk of QT interval prolongation); apply patch every 7 days; Previously taking 30–80 mg/day of morphine or equivalent: Initiate with 10 mcg/hr system; each dose titration may occur after 72 hr; do not exceed dose of 20 mcg/hr (due to ↑ risk of QT interval prolongation); apply patch every 7 days; Previously taking >80 mg/day of morphine or equivalent: Consider use of alternate analgesic.
(Adults ): Opioid-naive: Initiate therapy with 75 mcg once daily or every 12 hr for ≥4 days; then ↑ dose to 150 mcg every 12 hr; may then titrate dose in increments of 150 mcg every 12 hr no more frequently than every 4 days; do not exceed dose of 450 mcg every 12 hr (based on clinical studies); Previously taking <30 mg/day of morphine or equivalent: Initiate therapy with 75 mcg once daily or every 12 hr for ≥4 days; then ↑ dose to 150 mcg every 12 hr; may then titrate dose in increments of 150 mcg every 12 hr no more frequently than every 4 days; do not exceed dose of 900 mcg every 12 hr (due to ↑ risk of QT interval prolongation); Previously taking 30–89 mg/day of morphine or equivalent: Initiate therapy with 150 mcg every 12 hr for ≥4 days; may then titrate dose in increments of 150 mcg every 12 hr no more frequently than every 4 days; do not exceed dose of 900 mcg every 12 hr (due to ↑ risk of QT interval prolongation); Previously taking 90–160 mg/day of morphine or equivalent: Initiate therapy with 300 mcg every 12 hr for ≥4 days; may then titrate dose in increments of 150 mcg every 12 hr no more frequently than every 4 days; do not exceed dose of 900 mcg every 12 hr (due to ↑ risk of QT interval prolongation); Previously taking >160 mg/day of morphine or equivalent: Consider use of alternate analgesic; Patients with oral mucositis:↓ initial dose by 50% then titrate dose in increments of 75 mcg every 12 hr no more frequently than every 4 days.

Hepatic Impairment

Transdermal (Adults ): Mild to moderate hepatic impairment: Initiate with 5 mcg/hr system.

Hepatic Impairment

(Adults ): Severe hepatic impairment:↓ initial dose by 50%; then titrate dose in increments of 75 mcg every 12 hr no more frequently than every 4 days.

Treatment of Opioid Use Disorder

(Adults ): Induction: 8 mg once daily on Day 1; then 16 mg once daily on Day 2–4; Maintenance: Patients should preferably be transitioned to buprenorphine/naloxone; if patient cannot tolerate naloxone, then can use buprenorphine (usual dosage range = 4–24 mg/day); recommended target dose = 16 mg/day; dose can be ↑ or ↓ by 2–4 mg, as needed to prevent signs/symptoms of opioid withdrawal.
SC (Adults ): Sublocade: 300 mg once monthly for 2 mo, then 100 mg once monthly; may ↑ maintenance dose to 300 mg once monthly if patient reports illicit opioid use or has positive urine drug screen for illicit opioid use.
SC (Adults ): Patients not currently receiving buprenorphine treatment (Brixadi [weekly formulation] only): To avoid precipitating an opioid withdrawal syndrome, a single 4-mg test dose of transmucosal buprenorphine-containing product should be administered prior to administration of Brixadi weekly injection. If the test dose is tolerated without precipitating withdrawal, administer 16 mg (weekly formulation) initially, followed by an additional 8 mg (weekly formulation) within 3 days of the initial dose for a total recommended weekly dose of 24 mg. If needed, during the 1st wk of treatment, may administer an additional 8 mg (weekly formulation) after ≥24 hr after the previous dose, for a total weekly dose of 32 mg. Administer subsequent injections (weekly formulation) once weekly based on the total weekly dose that was established during Wk 1 (16–32 mg). Dose adjustments can be made at weekly intervals (max dose = 32 mg once weekly). Patients currently receiving buprenorphine treatment (Brixadi [weekly formulation]): If daily dose of SL buprenorphine ≤6 mg, administer 8 mg once weekly (weekly formulation). If daily dose of SL buprenorphine 8–10 mg, administer 16 mg once weekly (weekly formulation). If daily dose of SL buprenorphine 12–16 mg, administer 24 mg once weekly (weekly formulation). If daily dose of SL buprenorphine 18–24 mg, administer 32 mg once weekly (weekly formulation). Patients currently receiving buprenorphine treatment (Brixadi [monthly formulation]): If daily dose of SL buprenorphine 8–10 mg, administer 64 mg once monthly (monthly formulation). If daily dose of SL buprenorphine 12–16 mg, administer 96 mg once monthly (monthly formulation). If daily dose of SL buprenorphine 18–24 mg, administer 128 mg once monthly (monthly formulation). Transitioning between Brixadi (monthly formulation) and Brixadi (monthly formulation): If dose of weekly formulation 16 mg once weekly, convert to 64 mg once monthly (monthly formulation). If dose of weekly formulation 24 mg once weekly, convert to 96 mg once monthly (monthly formulation). If dose of weekly formulation 32 mg once weekly, convert to 128 mg once monthly (monthly formulation).

Hepatic Impairment

(Adults ): Severe hepatic impairment:↓ initial dose and adjustment dose by 50%.

(Generic available)

Buccal film (Belbuca): 75 mcg; 150 mcg; 300 mcg; 450 mcg; 600 mcg; 750 mcg; 900 mcg
Extended-release solution for SUBQ injection (prefilled syringes) (Sublocade): 100 mg/0.5 mL; 300 mg/1.5 mL
Extended-release solution for SUBQ injection (prefilled syringes) (Brixadi [weekly]): 8 mg/0.16 mL; 16 mg/0.32 mL; 24 mg/0.48 mL; 32 mg/0.64 mL
Extended-release solution for SUBQ injection (prefilled syringes) (Brixadi [monthly]): 64 mg/0.18 mL; 96 mg/0.27 mL; 128 mg/0.36 mL
Solution for injection: 0.3 mg/mL
Sublingual tablets: 2 mg; 8 mg
Transdermal systems (Butrans): 5 mcg/hr; 7.5 mcg/hr; 10 mcg/hr; 15 mcg/hr; 20 mcg/hr
In combination with: naloxone (Suboxone, Zubsolv). See Appendix [not included in this PDA edition].

Monitor for signs and symptoms of adrenal insufficiency (nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure) during therapy. If adrenal insufficiency is suspected, confirm with diagnostic testing. If confirmed, treat with physiologic doses of replacement corticosteroids. Wean patient off opioid to allow adrenal recovery and continue corticosteroids until adrenal function recovers. Other opioids may be tried.
Pain: Assess type, location, and intensity of pain before and 1 hr after IM and 5 min (peak) after IV administration. When titrating opioid doses, increases of 25–50% should be administered until there is either a 50% reduction in the patient’s pain rating on a numerical or visual analogue scale or the patient reports satisfactory pain relief. A repeat dose can be safely administered at the time of the peak if previous dose is ineffective and side effects are minimal. Single doses of 600 mcg (0.6 mg) should be administered IM. Patients requiring doses higher than 600 mcg (0.6 mg) should be converted to an opioid agonist. Buprenorphine is not recommended for prolonged use (except buccal or transdermal) or as first-line therapy for acute or cancer pain. SL formulations should not be used to relieve pain.
An equianalgesic chart (see Equianalgesic Dosing Guidelines) should be used when changing routes or when changing from one opioid to another.
Monitor patients for opioid-induced hyperalgesia occurs when an opioid paradoxically causes an ↑ in pain or an ↑ in sensitivity to pain. Opioid-induced hyperalgesia differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect. Symptoms of opioid-induced hyperalgesia include ↑ levels of pain upon opioid dosage ↑, ↓ levels of pain upon opioid dosage ↓, or pain from ordinarily nonpainful stimuli. If opioid-induced hyperalgesia suspected, consider ↓ buprenorphine dose.
Assess level of consciousness, BP, pulse, and respirations before and periodically during administration, especially within first 24–72 hr of buccal therapy. If respiratory rate is <10/min, assess level of sedation. Dose may need to be decreased by 25–50%. Buprenorphine 0.3–0.4 mg has approximately equal analgesic and respiratory depressant effects to morphine 10 mg. Monitor for respiratory depression, especially during initiation or following dose increase; serious, life-threatening, or fatal respiratory depression may occur. May cause sleep-related breathing disorders (central sleep apnea, sleep-related hypoxemia).
Assess previous analgesic history. Antagonistic properties may induce withdrawal symptoms (vomiting, restlessness, abdominal cramps, increased BP and temperature) in patients who are physically dependent on opioid agonists. Symptoms may occur up to 15 days after discontinuation and persist for 1–2 wk.
Buprenorphine has a lower potential for dependence than other opioids; however, prolonged use may lead to physical and psychological dependence and tolerance. This should not prevent patient from receiving adequate analgesia. Most patients receiving buprenorphine for pain rarely develop psychological dependence. If tolerance develops, changing to an opioid agonist may be required to relieve pain.
Assess bowel function routinely. Prevent constipation with increased intake of fluids and bulk, and laxatives to minimize constipating effects. Administer stimulant laxatives routinely if opioid use exceeds 2–3 days, unless contraindicated. Consider drugs for opioid-induced constipation.
Assess risk for opioid addiction, abuse, or misuse prior to administration. Monitor for respiratory depression, especially during initiation or following dose increase; serious, life-threatening, or fatal respiratory depression may occur. Misuse or abuse of Butrans by chewing, swallowing, snorting, or injecting buprenorphine extracted from transdermal system will result in the uncontrolled delivery of buprenorphine and risk of overdose and death.
Maintain frequent contact during periods of changing analgesic requirements, including initial titration, between the prescriber, other members of the health care team, the patient, and the caregiver/family.
Treatment of Opioid Dependence: Assess patient for signs and symptoms of opioid withdrawal before and during therapy.

Lab Test Considerations:

May cause ↑ serum amylase and lipase levels.
- Monitor liver function tests prior to and periodically during opioid dependence therapy.

Toxicity and Overdose:

If an opioid antagonist is required to reverse respiratory depression or coma, naloxone is the antidote. Dilute the 0.4-mg ampule of naloxone in 10 mL of 0.9% NaCl and administer 0.5 mL (0.02 mg) by IV push every 2 min. For children and patients weighing <40 kg, dilute 0.1 mg of naloxone in 10 mL of 0.9% NaCl for a concentration of 10 mcg/mL and administer 0.5 mcg/kg every 1–2 min. Titrate dose to avoid withdrawal, seizures, and severe pain. Naloxone may not completely reverse respiratory depressant effects of buprenorphine; may require mechanical ventilation, oxygen, IV fluids, and vasopressors.

Do not confuse buprenorphine with hydromorphone.
Pain: Explain therapeutic value of medication before administration to enhance the analgesic effect.
- Regularly administered doses may be more effective than prn administration. Analgesic is more effective if given before pain becomes severe.
- Coadministration with nonopioid analgesics has additive effects and may permit lower opioid doses.
- For patients taking forms of long-acting buprenorphine, if acute pain management or anesthesia is needed, treat with a nonopioid analgesic, if 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. Monitor patient closely.
FDA strongly encourages health care professionals to complete a REMS-compliant education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain, available at www.fda.gov/OpioidAnalgesicREMSBlueprint. Information on programs can be found at 1-800-503-0784 or www.opioidanalgesicrems.com.
Discuss availability of naloxone for emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing therapy, especially if patient has household members (including children) or other close contacts at risk for accidental exposure or overdose. Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. However, the presence of risk factors for overdose should not prevent the proper management of pain in any patient.
Have patient wet inside of cheek with tongue or rinse mouth with water. Apply film immediately after removal from package. Place yellow side of film against inside of cheek. Hold film in place with dry fingers for 5 sec, then leave in place on inside of cheek until fully dissolved. If chewed or swallowed, may result in lower peak concentrations and lower bioavailability. Do not administer if package seal is broken or film is cut, damaged, or changed. Avoid applying to areas of mouth with sores or lesions. To dispose of unused film, remove from foil package, drop into toilet, and flush.
IM: Administer IM injections deep into well-developed muscle. Rotate sites of injections.

IV Administration:

May give IV undiluted.
Administer slowly. Rapid administration may cause respiratory depression, hypotension, and cardiac arrest.
Buprenorphine may cause withdrawal in patients who are already taking opioids. For conversion from other opioids to buprenorphine transdermal, taper current around-the-clock opioids for up to 7 days to no more than 30 mg of morphine or equivalent per day before beginning treatment with buprenorphine transdermal. May use short-acting analgesics as needed until analgesic efficacy with buprenorphine transdermal is attained. Buprenorphine transdermal may not provide adequate analgesia for patients requiring greater than 80 mg/day oral morphine equivalents.
- Apply system to flat, hairless, nonirritated, and nonirradiated site on the upper outer arm, upper chest, upper back, or side of the chest. If skin preparation is necessary, use clear water and clip hair (do not shave). Allow skin to dry completely before application. Apply immediately after removing from package. Do not alter the system (i.e., cut) in any way before application. Remove liner from adhesive layer and press firmly in place with palm of hand for 30 sec, especially around the edges, to make sure contact is complete. Remove used system and fold so that adhesive edges are together. Flush system down toilet immediately on removal or follow the institutional policy. Apply new system to a different site. After removal, wait a minimum of 3 wk before applying to the same site. If patch falls off during 7-day dosing interval, dispose of patch and place a new patch on at a different site.
- May be titrated no less than every 72 hr. Dose adjustments in 5 mcg/hr, 7.5 mcg/hr, or 10 mcg/hr increments may be used by using no more than two patches.
- To discontinue, taper dose gradually to prevent signs and symptoms of withdrawal; consider introduction of immediate-release opioid medication. For patients taking buprenorphine regularly for a wk or more, initiate taper by a small enough increment (no more than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2–4 wk or longer. Provision of lower dose strengths may be necessary for a successful taper. Monitor for withdrawal symptoms (restlessness; lacrimation; rhinorrhea; yawning; perspiration; chills; myalgia; mydriasis; irritability; anxiety; backache; joint pain; weakness; abdominal cramps; insomnia; nausea; anorexia; vomiting; diarrhea; increased blood pressure, respiratory rate, or heart rate) during taper. If withdrawal symptoms occur, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose and then proceed with a slower taper. Monitor for changes in mood, emergence of suicidal thoughts, or use of other substances.
Treatment of Opioid Use Disorder: Must be prescribed by health care professional with special training.
Induction is usually started with buprenorphine SL over 3–4 days. Initial dose should be administered at least 4 hr after last opioid dose and preferably when early signs of opioid withdrawal appear. Once patient is on a stable dose, maintenance therapy with buprenorphine/naloxone (Suboxone) is preferred for continued, unsupervised treatment.
- Administer sublingually. Usually takes 2–10 min for tablets to dissolve. If more than one tablet is prescribed, place multiple tablets under the tongue or 2 at a time until all tablets are dissolved. Do not chew or swallow; decreases amount of medication absorbed. Not used for analgesia; may cause death in opioid-naive patients.
SC: Sublocade is for patients who have initiated treatment with a transmucosal buprenorphine product followed by dose adjustment for at least 7 days. Prepare and administer only by health care professional monthly with a minimum of 26 days between doses. Use syringe and needle provided by manufacturer. Remove from refrigerator at least 15 min before injection to allow to reach room temperature. Do not open foil pouch until patient has arrived. Discard if left at room temperature for >12 wk. Do not administer solutions that are discolored or contain particulate matter. Pinch injection site and administer into abdomen; do not rub. May cause a lump that will decrease over several wk. Do not administer IV or IM. If discontinued, withdrawal effects will be delayed (2–5 mo) due to long half-life. Monitor patients discontinuing for withdrawal signs and symptoms. May use transmucosal buprenorphine to treat withdrawal. In patients taking Sublocade for 4–6 mo or more, plasma and urine levels of buprenorphine may be detectable for 12 mo or longer following discontinuation. Administer missed doses as soon as possible with following dose given at least 26 days later. For patients with regular therapy of 100 mg monthly, a 2-mo dosing interval may be used on occasion (e.g., extended travel); a single 300-mg dose may be given to cover a 2-mo period, then resume 100 mg monthly regimen. Caution patient that 300-mg dose may cause sedation.
Brixandi is only available through a restricted program called the Brixandi REMS. Health care settings and pharmacies that order and dispense Brixandi must be certified in this program and comply with REMS requirements.
Treatment of Opioid Use Disorder: There are two formulations of Brixandi; one lasting 7 days and one lasting 1 mo. Doses of Brixandi (weekly) cannot be combined to yield a monthly dose.
Only health care providers should prepare and administer Brixandi. Administer Brixandi as a single injection. Do not divide.
For patients not currently receiving buprenorphine, begin with a test dose of 4 mg transmucosal buprenorphine to establish that buprenorphine is tolerated without precipitated withdrawal, and then transition to Brixandi (weekly)
Brixandi is only for SUBQ injection; do not administer IV, IM, or intradermally.
SC: Inject slowly at a 90° angle into SUBQ tissue of the buttock, thigh, abdomen, or upper arm. Hold safety syringe in place for an additional 2 seconds keeping plunger pressed down fully. Rotate injection sites. In patients not currently receiving buprenorphine, for Brixandi (weekly), use the upper arm site only after steady state has been achieved (4 consecutive doses). Injection in the arm site was associated with approximately 10% lower plasma levels than other sites.
Needle cap is synthetically derived from natural rubber latex; may cause allergic reactions in latex-sensitive individuals.
If a dose of Brixandi (weekly) is missed, administer next dose as soon as possible. Brixandi (weekly) should be administered in 7-day intervals and Brixandi monthly should be administered every 28 days.

Instruct patient on risk of addiction, abuse, and misuse, which could lead to death. Discuss safe use, risks, and proper storage and disposal of opioid analgesics with patients and caregivers with each Rx. The Patient Counseling Guide is available at www.fda.gov/OpioidAnalgesicREMSPCG. Advise patient not to share buprenorphine with others and to protect from theft or misuse. Advise patient to avoid abrupt discontinuation; may lead to withdrawal symptoms.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose. Inform patients and caregivers about various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (by prescription, directly from a pharmacist, or as part of a community-based program).
Medication may cause drowsiness or dizziness. Advise patient to call for assistance when ambulating and to avoid driving or other activities requiring alertness until response to medication is known, especially within 24–48 hr after subdermal implant insertion.
- Advise patient to avoid concurrent use of alcohol or other CNS depressants.
- Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care professional before taking any Rx, OTC, or herbal products, especially CNS depressants.
- Advise patient and family members to inform health care professionals of physical dependence on an opioid and of buprenorphine therapy.
- Advise patient to notify health care professional if pregnancy is planned or suspected and to avoid breastfeeding during therapy. Inform patient of potential for neonatal opioid withdrawal syndrome with prolonged use during pregnancy. Chronic use of buprenorphine may impair male and female fertility. Monitor infant for signs and symptoms of neonatal opioid withdrawal syndrome (irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight); usually occur in the first days after birth.
Pain: Instruct patient on how and when to ask for pain medication.
Encourage patients on bedrest to turn, cough, and breathe deeply every 2 hr to prevent atelectasis.
Instruct patient to change positions slowly to minimize orthostatic hypotension.
Advise patient that good oral hygiene, frequent mouth rinses, and sugarless gum or candy may decrease dry mouth.
Instruct patient on proper technique of buccal film and to avoid eating or drinking until film dissolves. Apply at same time each day. Avoid touching or moving buccal film with tongue or fingers. After product has completely dissolved, take a sip of water, swish gently around teeth and gums, and swallow. Wait for at least 1 hr after taking Belbuca before brushing teeth. Do not stop using buprenorphine without consulting health care professional. Advise patient to read Instructions for Use prior to starting therapy and with each Rx refill in case of changes.
Advise patient to notify health care professional if the dose does not control pain.
Instruct patient in correct method for application, removal, storage, and disposal of transdermal system. Wear patches for 7 days. May be worn while bathing, showering, or swimming. Do not discontinue or change dose without consulting health care professional. Instruct patient to read the Medication Guide prior to starting and with each Rx refill.
- Advise patients and caregivers/family members of the potential side effects. Instruct patient to notify health care professional if pain is not controlled or if bothersome side effects occur. Contact immediately if difficulty or changes in breathing; unusual deep "sighing" breathing; slow or shallow breathing; new or unusual snoring; slow heartbeat; severe sleepiness; cold, clammy skin; feeling faint, dizzy, or confused or difficulty thinking, walking, or talking normally; or swelling or blistering around patch occur.
- Advise patient that fever, electric blankets, heating pads, saunas, hot tubs, and heated water beds increase release of buprenorphine from patch.
- Advise patient referred for MRI test to discuss patch with referring health care professional and MRI facility to determine if removal of patch is necessary prior to test and for directions for replacing patch.
Opioid Use Disorder: Explain techniques for use to patient.
- Caution patient that buprenorphine may be a target for people who abuse drugs; store medications in a safe place to protect them from theft. Selling or giving this medication to others is against the law.
- Caution patient that injection of Suboxone can lead to severe withdrawal symptoms.
- Advise patient if admitted to the emergency department to inform treating health care professional and emergency room staff of physical dependence on opioids and of treatment regimen.
- Advise patient to notify health care professional promptly if faintness, dizziness, confusion, slowed breathing, skin or whites of eyes turning yellow, urine turning dark, light-colored stools, decreased appetite, nausea, or abdominal pain occur.
- SL
  Instruct patient in correct use of medication; directions for use must be followed exactly. Medication must be used regularly, not occasionally. Take missed doses as soon as remembered; if almost time for next dose, skip missed dose and return to regular dosing schedule. Do not take 2 doses at once unless directed by health care professional. Do not discontinue use without consulting health care professional; abrupt discontinuation may cause withdrawal symptoms. If medication is discontinued, flush unused tablets down the toilet if a drug take-back option is not readily available.
- SUBQ
  Inform patient Sublocade and Brixandi are only available through a restricted program, Sublocade or Brixandi REMS program. Sublocade can only be dispensed to directly to a health care provider. Brixandi can only be administered by a health care provider.

Decrease in severity of pain without a significant alteration in level of consciousness or respiratory status.
Suppression of withdrawal symptoms during detoxification and maintenance from heroin or other opioids.
Continued cessation of opioid use.

Belbuca, Brixadi, ~~Buprenex,~~ Butrans, Sublocade, ~~Subutex~~

Schedule III (C-III)

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