byoo-pre-NOR-feen/na-LOX-one

Therapeutic Classification:

Pharmacologic Classification: opioid agonists antagonists, opioid antagonists

• Treatment of opioid dependence as part of a comprehensive program including counseling and psychological support (Suboxone sublingual films and Zubsolv indicated for induction therapy for patients dependent on short-acting opioid products and maintenance treatment; Suboxone sublingual tablets indicated for maintenance treatment only).

• Buprenorphine: Binds to opiate receptors in the CNS.
• Sublingual naloxone: has no pharmacological effect; it is present in the formulation to discourage injection of the product by opioid-dependent patients.

• Suppression of withdrawal symptoms during detoxification and maintenance from opioids.

Absorption: Buprenorphine: Well absorbed following SL administration; naloxone: Negligible absorption follows SL administration.

Distribution: Buprenorphine: Crosses the placenta; enters breast milk. CNS concentration is 15–25% of plasma.

Protein Binding: Buprenorphine: 96%.

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

Half-life: Buprenorphine: 33 hr; Naloxone: 60–90 min (up to 3 hr in neonates).

† Blood level.

Contraindicated in:

• Hypersensitivity to buprenorphine or naloxone
• Severe hepatic impairment (induction or maintenance therapy)
• Moderate hepatic impairment (induction therapy).

Use Cautiously in:

• Compromised respiratory function including COPD, cor pulmonale, diminished respiratory reserve, hypoxia, hypercapnia, or respiratory depression of other causes
• Moderate hepatic impairment (maintenance therapy)
• Hypokalemia, hypomagnesemia, unstable atrial fibrillation, symptomatic bradycardia, unstable HF, QT interval prolongation, or myocardial ischemia
• OB: Use during pregnancy only if potential maternal benefit justifies potential fetal risk
• Lactation: Use while breastfeeding only if potential maternal benefit justifies potential risk to infant
• Pedi: Safety and effectiveness not established in children
• Geri: Older adults may be more sensitive to drug effects.

CV: QT interval prolongation, orthostatic hypotension.

Derm: ↑sweating.

Endo: ADRENAL INSUFFICIENCY.

F and E: peripheral edema.

GI: constipation, nausea, oral hypoesthesia, oral mucosal erythema, vomiting, glossodynia, hepatitis.

Neuro: headache, insomnia.

Resp: RESPIRATORY DEPRESSION (INCLUDING CENTRAL SLEEP APNEA AND SLEEP-RELATED HYPOXEMIA).
Misc: (INCLUDING ANAPHYLAXIS) HYPERSENSITIVITY REACTIONS , physical dependence, psychological dependence, tolerance, withdrawal phenomenon.

Drug-Drug:

• 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).
• Concurrent use with class Ia antiarrhythmics, class III antiarrhythmics, or other QT interval prolonging medications may ↑ risk of QT interval prolongation; avoid concurrent use.
• Concurrent use of CYP3A4 inhibitors, including ritonavir, ketoconazole, itraconazole, fluconazole, clarithromycin, erythromycin, nefazodone, diltiazem, verapamil, nelfinavir, and fosamprenavir, ↑ levels and risk of opioid toxicity; careful monitoring during initiation, dose changes, or discontinuation of the inhibitor is recommended.
• Concurrent use with CYP3A4 inducers, including barbiturates, carbamazepine, efavirenz, corticosteroids, modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, or rifampin, may ↓ fentanyl levels and analgesia; if inducers are discontinued or dose ↓, patients should be monitored for signs of opioid toxicity and necessary dose adjustments should be made.
• 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.
• 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.

Induction

• SL (Adults): Suboxone film: Initiate therapy on Day 1 with buprenorphine 2 mg/naloxone 0.5 mg or buprenorphine 4 mg/naloxone 1 mg; then titrate up in increments of buprenorphine 2–4 mg every 2 hr until achieve dose of buprenorphine 8 mg/naloxone 2 mg based on control of acute withdrawal symptoms. On Day 2, a single daily dose of up to buprenorphine 16 mg/naloxone 4 mg is recommended. Zubsolv: Induction: Initiate therapy on Day 1 with buprenorphine 1.4 mg/naloxone 0.36 mg; then follow with up to buprenorphine 4.2 mg/naloxone 1.08 mg given as 1–2 tablets of buprenorphine 1.4 mg/naloxone 0.36 mg every 1.5–2 hr on Day 1 (not to exceed 3 tablets). On Day 2, a single daily dose of up to buprenorphine 11.4 mg/naloxone 2.9 mg is recommended.

Maintenance

• Buccal, SL (Adults): Suboxone film: Dose taken once daily. Progressively ↑/adjust in increments of buprenorphine 2 mg/naloxone 0.5 mg or buprenorphine 4 mg/naloxone 1 mg. Titrate to keep patient engaged in treatment while suppressing opioid withdrawal; usual target dose is buprenorphine 16 mg/naloxone 4 mg once daily;.
• SL (Adults): Tablets (generic): Dose taken once daily. Progressively ↑/adjust in increments of buprenorphine 2 mg/naloxone 0.5 mg or buprenorphine 4 mg/naloxone 1 mg. Titrate to keep patient engaged in treatment while suppressing opioid withdrawal; usual target dose is buprenorphine 16 mg/naloxone 4 mg once daily. Zubsolv tablets: Dose taken once daily. Progressively ↑/adjust in increments of buprenorphine 1.4 mg/naloxone 0.36 mg or buprenorphine 2.8 mg/naloxone 0.72 mg. Titrate to keep patient engaged in treatment while suppressing opioid withdrawal; usual target dose is buprenorphine 11.4 mg/naloxone 2.8 mg once daily.

(Generic available)

• Sublingual film (Suboxone) (lime flavored): buprenorphine 2 mg/naloxone 0.5 mg; buprenorphine 4 mg/naloxone 1 mg; buprenorphine 8 mg/naloxone 2 mg; buprenorphine 12 mg/naloxone 3 mg; buprenorphine 16 mg/naloxone 4 mg;
• Sublingual tablets: buprenorphine 2 mg/naloxone 0.5 mg; buprenorphine 8 mg/naloxone 2 mg;
• Sublingual tablets (Zubsolv): buprenorphine 0.7 mg/naloxone 0.18 mg; buprenorphine 1.4 mg/naloxone 0.36 mg; buprenorphine 2.9 mg/naloxone 0.71 mg; buprenorphine 5.7 mg/naloxone 1.4 mg; buprenorphine 8.6 mg/naloxone 2.1 mg; buprenorphine 11.4 mg/naloxone 2.9 mg;

• During initial therapy, assess patient at least weekly during first mo and frequently thereafter for compliance, effectiveness of treatment plan, and overall patient progress. Once a stable dose is achieved, monthly assessment may be used. Determine absence of medication toxicity, medical, or behavioral adverse effect; responsible handling of medications by patient; compliance with treatment plan, including recovery-oriented activities and psychotherapy or other modalities; abstinence from illicit drug use.
• Monitor for signs and symptoms of adrenal insufficiency (nausea, vomiting, anorexia, fatigue, weakness, dizziness, 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.

• Monitor liver function test prior to beginning therapy and periodically during treatment.

• Buprenorphine/naloxone sublingual film and sublingual tablets are not appropriate as an analgesic.
• REMS: Can only be prescribed by clinicians who meet qualifying requirements, and who have notified the Secretary of Health and Human Services 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.
• Induction of therapy begins with patient being in a moderate state of opioid withdrawal and receiving buprenorphine or buprenorphine/naloxone, not <6 hr after patient last used opioids. Once the induction phase is completed, maintenance begins with buprenorphine/naloxone titration.
• Patients receiving buprenorphine/naloxone sublingual film may be switched to sublingual tablets of same dose. Due to the greater bioavailability of sublingual film, monitor patients switched from tablets to film for overdose and patients switched from film to tablets for withdrawal symptoms. Dose adjustments may be required.
• 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.
• SL: Film: Place film under tongue. If additional film is required for dose, place on opposite side of tongue from first film, minimizing overlap. Keep film under tongue until dissolved (5–7 min); do not chew, swallow, or move film after placement. Film may also be used buccally.
  • Tablets:Place under tongue until dissolves, about 5 min. Do not cut, chew, or swallow. Do not eat or drink anything until tablet is dissolved.
• Buccal: 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 if 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.

• Instruct patient to take medication as directed. Take missed doses as soon as remembered unless almost time for next dose; do not double doses. Do not take more often than prescribed or take other forms of buprenorphine/naloxone and consult health care professional before stopping; gradually discontinue dose to prevent withdrawal syndrome. Instruct patient to read Medication Guide before starting therapy and with each Rx refill in case of changes. Advise patient to keep medication in a safe place, out of reach of children, and protected from being stolen, and do not share with others, even if they have the same symptoms. Explain that buprenorphine/naloxone sublingual film may be fatal to children and individuals not tolerant to opioids. Advise patient that selling or giving medication away is against the law.
• To dispose of unused films, remove from foil pouch and drop each film into toilet and flush.
• 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).
• Caution patient of the danger of taking nonprescribed benzodiazepines or other CNS depressants, including alcohol, during therapy. Combination may be fatal.
• May cause dizziness. Caution patient to avoid driving and other activities requiring alertness until response to medication is known.
• Advise patient to make position changes slowly to prevent orthostatic hypotension.
• Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications.
• Advise patient to notify health care professional if signs and symptoms of adrenal insufficiency occur.
• Advise females of reproductive potential to notify health care professional if pregnancy is planned or suspected or if breastfeeding. Inform patient of potential for neonatal opioid withdrawal syndrome with prolonged use during pregnancy. Monitor neonate for signs and symptoms of withdrawal symptoms (irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight); usually occur the first days after birth. Advise breastfeeding women taking buprenorphine/naloxone to monitor infants for increased drowsiness and breathing difficulties. Chronic opioid use may cause impaired fertility in females and males of reproductive potential.
• Instruct patient to inform family that, in the event of an emergency, treating health care professionals should be informed that patient is physically dependent on an opioid and being treated with buprenorphine/naloxone sublingual film.

• Suppression of withdrawal symptoms during detoxification and maintenance from opioids.

Bunavail, Suboxone, Zubsolv

Schedule III (C-III)