Buprenorphine Hydrochloride

Pronunciation

Class: Opiate Partial Agonists
VA Class: CN101
Chemical Name: 6,14-Ethenomorphinan-7-methanol, 17 - (cyclopropylmethyl) - α - (1,1 - dimethylethyl) - 4,5 - epoxy - 18,19 - dihydro - 3 - hydroxy - 6 - methoxy - α - methyl - , [5α,7α,(S)]
Molecular Formula: C29H41NO4C29H41NO4•HCl
CAS Number: 52485-79-7
Brands: Buprenex, Butrans, Suboxone, Subutex

Warning(s)

  • Transdermal Systems
  • Indicated for management of moderate to severe chronic pain requiring continuous, around-the-clock opiate analgesia for an extended period.213

  • Potential for abuse of buprenorphine is similar to that of other opiates.213 Clinicians should consider abuse potential when prescribing or dispensing buprenorphine transdermal systems in situations where they are concerned about an increased risk of misuse, abuse, or diversion.213 Individuals at risk for opiate abuse include those with a personal or family history of substance abuse (e.g., alcohol or drug abuse or addiction) or psychiatric disorders (e.g., major depression).213 Assess patient for abuse or addiction potential before prescribing opiates; monitor for misuse, abuse, and addiction during therapy.213

  • Risk of QT interval prolongation; do not exceed a dosage of 20 mcg/hour of transdermal buprenorphine.213 (See Cardiac Effects under Cautions.)

  • Do not expose the transdermal application site or surrounding area to direct external heat sources; temperature-dependent increases in buprenorphine release from the system may result in overdosage and death.213 (See Patients with Fever or Exposure to High Temperatures under Cautions.)

REMS:

FDA approved a REMS for buprenorphine to ensure that the benefits outweigh the risk. (See REMS: Butrans and REMS: Suboxone, under Dosage and Administration.) The REMS may apply to one or more preparations of buprenorphine and may consist of the following: medication guide, elements to assure safe use, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Analgesic; opiate partial agonist.1 2 3 4 6 7 10 11 202 213 214

Uses for Buprenorphine Hydrochloride

Pain

Used parenterally for relief of moderate to severe pain1 2 3 4 124 183 185 such as that associated with acute and chronic medical disorders including cancer,31 65 71 99 134 143 trigeminal neuralgia,47 accidental trauma,73 ureteral calculi,98 and MI.4 71 150

Used parenterally for management of postoperative pain in patients who have undergone various types of surgery, including neurologic,138 cardiovascular (e.g., CABG, valve replacement),4 66 71 185 cesarean section,28 71 82 110 gynecologic,28 60 69 71 80 124 149 151 177 abdominal (e.g., cholecystectomy, bowel resection),28 32 44 54 64 69 71 73 76 103 145 151 184 185 urologic,28 124 185 general (e.g., head and neck, breast),53 60 151 and orthopedic (e.g., total hip replacement, spinal fusion).23 26 32 83 92 145 185

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Used transdermally for management of moderate to severe chronic pain in patients requiring continuous opiate administration for an extended period.213

Has been used parenterally for preoperative sedation and analgesia35 58 60 127 140 148 and as an adjunct to surgical anesthesia.24 49 58 60 62 71 121 135 142 149 192

Do not use sublingual formulations for analgesia.214 Fatal overdosage reported with such use in opiate-naive individuals.214

Opiate Dependence

Used sublingually for treatment of opiate dependence in an office-based outpatient setting (designated an orphan drug by FDA for this use); used alone and in fixed combination with naloxone.201 202 214

Buprenorphine alone is preferred for the initial (i.e., induction) phase of treatment, administered under the supervision of the prescribing physician in the office setting.202 203 Following induction, buprenorphine in fixed combination with naloxone is preferred for maintenance treatment when use includes unsupervised administration.202 214 Administration of buprenorphine without naloxone in an unsupervised setting should be limited to patients who cannot tolerate naloxone.202

Safety and efficacy of transdermal buprenorphine for treatment of opiate dependence not established.213

Buprenorphine Hydrochloride Dosage and Administration

General

  • REMS: Butrans
  • FDA has approved a REMS for buprenorphine transdermal systems (Butrans).215 (See REMS.)

  • The REMS requires that a medication guide be provided to the patient each time this formulation is dispensed and outlines a plan to ensure training is provided to clinicians who prescribe this formulation.215

  • Retraining will occur every 2 years, or sooner if the training materials require substantial revision.215 Submission of the training confirmation form does not affect the clinician’s ability to prescribe the drug.215

  • REMS: Suboxone
  • FDA has approved a REMS for sublingually dissolving strips containing buprenorphine in fixed combination with naloxone (Suboxone).216 (See REMS.)

  • The REMS requires that a medication guide be provided to the patient each time this formulation is dispensed and outlines steps to ensure documentation of safe use conditions and proper monitoring for each patient receiving the formulation.216

  • REMS communications are directed to physicians certified under the Drug Addiction Treatment Act (DATA) of 2000 and to pharmacists.216 (See Restricted Distribution Program under Administration.)

  • REMS requirement does not apply when the sublingually dissolving strips are dispensed to patients admitted to an opiate treatment program.216

  • Opiate Dependence
  • To avoid precipitating withdrawal, give the first dose of buprenorphine when clear, objective signs of opiate withdrawal are evident.202 214 In individuals using heroin or other short-acting opiates, administer the first dose ≥4 hours after the last use of the opiate; however, it is preferable to initiate buprenorphine when early signs of opiate withdrawal appear.202

  • Withdrawal symptoms can occur during buprenorphine induction in patients being transferred from methadone maintenance; withdrawal symptoms appear to be more likely in those receiving higher methadone dosages (>30 mg daily) and when the first dose of buprenorphine is given shortly after the last methadone dose.202

Administration

Administer by IM or IV injection for relief of pain.1 2 3 Administer transdermally for management of chronic pain only.213 Administer sublingually as a single agent or in fixed combination with naloxone for management of opiate dependence.202 214

Also administered by continuous IV infusion,32 33 34 by IM103 or IV76 79 injection using a patient-controlled infusion device, and by epidural injection for pain relief.23 24 25 26 28 29 30 31 50 78 92 192

For drug compatibility information, see Compatibility under Stability.

Sublingual Administration

Administer as a single daily dose.202 214

Sublingual Tablets

Place tablets under the tongue and allow to dissolve; swallowing the tablets reduces bioavailability.202 Drinking warm fluids prior to administration may aid dissolution.204

For doses requiring >2 tablets, all the tablets may be placed under the tongue at once.202 Alternatively, patients may place 2 tablets under the tongue at a time if they are unable to place >2 tablets comfortably.202

To ensure consistent bioavailability, patients should adhere to the same manner of dosing with continued use.202

Sublingually Dissolving Strips

Place up to 2 strips under the tongue (on either side near the base of the tongue) in a way that minimizes overlapping, and allow to dissolve; patient should not talk while the strip is dissolving, chew the strip, or swallow the strip; these activities may alter absorption.214 219 Drinking water prior to administration may aid dissolution.214 219

For doses requiring >2 strips, place additional strip(s) under the tongue after the first 2 strips have completely dissolved.219

IV Injection

Rate of Administration

Administer over ≥2 minutes.1 2 3

Continuous IV Infusion

Dilution

Dilute to a concentration of 15 mcg/mL in 0.9% sodium chloride.32

Rate of Administration

Administer via a controlled-infusion device.32

Epidural Injection

Dilution

Has been diluted to a concentration of 6–30 mcg/mL in 0.9% sodium chloride.23 24 25 26 28 29 30 31 78 92 192

Transdermal Administration

To expose the adhesive surface of the system, peel off and discard the protective-liner covering just prior to application.213

Apply the transdermal system to a dry, intact, nonirritated, hairless or nearly hairless surface on the upper chest, upper back, side of chest, or upper outer arm by firmly pressing the system by hand for 15 seconds with the adhesive side touching the skin and ensuring that contact is complete, particularly around the edges.213 220

Clip, not shave, hair at the application site prior to application if needed.213

Only water should be used if the site must be cleaned before transdermal application;213 do not use soaps, oils, lotions, alcohol, or abrasive devices that could alter absorption of the drug.213 220

Do not use transdermal system if the seal of the package is broken or if the system is altered in any way (e.g., cut, damaged).213

Each transdermal system is intended to be worn continuously for 7 days; apply subsequent systems to a different site after removal of the previous system.213 220 At least 21 days should elapse before reusing any single application site.213

If a system should inadvertently come off during the period of use, apply a new system to a different skin site and leave in place for 7 days.213 220 The edges of the system may be taped in place with first-aid tape if the patient experiences difficulty with system adhesion.213 If adhesion problems persist, an adhesive film dressing (e.g., Bioclusive, Tegaderm) may be applied over the system.220 221

Restricted Distribution Program

The Drug Addiction Treatment Act (DATA) of 2000 allows qualifying physicians to prescribe and dispense opiates in schedules III, IV, and V of the Federal Controlled Substances Act that have been approved by FDA for detoxification or maintenance treatment of opiate dependence.205 Prior to passage of this law, opiate dependence treatment could be provided only at specially registered clinics.203 Under DATA 2000, prescription use of buprenorphine and buprenorphine/naloxone fixed combination in the treatment of opiate dependence is limited to physicians who meet certain requirements and have notified the Secretary of the US Department of Health and Human Services of their intent to prescribe these preparations for this indication.202

Pharmacists may utilize the DATA physician locator (at ) or contact 866-287-2728 or info@buprenorphine.samhsa.gov to verify whether a physician is in compliance with the provisions of DATA.203 225

Dosage

Available as buprenorphine (transdermal systems) and buprenorphine hydrochloride (injection and sublingual tablets); dosage expressed in terms of buprenorphine.1 2 213

Also available as fixed combination of buprenorphine hydrochloride and naloxone hydrochloride (sublingual tablets, sublingually dissolving strips); dosage generally expressed in terms of the buprenorphine content.202 214

Pediatric Patients

Pain

Adjust dosage according to the severity of pain, physical status of the patient, and other drugs that the patient is receiving.1 2

IV or IM

Children 2–12 years of age: 2–6 mcg/kg every 4–6 hours; however, longer dosing intervals (e.g., every 6–8 hours) may be sufficient.1 Do not use a fixed around-the-clock dosing interval until an adequate dosing interval has been established by clinical observation of the patient.1

Children ≥13 years of age: 0.3 mg given at intervals of up to every 6 hours as necessary.1 2 3 Repeat initial dose (up to 0.3 mg) once in 30–60 minutes, if needed.1

Exercise particular caution with IV administration, especially with initial doses.1

Decrease dosage by approximately 50% in patients who are at increased risk of respiratory depression.1 (See Respiratory Depression under Cautions.)

Circumcision-related Pain
IM

Children 9 months to 9 years of age undergoing circumcision: Initial dosage of 3 mcg/kg as an adjunct to surgical anesthesia, followed by additional 3-mcg/kg doses as necessary to provide analgesia postoperatively, has been used.27

Adults

Pain

Adjust dosage according to the severity of pain, physical status of the patient, and other drugs that the patient is receiving.1 2

IV or IM

0.3 mg given at intervals of up to every 6 hours as necessary.1 2 3 Repeat initial dose (up to 0.3 mg) once in 30–60 minutes, if needed.1 A dosing interval longer than 6 hours may be adequate in some patients.71 72 97 99

It may be necessary to administer single doses of up to 0.6 mg, but the manufacturer recommends that such relatively high doses only be administered IM and only to adults who are not at increased risk of respiratory depression.1

A regimen including an initial dose of 0.3 mg followed by another 0.3-mg dose repeated in 3 hours is as effective as a single 0.6-mg dose in relieving postoperative pain.129

Exercise particular caution with IV administration, especially with initial doses.1

Decrease dosage by approximately 50% in patients who are at increased risk of respiratory depression.1 (See Respiratory Depression under Cautions.)

Continuous IV Infusion

Dosages of 25–250 mcg/hour have been used for the management of postoperative pain.33 34

Epidural Injection

Dosages of 0.15–0.3 mg have been administered in the management of severe, chronic pain (e.g., in terminally ill patients) as frequently as every 6 hours, up to a mean total daily dosage of 0.86 mg (range: 0.15–7.2 mg).31

60 mcg as a single dose, up to a mean total dose of 180 mcg administered over a 48-hour period, has been used for the management of postoperative pain.23

Supplement to Surgical Anesthesia
Epidural Injection

Dosage of 0.3 mg has been used as a supplement to surgical anesthesia with a local anesthetic.24 192

Chronic Pain
Transdermal

When selecting the initial transdermal dose, consider the dose, potency, and characteristics of previous opiate regimens and the reliability of the potency estimate used to calculate an equivalent buprenorphine dosage; the patient’s degree of tolerance to adverse effects; the patient’s age and medical status; type and severity of pain; concurrent therapy; the acceptable balance between efficacy and adverse effects; and the patient’s risk factors for abuse, addiction, or diversion.213 Fatal overdosage possible with the first transdermal dose if the dose is overestimated.213

Manufacturer considers the following dosage recommendations to be suggested approaches to the individual management of each patient.213

Opiate-naive patients: Initiate with buprenorphine 5 mcg/hour.213

Patients previously receiving <30 mg daily of morphine sulfate (or equivalent): Initiate with buprenorphine 5 mcg/hour.213

Patients previously receiving 30–80 mg daily of morphine sulfate (or equivalent): Taper current opiate regimen for up to 7 days to a total 24-hour dosage of ≤30 mg of morphine sulfate (or equivalent) and initiate with buprenorphine 10 mcg/hour.213

Titration: Increase at minimum intervals of 72 hours to a level providing adequate analgesia and acceptable adverse effects, taking into account patient’s requirement for supplemental short-acting analgesics.213 Maximum transdermal dosage is 20 mcg/hour (see Cardiac Effects under Cautions).213

Discontinuance: Periodically reassess need for continued around-the-clock opiate therapy.213 When discontinuing therapy, taper dosage to prevent manifestations of withdrawal.213 Consider use of a short-acting opiate during tapering process.213

Opiate Dependence
Induction
Sublingual

Initially, buprenorphine 8 mg on day 1 and 16 mg on day 2.202 From day 3 onward, administer buprenorphine in fixed combination with naloxone at the same buprenorphine dose as on day 2.202

To avoid precipitating withdrawal, give the first dose when objective and clear signs of opiate withdrawal are evident.202 214

Manufacturer recommends that an adequate maintenance dosage, titrated to clinical effectiveness, be achieved as rapidly as possible to prevent undue opiate withdrawal symptoms.202

Maintenance
Sublingual

Target dosage of buprenorphine in fixed combination with naloxone is 16 mg daily; however, dosages as low as 12 mg daily may be effective in some patients.202 214 Adjust dosage in increments/decrements of 2 or 4 mg daily to a dosage that suppresses opiate withdrawal symptoms and ensures that the patient continues treatment.202 214

Usual dosage: 4–24 mg daily depending on the individual patient.202 214

If switching between buprenorphine/naloxone sublingual tablets and sublingually dissolving strips, continue same dosage.214 However, not all doses and dose combinations are bioequivalent; monitor for efficacy and tolerability and adjust dosage if needed.214 (See Bioavailability under Pharmacokinetics.)

Discontinuance
Sublingual

The decision to discontinue therapy after a period of maintenance or brief stabilization should be made as part of a comprehensive treatment plan.202 214 Both gradual and abrupt discontinuance have been used; the best method for tapering dosage at the end of treatment has not been established.202 214

Prescribing Limits

Pediatric Patients

Pain
IV or IM

Children 2–12 years of age: Manufacturer states that there is insufficient evidence to recommend doses >6 mcg/kg or administration of a repeat dose within 30–60 minutes of the initial dose.1

Adults

Pain
IM

There are insufficient clinical data to recommend single doses >0.6 mg for long-term use.1 2

Chronic Pain
Transdermal

Maximum 20 mcg/hour (see Cardiac Effects under Cautions).213

Special Populations

Hepatic Impairment

Pain
Chronic Pain
Transdermal

Mild to moderate hepatic impairment: Initiate at 5 mcg/hour; titrate dosage to an effective, tolerable level under close supervision.213

Severe hepatic impairment: Transdermal buprenorphine not studied in this population; consider an alternative analgesic regimen that allows for greater dosing flexibility.213

Opiate Dependence
Sublingual

Adjust dosage and monitor for manifestations of opiate withdrawal.202 214 Although both buprenorphine and naloxone are extensively metabolized, not known whether both drugs are affected to the same degree by hepatic impairment; increased concentrations of both drugs expected in patients with moderate or severe hepatic impairment.214

Renal Impairment

No specific dosage recommendations at this time.1 202 213 214

Geriatric Patients

Pain

Reduce parenteral dosage by approximately 50%.1

While specific transdermal dosage adjustments are not necessary based on age, use caution to ensure safe use.213 (See Geriatric Use under Cautions.)

Opiate Dependence

Select sublingual dosage with caution, usually starting at the low end of the dosage range, because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.214

Cautions for Buprenorphine Hydrochloride

Contraindications

  • Known hypersensitivity to buprenorphine or any ingredient (e.g., naloxone) in the formulation.1 2 202 213 214

  • Transdermal Buprenorphine
  • Paralytic ileus (diagnosed or suspected).213

  • Substantial respiratory depression or severe bronchial asthma.213

  • Management of acute, short-term, postoperative, mild, or intermittent pain.213

Warnings/Precautions

Warnings

Respiratory Depression

The major toxicity associated with buprenorphine.1 2 4 18 28 33 39 44 48 58 59 62 64 71 73 75 76 84 89 93 95 97 184 185 213

Occurs more frequently in geriatric or debilitated patients, in those with conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation, or when given concomitantly with drugs that depress respiration.213

May occur especially with IV administration.202 214 Deaths have occurred when buprenorphine (usually in conjunction with a benzodiazepine) was misused via IV injection by opiate abusers.202 214 Deaths also have occurred when used with other depressants (e.g., alcohol, other opiates).202 214

Use with extreme caution in patients with pulmonary impairment or compromised respiratory function (e.g., those with COPD, cor pulmonale, decreased respiratory reserve [e.g., asthma, severe obesity, sleep apnea, myxedema, substantial kyphoscoliosis, CNS depression], hypoxia, hypercapnia, preexisting respiratory depression) and in those receiving other respiratory depressant drugs concomitantly.1 2 3 4 202 213 214

Naloxone1 2 3 4 9 21 40 64 71 84 and doxapram1 2 3 9 18 21 59 70 71 76 84 185 may be only partially effective in reversing buprenorphine-induced respiratory depression; use of assisted or controlled respiration may be necessary and should be considered the principal method of management.1 2 3 4 20 46 83

CNS Depression

May cause somnolence, dizziness, alterations in judgment, or alteration in level of consciousness, including coma.1 202 213 214 Use with caution in comatose patients or in patients with CNS depression.1

May impair mental alertness and/or physical coordination needed to perform potentially hazardous activities such as driving or operating machinery; warn patient about possible adverse CNS effects of opiate agonists.1 202 213 214

Concurrent use of other CNS depressants may potentiate CNS depression.1 202 213 214 (See Specific Drugs under Interactions.)

Hepatic Effects

Cytolytic hepatitis and hepatitis with jaundice reported in individuals receiving buprenorphine for opiate dependence.202 213 214

Other serious adverse hepatic events (e.g., hepatic failure, hepatic necrosis, hepatorenal syndrome, hepatic encephalopathy) reported.202 213 214 Some individuals had risk factors for such adverse events (i.e., preexisting hepatic enzyme abnormalities, HBV or HCV infection, concomitant use of potentially hepatotoxic drugs, ongoing illicit use of injectable drugs), but the possibility exists that buprenorphine had a causative or contributory role.202 213 214

Evaluate liver function prior to initiation of buprenorphine for the management of opiate dependence and periodically during treatment.202 214 Evaluate liver function prior to initiation of transdermal buprenorphine for analgesia and periodically during treatment in patients at increased risk of hepatotoxicity (e.g., history of excessive alcohol use, IV drug abuse, or liver disease).213 Evaluate carefully in the event of an adverse hepatic event.202 213 214

Cardiac Effects

QT-interval prolongation observed with transdermal dosage of 40 mcg/hour in healthy adults; do not exceed dosage of 20 mcg/hour.213

Take potential QT-interval prolongation into account when considering transdermal buprenorphine in patients with hypokalemia or clinically unstable cardiac disease (e.g., unstable atrial fibrillation, symptomatic bradycardia, unstable CHF, active myocardial ischemia).213

Avoid use of transdermal buprenorphine in patients with a personal or family (i.e., immediate family member) history of long QT syndrome and in patients who are receiving class IA (e.g., disopyramide, procainamide, quinidine) or class III (e.g., amiodarone, dofetilide, sotalol) antiarrhythmic agents.213

Hypotensive Effects

May cause severe hypotension, especially in patients whose ability to maintain their BP is compromised by depleted blood volume or concomitant drugs (e.g., phenothiazines).213 Use with caution in patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and BP.213

May produce orthostatic hypotension in ambulatory patients.202 213 214

Dependence and Abuse

Possible psychologic dependence to buprenorphine’s opiate agonist activity.1 12 112 Limited physical dependence may occur41 85 86 107 108 109 111 112 147 infrequently;1 2 4 74 178 tolerance to the drug’s opiate agonist activity develops rarely,107 109 171 178 if at all.84 96 123

Potential for abuse exists (see Boxed Warning).213 214

Clinicians should consider abuse potential when prescribing or dispensing buprenorphine in situations where they are concerned about an increased risk of misuse, abuse, or diversion.213 However, concerns about abuse, addiction, and diversion should not prevent the proper management of pain.213

When used for treatment of opiate dependence, clinical monitoring must be appropriate to patient’s level of stability.214 Do not authorize multiple refills during early stages of treatment or without appropriate follow-up visits.214

Withdrawal Effects

Sublingual administration of buprenorphine/naloxone fixed combination may cause withdrawal symptoms in individuals who are physically dependent on opiates if the fixed combination is administered before the agonist effects of the opiate have subsided.202 214

Marked and intense opiate withdrawal symptoms are likely if buprenorphine/naloxone fixed combination is misused via parenteral injection by individuals who are physically dependent on opiates.202 214

Buprenorphine may occasionally precipitate mild to moderate signs and symptoms of withdrawal in some patients physically dependent on opiates (because of the drug’s antagonist activity).1 2 87 100 112 183 202 Signs and symptoms of mild withdrawal may also appear following discontinuance of prolonged therapy with buprenorphine alone.4 71 84 100 112

Head Injury and Increased Intracranial Pressure

Respiratory depressant effects of buprenorphine (with CO2 retention and secondary elevation of CSF pressure) may be exaggerated in the presence of head injury, other intracranial lesions, or preexisting increase in intracranial pressure.1 213 214

Buprenorphine produces effects (e.g., pupillary changes) that may obscure neurologic signs of further increase in intracranial pressure in patients with head injuries.1 213 214

Use with caution in patients with head injury, other intracranial lesions, or preexisting elevation in intracranial pressure.1

Dermatologic Effects

Application site reactions (e.g., pruritus, erythema, rash) reported with transdermal administration;213 severe reactions (e.g., burning, discharge, vesicles) reported rarely.213 Reported days to months following initiation of therapy.213

Patients with Fever or Exposure to High Temperatures

Drug absorption from buprenorphine transdermal systems depends in part on the temperature of the skin and increases with increasing temperature.213

Monitor patients who develop a fever or whose core body temperature increases following strenuous exercise for manifestations of opiate toxicity and adjust dosage accordingly.213

Exposure of the application site or surrounding area to direct external heat sources (e.g., heating pads, electric blankets, heat or tanning lamps, saunas, hot tubs, hot baths, heated water beds, prolonged direct sunlight, hot water) may increase percutaneous absorption of buprenorphine; potential for overdosage and death.213 220 Avoid such exposure.213 220

Seizures

May lower seizure threshold and aggravate seizure disorders or induce seizures in some clinical settings.213 Use with caution in patients with a history of seizure disorders.213

Sensitivity Reactions

Hypersensitivity Reactions

Acute and chronic hypersensitivity reactions reported.202 213 Rash,202 213 214 urticaria,202 213 214 and pruritus202 213 214 are most common;202 213 214 bronchospasm,202 213 214 angioedema,202 213 214 and anaphylactic shock202 213 214 also have occurred.202 213 214 (See Contraindications.)

General Precautions

Pancreatic and Biliary Disease

May increase pressure within the common bile duct and cause spasm of sphincter of Oddi.1 2 21 40 52 54 202 213 214

Use with caution in patients with dysfunction of the biliary tract,1 2 202 213 214 including acute pancreatitis,213 and those undergoing biliary tract surgery.54

Acute Abdominal Conditions

May obscure the diagnosis and/or clinical course of patients with acute abdominal conditions.202 213 214

Use with caution in patients at risk of ileus.213

Hypothyroidism

Use with caution in patients with hypothyroidism.202 213 214

Addison’s Disease

Use with caution in patients with Addison’s disease.202 213 214

Prostatic Hypertrophy or Urethral Stricture

Use with caution in patients with prostatic hypertrophy or urethral stricture.202 213 214

Other Special Risk Patients

Use with caution in debilitated patients and in those with toxic psychoses, acute alcoholism, or delirium tremens.1 202 213 214

Fixed-combination Preparation

When buprenorphine is used in fixed combination with naloxone, consider the cautions, precautions, and contraindications associated with naloxone.202 214

Accidental Exposure

May cause severe or fatal respiratory depression in children accidentally exposed to the drug; store out of reach of children and promptly destroy unused dosage units.214 220

Interactions

Concomitant use with certain drugs is not recommended or requires particular caution.202 213 214 (See Interactions: Specific Drugs.)

Specific Populations

Pregnancy

Category C.1 202 213 214

Safety and efficacy during labor and delivery not established.1 2 213

Opiate withdrawal symptoms (e.g., hypertonia, tremor, agitation, myoclonus) reported in neonates after maternal use of buprenorphine or buprenorphine/naloxone for opiate dependence during pregnancy.202 214 Seizures, apnea, and bradycardia reported rarely.202 214 Onset of symptoms may occur on days 1–8 of life (usually day 1).202 214 Neonates whose mothers received transdermal buprenorphine during gestation also may be at risk; monitor closely for withdrawal signs.213

Lactation

Distributed into milk.1 202 213 214 Women should not breast-feed infants while receiving buprenorphine.1 202 213 214

Pediatric Use

Safety and efficacy of parenteral buprenorphine as an analgesic not established in children <2 years of age.1 2 Has been used parenterally as a supplement to surgical anesthesia27 and as an analgesic in the management of postoperative pain1 27 and severe chronic pain (e.g., in terminally ill patients)94 in a limited number of children 9 months to 18 years of age.1 27 94

Safety and efficacy of transdermal buprenorphine for analgesia not established in patients <18 years of age.213

Safety and efficacy of buprenorphine and buprenorphine/naloxone sublingual tablets not established for the management of opiate dependence in children <16 years of age;202 safety and efficacy of buprenorphine/naloxone sublingually dissolving strips not established in children.214

Geriatric Use

Use with caution.1 202

Reduce parenteral dosage.1 (See Geriatric Patients under Dosage and Administration.)

Insufficient experience with sublingual formulations in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; select dosage with caution.214

Constipation and urinary retention occurred more frequently in geriatric individuals than in younger adults receiving transdermal buprenorphine.213 While specific transdermal dosage adjustments are not necessary based on age, use caution to ensure safe use.213

Hepatic Impairment

Metabolized in the liver; therefore, activity of the drug may be increased and/or prolonged in patients with hepatic impairment.1 2 Use with caution in patients with severe hepatic impairment.1 2 202 213 (See Hepatic Impairment under Dosage.)

When used for the treatment of opiate dependence in patients with hepatic impairment, adjust dosage and observe the patient for potential withdrawal symptoms.202 214

Close supervision required when used transdermally for the treatment of chronic pain in patients with mild to moderate hepatic impairment.213 Consider use of alternative analgesic with greater dosing flexibility in patients with severe hepatic impairment.213

Renal Impairment

Use with caution in patients with severe renal impairment.1 2 202 213

Common Adverse Effects

Parenteral injection: Sedation (e.g., drowsiness),1 2 3 9 40 44 48 51 53 65 67 69 71 72 75 79 83 95 96 98 110 183 184 185 dizziness,1 2 3 4 9 44 71 99 183 185 vertigo,1 2 3 nausea.1 2 3 4 40 44 49 51 53 67 71 76 79 83 93 105 183 184 185 192

Sublingually dissolving strips: Oral hypoesthesia, glossodynia, oral mucosal erythema, headache, nausea, vomiting, hyperHIDrosis, constipation, manifestations of withdrawal, insomnia, pain, peripheral edema.214 Adverse effects of sublingual tablets generally are similar.214

Transdermal system: Nausea, headache, application site reactions (pruritus, erythema, rash), dizziness, constipation, somnolence, vomiting, dry mouth.213

Interactions for Buprenorphine Hydrochloride

Metabolized principally by CYP3A4.1 202 213 214 Buprenorphine and norbuprenorphine are conjugated by uridine diphosphate-glucuronosyltransferase (UGT) isoenzymes, mainly by UGT 1A1 and 2B7 and by UGT 1A3, respectively.213

Buprenorphine inhibits CYP2D6 and CYP3A4 in vitro; norbuprenorphine is a moderate CYP2D6 inhibitor.214

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased plasma buprenorphine concentrations).1 202 Closely monitor buprenorphine dosage; adjust dosage of one or both drugs if necessary.1 202 214 Pharmacokinetics of transdermally administered buprenorphine not expected to be affected by concomitant CYP3A4 inhibitors.213

CYP3A4 inducers: Potential pharmacokinetic interaction (decreased plasma buprenorphine concentrations).1 202 213 214 Closely monitor patient; adjust buprenorphine dosage if necessary.1 202 213 214

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2D6 or CYP3A4: Manufacturer of transdermal buprenorphine states that interactions are unlikely.214

Drugs Affecting Hepatic Blood Flow

Drugs that reduce hepatic blood flow may decrease the rate of hepatic elimination of buprenorphine.1 2 4 116 213 Use with caution; reduce dosage of at least one of the drugs.1 186 189

Drugs that Prolong QT Interval

Potential pharmacodynamic interaction (increased risk of QT-interval prolongation).213 (See Cardiac Effects under Cautions.)

Specific Drugs

Drug

Interaction

Comments

Anesthetics, local (e.g., bupivacaine, mepivacaine)

Possible potentiation of anesthetic effect24 92 and more rapid onset and prolonged duration of analgesia24

Antiarrhythmic agents, class IA or III (e.g., amiodarone, disopyramide, dofetilide, procainamide, quinidine, sotalol)

Increased risk of QT-interval prolongation reported with transdermal buprenorphine213

Avoid concomitant use with transdermal buprenorphine213

Anticoagulants, (phenprocoumon, no longer commercially available)

Possible purpuric response1 2

Anticonvulsants (carbamazepine, phenobarbital, phenytoin)

Possible decrease in plasma buprenorphine concentrations1 202 213 214

Monitor closely; adjust buprenorphine dosage, if necessary1 202 213 214

Antifungals, azoles (e.g., ketoconazole)

Ketoconazole: Increased plasma buprenorphine concentrations reported with sublingual buprenorphine;1 202 interaction not observed with transdermal buprenorphine213

Monitor closely; adjust dosage of one or both drugs, if necessary1 202 214

Benzodiazepines (e.g., diazepam, lorazepam)

Reports of death or coma when buprenorphine was misused (e.g., self-injection of crushed tablets) via IV injection with benzodiazepines by drug abusers202 213 214

May alter usual ceiling on buprenorphine-induced respiratory depression, making buprenorphine’s respiratory-depressant effects appear similar to those of full opiate agonists213 214

Respiratory and cardiovascular collapse reported in several patients receiving usual doses of IV buprenorphine and oral diazepam concomitantly1 2 59

Bradycardia, respiratory depression, and prolonged drowsiness reported following IV buprenorphine administration during surgery in a patient who had received oral lorazepam preoperatively36

Use with caution202 213 214

CNS depressants (e.g., opiate agonists, tranquilizers, general anesthetics, sedatives/hypnotics, alcohol)

Possible potentiation of CNS depression; deaths reported1 2 3 35 37 42 59 60 64 202 213 214

Use with caution; reduce dosage of at least one of the drugs1 2 3 202 213 214

Avoid alcohol use213 219

Droperidol

Concomitant administration has produced satisfactory analgesia (during and after surgery60 and also in a terminally ill patient with severe, chronic pain that was previously unresponsive to buprenorphine alone37 )

Fentanyl

Concomitant administration produced satisfactory analgesia of prolonged duration with minimal respiratory depression; patient was aroused quickly and easily following surgery70

Halothane

Potential for increased and/or prolonged activity of buprenorphine secondary to reduced hepatic elimination of the drug1 2 4 116 186 191 213

Use with caution; reduce dosage of at least one of the drugs1 186 189

HIV protease inhibitors (atazanavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir)

Atazanavir (with or without ritonavir): Increased plasma buprenorphine and norbuprenorphine concentrations and excessive opiate effects reported with sublingual buprenorphine;213 214 possible decreased atazanavir concentrations when used without low-dose ritonavir224

Indinavir, saquinavir: Possible increased buprenorphine concentrations202

Lopinavir/ritonavir, nelfinavir, ritonavir: Interaction not observed214

Ritonavir-boosted atazanavir: Monitor closely; adjust buprenorphine dosage, if necessary1 202

Atazanavir (without ritonavir): Concomitant use not recommended224

Indinavir, saquinavir: Monitor closely; reduce buprenorphine dosage, if necessary202

Macrolide antibiotics (e.g., erythromycin)

Possible increased plasma buprenorphine concentrations1 202 214

Monitor closely; adjust dosage of one or both drugs, if necessary1 202 214

MAO inhibitors

Possible additive effect or potentiation of CNS depression1 2 3 213

Use with caution;1 2 3 manufacturer recommends allowing 14 days to elapse following discontinuance of MAO inhibitor and initiation of transdermal buprenorphine213

Naloxone

In patients who received a single, high dose of buprenorphine before undergoing cholecystectomy with balanced anesthesia and experienced pain in the immediate postoperative phase, addition of naloxone resulted in adequate analgesia, possibly by counteracting dominant antagonistic effects of buprenorphine58 148

Nonnucleoside reverse transcriptase inhibitors (NNRTIs; efavirenz, delavirdine)

Pharmacokinetic interaction does not result in substantial pharmacodynamic effects213 214

In patients receiving chronic buprenorphine therapy who begin NNRTI therapy, monitor buprenorphine dosage214

Nucleoside reverse transcriptase inhibitors (NRTIs)

Interaction not considered likely213 214

Phenothiazines

Possible severe hypotension213

Rifampin

Possible decrease in plasma buprenorphine concentrations1 202 213

Monitor closely; adjust buprenorphine dosage, if necessary1 202 213 214

Skeletal muscle relaxants

Potential for enhanced neuromuscular blocking action and increased respiratory depression213

Use with caution213

Buprenorphine Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Approximately 40–90% absorbed following IM administration.116 118 Approximately 55% (range: 15–95%) absorbed following sublingual administration.118 119 Following oral administration, buprenorphine undergoes extensive first-pass metabolism in the GI mucosa and liver.122 131 Absolute bioavailability of about 15% following transdermal administration.213

Following IV administration of a single dose, mean peak plasma concentrations4 116 occurred within 2 minutes.4 116 118 Following IM administration of a dose 3 hours after an initial IV dose, mean peak plasma concentrations occurred within 2–5 minutes.4 9 116 118 Peak plasma concentrations occur about 1.5–1.7 hours after sublingual administration as a dissolving strip.214

Approximately 10 minutes after administration, plasma buprenorphine concentrations are similar following IV or IM injection.4 9 116 118

Pharmacokinetics of the sublingually dissolving strips and sublingual tablets are similar, but not all doses and dose combinations are bioequivalent.214 Bioavailability of sublingually dissolving films is potentially greater than that of sublingual tablets.214

Buprenorphine is quantifiable in plasma about 17 hours after application of a 10-mcg/hour transdermal system; steady-state concentrations attained by day 3 of treatment.213

Application of heat to a 10-mcg/hour transdermal system increased blood buprenorphine concentrations by 26–55%; concentrations returned to normal within 5 hours after removal of heat source.213

Onset

Following parenteral administration of single doses in postoperative patients,1 2 3 9 16 21 42 48 71 72 80 82 96 97 98 121 123 124 127 128 the onset of analgesia usually occurs within 10–30 minutes.1 2 3 9 16 17 96 123 124 128 185 Peak analgesia usually occurs within 60 minutes1 71 80 96 128 185 but may occur within 15 minutes in some patients.71

Duration

Analgesia generally persists for 6 hours following single IM or IV doses,1 2 3 16 21 71 72 82 96 121 124 185 but has persisted for 4–10 hours following single IM doses1 2 3 16 21 71 72 82 96 97 98 123 124 127 184 and 2–24 hours following single IV doses.42 48 71 80 121 152

Distribution

Extent

Rapidly (within several minutes) distributes into CSF following IV administration;3 63 117 120 CSF concentrations appear to be approximately 15–25% of concurrent plasma concentrations.117 213

Crosses the placenta in rats;71 not known whether buprenorphine crosses the placenta in humans.3

Distributes into human milk.1 2 3 4 213

Plasma Protein Binding

Approximately 96%4 15 71 213 214 (mainly α- and β-globulins;4 71 213 214 does not appear to bind substantially to albumin).4

Elimination

Metabolism

Almost completely metabolized in the liver,1 2 3 21 116 principally by N-dealkylation (mediated by CYP3A4)202 213 214 to form norbuprenorphine,3 4 71 113 114 115 118 122 125 202 213 214 which may have weak analgesic activity.122 213 Buprenorphine and norbuprenorphine undergo conjugation with glucuronic acid3 71 118 122 125 213 214 (mediated mainly by UGT 1A1 and 2B7 and by UGT 1A3, respectively).213

Elimination Route

Eliminated principally in feces (about 69%)3 4 113 202 214 via biliary excretion4 113 and also in urine (about 30%)114 122 170 202 214 as unchanged drug and metabolites.

Half-life

Biphasic or triphasic;114 116 118 terminal elimination half-life is approximately 2.2 hours (range: 1.2–7.2 hours) following IV administration,1 2 4 21 40 118 119 and mean plasma elimination half-life is 37 or 24–42 hours following sublingual administration of tablets or dissolving strips, respectively.202 214 Following transdermal administration, the terminal elimination half-life is approximately 26 hours.213

Limited data suggest clearance may be higher in children than in adults.1

Special Populations

Renal impairment does not substantially alter buprenorphine pharmacokinetics, although concentrations of norbuprenorphine and buprenorphine-3-glucuronide may be increased.214 218

Hemodialysis does not substantially alter plasma concentrations of transdermally administered buprenorphine.213

In a limited number of patients with mild or moderate hepatic impairment (Child-Pugh class A or B), buprenorphine exposure was similar to that in patients with normal hepatic function; effect of severe hepatic impairment (Child-Pugh class C) on pharmacokinetics not determined.213

In healthy geriatric adults, pharmacokinetic profile of transdermal buprenorphine generally is similar to that in younger adults.213

Stability

Storage

Sublingual

Sublingually Dissolving Strips

25°C (may be exposed to 15–30°C).214

Sublingual Tablets

25°C (may be exposed to 15–30°C).202

Parenteral

Injection

<40°C; protect from prolonged exposure to light.1

Topical

Transdermal System

25°C (may be exposed to 15–30°C).213

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Drug Compatibility
Admixture CompatibilityHID

Compatible

Bupivacaine HCl

Glycopyrrolate with haloperidol lactate

Incompatible

Furosemide

Floxacillin sodium

Y-site CompatibilityHID

Compatible

Allopurinol sodium

Amifostine

Aztreonam

Cefepime HCl

Cisatracurium besylate

Cladribine

Docetaxel

Etoposide phosphate

Filgrastim

Gemcitabine HCl

Granisetron HCl

Linezolid

Melphalan HCl

Oxaliplatin

Pemetrexed disodium

Piperacillin sodium–tazobactam sodium

Propofol

Remifentanil HCl

Teniposide

Thiotepa

Vinorelbine tartrate

Incompatible

Amphotericin B cholesteryl sulfate complex

Doxorubicin HCl liposome injection

Actions

  • Exhibits analgesic1 2 71 112 129 and opiate antagonist activities.1 2 4 8 71 74 86 111 112 148 Acts as a partial agonist at μ-opiate receptors8 10 112 147 160 173 175 178 189 194 202 213 214 in the CNS8 160 and peripheral tissues,8 an antagonist at κ-opiate receptors, and an agonist at δ-opiate receptors.202 213 214

  • Binds slowly with4 10 169 and dissociates slowly from the μ-receptor;1 2 3 4 8 10 169 178 179 may account for the prolonged duration of analgesia1 2 3 4 157 179 and possibly in part for the limited physical dependence potential observed.1 2 3 4 8 10 157 178

  • Single sublingual doses of buprenorphine produce physiologic and subjective effects that are similar to those produced by equivalent doses of the buprenorphine/naloxone fixed combination.202

  • Produces dose-related analgesia;4 67 118 128 129 appears to result from a high affinity of buprenorphine for μ- and possibly κ-opiate receptors in the CNS.1 2 8 10 112 117 147 160 173 176 178

  • Opiate agonist and antagonist activities appear to be dose related.160 163 165 At doses of ≤1 mg sub-Q, buprenorphine has a potent analgesic effect;71 160 163 165 at doses >1 mg sub-Q, the opiate agonist activity decreases and the opiate antagonist activity predominates.71 160 163 165 Following IM administration, opiate antagonist activity occurs principally at doses >0.8 mg.1 2 71 160 163

  • Usual parenteral doses potentially may depress respiration to the same degree as 10 mg of parenteral morphine sulfate;1 2 4 71 however, onset of buprenorphine-induced respiration depression is slower than that induced by morphine and appears to be more prolonged.71

Advice to Patients

  • Provide manufacturer’s patient information (medication guide) to the patient each time buprenorphine transdermal system or buprenorphine/naloxone sublingually dissolving strips are dispensed.213 214 215 216 (See REMS: Butrans and REMS: Suboxone, under Dosage and Administration.)

  • Importance of instructing patients in proper techniques for administering the sublingually dissolving strips and transdermal systems.213 214

  • Importance of informing patients that buprenorphine is a drug of abuse.213 214 Instruct patients to keep in a secure place to prevent theft or misuse.213 214 Risk of severe or fatal respiratory depression if misused or used in individuals for whom the drug was not prescribed.213 214

  • Importance of warning patients and/or their caregivers to keep buprenorphine preparations out of the reach of children and pets and to safely dispose of used or unneeded dosage units.213 214

  • Importance of warning patients receiving buprenorphine for the treatment of opiate dependence of the potential danger (e.g., serious overdosage, death) associated with concomitant self-administration of benzodiazepines or other CNS depressants.202 214 (See Cautions.) Importance of not drinking alcohol and of avoiding sleep aids and CNS depressants unless prescribed.213

  • Importance of patients or caregivers informing clinicians in the event of emergency that the patient is receiving buprenorphine or buprenorphine/naloxone and is dependent on opiates.202 214

  • Importance of taking the drug exactly as prescribed; do not exceed the recommended dosage.1 2 213 214

  • Potential for buprenorphine to impair mental alertness or physical coordination; avoid driving or operating machinery until effects on individual are known.1 202 213 214

  • Risk of withdrawal symptoms following abrupt discontinance; importance of consulting clinician prior to discontinuing the drug.213 214

  • Risk of orthostatic hypotension in ambulatory patients.202 214

  • Importance of informing clinicians if patient has a history of serious skin reactions to adhesives prior to initiating therapy with transdermal buprenorphine.213 Importance of promptly contacting a clinician if symptoms of a serious allergic reaction occur.213 220

  • Patients receiving transdermal buprenorphine should avoid exposing application site to external heat sources (e.g., heating pads, electric blankets, heat lamps, saunas, hot tubs, heated water bed) because of risk of increased buprenorphine exposure, overdosage, and death.213

  • Importance of informing clinician of any breakthrough pain or adverse effects that occur during analgesic therapy, so that therapy may be adjusted based on individual patient requirements.213

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and alcohol consumption, as well as any concomitant illnesses.1 202 213 214

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 202 213 214

  • Importance of advising patients of other important precautionary information.1 202 213 214 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule III (C-III) drug.202 206 213 214

Under the Drug Addiction Treatment Act (DATA) of 2000, use of buprenorphine hydrochloride and buprenorphine hydrochloride in fixed combination with naloxone hydrochloride for the treatment of opiate dependence is restricted to physicians who meet certain qualifying requirements and have notified the Secretary of the US Department of Health and Human Services of their intention to prescribe these preparations for this indication.202 (See Restricted Distribution Program under Dosage and Administration.)

Buprenorphine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Topical

Transdermal System

5 mcg/hour (5 mg/6.25 cm2)

Butrans ( C-III)

Purdue Pharma

10 mcg/hour (10 mg/12.5 cm2)

Butrans ( C-III)

Purdue Pharma

20 mcg/hour (20 mg/25 cm2)

Butrans ( C-III)

Purdue Pharma

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Buprenorphine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection

0.3 mg (of buprenorphine) per mL*

Buprenex ( C-III)

Reckitt Benckiser

Buprenorphine Hydrochloride Injection ( C-III)

Sublingual

Tablets

2 mg (of buprenorphine)

Subutex ( C-III)

Reckitt Benckiser

8 mg (of buprenorphine)

Subutex ( C-III)

Reckitt Benckiser

Buprenorphine Hydrochloride Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Sublingual

Strips, sublingually dissolving

2 mg (of buprenorphine) with Naloxone Hydrochloride 0.5 mg (of naloxone)

Suboxone ( C-III)

Reckitt Benckiser

8 mg (of buprenorphine) with Naloxone Hydrochloride 2 mg (of naloxone)

Suboxone ( C-III)

Reckitt Benckiser

Sublingual Tablets

2 mg (of buprenorphine) with Naloxone Hydrochloride 0.5 mg (of naloxone)*

8 mg (of buprenorphine) with Naloxone Hydrochloride 2 mg (of naloxone)*

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Buprenorphine HCl 2MG Sublingual Tablets (ROXANE): 30/$75.99 or 90/$199.97

Buprenorphine HCl 8MG Sublingual Tablets (ROXANE): 30/$99.99 or 60/$195.00

Subutex 2MG Sublingual Tablets (RECKITT BENCKISER): 30/$193.99 or 90/$553.97

Subutex 8MG Sublingual Tablets (RECKITT BENCKISER): 30/$357.01 or 90/$1,039.00

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 2, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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