Buprenorphine

Buprenorphine is the generic form of Subutex, a prescription drug used to treat dependence on opioid painkillers such as oxycodone (OxyContin). It's also prescribed in lower dosages to treat pain.

If you are recovering from surgery, your doctor may start you on buprenorphine to treat your post-operative pain. The drug works on your nervous system and in your brain to reduce the way you feel pain.

Buprenorphine is also used in the treatment of some narcotic drug addictions. When it is used for this purpose, buprenorphine is often combined with naloxone, an ingredient that counters the effects of an overdose of buprenorphine. This combination drug, called Suboxone, is normally given in the privacy and safety of a doctor's office.

Buprenorphine is a narcotic and a controlled substance. If your doctor prescribes buprenorphine, it is only for your use. Do not share buprenorphine with anyone else, even if their symptoms seem to be the same as yours.

Buprenorphine Warnings

Like other narcotic medicines, buprenorphine can slow your breathing. Using buprenorphine improperly will increase your risk of serious side effects and could cause death. You should tell your health care provider if the medicine seems to no longer relieve your pain.

If you doctors is treating you with buprenorphine, you should not take any other narcotic pain medications or sedatives, tranquilizers, sleeping pills, or other medicines that can make you sleepy or slow your breathing. Dangerous side effects may result.

Do not drink alcohol with buprenorphine. Buprenorphine can increase the effects of alcohol, which could be dangerous.

Buprenorphine may be habit-forming.

You should let your doctor know if you have liver or kidney problems, or any problems breathing such as chronic obstructive pulmonary disease (COPD), before taking buprenorphine.

Do not take buprenorphine for longer than you have been advised by your doctor. This is because repeated use may lead to dependency and may cause you to have withdrawal symptoms once you stop.

Pregnancy and Buprenorphine

If you are pregnant or trying to get pregnant you should not use buprenorphine. You should also let your doctor know if you are breastfeeding.

Buprenorphine is passed through a mother's breast milk and could be dangerous for a nursing baby.

Manifestations: Clinical experience with Buprenex (buprenorphine) overdosage has been insufficient to define the signs of this condition at this time. Although the antagonist activity of buprenorphine may become manifest at doses somewhat above the recommended therapeutic range, doses in the recommended therapeutic range may produce clinically significant respiratory depression in certain circumstances. (See WARNINGS.)

Treatment: The respiratory and cardiac status of the patients should be monitored carefully. Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. Doxapram, a respiratory stimulant, may be used.

NALOXONE MAY NOT BE EFFECTIVE IN REVERSING THE RESPIRATORY DEPRESSION PRODUCED BY BUPRENEX (buprenorphine) . THEREFORE, AS WITH OTHER POTENT OPIOIDS, THE PRIMARY MANAGEMENT OF OVERDOSE SHOULD BE THE REESTABLISHMENT OF ADEQUATE VENTILATION WITH MECHANICAL ASSISTANCE OF RESPIRATION, IF REQUIRED.

The effects of Buprenex (buprenorphine) , particularly drowsiness, may be potentiated by other centrally acting agents such as alcohol or benzodiazepines. It is particularly important that in these circumstances patients must not drive or operate machinery. Buprenex (buprenorphine) has some pharmacologic effects similar to morphine which in susceptible patients may lead to self-administration of the drug when pain no longer exists. Patients must not exceed the dosage of Buprenex (buprenorphine) prescribed by their physician. Patients should be urged to consult their physician if other prescription medications are currently being used or are prescribed for future use.

SUBUTEX sublingual tablet is indicated for the treatment of opioid dependence and is preferred for induction. SUBUTEX sublingual tablet should be used as part of a complete treatment plan to include counseling and psychosocial support.

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

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Some medicines may cause serious or life-threatening medical problems when taken with buprenorphine. Sometimes, the doses of certain medicines and buprenorphine need to be changed if used together.

Especially tell your doctor if you take:

• other pain medicines
• antidepressant medicines
• sleeping pills
• antihistamines
• anti-anxiety medicines
• muscle relaxants
• anti-nausea medicines
• sedative or tranquilizer medicines (medicines that make you sleepy)
• a medicine for abnormal heartbeats

You should not take buprenorphine if you already take a monoamine oxidase inhibitor medicine (MAOI) or within 14 days after you stop taking an MAOI medicine.

Ask your doctor if you are not sure if your medicine is one listed above.

Know the medicines you take. Keep a list of your medicines to show your doctor and pharmacist. Your doctor will tell you if it is safe to take other medicines while you are using buprenorphine.

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of buprenorphine, grapefruit and grapefruit juice may interact with buprenorphine and lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor.

Oral:

• Always take buprenorphine sublingual (under the tongue) tablets exactly as your doctor tells you. Your doctor may change your dose after seeing how it affects you. Do not change your dose unless your doctor tells you to change it.
• Do not take buprenorphine sublingual tablets more often than prescribed by your doctor. Ask your doctor for instructions on the right way to take buprenorphine sublingual tablets.
• Follow the same instructions every time you take a dose of buprenorphine sublingual tablets.
• Put the tablets under your tongue. Let them dissolve completely.
• While buprenorphine sublingual tablets are dissolving, do not chew or swallow the tablet because the medicine will not work as well.
• Talking while the tablet is dissolving can affect how well the medicine in buprenorphine sublingual tablets is absorbed.
• If you miss a dose of buprenorphine sublingual tablets, take your medicine when you remember. If it is almost time for your next dose, skip the missed dose and take the next dose at your regular time. Do not take 2 doses at the same time unless your doctor tells you to. If you are not sure about your dosing, call your doctor.
• Do not stop taking buprenorphine sublingual tablets suddenly. You could become sick and have withdrawal symptoms because your body has become used to the medicine. Physical dependence is not the same as drug addiction. Your doctor can tell you more about the differences between physical dependence and drug addiction. To have fewer withdrawal symptoms, ask your doctor how to stop using buprenorphine sublingual tablets the right way.

Topical:

• Before applying the buprenorphine patch:
  • Do not use soap, alcohol, lotions, oils, or other products to remove any leftover medicine gel from a patch because this may cause more buprenorphine to pass through the skin.
  • Each patch is sealed in its own protective pouch. Do not remove a patch from the pouch until you are ready to use it.
  • Do not use a patch if the seal on the protective pouch is broken or if the patch is cut, damaged or changed in any way.
  • Buprenorphine patches are available in different strengths and patch sizes. Make sure you have the right strength patch that has been prescribed for you
• Where to apply buprenorphine patches:
  • Buprenorphine patches should be applied to the upper outer arm, upper chest, upper back, or the side of the chest. These 4 sites (located on both sides of the body) provide 8 possible application sites. You should change the skin site where you apply a a patch each week, making sure that at least 3 weeks (21 days) pass before you re-use the same skin site.
  • Apply the patch to a hairless or nearly hairless skin site. If needed, you can clip the hair at the skin site. Do not shave the area. The skin site should not be irritated. Use only water to clean the application site. You should not use soaps, alcohol, oils, lotions, or abrasive devices. Allow the skin to dry before you apply the patch.
  • The skin site should be free of cuts and irritation (rashes, swelling, redness, or other skin problems).
• When to apply the patch:
  • When you apply a new patch, write down the date and time that the patch is applied. Use this to remember when the patch should be removed.
  • Change the patch at the same time of day, one week (exactly 7 days) after you apply it.
  • After removing and disposing of the patch, write down the time it was removed and how it was disposed.
• How to apply the patch:
  • If you are wearing a patch, remember to remove it before applying a new one.
  • Each patch is sealed in its own protective pouch.
  • Use scissors to cut open the pouch along the dotted line and remove the patch. Do not remove the patch from the pouch until you are ready to use it. Do not use patches that have been cut or damaged in any way.
  • Hold the patch with the protective liner facing you.
  • Gently bend the patch along the faint line and slowly peel the larger portion of the liner, which covers the sticky surface of the patch.
  • Do not touch the sticky side of the patch with your fingers.
  • Using the smaller portion of the protective liner as a handle, apply the sticky side of the patch to one of the 8 body locations described above
  • While still holding the sticky side down, gently fold back the smaller portion of the patch. Grasp an edge of the remaining protective liner and slowly peel it off.
  • Press the entire patch firmly into place with the palm (See Figure 7) of your hand over the patch, for about 15 seconds. Do not rub the patch.
  • Make sure that the patch firmly sticks to the skin.
  • Go over the edges with your fingers to assure good contact around the patch.
  • Always wash your hands after applying or handling a patch.
  • After the patch is applied, write down the date and time that the patch is applied. Use this to remember when the patch should be removed.
• If the patch falls off right away after applying, throw it away and put a new one on at a different skin site.
• If a patch falls off, do not touch the sticky side of the patch with your fingers. A new patch should be applied to a different site. Patches that fall off should not be re-applied. They must be thrown away correctly.
• If the edges of the patch start to loosen:
  • Apply first aid tape only to the edges of the patch.
  • If problems with the patch not sticking continue, cover the patch with special see-through adhesive dressings (for example Bioclusive or Tegaderm).
    • Remove the backing from the transparent adhesive dressing and place it carefully and completely over the patch, smoothing it over the patch and your skin.
• Never cover a patch with any other bandage or tape. It should only be covered with a special see-through adhesive dressing. Talk to your doctor or pharmacist about the kinds of dressing that should be used.
• If your patch falls off later, but before 1 week (7 days) of use, throw it away properly and apply a new patch at a different skin site. Be sure to let your doctor know that this has happened. Do not replace the new patch until 1 week (7 days) after you put it on (or as directed by your doctor).
• Disposing a buprenorphine patch:
  • Patches must be disposed of by flushing them down the toilet or using the Patch-Disposal Unit.
  • To flush your patch down the toilet:
    • Remove your patch, fold the sticky sides of a used patch together and flush it down the toilet right away.
  • When disposing of unused patches you no longer need, remove the leftover patches from their protective pouch and remove the protective liner. Fold the patches in half with the sticky sides together, and flush the patches down the toilet.
  • Do not flush the pouch or the protective liner down the toilet. These items can be thrown away in the trash.
  • If you prefer not to flush the used patch down the toilet, you must use the Patch-Disposal Unit provided to you to discard the patch.
  • Never put used patches in the trash without first sealing them in the Patch-Disposal Unit.
  • To dispose of patches in household trash using the Patch-Disposal Unit:
    • Remove your patch and follow the directions printed on the Patch-Disposal Unit (See Figure 9) or see complete instructions below. Use one Patch-Disposal Unit for each patch.
    1. Peel back the disposal unit liner to show the sticky surface.
    2. Place the sticky side of the used or unused patch to the indicated area on the disposal unit.
    3. Close the disposal unit by folding the sticky sides together, Press firmly and smoothly over the entire disposal unit so that the patch is sealed within.
    4. The closed disposal unit, with the patch sealed inside may be thrown away in the trash.
    • Do not put unused patches in household trash without first sealing them in the Patch-Disposal Unit.
    • Always remove the leftover patches from their protective pouch and remove the protective liner. The pouch and liner can be disposed of separately in the trash and should not be sealed in the Patch-Disposal Unit.

Implantable Rod (Probuphine):

This medication is available as an implant that is surgically inserted under the skin on the inside of the upper arm. It consists of four one-inch rods. Once inserted, it will provide a constant low dose of buprenorphine. If after six months treatment is still warranted, it may be inserted in the opposite arm for an additional six months.

Injectable:

• This medication is additionally available in an injectable form to be given directly into a vein (IV) or muscle (IM) by a healthcare professional.

The buprenorphine dose your doctor recommends will be based on the following:

• other medical conditions you have
• other medications you are taking
• how you respond to this medication
• your weight
• your age

Oral:

The recommended dose range with buprenorphine sublingual tablets is 4 mg to 24 mg per day.

• If you have not been taking other opioids, the standard starting dosage is one buprenorphine patch 5 mcg/hour patch applied once a week. If your pain is not adequately controlled after three days, your healthcare provider may increase your dosage. The increase will be based on the amount of short-acting pain medication you needed, or how much "breakthrough" pain you experienced, in the two to three days after starting this medication.
• The maximum buprenorphine patch dose is one 20-mcg/hour patch applied once a week. Higher doses increase the risk for dangerous changes in the heart rhythm (QTc interval prolongation).

Injectable:

• The usual dosage for buprenorphine injectable will vary according to age, severity of the condition, and other factors.

WARNING: IMPORTANCE OF PROPER PATIENT SELECTION, POTENTIAL FOR ABUSE, AND LIMITATIONS OF USE

Proper Patient Selection:

Buprenorphine is a transdermal formulation of buprenorphine indicated for the management of moderate to severe chronic pain in patients requiring a continuous, around-the-clock opioid analgesic for an extended period of time. 

Potential for Abuse:

Buprenorphine is a mu opioid partial agonist and a Schedule III controlled substance. Buprenorphine can be abused in a manner similar to other opioid agonists, legal or illicit. Consider the abuse potential when prescribing or dispensing buprenorphine in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. 

Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Assess patients for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. Routinely monitor all patients receiving opioids for signs of misuse, abuse, and addiction. 

Limitations of Use:

Do not exceed a dose of one 20 mcg/hour buprenorphine system due to the risk of QTc interval prolongation. 

Avoid exposing the buprenorphine application site and surrounding area to direct external heat sources. Temperature-dependent increases in buprenorphine release from the system may result in overdose and death.

Buprenorphine exerts its analgesic effect via high-affinity binding to mu opiate receptors in the CNS; displays partial mu agonist and weak kappa antagonist activity. Due to it being a partial mu agonist, its analgesic effects plateau at higher doses and it then behaves like an antagonist.

Absorption

IM, SubQ: 30% to 40%. Application of a heating pad onto the transdermal system may increase blood concentrations of buprenorphine 26% to 55%. Ingestion of liquids decreases systemic exposure to buprenorphine from buccal film by 23% to 37%.

Distribution

CSF concentrations are ~15% to 25% of plasma concentrations

Vd:

Premature neonates (GA: 27 to 32 weeks): 6.2 ± 2.1 L/kg (Barrett 1993)

Children 4 to 7 years: 3.2 ± 2 L/kg (Olkkola 1989)

Adults: 97 to 187 L/kg

Metabolism

Primarily hepatic via N-dealkylation by CYP3A4 to norbuprenorphine (active metabolite), and to a lesser extent via glucuronidation by UGT1A1 and 2B7 to buprenorphine 3-O-glucuronide; the major metabolite, norbuprenorphine, also undergoes glucuronidation via UGT1A3; extensive first-pass effect

Excretion

Feces (~70%; 33% as unchanged drug; 5% as conjugated drug; 21% as norbuprenorphine; and 2% as conjugated norbuprenorphine); urine (27% to 30%; 1% as unchanged drug; 9.4% as conjugated drug; 2.7% as norbuprenorphine; and 11% as conjugated norbuprenorphine)

Clearance: Related to hepatic blood flow

Premature neonates (GA: 27 to 32 weeks): 0.23 ± 0.07 L/hour/kg (Barrett 1993)

Children 4 to 7 years: 3.6 ± 1.1 L/hour/kg (Olkkola 1989)

Adults: 0.78 to 1.32 L/hour/kg

Opioid dependence:

Subdermal implant: Maintenance treatment of opioid dependence in patients who have achieved and sustained prolonged clinical stability on low to moderate doses (≤8 mg/day) of a transmucosal buprenorphine-containing product for 3 months or longer with no need for supplemental dosing or adjustments

Sublingual tablet: Treatment of opioid dependence

Pain management:

Buccal film, transdermal patch: Management of pain severe enough to require around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate

Injection: Management of pain severe enough to require an opioid analgesic and for which treatments are inadequate

Limitations of use: Reserve buprenorphine for use in patients for whom alternative treatment options (eg, nonopioid analgesics, opioid combination products, immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Buprenorphine buccal film and transdermal patch are not indicated as an as needed analgesic.

Your pharmacist has information about buprenorphine written for health professionals that you may read.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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