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{{drugbox
{{DrugProjectFormSinglePage
| IUPAC_name = (2S)-2-[(-)-(5R,6R,7R,14S)-<BR>9α-cyclopropylmethyl-4,5-epoxy-<BR>6,14-ethanomorphinan-7-yl]-3-hydroxy-<BR>6-methoxy-3,3-dimethylbutan-2-ol
|authorTag={{chetan}}
| image = Buprenorphine structure.jpg
|genericName=Buprenorphine
| CAS_number = 52485-79-7
|aOrAn=an
| ATC_prefix = N02
|drugClass=[[opioid]] [[analgesic]]
| ATC_suffix = AE01
|indicationType=treatment
| ATC_supplemental = {{ATC|N07|BC01}}
|indication=chronic, severe pain in patients requiring long-term daily around-the-clock [[opioid]] [[analgesic]]
| PubChem = 40400
|adverseReactions=application site [[erythema]], application site [[irritation]], application site [[rash]], [[pruritus]], [[constipation]], [[nausea]], [[vomiting]], [[xerostomia]], [[dizziness]], [[headache]], and [[somnolence]]
| DrugBank = APRD00670
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
| C=29|H=41|N=1|O=4
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
| molecular_weight = 467.64 g/mol
|fdaLIADAdult=* Prior to initiating, discontinue all other around-the-clock opioid drugs.
| bioavailability = 31% (sublingual, from [[ethanol]]ic solution)<br> ~50-60% (sublingual, high-dose tablet)<br> ~50% (transdermal)
* Pain, chronic (severe), in patients requiring long-term daily around-the-clock opioid analgesic: individualize dose; initial dose selection must take into account patient's prior analgesic treatment experience and risk factors for addiction, abuse, and misuse; use of 10, 15, and 20 mcg/hr strengths is restricted to opioid-tolerant patients only
| protein_bound = 96%
* Pain, chronic (severe), in patients requiring long-term daily around-the-clock opioid analgesic: (as first opioid) initial, 5 mcg/hr transdermally; titrate based on analgesic requirement and tolerance at a minimum interval of every 72 hours; replace patch every 7 days; max 20 mcg/hr.
| metabolism = [[Liver|hepatic]]
* Pain, chronic (severe), in patients requiring long-term daily around-the-clock opioid analgesic: (prior total daily dose of opioids less than 30 mg of oral morphine equivalents per day) discontinue around-the-clock opioid drugs; initiate 5 mcg/hr transdermally at next dosing interval; replace patch every 7 days; titrate based on analgesic requirement and tolerance at a minimum interval of every 72 hours; max 20 mcg/hr.
| elimination_half-life = 20-70, mean 37 hours
* Pain, chronic (severe), in patients requiring long-term daily around-the-clock opioid analgesic: (prior total daily dose of opioids between 30 and 80 mg of oral morphine equivalents per day) taper previous around-the-clock opioids for up to 7 days to no more than 30 mg of oral morphine equivalents per day; then discontinue around-the-clock opioid drugs and initiate 10 mcg/hr TRANSDERMALLY at next dosing interval; replace patch every 7 days; titrate based on analgesic requirement and tolerance at a minimum interval of every 72 hours; max 20 mcg/hr; short-acting analgesics may be used as needed until efficacy is attained
| pregnancy_category = C (USA)
* Pain, chronic (severe), in patients requiring long-term daily around-the-clock opioid analgesic: (total daily dose of opioids greater than 80 mg of oral morphine equivalents per day) consider an alternative analgesic as buprenorphine 20 mcg/hr may not provide adequate analgesia
| legal_status = Schedule III (USA)<br>Schedule 8 (Aust)<br> Schedule III (UK)<br> Cat. A{Singapore}
|offLabelAdultGuideSupport=There is limited information about <i>Off-Label Guideline-Supported Use</i> of Buprenorphine in adult patients.
| routes_of_administration = sublingual, [[intramuscular|IM]], [[intravenous|IV]],[[transdermal]]
|offLabelAdultNoGuideSupport=There is limited information about <i>Off-Label Non–Guideline-Supported Use</i> of Buprenorphine in adult patients.
| excretion = [[bile|biliary]] and [[renal]]
|fdaLIADPed=There is limited information about safety and efficacy of buprenorphine transdermal have not been established in patients younger than 18 years.
}}
|offLabelPedGuideSupport=There is limited information about <i>Off-Label Guideline-Supported Use</i> of Buprenorphine in pediatric patients.
{{SI}}
|offLabelPedNoGuideSupport=There is limited information about <i>Off-Label Non–Guideline-Supported Use</i> of Buprenorphine in pediatric patients.
{{CMG}}
|contraindications=* Buprenorphine sublingual tablet should not be administered to patients who have been shown to be hypersensitive to buprenorphine or naloxone as serious adverse reactions, including [[anaphylactic shock]], have been reported.
|warnings======Abuse Potential=====
* Buprenorphine can be abused in a manner similar to other opioids, legal or illicit. Prescribe and dispense buprenorphine with appropriate precautions to minimize risk of misuse, abuse, or diversion, and ensure appropriate protection from theft, including in the home. Clinical monitoring appropriate to the patient's level of stability is essential. Multiple refills should not be prescribed early in treatment or without appropriate patient follow-up visits.
=====Respiratory Depression=====
* Buprenorphine, particularly when taken by the IV route, in combination with benzodiazepines or other CNS depressants (including [[alcohol]]), has been associated with significant respiratory depression and death. Many, but not all, post-marketing reports regarding coma and death associated with the concomitant use of [[buprenorphine]] and [[benzodiazepines]] involved misuse by self-injection. Deaths have also been reported in association with concomitant administration of buprenorphine with other depressants such as alcohol or other CNS depressant drugs. Patients should be warned of the potential danger of self-administration of benzodiazepines or other depressants while under treatment with buprenorphine sublingual tablets.
* In the case of overdose, the primary management should be the re-establishment of adequate ventilation with mechanical assistance of respiration, if required. Naloxone may be of value for the management of buprenorphine overdose. Higher than normal doses and repeated administration may be necessary.
* Buprenorphine sublingual tablets should be used with caution in patients with compromised respiratory function (e.g., [[chronic obstructive pulmonary disease]], [[cor pulmonale]], decreased respiratory reserve, [[hypoxia]], [[hypercapnia]], or pre-existing respiratory depression).
 
=====CNS Depression=====
* Patients receiving buprenorphine in the presence of [[opioid analgesics]], [[general anesthetics]], [[benzodiazepines]], [[phenothiazines]], other tranquilizers, [[sedative]]/[[hypnotics]], or other [[CNS depressants]] (including [[alcohol]]) may exhibit increased CNS depression. Consider dose reduction of CNS depressants, buprenorphine sublingual tablets, or both in situations of concomitant prescription.
 
=====Unintentional Pediatric Exposure=====
* Buprenorphine can cause fatal respiratory depression in children who are accidentally exposed to it. Store buprenorphine containing medications safely out of the sight and reach of children and destroy any unused medication appropriately.
 
=====Dependence=====
* Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation or rapid taper. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset. Buprenorphine can be abused in a manner similar to other opioids. This should be considered when prescribing or dispensing buprenorphine in situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion.
 
=====Hepatitis, Hepatic Events=====
* Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine in clinical trials and through post-marketing adverse event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in [[hepatic transaminases]] to case reports of death, [[hepatic failure]], [[hepatic necrosis]], [[hepatorenal syndrome]], and [[hepatic encephalopathy]]. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with [[hepatitis B]] or [[hepatitis C]] virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injecting drug use may have played a causative or contributory role. In other cases, insufficient data were available to determine the etiology of the abnormality. Withdrawal of buprenorphine has resulted in amelioration of acute hepatitis in some cases; however, in other cases no dose reduction was necessary. The possibility exists that buprenorphine had a causative or contributory role in the development of the hepatic abnormality in some cases. Liver function tests, prior to initiation of treatment is recommended to establish a baseline. Periodic monitoring of liver function during treatment is also recommended. A biological and etiological evaluation is recommended when a hepatic event is suspected. Depending on the case, buprenorphine sublingual tablet may need to be carefully discontinued to prevent withdrawal signs and symptoms and a return by the patient to illicit drug use, and strict monitoring of the patient should be initiated.
 
=====Allergic Reactions=====
* Cases of hypersensitivity to buprenorphine and naloxone containing products have been reported both in clinical trials and in the post-marketing experience. cases of [[bronchospasm]], [[angioneurotic edema]], and [[anaphylactic shock]] have been reported. the most common signs and symptoms include [[rashes]], [[hives]], and [[pruritus]]. a history of hypersensitivity to buprenorphine or [[naloxone]] is a contraindication to the use of buprenorphine sublingual tablet.
 
=====Precipitation of Opioid Withdrawal Signs and Symptoms=====
* Because it contains naloxone, buprenorphine msublingual tablet is likely to produce withdrawal signs and symptoms if misused parenterally by individuals dependent on full opioid agonists such as heroin, morphine, or methadone. Because of the partial agonist properties of buprenorphine, buprenorphine sublingual tablet may precipitate opioid withdrawal signs and symptoms in such persons if administered sublingually before the agonist effects of the opioid have subsided.
 
=====Neonatal Abstinence Syndrome=====
* Neonatal abstinence syndrome has been reported in the infants of women treated with buprenorphine during pregnancy. From post-marketing reports, the time to onset of neonatal withdrawal signs ranged from Day 1 to Day 8 of life with most cases occurring on Day 1. Adverse events associated with the neonatal abstinence syndrome included [[hypertonia]], [[neonatal tremor]], [[neonatal agitation]], and [[myoclonus]], and there have been reports of [[convulsions]], [[apnea]], [[respiratory depression]], and [[bradycardia]].
 
=====Use in Opioid Naïve Patients=====
* There have been reported deaths of opioid naive individuals who received a 2 mg dose of buprenorphine as a sublingual tablet for analgesia. buprenorphine sublingual tablet is not appropriate as an analgesic.
 
=====Impairment of Ability to Drive or Operate Machinery=====
* Buprenorphine sublingual tablet may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery, especially during treatment induction and dose adjustment. Patients should be cautioned about driving or operating hazardous machinery until they are reasonably certain that buprenorphine sublingual tablet therapy does not adversely affect his or her ability to engage in such activities.
 
=====Orthostatic Hypotension=====
* Like other opioids, buprenorphine sublingual tablets may produce [[orthostatic hypotension]] in ambulatory patients.
 
=====Elevation of Cerebrospinal Fluid Pressure=====
* Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal pressure may be increased. Buprenorphine can produce [[miosis]] and changes in the level of consciousness that may interfere with patient evaluation.
 
=====Elevation of Intracholedochal Pressure=====
* Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract.
 
=====Effects in Acute Abdominal Conditions=====
* As with other opioids, buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.
 
=====General Precautions=====
* Buprenorphine sublingual tablet should be administered with caution in debilitated patients and those with [[myxedema]] or [[hypothyroidism]], [[adrenal cortical insufficiency]] (e.g., [[Addison's disease]]); [[CNS depression]] or [[coma]]; [[toxic psychoses]]; [[prostatic hypertrophy]] or [[urethral stricture]]; [[acute alcoholism]]; [[delirium tremens]]; or [[kyphoscoliosis]].
|clinicalTrials=* Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
 
=====Clinical Trials Experience=====
:* The safety of [[buprenorphine]]/naloxone was evaluated in 497 opioid-dependent subjects. The prospective evaluation of buprenorphine/naloxone was supported by clinical trials using buprenorphine tablets without naloxone and other trials using buprenorphine sublingual solutions. In total, safety data were available from 3214 opioid-dependent subjects exposed to buprenorphine at doses in the range used in treatment of opioid addiction.
 
[[File:Buprenorphine adverse efects.png|thumb|none|400px|left|This image is provided by the National Library of Medicine.]]
|postmarketing=* The following adverse reactions have been identified during post-approval use of buprenorphine and naloxone sublingual tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate a causal relationship to drug exposure.
 
* The most frequently reported post-marketing adverse event not observed in clinical trials was [[peripheral edema]].
|drugInteractions======Cytochrome P-450 3A4 (CYP3A4) Inhibitors and Inducers=====
* Buprenorphine is metabolized to norbuprenorphine primarily by cytochrome CYP3A4; therefore, potential interactions may occur when buprenorphine sublingual tablets is given concurrently with agents that affect CYP3A4 activity. The concomitant use of buprenorphine sublingual tablet with CYP3A4 inhibitors (e.g., [[azole antifungals]] such as [[ketoconazole]], [[macrolide]] antibiotics such as [[erythromycin]], and [[HIV protease inhibitors]]) should be monitored and may require dose-reduction of one or both agents.
* The interaction of buprenorphine with CYP3A4 inducers has not been studied; therefore, it is recommended that patients receiving buprenorphine sublingual tablets be monitored for signs and symptoms of opioid withdrawal if inducers of CYP3A4 (e.g., [[efavirenz]], [[phenobarbital]], [[carbamazepine]], [[phenytoin]], [[rifampicin]]) are co-administered.
 
=====Antiretrovirals=====
* Three classes of antiretroviral agents have been evaluated for CYP3A4 interactions with [[buprenorphine]]. [[Nucleoside reverse transcriptase inhibitors]] (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected. [[Non-nucleoside reverse transcriptase inhibitors]] (NNRTIs) are metabolized principally by CYP3A4. [[Efavirenz]], [[nevirapine]] and [[etravirine]] are known CYP3A inducers whereas [[delaviridine]] is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., [[efavirenz]] and [[delavirdine]]) and [[buprenorphine]] have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects. It is recommended that patients who are on chronic buprenorphine treatment have their dose monitored if NNRTIs are added to their treatment regimen. Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity ([[nelfinavir]], [[lopinavir]]/[[ritonavir]], [[ritonavir]]) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity ([[atazanavir]] and [[atazanavir]]/[[ritonavir]]) resulted in elevated levels of buprenorphine and norbuprenorphine and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly. Monitoring of patients taking buprenorphine and atazanavir with and without ritonavir is recommended, and dose reduction of buprenorphine may be warranted.
 
=====[[Benzodiazepines]]=====
* There have been a number of post-marketing reports regarding coma and death associated with the concomitant use of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists. Buprenorphine sublingual tablets should be prescribed with caution to patients taking benzodiazepines or other drugs that act on the CNS, regardless of whether these drugs are taken on the advice of a physician or are being abused/misused. Patients should be warned that it is extremely dangerous to self-administer non-prescribed benzodiazepines while taking buprenorphine sublingual tablets, and should also be cautioned to use benzodiazepines concurrently with buprenorphine sublingual tablets only as directed by their physician.
|FDAPregCat=C
|useInPregnancyFDA======Risk Summary=====
* There are no adequate and well-controlled studies of buprenorphine sublingual tablets or [[buprenorphine]]/[[naloxone]] in pregnant women. . Limited published data on use of buprenorphine, the active ingredient in buprenorphine, in pregnancy, have not shown an increased risk of major malformations. All pregnancies, regardless of drug exposure, have a background risk of 2-4% for major birth defects, and 15-20% for pregnancy loss. Reproductive and developmental studies in rats and rabbits identified adverse events at clinically relevant doses. Pre- and postnatal development studies in rats demonstrated [[dystocia]], increased neonatal deaths, and developmental delays. No clear teratogenic effects were seen with a range of doses equivalent to or greater than the human dose. However, in a few studies, some events such as [[acephalus]], [[omphalocele]], and skeletal abnormalities were observed but these findings were not clearly treatment-related. Embryofetal death was also observed in both rats and rabbits.
* Buprenorphine sublingual tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
 
=====Clinical Considerations=====
* Disease-associated maternal and embryo-fetal risk
:* Opioid dependence in pregnancy is associated with adverse obstetrical outcomes such as [[low birth weight]], [[preterm birth]], and [[fetal death]].


==Overview==
* Fetal/neonatal adverse reactions
'''Buprenorphine''', is an [[opioid]] [[drug]] with [[agonist|partial agonist]] and [[receptor antagonist|antagonist]] actions. Buprenorphine [[hydrochloride]] was first marketed in the 1980s by Reckitt & Colman (now Reckitt Benckiser) as an [[analgesic]], available generally as Buprenex in a 0.3 mg/ml injectable formulation in the United States. In October 2002, the [[FDA]] additionally approved Suboxone and Subutex, buprenorphine's high-dose [[sublingual|sublingual pill]] preparations for [[opioid]] [[addiction]], and as such the drug is now also used for this purpose. It has been a [[Controlled Substances Act|Schedule III drug]] under the [[Convention on Psychotropic Substances]]<ref>[http://www.incb.org/pdf/e/list/green.pdf List of psychotropic Substances under international control]</ref> since it was rescheduled from [[Controlled Substances Act|Schedule V]] (the schedule with the lowest restrictions and penalties) just before FDA approval of Suboxone and Subutex.
:* Neonatal abstinence syndrome may occur in newborn infants of mothers who were on buprenorphine maintenance treatment. Observe newborns for [[poor feeding]], [[diarrhea]], [[irritability]], [[tremor]], [[rigidity]], and [[seizures]], and manage accordingly.
In the recent years, buprenorphine has been introduced in most European countries as transdermal formulation ("patch") for the treatment of chronic pain.
|useInLaborDelivery=* As with all opioids, use of buprenorphine prior to delivery may result in respiratory depression in the newborn. Closely monitor neonates for signs of respiratory depression. An opioid antagonist such as naloxone should be available for reversal of opioid induced respiratory depression in the neonate.
===== Data=====
:* Human Data
::* Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine during pregnancy. Limited published data on malformations from trials, observational studies, case series, and case reports on buprenorphine use in pregnancy have not shown an increased risk of major malformations. Based on these studies the incidence of neonatal abstinence syndrome is not clear and there does not appear to be a dose-response relationship.


==Commercial preparations==
:* Animal Data
[[United Kingdom|British]] firm Reckitt & Colman (now Reckitt Benckiser) first marketed buprenorphine under the trade names '''Temgesic''' ([[sublingual]]/[[parenteral]] preparations, no active [[food additive|additives]]) and '''Buprenex''' ([[parenteral]], no active [[food additive|additives]]). Two more recent formulations from Reckitt Benckiser have been [[approved drug|approved]] for [[opioid]] [[addiction]] treatment in the U.S.: '''Subutex''' (bitter [[sublingual]], no active [[food additive|additives]]; in 2 mg and 8 mg dosages) and '''Suboxone''' (Lemon-lime flavored [[sublingual]], one part [[naloxone]] for every four parts buprenorphine; hexagon shaped [[tablet]] in 2 mg and 8 mg dosages). Suboxone contains opiate agonist as well as the [[opioid]] [[receptor antagonist|antagonist]] [[naloxone]] to deter illicit [[intravenous]] preparation of the [[tablet]]. This is intended to attenuate the effects of buprenorphine on [[opioid]]-naive users should this formulation be [[injection (medicine)|injected]] - however no [[human]] [[experiment|studies]] have been done demonstrating the [[efficacy]] of this approach with buprenorphine and a growing number of street reports indicate that the [[naloxone]] is ineffective. The small amount of naloxone has no effect on the buprenorphine only opioids with lower affinities. <ref> [http://www.drugabuse.gov/NIDA_notes/NNvol19N3/Successful.html  NIDA study]</ref>
::* Buprenorphine has been shown to have differences in bioavailability compared to other buprenorphine/naloxone-containing sublingual products. The exposure margins listed below are based on body surface area comparisons (mg/m2) to the recommended human sublingual dose of 16 mg buprenorphine via Suboxone, which is equivalent to a human sublingual dose of 11.4 mg buprenorphine via Zubsolv.
::* Effects on embryo-fetal development were studied in Sprague-Dawley rats and Russian white rabbits following oral (1:1) and intramuscular (IM) (3:2) administration of mixtures of buprenorphine and naloxone. Following oral administration to rats and rabbits, no teratogenic effects were observed at buprenorphine doses up to 250 mg/kg/day and 40 mg/kg/day, respectively (estimated exposure approximately 150 times and 50 times, respectively, the recommended human sublingual dose). No definitive drug-related teratogenic effects were observed in rats and rabbits at IM doses up to 30 mg/kg/day (estimated exposure approximately 20 times and 35 times, respectively, the recommended human sublingual dose). Acephalus was observed in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group. Following oral administration of buprenorphine to rats, dose-related post-implantation losses, evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure approximately 6 times the recommended human sublingual dose). In the rabbit, increased post-implantation losses occurred at an oral dose of 40 mg/kg/day. Following IM administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live fetuses and increases in resorptions, occurred at 30 mg/kg/day. Buprenorphine was not teratogenic in rats or rabbits after IM or subcutaneous (SC) doses up to 5 mg/kg/day (estimated exposure was approximately 3 and 6 times, respectively, the recommended human sublingual dose), after IV doses up to 0.8 mg/kg/day (estimated exposure was approximately 0.5 times and equal to, respectively, the recommended human sublingual dose), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 95 times the recommended human sublingual dose) and 25 mg/kg/day in rabbits (estimated exposure was approximately 30 times the recommended human sublingual dose). Significant increases in skeletal abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC administration of 1 mg/kg/day and up (estimated exposure was approximately 0.6 times the recommended human sublingual dose), but were not observed at oral doses up to 160 mg/kg/day. Increases in skeletal abnormalities in rabbits after IM administration of 5 mg/kg/day (estimated exposure was approximately 6 times the recommended human sublingual dose) or oral administration of 1 mg/kg/day or greater (estimated exposure was approximately equal to the recommended human sublingual dose) were not statistically significant.
::* In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 mg/kg/day or greater and post-implantation losses that were statistically significant at IV doses of 0.2 mg/kg/day or greater (estimated exposure approximately 0.3 times the recommended human sublingual dose).
::* Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine 5 mg/kg/day (approximately 3 times the recommended human sublingual dose). Fertility, peri-, and post-natal development studies with buprenorphine in rats indicated increases in neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 0.5 times the recommended human sublingual dose), after IM doses of 0.5 mg/kg/day and up (approximately 0.3 times the recommended human sublingual dose), and after SC doses of 0.1 mg/kg/day and up (approximately 0.06 times the recommended human sublingual dose). An apparent lack of milk production during these studies likely contributed to the decreased pup viability and lactation indices. Delays in the occurrence of righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day (approximately 50 times the recommended human sublingual dose).
|useInNursing======Risk Summary=====
* Based on two studies in 13 lactating women, buprenorphine and its metabolite norbuprenorphine are present in low levels in human milk and infant urine, and available data have not shown adverse reactions in breastfed infants . There are no data on the combination product buprenorphine/naloxone in breastfeeding , however oral absorption of naloxone is minimal. Caution should be exercised when Zubsolv is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Zubsolv and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.


TIP-40, a publication dealing with clincal use of Suboxone/Subutex, concede that the naloxone contained in the tablets would not effect someone stabilized on suboxone, even if injected. It mainly serves to deter diversion of the drug, as injecting it is not a viable alternative to injecting other short acting opioids. The naloxone would cause 15-45 minutes of extreme withdrawal (PWS, precipitated withdrawal syndrome) and even after that, the partial agonist nature of buprenorphine could cause continued withdrawal symptoms. Injecting a crushed tablet in an opioid naive person would cause a high, as the naloxone has nothing to displace in such people, and it is of insufficient binding strength to compete with buprenorphine for receptors.
=====Clinical Considerations=====
* Advise the nursing mother taking Zubsolv to monitor the infant for increased drowsiness and breathing difficulties.


A solution for injection (usually by the [[intramuscular]] route) is marketed for the UK veterinary market by Alstoe Animal Health as '''Vetergesic''', licenced for analgesia and sedation in dogs.
* Data
:* Based on limited data from a study of 6 lactating women who were taking a median oral dose of buprenorphine of 0.29 mg/kg/day 5-8 days after delivery, breast milk contained a median infant dose of 0.42 mcg/kg/day of buprenorphine and 0.33 mg/kg/day of norbuprenorphine, which are equal to 0.2% and 0.12% of the maternal weight-adjusted dose.
:* Based on limited data from a study of 7 lactating women who were taking a median oral dose of buprenorphine of 7 mg/day an average of 1.12 months after delivery, the mean milk concentrations of buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L respectively. Based on the limited data from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively breastfed infant would receive an estimated mean of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of norbuprenorphine, which are 0.38% and 0.18% of the maternal weight-adjusted dose.
:* No adverse reactions were observed in the infants in these two studies.
|useInPed=* The safety and effectiveness of buprenorphine sublingual tablets have not been established in pediatric patients. This product is not appropriate for the treatment of [[neonatal abstinence syndrome]] in neonates, because it contains naloxone, an opioid antagonist.
|useInGeri=* Clinical studies of buprenorphine/naloxone sublingual tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
|useInRenalImpair=* No differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent and 6 normal patients following IV administration of 0.3 mg buprenorphine. The effects of renal failure on naloxone pharmacokinetics are unknown.
|useInHepaticImpair=* The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone is unknown. Since both drugs are extensively metabolized, the plasma levels will be expected to be higher in patients with moderate and severe hepatic impairment. However, it is not known whether both drugs are affected to the same degree. Therefore, dosage should be adjusted and patients should be watched for signs and symptoms of precipitated opioid withdrawal.
|administration=* Do not cut, chew, or swallow buprenorphine sublingual tablets. ZUBSOLV sublingual tablet should be placed under the tongue until dissolved. The dissolve time for Zubsolv varies between individuals, and the median dissolve time observed was 5 minutes. For dosages requiring more than one sublingual tablet, place all tablets in different places under the tongue at the same time. Patients should keep the tablets under the tongue until dissolved; swallowing the tablets reduces the bioavailability of the drug. Advise patients not to eat or drink anything until the tablet is completely dissolved. To ensure consistency in bioavailability, patients should follow the same manner of dosing with continued use of the product.
* If a sequential mode of administration is preferred, patients should follow the same manner of dosing with continued use of the product, to ensure consistency in bioavailability.
* Proper administration technique should be demonstrated to the patient.
|overdose=* The manifestations of acute overdose include [[pinpoint pupils]], [[sedation]], [[hypotension]], [[respiratory depression]], and death.
* In the event of overdose, the respiratory and cardiac status of the patient should be monitored carefully. When respiratory or cardiac functions are depressed, primary attention should be given to the re-establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Oxygen, IV fluids, vasopressors, and other supportive measures should be employed as indicated.
* In the case of overdose, the primary management should be the re-establishment of adequate ventilation with mechanical assistance of respiration, if required. Naloxone may be of value for the management of buprenorphine overdose. Higher than normal doses and repeated administration may be necessary. The long duration of action of ZUBSOLV should be taken into consideration when determining the length of treatment and medical surveillance needed to reverse the effects of an overdose. Insufficient duration of monitoring may put patients at risk.
|drugBox={{Drugbox2
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 457118559
| IUPAC_name = (2''S'')-2-[(5''R'',6''R'',7''R'',14''S'')-9α-Cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylbutan-2-ol
| image = Buprenorphine1.svg.png
| width = 200
| image2 = Buprenorphine2.gif
| width2 = 200


Since 2001 buprenorphine is also available transdermally in 35, 52.5 and 70 mcg/hour [[transdermal patch]], that delivers the dose over 96 hours. This application form is marketed as '''Transtec''' in most European countries by Grunenthal <ref> Transtec Summary of Product Characteristics </ref> (Napp Pharmaceuticals.in the UK <ref>[http://www.napp.co.uk Napp Pharmaceuticals]</ref> Norpharma in Denmark) for the treatment of moderate to severe cancer pain and severe non-cancer pain not responding to non-opioids. Moreover, a new 5, 10 and 20 mcg/hour [[Transdermal patch|patch]] is marketed as '''Butrans''' or '''Norspan''', a once weekly patch for severe chronic pain not responding to non-opioids, marketed by Napp Pharmaceuticals Ltd., and Mundipharma and Grunenthal respectively.
<!--Clinical data-->
| tradename = Buprenex, Subutex, Suboxone, Butrans
| Drugs.com = {{drugs.com|monograph|buprenorphine-hydrochloride}}
| MedlinePlus = a605002
| pregnancy_AU = C
| pregnancy_US = C
| legal_status = Schedule III (USA)
| legal_AU = S8
| legal_UK = Class C
| legal_SG = Category A
| legal_DE = Schedule III
| routes_of_administration = [[sublingual]], [[intramuscular|IM]], [[intravenous|IV]], [[transdermal]], [[intranasal]], [[rectally]]


==Pharmacology and pharmacokinetics==
<!--Pharmacokinetic data-->on
Buprenorphine is a [[thebaine]] derivative with powerful analgesia approximately 25 to 40 times as potent as morphine<ref> http://coretext.org/show_detail.asp?recno=6481 Reckitt Benckiser Buprenorphine Bibliography </ref>, and its [[analgesic]] effect is due to [[agonist|partial agonist]] activity at μ-[[opioid receptor]]s, i.e., when the [[molecule]] binds to a [[receptor (biochemistry)|receptor]], it is only partially activated in contrast to a [[agonist|full agonist]] such as [[morphine]]. Buprenorphine also has very high [[chemical affinity|binding affinity]] for the  [[Mu opioid receptor|μ receptor]] such that [[opioid receptor]] [[receptor antagonist|antagonists]] (e.g. [[naloxone]]) only partially reverse its effects. These two [[chemical property|properties]] must be carefully considered by the [[general practitioner|practitioner]], as an [[overdose]] cannot be easily reversed (although overdose is unlikely in addicted patients or people with tolerance to [[opioids]] who use the drug sublingually as meant in the case of Subutex/Suboxone, especially if there are no [[benzodiazepines]] involved), and use in persons [[addiction|physically dependent]] on [[agonist|full-agonist]] [[opioids]] may trigger [[opioid]] [[withdrawal]] that also cannot be easily reversed and can last over 24 hours, as the drug's mean half-life is 37 hours.
| bioavailability = 55%(sublingual)<ref>{{cite pmid|2458208}}</ref>/48.2% +/- 8.35%(intranasal)<ref>{{cite pmid|2576057}}</ref>
| protein_bound = 96%
| metabolism = [[Liver|hepatic]]<br />[[CYP3A4]], [[CYP2C8]]
| elimination_half-life = 20–70, mean 37 hours
| excretion = [[bile|biliary]] and [[renal]]


Buprenorphine is also a [[Kappa opioid receptor|κ-opioid]] receptor antagonist, and partial/full agonist at the recombinant human ORL1 [[nociceptin]] receptor.<ref name="Huang">Huang P. ''et al.'' (2001): "Comparison of pharmacological activities of buprenorphine and norbuprenorphine: norbuprenorphine is a potent opioid agonist", ''J. Pharmacol. Exp. Ther.'' 297(2):688-95. PMID 11303059</ref>
<!--Identifiers-->
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 52485-79-7
| ATC_prefix = N02
| ATC_suffix = AE01
| ATC_supplemental =  {{ATC|N07|BC01}}
| PubChem = 644073
| IUPHAR_ligand = 1670
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00921
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 559124
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 40D3SCR4GZ
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07132
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 3216
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 1201894


Buprenorphine [[hydrochloride]] is administered by [[intramuscular]] injection, [[intravenous]] infusion, via a [[transdermal]] patch, or as a sublingual tablet. It is not administered orally, due to very high [[first-pass metabolism]]. Buprenorphine is metabolised by the [[liver]], via the [[CYP3A4]] isozyme of the [[Cytochrome P450 oxidase|cytochrome P450]] enzyme system, into [[norbuprenorphine]] (by ''N''-dealkylation) and other metabolites. The metabolites are further conjugated with [[glucuronic acid]] and eliminated mainly through excretion into the bile. The [[elimination half-life]] of buprenorphine is 20–73 hours (mean 37). Due to the mainly hepatic elimination there is no risk of accumulation in patients with renal impairment and in the elderly.
<!--Chemical data-->
| C=29 | H=41 | N=1 | O=4
| molecular_weight = 467.64 g/mol
| smiles = Oc7ccc5c1c7O[C@H]3[C@]6(OC)[C@H](C[C@@]2([C@H](N(CC[C@@]123)CC4CC4)C5)CC6)[C@@](O)(C)C(C)(C)C
| InChI = 1/C29H41NO4/c1-25(2,3)26(4,32)20-15-27-10-11-29(20,33-5)24-28(27)12-13-30(16-17-6-7-17)21(27)14-18-8-9-19(31)23(34-24)22(18)28/h8-9,17,20-21,24,31-32H,6-7,10-16H2,1-5H3/t20-,21-,24-,26+,27-,28+,29-/m1/s1
| InChIKey = RMRJXGBAOAMLHD-IHFGGWKQBA
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C29H41NO4/c1-25(2,3)26(4,32)20-15-27-10-11-29(20,33-5)24-28(27)12-13-30(16-17-6-7-17)21(27)14-18-8-9-19(31)23(34-24)22(18)28/h8-9,17,20-21,24,31-32H,6-7,10-16H2,1-5H3/t20-,21-,24-,26+,27-,28+,29-/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = RMRJXGBAOAMLHD-IHFGGWKQSA-N
}}
|mechAction=* Buprenorphine sublingual tablet contains buprenorphine and naloxone. Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor. Naloxone is a potent antagonist at mu-opioid receptors and produces opioid withdrawal signs and symptoms, if administered parenterally, in individuals physically dependent on full opioid agonists.
|structure=* ZUBSOLV (buprenorphine and naloxone) sublingual tablets are white menthol-flavored tablets in a triangular shape for the lower dosage strength (1.4 mg /0.36 mg) and a round shape for the higher dosage strength (5.7 mg/1.4 mg). They are debossed with the respective dosage strength of buprenorphine. They contain buprenorphine HCl, a mu-opioid receptor partial agonist and a kappa-opioid receptor antagonist, and naloxone HCl dihydrate, an opioid receptor antagonist, at a ratio of 4:1 (ratio of free bases). ZUBSOLV is intended for sublingual administration and is available in two dosage strengths, 1.4 mg buprenorphine with 0.36 mg naloxone and 5.7 mg buprenorphine with 1.4 mg naloxone. Each sublingual tablet also contains mannitol, citric acid, sodium citrate, microcrystalline cellulose, croscarmellose sodium, sucralose, menthol, silicon dioxide and sodium stearyl fumarate and menthol flavor.
* Chemically, buprenorphine HCl is (2S)-2-[17-(cyclopropylmethyl)-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol hydrochloride. It has the following chemical structure:
[[File:Buprenorphine structure 1.jpg|thumb|none|400px|left|This image is provided by the National Library of Medicine.]]


The main active metabolite, norbuprenorphine, is a [[Delta opioid receptor|δ-opioid receptor]] and ORL1 receptor agonist, μ- and κ-opioid receptor partial agonist, but buprenorphine antagonizes its effects.<ref name="Huang"/>
* Buprenorphine HCl has the molecular formula C29 H41 NO4 • HCl and the molecular weight is 504.10. It is a white or off-white crystalline powder, sparingly soluble in water, freely soluble in methanol, soluble in alcohol, and practically insoluble in cyclohexane.
* Chemically, naloxone HCl dihydrate is 17-Allyl-4,-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride dihydrate. It has the following chemical structure:


Plasma concentrations after application of transdermal buprenorphine increase steadily and the minimum effective therapeutic dose (100 pg/ml) is reached at 11 hours and 21 hours for a single 35 and 70 μg/h patch, respectively. Peak plasma concentration (Cmax) is reached in about 60 hours (305 and 624 pg/ml for the 35 and 70 μg/h strength patch, respectively), and is markedly longer than with 0.3 mg intravenous buprenorphine (0.41 hours). Transdermal buprenorphine has a half-life of approx. 30 hours, and a bioavailability of approximately 50%, which is comparable to sublingual buprenorphine .
[[File:Buprenorphine structure 2.jpg|thumb|none|400px|left|This image is provided by the National Library of Medicine.]]


==Clinical use==
* Naloxone HCl dihydrate has the molecular formula C19H21NO4 • HCl • 2H20 and the molecular weight is 399.87. It is a white to slightly off-white powder and is freely soluble in water, soluble in alcohol, and practically insoluble in toluene and ether.
===Indications===
|PD=* ZUBSOLV has been shown to have different bioavailability compared to SUBOXONE tablet. One ZUBSOLV 5.7 mg/1.4 mg tablet provides equivalent buprenorphine exposure and 12% lower naloxone exposure to one SUBOXONE 8 mg/2 mg tablet. The pharmacodynamic information of other currently marketed buprenorphine/naloxone-containing sublingual products is not directly comparable on a mg basis to ZUBSOLV.
====Pain indications====
======Subjective Effects======
Depending on the application form, buprenorphine is indicated for the treatment of moderate to severe chronic pain or for peri-operative analgesia. For the treatment of chronic pain, the transdermal formulations are nowadays preferred, which can be used both for chronic cancer pain as well as chronic non-malignant pain e.g. musculosceletal and neuropathic pain. The intravenous formulation is mainly used in postoperative pain (e.g. as PCA- patient controlled analgesia) and the sublingual formulation is e.g. used as breakthrough medication for patients with basic transdermal treatment.
* Comparisons of buprenorphine to full opioid agonists such as methadone and hydromorphone suggest that sublingual buprenorphine produces typical opioid agonist effects which are limited by a ceiling effect.
Advantages of buprenorphine in the treatment of chronic pain are – from a clinical perspective- its relatively long half-life, the option of sublingual and transdermal application and the excellent safety profile (ceiling effect for respiratory depression, lack of immunosuppressive effect, low pharmacokinetic interaction potential, no accumulation in renal impairment).
* In opioid-experienced subjects who were not physically dependent, acute sublingual doses of Suboxone tablets produced opioid agonist effects which reached a maximum between doses of 8/2 mg and 16/4 mg buprenorphine/naloxone.
* Opioid agonist ceiling-effects were also observed in a double-blind, parallel group, dose-ranging comparison of single doses of buprenorphine sublingual solution (1, 2, 4, 8, 16, or 32 mg), placebo and a full agonist control at various doses. The treatments were given in ascending dose order at intervals of at least one week to 16 opioid-experienced subjects who were not physically dependent. Both active drugs produced typical opioid agonist effects. For all measures for which the drugs produced an effect, buprenorphine produced a dose-related response. However, in each case, there was a dose that produced no further effect. In contrast, the highest dose of the full agonist control always produced the greatest effects. Agonist objective rating scores remained elevated for the higher doses of buprenorphine (8-32 mg) longer than for the lower doses and did not return to baseline until 48 hours after drug administration. The onset of effects appeared more rapidly with buprenorphine than with the full agonist control, with most doses nearing peak effect after 100 minutes for buprenorphine compared to 150 minutes for the full agonist control.


====Antidepressant features====
======Physiologic Effects======
A clinical trial conducted at Harvard Medical School in the mid-1990s demonstrated that a majority of unipolar non-[[psychotic]] patients with major [[Clinical depression|depression]] refractory to conventional [[thymoleptic]] antidepressants could be successfully treated with buprenorphine.<ref>Bodkin JA. ''et al.'' (1995): "Buprenorphine treatment of refractory depression", ''Journal of Clinical Psychopharmacology'' 15:49-57. PMID 7714228</ref> See [[opioids#clinical use|opioids]] for other (predominantly favorable) experiments with buprenorphine and other opioids for psychological relief.
* Buprenorphine in IV (2, 4, 8, 12 and 16 mg) and sublingual (12 mg) doses has been administered to opioid-experienced subjects who were not physically dependent to examine cardiovascular, respiratory, and subjective effects at doses comparable to those used for treatment of opioid dependence. Compared to placebo, there were no statistically significant differences among any of the treatment conditions for blood pressure, heart rate, respiratory rate, O2 saturation, or skin temperature across time. Systolic BP was higher in the 8 mg group than placebo (3-hour AUC values). Minimum and maximum effects were similar across all treatments. Subjects remained responsive to low voice and responded to computer prompts. Some subjects showed irritability, but no other changes were observed.
However, psychological distress is currently not an approved indication for the use of any opioid, and legally it falls in a "grey zone" that is technically legal but a doctor could still face charges regardless (but not for off-label scripting in itself, simply being singled out by the Drug Enforcement Administration, who prosecute doctors often for using controlled substances for '''approved''' uses ("too much"). [http://www.aapsonline.org/press/hurwitz1002.htm][http://www.lewrockwell.com/paul/paul179.html] The doctor still needs the proper DEA licensing under the ''Drug Addiction Treatment Act of 2000'' to prescribe Subutex or Suboxone for opioid addiction/dependence.
* The respiratory effects of sublingual buprenorphine were compared with the effects of methadone in a double-blind, parallel group, dose ranging comparison of single doses of buprenorphine sublingual solution (1, 2, 4, 8, 16, or 32 mg) and oral methadone (15, 30, 45, or 60 mg) in non-dependent, opioid-experienced volunteers. In this study, hypoventilation not requiring medical intervention was reported more frequently after buprenorphine doses of 4 mg and higher than after methadone. Both drugs decreased O2 saturation to the same degree.


===Contraindication===
======Effect of Naloxone======
Like full agonist opiates, buprenorphine can cause [[drowsiness]], [[vomiting]] and [[respiratory depression]]. Taking buprenorphine in conjunction with [[Central nervous system|central nervous system (CNS) depressants]] such as [[sedative]]s, [[Sedative|tranquilizers]], [[Alcoholic beverage|alcohol]], and ''especially'' [[benzodiazepines]] can be particularly dangerous <ref>[http://www.suboxone.com/patients/suboxone/faqs.aspx#35 Suboxone FAQ]</ref>. Falling asleep while abusing this drug, especially while combining it with other central nervous system depressants, can be extremely dangerous and thus greatly increases the chance of serious complications or death.
:* Physiologic and subjective effects following acute sublingual administration of buprenorphine tablets and Suboxone tablets were similar at equivalent dose levels of buprenorphine. Naloxone had no clinically significant effect when administered by the sublingual route, although blood levels of the drug were measurable. Buprenorphine/naloxone, when administered sublingually to an opioid-dependent cohort, was recognized as an opioid agonist, whereas when administered intramuscularly, combinations of buprenorphine with naloxone produced opioid antagonist actions similar to naloxone. This finding suggests that the naloxone in buprenorphine/naloxone tablets may deter injection of buprenorphine/naloxone tablets by persons with active substantial heroin or other full mu-opioid dependence. However, clinicians should be aware that some opioid-dependent persons, particularly those with a low level of full mu-opioid physical dependence or those whose opioid physical dependence is predominantly to buprenorphine, abuse buprenorphine/naloxone combinations by the intravenous or intranasal route. In methadone-maintained patients and heroin-dependent subjects, IV administration of buprenorphine/naloxone combinations precipitated opioid withdrawal signs and symptoms and was perceived as unpleasant and dysphoric. In morphine-stabilized subjects, intravenously administered combinations of buprenorphine with naloxone produced opioid antagonist and withdrawal signs and symptoms that were ratio-dependent; the most intense withdrawal signs and symptoms were produced by 2:1 and 4:1 ratios, less intense by an 8:1 ratio.
|PK=======Absorption======
* Plasma levels of buprenorphine and naloxone increased with the sublingual dose of ZUBSOLV sublingual tablet. There was wide inter-patient variability in the sublingual absorption of buprenorphine and naloxone, but within subjects the variability was low. Both Cmax and AUC of buprenorphine increased with the increase in dose (in the range of 1.4 to 11.4 mg), although the increase was not directly dose-proportional. Naloxone did not affect the pharmacokinetics of buprenorphine.
:* Buprenorphine has been shown to have different bioavailability compared to SUBOXONE tablet. One ZUBSOLV 5.7 mg/1.4 mg tablet provides equivalent buprenorphine exposure and 12% lower naloxone exposure to one SUBOXONE 8 mg/2 mg tablet.


===Adverse effects===
======Distribution======
Common [[adverse drug reaction]]s associated with the use of buprenorphine are similar to those of other opioids and include: nausea and vomiting, drowsiness, dizziness, headache, itch, dry mouth, [[miosis]], [[orthostatic hypotension]], male ejaculatory difficulty, decreased libido, urinary retention. [[Constipation]] and CNS effects are seen less frequently than with e.g. morphine <ref name="Budd"> Budd K, Raffa RB. (edts.) Buprenorphine- The unique opioid analgesic. Thieme 2005 (ISBN 3-13-1342211-0)</ref> Hepatic necrosis and hepatitis with jaundice have been reported with the use of buprenorphine, especially after intravenous injection of crushed tablets.
* Buprenorphine is approximately 96% protein bound, primarily to alpha and beta globulin.
* Naloxone is approximately 45% protein bound, primarily to albumin.


The most severe and serious adverse reaction associated with opioid use in general is respiratory depression, the mechanism behind fatal overdose. Buprenorphine behaves differently than other opioids in this respect, as it shows a ceiling effect for respiratory depression <ref name="Budd"/>.Moreover, former doubts on the antagonisation of the respiratory effects by Naloxone have been disproved: Buprenorphine effects can be antogonised with a continuous infusion of Naloxone <ref>Van Dorp E. et al. (2006) Naloxone reversal of buprenorphine- induced respiratory depression. Anesthesiology 105 (1): 51-57 </ref>. Of course, concurrent use of buprenorphine and CNS depressants (such as alcohol or benzodiazepines) is contraindicated as it may lead to fatal respiratory depression.
======Metabolism======
* Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation. The N-dealkylation pathway is mediated primarily by the CYP3A4. Norbuprenorphine, the major metabolite, can further undergo glucuronidation. Norbuprenorphine has been found to bind opioid receptors in-vitro; however, it has not been studied clinically for opioid-like activity. Naloxone undergoes direct glucuronidation to naloxone-3-glucuronide as well as N-dealkylation, and reduction of the 6-oxo group.
In people on medium- to long-term maintenance with Suboxone or Subutex do not have a major risk of overdose, as long as the drug is used properly (as prescribed), and benzodiazepines are not prescribed to individuals without a tolerance to [[opioids]].


As with other [[Opioids]], dependence and tolerance are rarely a problem when used safely. There is little evidence that buprenorphine is less likely to cause such problems. Maintenance dosages can remain at the same moderate level indefinitely, and in many cases even lowered, without discomfort. Due to buprenorphine's pharmacological actions, raising the dosage will not result in a stronger analgesic effect after a certain point (around 16–32 mg), beyond which the drug will actually have a reduced analgesic effect.  
======Elimination======
* A mass balance study of buprenorphine showed complete recovery of radiolabel in urine (30%) and feces (69%) collected up to 11 days after dosing. Almost all of the dose was accounted for in terms of buprenorphine, norbuprenorphine, and two unidentified buprenorphine metabolites. In urine, most of buprenorphine and norbuprenorphine was conjugated (buprenorphine, 1% free and 9.4% conjugated; norbuprenorphine, 2.7% free and 11% conjugated). In feces, almost all of the buprenorphine and norbuprenorphine were free (buprenorphine, 33% free and 5% conjugated; norbuprenorphine, 21% free and 2% conjugated). Buprenorphine has a mean elimination half-life from plasma ranging from 24 to 42 hours and naloxone has a mean elimination half-life from plasma ranging from 2 to 12 hours.


The partial agonist activity of buprenorphine combined with its high affinity for μ-[[opioid receptor]] means that it may act clinically as an antagonist and thus precipitate opioid withdrawal symptoms when an opioid-dependent patient is commenced on the drug soon after the use of another opioid drug. Patients are advised to wait between 24 and 36 hours after their last use of short-acting opioids (such as [[heroin]] or [[oxycodone]]) before beginning treatment with buprenorphine. Those using long-acting opioids, such as [[methadone]], should only commence treatment once withdrawal symptoms are present. Beginning any earlier may result in extreme cases of opioid withdrawal. Additionally, it is recommended that the patient be on no more than 30 mg of [[methadone]] per day when switching to buprenorphine.
======Drug-drug Interactions======
* CYP3A4 Inhibitors and Inducers: Subjects receiving buprenorphine sublingual tablet should be monitored if inhibitors of CYP3A4 such as [[azole antifungal agents]] (e.g., [[ketoconazole]]), [[macrolide antibiotics]] (e.g., [[erythromycin]]) or [[HIV protease inhibitors]] and may require dose-reduction of one or both agents. The interaction of buprenorphine with all CYP3A4 inducers has not been studied, therefore it is recommended that patients receiving buprenorphine sublingual tablet be monitored for signs and symptoms of opioid withdrawal if inducers of CYP3A4 (e.g., [[phenobarbital]], [[carbamazepine]], [[phenytoin]], [[rifampicin]]) are co-administered.
* Buprenorphine has been found to be a CYP2D6 and CYP3A4 inhibitor and its major metabolite, norbuprenorphine, has been found to be a moderate CYP2D6 inhibitor in in-vitro studies employing human liver microsomes. However, the relatively low plasma concentrations of buprenorphine and norbuprenorphine resulting from therapeutic doses are not expected to raise significant drug-drug interaction concerns.
|nonClinToxic======Carcinogenesis, Mutagenesis, Impairment of Fertility=====
* Buprenorphine has been shown to have differences in bioavailability compared to other buprenorphine/[[naloxone]]-containing sublingual products. The exposure margins listed below are based on body surface area comparisons (mg/m2) to the recommended human sublingual dose of 16 mg buprenorphine via Suboxone, which is equivalent to a human sublingual dose of 11.4 mg buprenorphine via ZUBSOLV.


==Dependence treatment==
=====Carcinogenicity=====
Buprenorphine sublingual preparations are often used in the management of opioid [[Chemical dependency|dependence]] (that is, dependence on [[heroin]], [[oxycodone]], [[hydrocodone]], [[morphine]], [[oxymorphone]], [[fentanyl]] or other opioids). The Suboxone and Subutex preparations were approved for this indication by the [[United States]] [[Food and Drug Administration|FDA]] in October 2002. This was only possible due to the Drug Addiction Treatment Act of 2000 that for the first time since 1914-1920 (conflicting Supreme Court rulings - rulings that would not stand to today's Supreme Court as they ruled that maintenance or detox treatment is not medical treatment, and likely was not what was intended by Congress) made it legal for doctors to prescribe opioids themselves to manage addiction ("maintenance") or for short-term detox (special doctors in registered clinics are excluded from these blanket restrictions). This law is limited to Schedules III through V only - thus excluding methadone and stronger opioids.
* A carcinogenicity study of buprenorphine/naloxone (4:1 ratio of the free bases) was performed in Alderley Park rats. Buprenorphine/naloxone was administered in the diet at doses of approximately 7, 31, and 123 mg/kg/day for 104 weeks (estimated exposure was approximately 4, 18, and 44 times the recommended human sublingual dose based on buprenorphine AUC comparisons). A statistically significant increase in [[Leydig cell adenomas]] was observed in all dose groups. No other drug-related tumors were noted.
* Carcinogenicity studies of buprenorphine were conducted in Sprague-Dawley rats and CD-1 mice. Buprenorphine was administered in the diet to rats at doses of 0.6, 5.5, and 56 mg/kg/day (estimated exposure was approximately 0.4, 3, and 35 times the recommended human sublingual dose) for 27 months. As in the buprenorphine/naloxone carcinogenicity study in rat, statistically significant dose-related increases in Leydig cell tumors occurred. In an 86-week study in CD-1 mice, buprenorphine was not carcinogenic at dietary doses up to 100 mg/kg/day (estimated exposure was approximately 30 times the recommended human sublingual dose).


The use of Medication assisted treatment in the management of opioid dependence is highly regulated, owing to the sometimes controversial nature of this aspect of [[harm reduction]] policy. In the United States, a special federal waiver is required to prescribe Subutex and Suboxone for opioid addiction treatment on an outpatient basis. However, if the doctor meets none of the other clarifications, an 8-hour course is all that is required). Each approved prescriber is allowed to manage only 30 patients on buprenorphine for opioid addiction as outpatients;<ref>[http://naabt.org/30_patient_limit.cfm/ naabt.org]</ref> the U.S. Senate has passed a bill relaxing this restriction for group practices only as of May 25, 2006 {{Fact|date=February 2007}}. Legislation was passed by Congress in the last few hours prior to Holiday recess in December, 2006 allowing physicians with one year <s>of clinical experience</s> Physicians are only required to have had their original waiver for 1 year, NO clinical expirience is required to request an additional exemption within DATA 2000 allowing 100 patient limit effective  12/29/2006 (public law 109-469). Similar restrictions are placed on prescribers in many other jurisdictions. Buprenorphine is ''heavily'' regulated in Australia relatively, and while the number of patients isn't limited generally daily visits for supervised dosing at a pharmacy is required, such as methadone, and methadone where used is used in lower relative doses.  
=====Mutagenicity=====
* The 4:1 combination of buprenorphine and naloxone was not mutagenic in a bacterial mutation assay (Ames test) using four strains of S. typhimurium and two strains of [[E. coli]]. The combination was not clastogenic in an in vitro cytogenetic assay in human [[lymphocytes]] or in an IV micronucleus test in the rat.
* Buprenorphine was studied in a series of tests utilizing gene, [[chromosome]], and DNA interactions in both prokaryotic and eukaryotic systems. Results were negative in yeast (S. cerevisiae) for recombinant, gene convertant, or forward mutations; negative in Bacillus subtilis "rec" assay, negative for clastogenicity in CHO cells, Chinese hamster bone marrow and spermatogonia cells, and negative in the mouse lymphoma L5178Y assay.
* Results were equivocal in the Ames test: negative in studies in two laboratories, but positive for frame shift mutation at a high dose (5mg/plate) in a third study. Results were positive in the Green-Tweets (E. coli) survival test, positive in a DNA synthesis inhibition (DSI) test with testicular tissue from mice, for both in vivo and in vitro incorporation of [3H]thymidine, and positive in unscheduled DNA synthesis (UDS) test using testicular cells from mice.


===Buprenorphine vs Methadone===
=====Impairment of Fertility=====
Buprenorphine and [[methadone]] are both used for short-term and long-term opioid maintenance therapy. Each agent has its relative advantages and disadvantages.
* Dietary administration of buprenorphine in the rat at dose levels of 500 ppm or greater (equivalent to approximately 47 mg/kg/day or greater; estimated exposure approximately 28 times the recommended human sublingual dose) produced a reduction in fertility demonstrated by reduced female conception rates. A dietary dose of 100 ppm (equivalent to approximately 10 mg/kg/day; estimated exposure approximately 6 times the recommended human sublingual dose) had no adverse effect on fertility.
|howSupplied=* Buprenorphine sublingual tablets are,menthol-flavored white tablets supplied in aluminum/aluminum child resistant unit dose blister packages. Buprenorphine is available in two dosage strengths:
:* Buprenorphine/naloxone 1.4 mg/0.36 mg, triangular shape, and
:* Buprenorphine/naloxone 5.7 mg/1.4 mg, round shape
:* NDC 54123-914-30 (buprenorphine/naloxone 1.4 mg /0.36 mg) sublingual tablet – 3×10 tablets per carton
:* NDC 54123-957-30 (buprenorphine/naloxone 5.7 mg/1.4 mg) sublingual tablet– 3×10 tablets per carton
|storage=* Store at 20-25°C (68-77°F), excursions permitted to 15-30°C (59-86°F)
* Patients should be advised to store buprenorphine-containing medications safely and out of sight and reach of children. Destroy any unused medication appropriately
|fdaPatientInfo=* Before initiating treatment with buprenorphine sublingual tablets, explain the points listed below to caregivers and patients. Instruct patients to read the Medication Guide each time buprenorphine is dispensed because new information may be available.
:* Patients should be warned that it is extremely dangerous to self-administer non-prescribed benzodiazepines or other CNS depressants (including alcohol) while taking buprenorphine sublingual tablets. Patients prescribed benzodiazepines or other CNS depressants should be cautioned to use them only as directed by their physician.
:* Patients should be advised that buprenorphine sublingual tablets contain an opioid that can be a target for people who abuse prescription medications or street drugs. Patients should be cautioned to keep their tablets in a safe place, and to protect them from theft.
:* Patients should be instructed to keep buprenorphine sublingual tablets in a secure place, out of the sight and reach of children. Accidental or deliberate ingestion by a child may cause respiratory depression that can result in death. Patients should be advised that if a child is exposed to buprenorphine sublingual tablets, medical attention should be sought immediately.
:* Patients should be advised never to give buprenorphine sublingual tablets to anyone else, even if he or she has the same signs and symptoms. It may cause harm or death.
:* Patients should be advised that selling or giving away this medication is against the law.
:* Patients should be cautioned that buprenorphine sublingual tablets may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving or operating machinery. Caution should be taken especially during drug induction and dose adjustment and until individuals are reasonably certain that buprenorphine therapy does not adversely affect their ability to engage in such activities.
:* Patients should be advised not to change the dosage of buprenorphine sublingual tablets without consulting their physician.
:* Patients should be advised to take buprenorphine sublingual tablets once a day.
:* Patients should be advised that if they miss a dose of buprenorphine they should take it as soon as they remember. If it is almost time for the next dose, they should skip the missed dose and take the next dose at the regular time.
:* Patients should be informed that buprenorphine sublingual tablets can cause drug dependence and that withdrawal signs and symptoms may occur when the medication is discontinued.
:* Patients seeking to discontinue treatment with buprenorphine for opioid dependence should be advised to work closely with their physician on a tapering schedule and should be apprised of the potential to relapse to illicit drug use associated with discontinuation of opioid agonist/partial agonist medication-assisted treatment.
:* Patients should be cautioned that, like other opioids, buprenorphine sublingual tablets may produce orthostatic hypotension in ambulatory individuals.
:* Patients should inform their physician if any other prescription medications, over-the-counter medications, or herbal preparations are prescribed or currently being used.
:* Advise females of reproductive potential, who become pregnant or are planning to become pregnant, to consult their physician regarding the possible effects of using buprenorphine sublingual tablets during pregnancy.
:* Advise women who are breastfeeding to monitor the infant for drowsiness and difficulty breathing.
:* Patients should inform their family members that, in the event of emergency, the treating physician or emergency room staff should be informed that the patient is physically dependent on an opioid and that the patient is being treated with buprenorphine sublingual tablets.
:* Refer to the Medication Guide for additional information regarding the counseling information.


In terms of efficacy (i.e. treatment retention, negative urine samples), high-dose buprenorphine (such as that commonly found with Subutex/Suboxone treatment; 8-16 mg typically) has been found to be superior to 20-40 mg of methadone/day (low dose) and equatable anywhere between 50 mg-70 mg (moderate dose)<ref name="Schottenfeld">R. S. Schottenfeld et. al (1997) Department of Psychiatry, Yale University School of Medicine</ref> to up to 100 mg (high dose)<ref name="Johnson">Rolley Johnson ''et al.'', NEJM, 343(18):1290-1297, 2000</ref> methadone/day. (Methadone, however, can continue to increase in effectiveness over 100 mg, although it is a debatable topic, but this would consistute "very high dose" in this measurement commonly used by studies, including those quoted). In all cases, high-dose buprenorphine has been found to be far superior to placebo and an effective treatment for opioid addiction, with retention rates of 50% as a minimum.<ref name="Schottenfeld"/><ref name="Johnson"/><ref>Strain ''et al.'' (1998)</ref><ref>Ling ''et al.'' (1998)</ref>
* Disposal of Unused buprenorphine Sublingual Tablets
:* Unused buprenorphine sublingual tablets should be disposed of as soon as they are no longer needed. Unused tablets should be flushed down the toilet.


Buprenorphine sublingual tablets (Suboxone and Subutex for opioid addiction) have a long duration of action which may allow for dosing every two or three days, as tolerated by the patient, compared with the daily dosing required to prevent withdrawals with methadone. In the United States, following initial management, a patient is typically prescribed up to a one month supply for self-administration. It is often misunderstood that the patient '''has''' to receive other therapy in this situation, but the law simply states that the prescribing physician needs to be '''capable''' of referring the patient to other addiction treatment (i.e. psychotherapy or support groups,) and many (but not all) physicians are aware of this and simply recommend therapy, or as they deem fit have therapy required.
* Manufactured for Orexo US, Inc. by Orexo AB with AAIPharma Wilmington, North Carolina
: Distributed by Orexo US, Inc.
: New York, New York
: Buprenorphine is a licensed trademark of Orexo US, Inc.
: © 2013 Orexo US, Inc. All rights reserved.
: MEDICATION GUIDE
: buprenorphine® (Zub-solve)
: (buprenorphine and naloxone)
: Sublingual Tablet (CIII)


Buprenorphine may be more convenient for some users because patients can be given a 30 day take home dose relatively soon after starting treatment, hence making them more compliant relative to those who need to visit a methadone dispensing facility daily to receive their methadone. The facilities, which are regulated at the state and federal level, initially only allow patients to take home weekend and holiday doses and after months of compliance without missing a day, they are given a week or more worth of methadone to take home. However, at many clinics, patients are given enough methadone to last for 2 weeks or 1 month, after significant time in treatment. ''At some US clinics, patients may get enough methadone to last 3 months.'' Therefore, buprenorphine ''does not'' have an advantage in terms of convenience for patients who have access to relatively liberal clinics, stay free of other drugs, and who stay on methadone long enough to earn the take-homes. In fact, users who are taking home a supply of methadone which lasts 3 months, 1 month, or even 2 weeks at a time may have difficulty finding a buprenorphine doctor who would offer equally convenient accommodations in some areas. There are also many professionals who are advocating for office-based methadone treatment, like office-based buprenorphine treatment, in the US and elsewhere. Such treatment with full opiate agonists is already available in the UK, and has been ever since heroin was made illegal, with an interruption of a few decades which occurred, likely under pressure from the United States, during the worldwide escalation of the War on Drugs which occurred during the 1960's and 1970's. In fact, in the UK a doctor may prescribe any opiate to a person, regardless of their complaint. In practice, methadone is most often used, although morphine and heroin are also frequently prescribed. The UK has a smaller number of opiate users, per capita, than the United States, which many attribute to the availability of full opiate agonist prescriptions to users, which reduces the amount of opiates sold illicitly and, in turn, the number of users of other drugs who encounter and begin using the opiates. Therefore, buprenorphine holds no advantage in convenience over methadone for users in the UK, and elsewhere in the world where prescriptions of full opiate agonists to opiate users are not discouraged.
=====IMPORTANT=====
* Keep buprenorphine in a secure place away from children. If a child accidentally takes buprenorphine, this is a medical emergency and can result in death. Get emergency help right away.
* Read this Medication Guide before you start taking buprenorphine and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor. Talk to your doctor or pharmacist if you have questions about buprenorphine.
* nShare the important information in this Medication Guide with members of your household.


Buprenorphine may and is generally viewed to have a lower dependence-liability than methadone. In other words, withdrawal from buprenorphine is less difficult. Buprenorphine treatment can last anywhere from several days (for detoxification purposes) to several months (sometimes for only a few weeks or up to two or three years) or longer. While not the general goal, and often not intentional with buprenorphine, it can sometimes but rarely be used in an indefinite, often life-long regimen just as methadone can be. The '''choice''' of buprenorphine vs. methadone in the mentioned situation (by the patient) is usually due to the benefits of the less-restrictive outpatient treatment; prescriptions for take-home doses for up to a month vs. the heavy restrictions for take-home methadone doses and frequent visits to the clinic, as well as the stigma of going to a methadone clinic.  
=====What is the most important information I should know about buprenorphine?=====
* Buprenorphine can cause serious and life-threatening breathing problems. Call your doctor right away or get emergency help if:
* You feel faint, dizzy, or confused
* Your breathing gets much slower than is normal for you
* These can be signs of an overdose or other serious problems.
* Do not switch from buprenorphine to other medicines that contain buprenorphine without talking with your doctor. The amount of buprenorphine in a dose of buprenorphine is not the same as the amount of buprenorphine in other medicines that contain buprenorphine. Your doctor will prescribe a starting dose of buprenorphine that may be different than other buprenorphine containing medicines you may have been taking.
* Buprenorphine contains an opioid that can cause physical dependence.
* Do not stop taking buprenorphine without talking to your doctor. You could become sick with uncomfortable withdrawal signs and symptoms because your body has become used to this medicine.
* Physical dependence is not the same as drug addiction.
* Buprenorphine is not for occasional or "as needed" use.
* An overdose, and even death, can happen if you take benzodiazepines, sedatives, tranquilizers, or alcohol while using buprenorphine. Ask your doctor what you should do if you are taking one of these.
* Call a doctor or get emergency help right away if you:
:* Feel sleepy and uncoordinated
:* Have [[blurred vision]]
:* Have [[slurred speech]]
:* Cannot think well or clearly
:* Have slowed reflexes and breathing
:* Do not inject ("shoot-up") buprenorphine. Injecting buprenorphine may cause life-threatening infections and other serious health problems.
:* Injecting buprenorphine may cause serious withdrawal symptoms such as pain, cramps, vomiting, diarrhea, anxiety, sleep problems, and cravings.
:* In an emergency, have family members tell the emergency department staff that you are physically dependent on an opioid and are being treated with buprenorphine.


The usually less-severe withdrawal effects make it usually much easier to discontinue use as opposed to methadone, but no evidence thus far exists that sustaining abstinence post-buprenorphine maintenance is any more likely than post-methadone maintenance, or post-heroin withdrawal. On the other side, going from heroin/other potent opioids to buprenorphine is generally harder than going from the same to methadone. For patients making decisions about whether to use buprenorphine or methadone, avoiding withdrawal symptoms is very important -- the discomfort which is more likely to occur while switching to buprenorphine from illicit opiates may interfere with daily life, whereas withdrawal symptoms while getting on methadone are less likely, and more easily remedied by increasing dosage. Many doctors believe buprenorphine has a ceiling, and further increases in buprenorphine dose will not ease the discomfort of a person switching from illicit opiates to buprenorphine, whereas methadone has no ceiling, and even the heaviest users' withdrawal symptoms can be stopped by an appropriate methadone dose.
=====What is buprenorphine?=====
* Buprenorphine is a prescription medicine used to treat adults who are addicted to opioid drugs (either prescription or illegal); as part of a complete treatment program that also includes counseling and behavioral therapy.
* Buprenorphine is a controlled substance (CIII) because it contains buprenorphine, which can be a target for people who abuse prescription medicines or street drugs. Keep your buprenorphine in a safe place to protect it from theft. Never give your buprenorphine to anyone else; it can cause death or harm them. Selling or giving away this medicine is against the law.
* It is not known if buprenorphine is safe or effective in children.


Buprenorphine, as a partial μ-opioid receptor agonist, has been claimed and is generally viewed to have a less euphoric effect compared to the full agonist methadone, and was therefore predicted less likely to be diverted to the black market (as reflected by its CIII status vs. methadone's more restrictive CII status), as well as that buprenorphine is generally accepted as unable to be abused (for euphoria) by those with a heroin or other potent opioid habit (however neither drug is supposed to have a euphoric effect when used long-term). However, in at least one study in which opiate users who were currently not using were given buprenorphine, several other opioids, and placebo intramusuclarly, subjects identified the drug they were injected with as heroin when it was actually buprenorphine.<ref>http://opioids.com/buprenorphine/buprenreward.html</ref> This evidence tends to support the contentions of those who reject the notion that buprenorphine, when injected, is only marginally euphoric, or significantly less euphoric than other opiates. It should be noted that, in an effort to prevent injection of the drug, the Suboxone formulation includes naloxone in addition to the buprenorphine. When naloxone is injected, it precipitates opiate withdrawal and blocks the effects of any opiate, thus making "getting high" on Suboxone an impossibility. (The naloxone does not precipitate withdrawal or block the effect of the buprenorphine when taken sublingually.) However, the Subutex formulation does not include naloxone and may thus be injected by users to achieve the effect which was sufficiently heroin-like as to fool experienced users. Methadone, on the other hand, is given to patients at clinics in solution, with large amounts of water. This makes injection difficult without evaporating the liquid and taking other measures. Therefore, injection of buprenorphine as found in the preparations provided to opiate users simpler than injection of methadone, although data on the relative incidence is not currently available. Thus far in the United States buprenorphine is far less often found on the black market vs. methadone, but most street heroin addicts don't even know it exists, and its (legitimate) usage is far less than methadone (and according to many newspapers "underused"). It should also be noted that the vast majority of the black market methadone does '''not''' come from prescriptions to opiate users, but rather from prescriptions of methadone for pain. Since buprenorphine is used rarely for this purpose in the United States due to its comparatively poor efficacy in pain management, this is not surprising.  In France where it is used more often than methadone there is more black market availability, although this and the apparent attraction is '''possibly''' due to a heroin dry-spell. Evidence indicates buprenorphine is often combined with [[benzodiazepines]] for more of an effect.  
=====Who should not take buprenorphine?=====
* Do not take buprenorphine if you are allergic to buprenorphine or naloxone.


====Blockade effect====
=====What should I tell my doctor before taking buprenorphine?=====
* Buprenorphine may not be right for you. Before taking buprenorphine, tell your doctor if you:
:* Have trouble breathing or lung problems
:* Have an enlarged prostate gland (men)
:* Have a head injury or brain problem
:* Have problems urinating
:* Have a curve in your spine that affects your breathing
:* Have liver or kidney problems
:* Have gallbladder problems
:* Have adrenal gland problems
:* Have [[Addison's disease]]
:* Have low thyroid ([[hypothyroidism]])
:* Have a history of alcoholism
:* Have mental problems such as hallucinations (seeing or hearing things that are not there)
:* Have any other medical condition
:* Are pregnant or plan to become pregnant. It is not known if buprenorphine will harm your unborn baby. If you take buprenorphine while pregnant, your baby may have symptoms of withdrawal at birth. Talk to your doctor if you are pregnant or plan to become pregnant.
:* Are breastfeeding or plan to breastfeed. buprenorphine can pass into your breast milk and may harm your baby. Talk to your doctor about the best way to feed your baby if you take buprenorphine. Monitor your baby for increased sleepiness and breathing problems.


The Suboxone preparation contains the μ-opioid receptor antagonist [[naloxone]] which is intended '''only''' to prevent abuse (i.e. injection) of the buprenorphine, '''not''', as is commonly misunderstood, to block the effects of other opiates. Buprenorphine itself is mixed agonist/'''antagonist''', and, as such, buprenorphine blocks the activity of other opiates and induces withdrawal in opiate dependent individuals who are currently physically dependent on another opiate. This is why users must wait until they are in withdrawal before beginning treatment with buprenorphine.  
* Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
* Buprenorphine may affect the way other medicines work and other medicines may affect how buprenorphine works. Some medicines may cause serious or life-threatening medical problems when taken with buprenorphine.
* Sometimes the doses of certain medicines and buprenorphine may need to be changed if used together. Do not take any medicine while using buprenorphine until you have talked with your doctor. Your doctor will tell you if it is safe to take other medicines while you are using buprenorphine.
* Be especially careful about taking other medicines that may make you sleepy, such as pain medicines, tranquilizers, sleeping pills, anxiety medicines, or antihistamines.
* Know the medicines you take. Keep a list of them to show your doctor or pharmacist each time you get a new medicine.


Buprenorphine itself binds more strongly to receptors in the brain than do other opioids, making it more difficult to become intoxicated via other opioids when buprenorphine is in the system, regardless of the presence of the naloxone. (Measurable, but small, amounts of naloxone can be absorbed and detected via the sublingual route, and while this is insignificant and has no subjective effect, there are anecdotal reports of hypersensitivity to naloxone in rare cases. These reports are not fully substantiated.) If enough buprenorphine is in the system, however, it has the same type of effect as naloxone, i.e. it completely or nearly completely blocks or reverses opiate effects from '''other''' opioids. 0.3 mg of buprenorphine parenterally is equivalent in antagonistic effect to between 0.4 and 2.0 mg of [[naloxone]] parenterally, but with a much longer half-life. Methadone also blocks the effects of other opioids, and at commonly used methadone maintenance doses, the degree of blockade is similar. Unlike buprenorphine, however, this is not due to any opiate antagonist-like action of methadone. Instead, daily use of methadone, like daily use of all opiate agonists, results in tolerance to all opiates, called [["cross-tolerance"]]. However, it is still possible to abuse other opioids on either treatment regime, although many people find "getting high" to be impossible.
=====How should I take buprenorphine?=====
In the case of preganancy, buprenorphine causes milder neo-natal withdrawals than methadone.<ref>G Fischer, P Etzersdorfer, H Eder, R Jagsch, M Langer, M Weninger (1998). Buprenorphine Maintenance in Pregnant Opioid Addicts. European Addiction Research;4 (suppl 1):32-36</ref> (and is one of the few cases where Subutex is likely to be used over Suboxone in the United States.) Thus, buprenorphine is preferable during pregnancy, although methadone and the common opiate agonists are safe.
* Always take buprenorphine 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 more often than prescribed by your doctor.
* You may be prescribed a dose of 2 or more buprenorphine sublingual tablets at the same time.
* Take buprenorphine 1 time a day.
* Do not cut, crush, break, chew or swallow the tablet. Your doctor should show you how to take buprenorphine the right way.
* Follow the same instructions every time you take a dose of buprenorphine.
* Buprenorphine comes in a blister pack with 10 blister units. Each blister unit contains a buprenorphine tablet.
* Take the dose prescribed by your doctor as follows:


Switching to buprenorphine from methadone is often difficult and withdrawals lasting several days or more are often encountered mostly when the methadone dose is any higher than 30 mg/day (the suggested and usual dose for switching to buprenorphine). A 30 mg dose of methadone is relatively low, and some patients have difficulty reaching that dose, for a variety of reasons.{{Fact|date=April 2007}} Healthy users of methadone who commit to a slow taper, however, frequently find success in tapering to 30 mg in order to switch to buprenorphine, as well as in tapering off of methadone completely without the use of buprenorphine. Switching to buprenorphine at higher doses of methadone may be uncomfortable for the user. One reason is that users must be in withdrawal before switching to buprenorphine, and users of opiates with long half-lives, like methadone, may need to wait several days after their last dose of methadone before they are fully in withdrawal and ready to begin buprenorphine. User of heroin, hydrocodone, oxycodone, and morphine, as well as most other common opiates, only need to wait a maximum of 24 hours before they are fully in withdrawal and ready to begin buprenorphine. For this reason, some doctors switch methadone users to a shorter acting opiate, such as morphine, before allowing withdrawal to occur and beginning buprenorphine. Unfortunately, due to the unique qualities of both methadone and buprenorphine, switching to and using buprenorphine during pregnancy instead of methadone is unlikely to be helpful, since the strain of withdrawal on the body is far more dangerous for a fetus than the use of an opiate such as methadone. Also, data regarding buprenorphine's safety during pregnancy is less available than data on methadone during pregnancy -- data which has established the safety of methadone during pregnancy and the lack of lasting effects on children of mothers on methadone during preganancy. On the other hand, switching from buprenorphine to methadone is relatively easy as methadone is a full opiate agonist which does not have a ceiling, and can stop the withdrawal symptoms of users at any dosage of other opiates, including buprenorphine.
[[File:Buprenorphoine patient information.png|thumb|none|400px|left|This image is provided by the National Library of Medicine.]]


===Inpatient rehabilitation===
* While buprenorphine is dissolving, do not chew or swallow the tablet because the medicine will not work as well.
The practice of using buprenorphine (Subutex or Suboxone) in an inpatient rehabilitation setting is increasing rapidly {{Fact|date=February 2007}}, whereas methadone-based detox is the standard. It is also being used in social model treatment settings. These rehabilitation programs consist of "detox" and "treatment" phases. The detoxification ("detox") phase consists of medically-supervised withdrawal from the drug of dependency on to buprenorphine, sometimes aided by the use of medications such as [[benzodiazepines]] like [[oxazepam]] or [[diazepam]] (modern milder tranquilizers that assist with anxiety, sleep, and muscle relaxation), [[clonidine]] (a blood-pressure medication that may reduce some opioid withdrawal symptoms), and [[NSAID|anti-inflammatory/pain relief]] drugs such as [[ibuprofen]]. Switching to buprenorphine from a short-acting drug including [[Heroin]], [[morphine]], [[fentanyl]], [[hydromorphone]] and [[hydrocodone|hydrocodone (Vicodin)]], or [[oxycodone|oxycodone (Oxycontin and Percocet)]] is not too difficult for most people, and as long as the patient waited until they were in full withdrawals or longer before starting the buprenorphine medication, little further acute symptoms are an issue; The patient needs to be stabilized on a proper dose and monitored regardless. Switching from methadone is much more difficult, and with all cases if the patient takes buprenorphine prematurely (before full withdrawal symptoms) it can precipitate worse withdrawals than would have been had if the person had waited properly, and they can be long-lasting.  
* Do not eat or drink anything until the buprenorphine tablet has completely dissolved.
The treatment phase begins once the patient is stabilized and receives medical clearance. This portion of treatment is comprised of multiple therapy sessions, which include both group and individual counseling with various chemical dependency counselors, psychologists, psychiatrists, social workers, and other professionals. Additionally, many treatment centers strongly base their treatment models on 12-step principles, such as those practiced by [[Alcoholics Anonymous]] and [[Narcotics Anonymous]]. [[Narcotics Anonymous]] and other 12-step programs do not have any organizational position on the use of any medically prescribed medications, it is each individual members personal decision to determine if their use of prescribed medications has compromised their sobriety or recovery. There are systems similar to or modeled after 12-step programs that accept its use and even acknowledge its power as a tool.
* Talking while the tablet is dissolving can affect how well the medicine in buprenorphine is absorbed.
* If you miss a dose of buprenorphine, 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 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 the right way.
* If you take too much buprenorphine go to the nearest hospital emergency room right away.


Patients who enter rehabilitation voluntarily (as opposed to those who are court-ordered) can often choose a facility with the option of only staying for detox. Alternatively they can enter treatment facilities that provide the option to complete both detox and longer-term treatment. Completing both increases the probability of success.. Abstinence alone has a very low efficacy in rehabilitating patients. In contrast, buprenorphine maintenance has a high efficacy <ref name="Johnson" /> <ref name="Schottenfeld" />.  Most rehabilitation programs do not have or do not allow scientific studies to be conducted to contrast to abstinence alone and buprenorphine or [[methadone]] maintenance, including [[Narcotics Anonymous]]. NA's 12 traditions and overriding principle of anonymity would make such research potentially contentious and internally problematic. Whilst the maintenance / abstinence debate is a hot topic and strong arguments in support of both [[Narcotics Anonymous]] and buprenorphine maintenance have been made, individuals tend to gravitate the alternative that works best for them. Furthermore, the two approaches need not necessarily be mutually exclusive.  Rehabilitation programs typically average about 30 days for primary care, but some may extend anywhere from 90 days to 6 months in an extended care unit. It is considered essential by the programs that administer them that patients in abstinence-based treatment form networks with other addiction survivors and engage in mutual-help groups, aftercare and other related activities after treatment in order to improve their chances of achieving long-term abstinence from opioids. Statistically, long-term abstinence is not widely prevalent.
=====What should I avoid while taking buprenorphine?=====
* Do not drive, operate heavy machinery, or perform any other dangerous activities until you know how this medication affects you. Buprenorphine can cause drowsiness and slow reaction times. This may happen more often in the first few weeks of treatment when your dose is being changed, but can also happen if you drink alcohol or take other sedative drugs when you take buprenorphine.
* You should not drink alcohol while taking buprenorphine, as this can lead to loss of consciousness or even death.


Buprenorphine is sometimes used only during the detox protocol with the purpose of reducing the patient's use of mood-altering substances.  It considerably reduces acute opioid withdrawal symptoms that are normally experienced by opioid-dependent patients on cessation of those opioids, including diarrhea, vomiting, fever, chills, cold sweats, muscle and bone aches, muscle cramps and spasms, restless legs, agitation, gooseflesh, insomnia, nausea, watery eyes, runny nose and post-nasal drip, nightmares, etc. The buprenorphine detox protocol usually lasts about 7-10 days, provided that the patient does not need to be detoxed from any additional addictive substances, as previously mentioned.
=====What are the possible side effects of buprenorphine?=====
* Buprenorphine can cause serious side effects, including:
:* See "What is the most important information I should know about buprenorphine?"
:* Respiratory problems. You have a higher risk of death and coma if you take buprenorphine with other medicines, such as benzodiazepines.
:* Sleepiness, dizziness, and problems with coordination
:* Dependency or abuse
:* Liver problems. Call your doctor right away if you notice any of these signs of liver problems: Your skin or the white part of your eyes turning yellow (jaundice), urine turning dark, stools turning light in color, you have less of an appetite, or you have stomach (abdominal) pain or nausea. Your doctor should do tests before you start taking and while you take buprenorphine.
:* Allergic reaction. You may have a rash, hives, swelling of your face, wheezing, or loss of blood pressure and consciousness. Call a doctor or get emergency help right away.
:* Opioid withdrawal. This can include: shaking, sweating more than normal, feeling hot or cold more than normal, runny nose, watery eyes, goose bumps, diarrhea, vomiting and muscle aches. Tell your doctor if you develop any of these symptoms
:* Decrease in blood pressure. You may feel dizzy if you get up too fast from sitting or lying down.


During this time, Suboxone or Subutex will be administered or the patient will be monitored taking the medication. Generally, the patient takes a single dose each day (a single dose may keep the patient comfortable for up to 48-72 hours, but medical professionals in many treatment facilities prescribe one or more than one dose every 24 hours to ensure that a consistent, active level of the medication remains in the patient's central nervous system, a key element of maintenance; also the level of dosage is usually around the previously described plateau, after which there is no noticeable increase in the effects of the drug. Typically, the first day dosage is no more than 8 mg or it may precipitate withdrawals as antagonistic effects overwhelm agonistic effects, after which initial daily dose totals around 8-16 mg (of either Suboxone or Subutex). The dosage is slowly tapered each day and the medication is usually stopped 36-48 hours prior to the end of the detox program, with the patient's vitals monitored up until discharge from the detox program.
=====The most common side effects of buprenorphine include:=====
* [[Headache]]
* [[Nausea]]
* [[Vomiting]]
* Increased [[sweating]]
* [[Constipation]]
* Drug withdrawal syndrome
* Decrease in sleep ([[insomnia]])
* [[Pain]]
* Swelling of the extremities


During the detox period of any situation, despite the evidence that suggests that the naloxone in Suboxone has no clinically significant effect (except for anecdotal reports of hypersensitivity in (if proven) rare cases), Subutex is urged over Suboxone by the manufacturer and you are likely to receive it during the first few days.
* Tell your doctor about any side effect that bothers you or that does not go away.
* These are not all the possible side effects of buprenorphine. For more information, ask your doctor or pharmacist.
* Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.


==References==
=====How should I store buprenorphine?=====
{{reflist|2}}
* Store buprenorphine at room temperature between 68°F to 77°F (20°C to 25°C).
* Keep buprenorphine in a safe place, out of the sight and reach of children.


{{Analgesics}}
=====How should I dispose of unused buprenorphine?=====
{{Drugs used in addictive disorders}}
* Dispose of unused buprenorphine sublingual tablets as soon as you no longer need them.
* Flush unused tablets down the toilet.


[[cs:Buprenorfin]]
=====General information about the safe and effective use of buprenorphine=====
[[da:Buprenorfin]]
* Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use buprenorphine for a condition for which it was not prescribed. Do not give buprenorphine to other people, even if they have the same symptoms you have. It may harm them and it is against the law.
[[de:Buprenorphin]]
* This Medication Guide summarizes the most important information about buprenorphine. If you would like more information, talk to your doctor or pharmacist. You can ask your doctor or pharmacist for information that is written for health professionals.
[[fr:Buprénorphine]]
* For more information, call 1-888-buprenorphine (1-888-982-7658).
[[hu:Buprenorfin]]
[[ja:ブプレノルフィン]]
[[no:Buprenorfin]]
[[pl:Buprenorfina]]
[[pt:Buprenorfina]]
[[ru:Бупренорфин]]
[[fi:Buprenorfiini]]
[[sv:Buprenorfin]]
[[th:บิวพรีนอร์ฟีน]]


=====What are the ingredients in buprenorphine?=====
* Active Ingredients: buprenorphine and naloxone
* Inactive Ingredients: mannitol, citric acid, sodium citrate, microcrystalline cellulose, croscarmellose sodium, sucralose, silicon dioxide, sodium stearyl fumarate, and menthol flavor.
* This Medication Guide has been approved by the U.S. Food and Drug Administration.
: Manufactured for Orexo US, Inc. by Orexo AB with AAIPharma Wilmington, North Carolina
: Distributed by Orexo US, Inc.
: New York, New York
: ZUBSOLV is a licensed trademark of Orexo US, Inc.
: © 2013 Orexo US, Inc. All rights reserved.
: Issued: 07/2013
: Printed in USA    Code # ZUB 01
|alcohol=Alcohol-Buprenorphine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
}}
{{PillImage
|fileName=Buprenorphine_HCl_NDC_00540177.jpg
|drugName=Buprenorphine HCl
|NDC=00540177
|drugAuthor=Roxane Laboratories, Inc
|ingredients=BUPRENORPHINE HYDROCHLORIDE[BUPRENORPHINE]
|pillImprint=54;411
|dosageValue=8
|dosageUnit=mg
|pillColor=White
|pillShape=Round
|pillSize=10
|pillScore=1
}}
{{LabelImage
|fileName=Buprenoprhine label.png
}}


[[Category:Drugs]]
[[Category:Drug]]
[[Category:Substance abuse]]
[[Category:Abuse]]
[[Category:Anesthesiology]]
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Latest revision as of 18:23, 18 August 2015

Buprenorphine (mucous membrane)
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]

Disclaimer

WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.

Overview

Buprenorphine (mucous membrane) is an opioid analgesic that is FDA approved for the treatment of chronic, severe pain in patients requiring long-term daily around-the-clock opioid analgesic. Common adverse reactions include application site erythema, application site irritation, application site rash, pruritus, constipation, nausea, vomiting, xerostomia, dizziness, headache, and somnolence.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

  • Prior to initiating, discontinue all other around-the-clock opioid drugs.
  • Pain, chronic (severe), in patients requiring long-term daily around-the-clock opioid analgesic: individualize dose; initial dose selection must take into account patient's prior analgesic treatment experience and risk factors for addiction, abuse, and misuse; use of 10, 15, and 20 mcg/hr strengths is restricted to opioid-tolerant patients only
  • Pain, chronic (severe), in patients requiring long-term daily around-the-clock opioid analgesic: (as first opioid) initial, 5 mcg/hr transdermally; titrate based on analgesic requirement and tolerance at a minimum interval of every 72 hours; replace patch every 7 days; max 20 mcg/hr.
  • Pain, chronic (severe), in patients requiring long-term daily around-the-clock opioid analgesic: (prior total daily dose of opioids less than 30 mg of oral morphine equivalents per day) discontinue around-the-clock opioid drugs; initiate 5 mcg/hr transdermally at next dosing interval; replace patch every 7 days; titrate based on analgesic requirement and tolerance at a minimum interval of every 72 hours; max 20 mcg/hr.
  • Pain, chronic (severe), in patients requiring long-term daily around-the-clock opioid analgesic: (prior total daily dose of opioids between 30 and 80 mg of oral morphine equivalents per day) taper previous around-the-clock opioids for up to 7 days to no more than 30 mg of oral morphine equivalents per day; then discontinue around-the-clock opioid drugs and initiate 10 mcg/hr TRANSDERMALLY at next dosing interval; replace patch every 7 days; titrate based on analgesic requirement and tolerance at a minimum interval of every 72 hours; max 20 mcg/hr; short-acting analgesics may be used as needed until efficacy is attained
  • Pain, chronic (severe), in patients requiring long-term daily around-the-clock opioid analgesic: (total daily dose of opioids greater than 80 mg of oral morphine equivalents per day) consider an alternative analgesic as buprenorphine 20 mcg/hr may not provide adequate analgesia

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information about Off-Label Guideline-Supported Use of Buprenorphine in adult patients.

Non–Guideline-Supported Use

There is limited information about Off-Label Non–Guideline-Supported Use of Buprenorphine in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information about safety and efficacy of buprenorphine transdermal have not been established in patients younger than 18 years.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information about Off-Label Guideline-Supported Use of Buprenorphine in pediatric patients.

Non–Guideline-Supported Use

There is limited information about Off-Label Non–Guideline-Supported Use of Buprenorphine in pediatric patients.

Contraindications

  • Buprenorphine sublingual tablet should not be administered to patients who have been shown to be hypersensitive to buprenorphine or naloxone as serious adverse reactions, including anaphylactic shock, have been reported.

Warnings

Abuse Potential
  • Buprenorphine can be abused in a manner similar to other opioids, legal or illicit. Prescribe and dispense buprenorphine with appropriate precautions to minimize risk of misuse, abuse, or diversion, and ensure appropriate protection from theft, including in the home. Clinical monitoring appropriate to the patient's level of stability is essential. Multiple refills should not be prescribed early in treatment or without appropriate patient follow-up visits.
Respiratory Depression
  • Buprenorphine, particularly when taken by the IV route, in combination with benzodiazepines or other CNS depressants (including alcohol), has been associated with significant respiratory depression and death. Many, but not all, post-marketing reports regarding coma and death associated with the concomitant use of buprenorphine and benzodiazepines involved misuse by self-injection. Deaths have also been reported in association with concomitant administration of buprenorphine with other depressants such as alcohol or other CNS depressant drugs. Patients should be warned of the potential danger of self-administration of benzodiazepines or other depressants while under treatment with buprenorphine sublingual tablets.
  • In the case of overdose, the primary management should be the re-establishment of adequate ventilation with mechanical assistance of respiration, if required. Naloxone may be of value for the management of buprenorphine overdose. Higher than normal doses and repeated administration may be necessary.
  • Buprenorphine sublingual tablets should be used with caution in patients with compromised respiratory function (e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression).
CNS Depression
Unintentional Pediatric Exposure
  • Buprenorphine can cause fatal respiratory depression in children who are accidentally exposed to it. Store buprenorphine containing medications safely out of the sight and reach of children and destroy any unused medication appropriately.
Dependence
  • Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation or rapid taper. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset. Buprenorphine can be abused in a manner similar to other opioids. This should be considered when prescribing or dispensing buprenorphine in situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion.
Hepatitis, Hepatic Events
  • Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine in clinical trials and through post-marketing adverse event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injecting drug use may have played a causative or contributory role. In other cases, insufficient data were available to determine the etiology of the abnormality. Withdrawal of buprenorphine has resulted in amelioration of acute hepatitis in some cases; however, in other cases no dose reduction was necessary. The possibility exists that buprenorphine had a causative or contributory role in the development of the hepatic abnormality in some cases. Liver function tests, prior to initiation of treatment is recommended to establish a baseline. Periodic monitoring of liver function during treatment is also recommended. A biological and etiological evaluation is recommended when a hepatic event is suspected. Depending on the case, buprenorphine sublingual tablet may need to be carefully discontinued to prevent withdrawal signs and symptoms and a return by the patient to illicit drug use, and strict monitoring of the patient should be initiated.
Allergic Reactions
  • Cases of hypersensitivity to buprenorphine and naloxone containing products have been reported both in clinical trials and in the post-marketing experience. cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. the most common signs and symptoms include rashes, hives, and pruritus. a history of hypersensitivity to buprenorphine or naloxone is a contraindication to the use of buprenorphine sublingual tablet.
Precipitation of Opioid Withdrawal Signs and Symptoms
  • Because it contains naloxone, buprenorphine msublingual tablet is likely to produce withdrawal signs and symptoms if misused parenterally by individuals dependent on full opioid agonists such as heroin, morphine, or methadone. Because of the partial agonist properties of buprenorphine, buprenorphine sublingual tablet may precipitate opioid withdrawal signs and symptoms in such persons if administered sublingually before the agonist effects of the opioid have subsided.
Neonatal Abstinence Syndrome
Use in Opioid Naïve Patients
  • There have been reported deaths of opioid naive individuals who received a 2 mg dose of buprenorphine as a sublingual tablet for analgesia. buprenorphine sublingual tablet is not appropriate as an analgesic.
Impairment of Ability to Drive or Operate Machinery
  • Buprenorphine sublingual tablet may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery, especially during treatment induction and dose adjustment. Patients should be cautioned about driving or operating hazardous machinery until they are reasonably certain that buprenorphine sublingual tablet therapy does not adversely affect his or her ability to engage in such activities.
Orthostatic Hypotension
Elevation of Cerebrospinal Fluid Pressure
  • Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal pressure may be increased. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation.
Elevation of Intracholedochal Pressure
  • Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract.
Effects in Acute Abdominal Conditions
  • As with other opioids, buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.
General Precautions

Adverse Reactions

Clinical Trials Experience

  • Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Clinical Trials Experience
  • The safety of buprenorphine/naloxone was evaluated in 497 opioid-dependent subjects. The prospective evaluation of buprenorphine/naloxone was supported by clinical trials using buprenorphine tablets without naloxone and other trials using buprenorphine sublingual solutions. In total, safety data were available from 3214 opioid-dependent subjects exposed to buprenorphine at doses in the range used in treatment of opioid addiction.
This image is provided by the National Library of Medicine.

Postmarketing Experience

  • The following adverse reactions have been identified during post-approval use of buprenorphine and naloxone sublingual tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate a causal relationship to drug exposure.
  • The most frequently reported post-marketing adverse event not observed in clinical trials was peripheral edema.

Drug Interactions

Cytochrome P-450 3A4 (CYP3A4) Inhibitors and Inducers
  • Buprenorphine is metabolized to norbuprenorphine primarily by cytochrome CYP3A4; therefore, potential interactions may occur when buprenorphine sublingual tablets is given concurrently with agents that affect CYP3A4 activity. The concomitant use of buprenorphine sublingual tablet with CYP3A4 inhibitors (e.g., azole antifungals such as ketoconazole, macrolide antibiotics such as erythromycin, and HIV protease inhibitors) should be monitored and may require dose-reduction of one or both agents.
  • The interaction of buprenorphine with CYP3A4 inducers has not been studied; therefore, it is recommended that patients receiving buprenorphine sublingual tablets be monitored for signs and symptoms of opioid withdrawal if inducers of CYP3A4 (e.g., efavirenz, phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered.
Antiretrovirals
  • Three classes of antiretroviral agents have been evaluated for CYP3A4 interactions with buprenorphine. Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine and etravirine are known CYP3A inducers whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects. It is recommended that patients who are on chronic buprenorphine treatment have their dose monitored if NNRTIs are added to their treatment regimen. Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly. Monitoring of patients taking buprenorphine and atazanavir with and without ritonavir is recommended, and dose reduction of buprenorphine may be warranted.
Benzodiazepines
  • There have been a number of post-marketing reports regarding coma and death associated with the concomitant use of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists. Buprenorphine sublingual tablets should be prescribed with caution to patients taking benzodiazepines or other drugs that act on the CNS, regardless of whether these drugs are taken on the advice of a physician or are being abused/misused. Patients should be warned that it is extremely dangerous to self-administer non-prescribed benzodiazepines while taking buprenorphine sublingual tablets, and should also be cautioned to use benzodiazepines concurrently with buprenorphine sublingual tablets only as directed by their physician.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C

Risk Summary
  • There are no adequate and well-controlled studies of buprenorphine sublingual tablets or buprenorphine/naloxone in pregnant women. . Limited published data on use of buprenorphine, the active ingredient in buprenorphine, in pregnancy, have not shown an increased risk of major malformations. All pregnancies, regardless of drug exposure, have a background risk of 2-4% for major birth defects, and 15-20% for pregnancy loss. Reproductive and developmental studies in rats and rabbits identified adverse events at clinically relevant doses. Pre- and postnatal development studies in rats demonstrated dystocia, increased neonatal deaths, and developmental delays. No clear teratogenic effects were seen with a range of doses equivalent to or greater than the human dose. However, in a few studies, some events such as acephalus, omphalocele, and skeletal abnormalities were observed but these findings were not clearly treatment-related. Embryofetal death was also observed in both rats and rabbits.
  • Buprenorphine sublingual tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Clinical Considerations
  • Disease-associated maternal and embryo-fetal risk
  • Fetal/neonatal adverse reactions


Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Buprenorphine (mucous membrane) in women who are pregnant.

Labor and Delivery

  • As with all opioids, use of buprenorphine prior to delivery may result in respiratory depression in the newborn. Closely monitor neonates for signs of respiratory depression. An opioid antagonist such as naloxone should be available for reversal of opioid induced respiratory depression in the neonate.
Data
  • Human Data
  • Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine during pregnancy. Limited published data on malformations from trials, observational studies, case series, and case reports on buprenorphine use in pregnancy have not shown an increased risk of major malformations. Based on these studies the incidence of neonatal abstinence syndrome is not clear and there does not appear to be a dose-response relationship.
  • Animal Data
  • Buprenorphine has been shown to have differences in bioavailability compared to other buprenorphine/naloxone-containing sublingual products. The exposure margins listed below are based on body surface area comparisons (mg/m2) to the recommended human sublingual dose of 16 mg buprenorphine via Suboxone, which is equivalent to a human sublingual dose of 11.4 mg buprenorphine via Zubsolv.
  • Effects on embryo-fetal development were studied in Sprague-Dawley rats and Russian white rabbits following oral (1:1) and intramuscular (IM) (3:2) administration of mixtures of buprenorphine and naloxone. Following oral administration to rats and rabbits, no teratogenic effects were observed at buprenorphine doses up to 250 mg/kg/day and 40 mg/kg/day, respectively (estimated exposure approximately 150 times and 50 times, respectively, the recommended human sublingual dose). No definitive drug-related teratogenic effects were observed in rats and rabbits at IM doses up to 30 mg/kg/day (estimated exposure approximately 20 times and 35 times, respectively, the recommended human sublingual dose). Acephalus was observed in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group. Following oral administration of buprenorphine to rats, dose-related post-implantation losses, evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure approximately 6 times the recommended human sublingual dose). In the rabbit, increased post-implantation losses occurred at an oral dose of 40 mg/kg/day. Following IM administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live fetuses and increases in resorptions, occurred at 30 mg/kg/day. Buprenorphine was not teratogenic in rats or rabbits after IM or subcutaneous (SC) doses up to 5 mg/kg/day (estimated exposure was approximately 3 and 6 times, respectively, the recommended human sublingual dose), after IV doses up to 0.8 mg/kg/day (estimated exposure was approximately 0.5 times and equal to, respectively, the recommended human sublingual dose), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 95 times the recommended human sublingual dose) and 25 mg/kg/day in rabbits (estimated exposure was approximately 30 times the recommended human sublingual dose). Significant increases in skeletal abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC administration of 1 mg/kg/day and up (estimated exposure was approximately 0.6 times the recommended human sublingual dose), but were not observed at oral doses up to 160 mg/kg/day. Increases in skeletal abnormalities in rabbits after IM administration of 5 mg/kg/day (estimated exposure was approximately 6 times the recommended human sublingual dose) or oral administration of 1 mg/kg/day or greater (estimated exposure was approximately equal to the recommended human sublingual dose) were not statistically significant.
  • In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 mg/kg/day or greater and post-implantation losses that were statistically significant at IV doses of 0.2 mg/kg/day or greater (estimated exposure approximately 0.3 times the recommended human sublingual dose).
  • Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine 5 mg/kg/day (approximately 3 times the recommended human sublingual dose). Fertility, peri-, and post-natal development studies with buprenorphine in rats indicated increases in neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 0.5 times the recommended human sublingual dose), after IM doses of 0.5 mg/kg/day and up (approximately 0.3 times the recommended human sublingual dose), and after SC doses of 0.1 mg/kg/day and up (approximately 0.06 times the recommended human sublingual dose). An apparent lack of milk production during these studies likely contributed to the decreased pup viability and lactation indices. Delays in the occurrence of righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day (approximately 50 times the recommended human sublingual dose).

Nursing Mothers

Risk Summary
  • Based on two studies in 13 lactating women, buprenorphine and its metabolite norbuprenorphine are present in low levels in human milk and infant urine, and available data have not shown adverse reactions in breastfed infants . There are no data on the combination product buprenorphine/naloxone in breastfeeding , however oral absorption of naloxone is minimal. Caution should be exercised when Zubsolv is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Zubsolv and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.
Clinical Considerations
  • Advise the nursing mother taking Zubsolv to monitor the infant for increased drowsiness and breathing difficulties.
  • Data
  • Based on limited data from a study of 6 lactating women who were taking a median oral dose of buprenorphine of 0.29 mg/kg/day 5-8 days after delivery, breast milk contained a median infant dose of 0.42 mcg/kg/day of buprenorphine and 0.33 mg/kg/day of norbuprenorphine, which are equal to 0.2% and 0.12% of the maternal weight-adjusted dose.
  • Based on limited data from a study of 7 lactating women who were taking a median oral dose of buprenorphine of 7 mg/day an average of 1.12 months after delivery, the mean milk concentrations of buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L respectively. Based on the limited data from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively breastfed infant would receive an estimated mean of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of norbuprenorphine, which are 0.38% and 0.18% of the maternal weight-adjusted dose.
  • No adverse reactions were observed in the infants in these two studies.

Pediatric Use

  • The safety and effectiveness of buprenorphine sublingual tablets have not been established in pediatric patients. This product is not appropriate for the treatment of neonatal abstinence syndrome in neonates, because it contains naloxone, an opioid antagonist.

Geriatic Use

  • Clinical studies of buprenorphine/naloxone sublingual tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Gender

There is no FDA guidance on the use of Buprenorphine (mucous membrane) with respect to specific gender populations.

Race

There is no FDA guidance on the use of Buprenorphine (mucous membrane) with respect to specific racial populations.

Renal Impairment

  • No differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent and 6 normal patients following IV administration of 0.3 mg buprenorphine. The effects of renal failure on naloxone pharmacokinetics are unknown.

Hepatic Impairment

  • The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone is unknown. Since both drugs are extensively metabolized, the plasma levels will be expected to be higher in patients with moderate and severe hepatic impairment. However, it is not known whether both drugs are affected to the same degree. Therefore, dosage should be adjusted and patients should be watched for signs and symptoms of precipitated opioid withdrawal.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Buprenorphine (mucous membrane) in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Buprenorphine (mucous membrane) in patients who are immunocompromised.

Administration and Monitoring

Administration

  • Do not cut, chew, or swallow buprenorphine sublingual tablets. ZUBSOLV sublingual tablet should be placed under the tongue until dissolved. The dissolve time for Zubsolv varies between individuals, and the median dissolve time observed was 5 minutes. For dosages requiring more than one sublingual tablet, place all tablets in different places under the tongue at the same time. Patients should keep the tablets under the tongue until dissolved; swallowing the tablets reduces the bioavailability of the drug. Advise patients not to eat or drink anything until the tablet is completely dissolved. To ensure consistency in bioavailability, patients should follow the same manner of dosing with continued use of the product.
  • If a sequential mode of administration is preferred, patients should follow the same manner of dosing with continued use of the product, to ensure consistency in bioavailability.
  • Proper administration technique should be demonstrated to the patient.

Monitoring

There is limited information regarding Buprenorphine (mucous membrane) Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Buprenorphine (mucous membrane) and IV administrations.

Overdosage

  • The manifestations of acute overdose include pinpoint pupils, sedation, hypotension, respiratory depression, and death.
  • In the event of overdose, the respiratory and cardiac status of the patient should be monitored carefully. When respiratory or cardiac functions are depressed, primary attention should be given to the re-establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Oxygen, IV fluids, vasopressors, and other supportive measures should be employed as indicated.
  • In the case of overdose, the primary management should be the re-establishment of adequate ventilation with mechanical assistance of respiration, if required. Naloxone may be of value for the management of buprenorphine overdose. Higher than normal doses and repeated administration may be necessary. The long duration of action of ZUBSOLV should be taken into consideration when determining the length of treatment and medical surveillance needed to reverse the effects of an overdose. Insufficient duration of monitoring may put patients at risk.

Pharmacology

Template:Px
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Buprenorphine (mucous membrane)
Systematic (IUPAC) name
(2S)-2-[(5R,6R,7R,14S)-9α-Cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylbutan-2-ol
Identifiers
CAS number 52485-79-7
ATC code N02AE01 N07BC01 (WHO)
PubChem 644073
DrugBank DB00921
Chemical data
Formula Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox 
Mol. mass 467.64 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 55%(sublingual)[1]/48.2% +/- 8.35%(intranasal)[2]
Protein binding 96%
Metabolism hepatic
CYP3A4, CYP2C8
Half life 20–70, mean 37 hours
Excretion biliary and renal
Therapeutic considerations
Pregnancy cat.

C(AU) C(US)

Legal status

Controlled (S8)(AU) Class C(UK) Schedule III (USA)

Routes sublingual, IM, IV, transdermal, intranasal, rectally

on

Mechanism of Action

  • Buprenorphine sublingual tablet contains buprenorphine and naloxone. Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor. Naloxone is a potent antagonist at mu-opioid receptors and produces opioid withdrawal signs and symptoms, if administered parenterally, in individuals physically dependent on full opioid agonists.

Structure

  • ZUBSOLV (buprenorphine and naloxone) sublingual tablets are white menthol-flavored tablets in a triangular shape for the lower dosage strength (1.4 mg /0.36 mg) and a round shape for the higher dosage strength (5.7 mg/1.4 mg). They are debossed with the respective dosage strength of buprenorphine. They contain buprenorphine HCl, a mu-opioid receptor partial agonist and a kappa-opioid receptor antagonist, and naloxone HCl dihydrate, an opioid receptor antagonist, at a ratio of 4:1 (ratio of free bases). ZUBSOLV is intended for sublingual administration and is available in two dosage strengths, 1.4 mg buprenorphine with 0.36 mg naloxone and 5.7 mg buprenorphine with 1.4 mg naloxone. Each sublingual tablet also contains mannitol, citric acid, sodium citrate, microcrystalline cellulose, croscarmellose sodium, sucralose, menthol, silicon dioxide and sodium stearyl fumarate and menthol flavor.
  • Chemically, buprenorphine HCl is (2S)-2-[17-(cyclopropylmethyl)-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol hydrochloride. It has the following chemical structure:
This image is provided by the National Library of Medicine.
  • Buprenorphine HCl has the molecular formula C29 H41 NO4 • HCl and the molecular weight is 504.10. It is a white or off-white crystalline powder, sparingly soluble in water, freely soluble in methanol, soluble in alcohol, and practically insoluble in cyclohexane.
  • Chemically, naloxone HCl dihydrate is 17-Allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride dihydrate. It has the following chemical structure:
This image is provided by the National Library of Medicine.
  • Naloxone HCl dihydrate has the molecular formula C19H21NO4 • HCl • 2H20 and the molecular weight is 399.87. It is a white to slightly off-white powder and is freely soluble in water, soluble in alcohol, and practically insoluble in toluene and ether.

Pharmacodynamics

  • ZUBSOLV has been shown to have different bioavailability compared to SUBOXONE tablet. One ZUBSOLV 5.7 mg/1.4 mg tablet provides equivalent buprenorphine exposure and 12% lower naloxone exposure to one SUBOXONE 8 mg/2 mg tablet. The pharmacodynamic information of other currently marketed buprenorphine/naloxone-containing sublingual products is not directly comparable on a mg basis to ZUBSOLV.
Subjective Effects
  • Comparisons of buprenorphine to full opioid agonists such as methadone and hydromorphone suggest that sublingual buprenorphine produces typical opioid agonist effects which are limited by a ceiling effect.
  • In opioid-experienced subjects who were not physically dependent, acute sublingual doses of Suboxone tablets produced opioid agonist effects which reached a maximum between doses of 8/2 mg and 16/4 mg buprenorphine/naloxone.
  • Opioid agonist ceiling-effects were also observed in a double-blind, parallel group, dose-ranging comparison of single doses of buprenorphine sublingual solution (1, 2, 4, 8, 16, or 32 mg), placebo and a full agonist control at various doses. The treatments were given in ascending dose order at intervals of at least one week to 16 opioid-experienced subjects who were not physically dependent. Both active drugs produced typical opioid agonist effects. For all measures for which the drugs produced an effect, buprenorphine produced a dose-related response. However, in each case, there was a dose that produced no further effect. In contrast, the highest dose of the full agonist control always produced the greatest effects. Agonist objective rating scores remained elevated for the higher doses of buprenorphine (8-32 mg) longer than for the lower doses and did not return to baseline until 48 hours after drug administration. The onset of effects appeared more rapidly with buprenorphine than with the full agonist control, with most doses nearing peak effect after 100 minutes for buprenorphine compared to 150 minutes for the full agonist control.
Physiologic Effects
  • Buprenorphine in IV (2, 4, 8, 12 and 16 mg) and sublingual (12 mg) doses has been administered to opioid-experienced subjects who were not physically dependent to examine cardiovascular, respiratory, and subjective effects at doses comparable to those used for treatment of opioid dependence. Compared to placebo, there were no statistically significant differences among any of the treatment conditions for blood pressure, heart rate, respiratory rate, O2 saturation, or skin temperature across time. Systolic BP was higher in the 8 mg group than placebo (3-hour AUC values). Minimum and maximum effects were similar across all treatments. Subjects remained responsive to low voice and responded to computer prompts. Some subjects showed irritability, but no other changes were observed.
  • The respiratory effects of sublingual buprenorphine were compared with the effects of methadone in a double-blind, parallel group, dose ranging comparison of single doses of buprenorphine sublingual solution (1, 2, 4, 8, 16, or 32 mg) and oral methadone (15, 30, 45, or 60 mg) in non-dependent, opioid-experienced volunteers. In this study, hypoventilation not requiring medical intervention was reported more frequently after buprenorphine doses of 4 mg and higher than after methadone. Both drugs decreased O2 saturation to the same degree.
Effect of Naloxone
  • Physiologic and subjective effects following acute sublingual administration of buprenorphine tablets and Suboxone tablets were similar at equivalent dose levels of buprenorphine. Naloxone had no clinically significant effect when administered by the sublingual route, although blood levels of the drug were measurable. Buprenorphine/naloxone, when administered sublingually to an opioid-dependent cohort, was recognized as an opioid agonist, whereas when administered intramuscularly, combinations of buprenorphine with naloxone produced opioid antagonist actions similar to naloxone. This finding suggests that the naloxone in buprenorphine/naloxone tablets may deter injection of buprenorphine/naloxone tablets by persons with active substantial heroin or other full mu-opioid dependence. However, clinicians should be aware that some opioid-dependent persons, particularly those with a low level of full mu-opioid physical dependence or those whose opioid physical dependence is predominantly to buprenorphine, abuse buprenorphine/naloxone combinations by the intravenous or intranasal route. In methadone-maintained patients and heroin-dependent subjects, IV administration of buprenorphine/naloxone combinations precipitated opioid withdrawal signs and symptoms and was perceived as unpleasant and dysphoric. In morphine-stabilized subjects, intravenously administered combinations of buprenorphine with naloxone produced opioid antagonist and withdrawal signs and symptoms that were ratio-dependent; the most intense withdrawal signs and symptoms were produced by 2:1 and 4:1 ratios, less intense by an 8:1 ratio.

Pharmacokinetics

Absorption
  • Plasma levels of buprenorphine and naloxone increased with the sublingual dose of ZUBSOLV sublingual tablet. There was wide inter-patient variability in the sublingual absorption of buprenorphine and naloxone, but within subjects the variability was low. Both Cmax and AUC of buprenorphine increased with the increase in dose (in the range of 1.4 to 11.4 mg), although the increase was not directly dose-proportional. Naloxone did not affect the pharmacokinetics of buprenorphine.
  • Buprenorphine has been shown to have different bioavailability compared to SUBOXONE tablet. One ZUBSOLV 5.7 mg/1.4 mg tablet provides equivalent buprenorphine exposure and 12% lower naloxone exposure to one SUBOXONE 8 mg/2 mg tablet.
Distribution
  • Buprenorphine is approximately 96% protein bound, primarily to alpha and beta globulin.
  • Naloxone is approximately 45% protein bound, primarily to albumin.
Metabolism
  • Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation. The N-dealkylation pathway is mediated primarily by the CYP3A4. Norbuprenorphine, the major metabolite, can further undergo glucuronidation. Norbuprenorphine has been found to bind opioid receptors in-vitro; however, it has not been studied clinically for opioid-like activity. Naloxone undergoes direct glucuronidation to naloxone-3-glucuronide as well as N-dealkylation, and reduction of the 6-oxo group.
Elimination
  • A mass balance study of buprenorphine showed complete recovery of radiolabel in urine (30%) and feces (69%) collected up to 11 days after dosing. Almost all of the dose was accounted for in terms of buprenorphine, norbuprenorphine, and two unidentified buprenorphine metabolites. In urine, most of buprenorphine and norbuprenorphine was conjugated (buprenorphine, 1% free and 9.4% conjugated; norbuprenorphine, 2.7% free and 11% conjugated). In feces, almost all of the buprenorphine and norbuprenorphine were free (buprenorphine, 33% free and 5% conjugated; norbuprenorphine, 21% free and 2% conjugated). Buprenorphine has a mean elimination half-life from plasma ranging from 24 to 42 hours and naloxone has a mean elimination half-life from plasma ranging from 2 to 12 hours.
Drug-drug Interactions
  • CYP3A4 Inhibitors and Inducers: Subjects receiving buprenorphine sublingual tablet should be monitored if inhibitors of CYP3A4 such as azole antifungal agents (e.g., ketoconazole), macrolide antibiotics (e.g., erythromycin) or HIV protease inhibitors and may require dose-reduction of one or both agents. The interaction of buprenorphine with all CYP3A4 inducers has not been studied, therefore it is recommended that patients receiving buprenorphine sublingual tablet be monitored for signs and symptoms of opioid withdrawal if inducers of CYP3A4 (e.g., phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered.
  • Buprenorphine has been found to be a CYP2D6 and CYP3A4 inhibitor and its major metabolite, norbuprenorphine, has been found to be a moderate CYP2D6 inhibitor in in-vitro studies employing human liver microsomes. However, the relatively low plasma concentrations of buprenorphine and norbuprenorphine resulting from therapeutic doses are not expected to raise significant drug-drug interaction concerns.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility
  • Buprenorphine has been shown to have differences in bioavailability compared to other buprenorphine/naloxone-containing sublingual products. The exposure margins listed below are based on body surface area comparisons (mg/m2) to the recommended human sublingual dose of 16 mg buprenorphine via Suboxone, which is equivalent to a human sublingual dose of 11.4 mg buprenorphine via ZUBSOLV.
Carcinogenicity
  • A carcinogenicity study of buprenorphine/naloxone (4:1 ratio of the free bases) was performed in Alderley Park rats. Buprenorphine/naloxone was administered in the diet at doses of approximately 7, 31, and 123 mg/kg/day for 104 weeks (estimated exposure was approximately 4, 18, and 44 times the recommended human sublingual dose based on buprenorphine AUC comparisons). A statistically significant increase in Leydig cell adenomas was observed in all dose groups. No other drug-related tumors were noted.
  • Carcinogenicity studies of buprenorphine were conducted in Sprague-Dawley rats and CD-1 mice. Buprenorphine was administered in the diet to rats at doses of 0.6, 5.5, and 56 mg/kg/day (estimated exposure was approximately 0.4, 3, and 35 times the recommended human sublingual dose) for 27 months. As in the buprenorphine/naloxone carcinogenicity study in rat, statistically significant dose-related increases in Leydig cell tumors occurred. In an 86-week study in CD-1 mice, buprenorphine was not carcinogenic at dietary doses up to 100 mg/kg/day (estimated exposure was approximately 30 times the recommended human sublingual dose).
Mutagenicity
  • The 4:1 combination of buprenorphine and naloxone was not mutagenic in a bacterial mutation assay (Ames test) using four strains of S. typhimurium and two strains of E. coli. The combination was not clastogenic in an in vitro cytogenetic assay in human lymphocytes or in an IV micronucleus test in the rat.
  • Buprenorphine was studied in a series of tests utilizing gene, chromosome, and DNA interactions in both prokaryotic and eukaryotic systems. Results were negative in yeast (S. cerevisiae) for recombinant, gene convertant, or forward mutations; negative in Bacillus subtilis "rec" assay, negative for clastogenicity in CHO cells, Chinese hamster bone marrow and spermatogonia cells, and negative in the mouse lymphoma L5178Y assay.
  • Results were equivocal in the Ames test: negative in studies in two laboratories, but positive for frame shift mutation at a high dose (5mg/plate) in a third study. Results were positive in the Green-Tweets (E. coli) survival test, positive in a DNA synthesis inhibition (DSI) test with testicular tissue from mice, for both in vivo and in vitro incorporation of [3H]thymidine, and positive in unscheduled DNA synthesis (UDS) test using testicular cells from mice.
Impairment of Fertility
  • Dietary administration of buprenorphine in the rat at dose levels of 500 ppm or greater (equivalent to approximately 47 mg/kg/day or greater; estimated exposure approximately 28 times the recommended human sublingual dose) produced a reduction in fertility demonstrated by reduced female conception rates. A dietary dose of 100 ppm (equivalent to approximately 10 mg/kg/day; estimated exposure approximately 6 times the recommended human sublingual dose) had no adverse effect on fertility.

Clinical Studies

There is limited information regarding Buprenorphine (mucous membrane) Clinical Studies in the drug label.

How Supplied

  • Buprenorphine sublingual tablets are,menthol-flavored white tablets supplied in aluminum/aluminum child resistant unit dose blister packages. Buprenorphine is available in two dosage strengths:
  • Buprenorphine/naloxone 1.4 mg/0.36 mg, triangular shape, and
  • Buprenorphine/naloxone 5.7 mg/1.4 mg, round shape
  • NDC 54123-914-30 (buprenorphine/naloxone 1.4 mg /0.36 mg) sublingual tablet – 3×10 tablets per carton
  • NDC 54123-957-30 (buprenorphine/naloxone 5.7 mg/1.4 mg) sublingual tablet– 3×10 tablets per carton

Storage

  • Store at 20-25°C (68-77°F), excursions permitted to 15-30°C (59-86°F)
  • Patients should be advised to store buprenorphine-containing medications safely and out of sight and reach of children. Destroy any unused medication appropriately

Images

Drug Images

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Patient Counseling Information

  • Before initiating treatment with buprenorphine sublingual tablets, explain the points listed below to caregivers and patients. Instruct patients to read the Medication Guide each time buprenorphine is dispensed because new information may be available.
  • Patients should be warned that it is extremely dangerous to self-administer non-prescribed benzodiazepines or other CNS depressants (including alcohol) while taking buprenorphine sublingual tablets. Patients prescribed benzodiazepines or other CNS depressants should be cautioned to use them only as directed by their physician.
  • Patients should be advised that buprenorphine sublingual tablets contain an opioid that can be a target for people who abuse prescription medications or street drugs. Patients should be cautioned to keep their tablets in a safe place, and to protect them from theft.
  • Patients should be instructed to keep buprenorphine sublingual tablets in a secure place, out of the sight and reach of children. Accidental or deliberate ingestion by a child may cause respiratory depression that can result in death. Patients should be advised that if a child is exposed to buprenorphine sublingual tablets, medical attention should be sought immediately.
  • Patients should be advised never to give buprenorphine sublingual tablets to anyone else, even if he or she has the same signs and symptoms. It may cause harm or death.
  • Patients should be advised that selling or giving away this medication is against the law.
  • Patients should be cautioned that buprenorphine sublingual tablets may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving or operating machinery. Caution should be taken especially during drug induction and dose adjustment and until individuals are reasonably certain that buprenorphine therapy does not adversely affect their ability to engage in such activities.
  • Patients should be advised not to change the dosage of buprenorphine sublingual tablets without consulting their physician.
  • Patients should be advised to take buprenorphine sublingual tablets once a day.
  • Patients should be advised that if they miss a dose of buprenorphine they should take it as soon as they remember. If it is almost time for the next dose, they should skip the missed dose and take the next dose at the regular time.
  • Patients should be informed that buprenorphine sublingual tablets can cause drug dependence and that withdrawal signs and symptoms may occur when the medication is discontinued.
  • Patients seeking to discontinue treatment with buprenorphine for opioid dependence should be advised to work closely with their physician on a tapering schedule and should be apprised of the potential to relapse to illicit drug use associated with discontinuation of opioid agonist/partial agonist medication-assisted treatment.
  • Patients should be cautioned that, like other opioids, buprenorphine sublingual tablets may produce orthostatic hypotension in ambulatory individuals.
  • Patients should inform their physician if any other prescription medications, over-the-counter medications, or herbal preparations are prescribed or currently being used.
  • Advise females of reproductive potential, who become pregnant or are planning to become pregnant, to consult their physician regarding the possible effects of using buprenorphine sublingual tablets during pregnancy.
  • Advise women who are breastfeeding to monitor the infant for drowsiness and difficulty breathing.
  • Patients should inform their family members that, in the event of emergency, the treating physician or emergency room staff should be informed that the patient is physically dependent on an opioid and that the patient is being treated with buprenorphine sublingual tablets.
  • Refer to the Medication Guide for additional information regarding the counseling information.
  • Disposal of Unused buprenorphine Sublingual Tablets
  • Unused buprenorphine sublingual tablets should be disposed of as soon as they are no longer needed. Unused tablets should be flushed down the toilet.
  • Manufactured for Orexo US, Inc. by Orexo AB with AAIPharma Wilmington, North Carolina
Distributed by Orexo US, Inc.
New York, New York
Buprenorphine is a licensed trademark of Orexo US, Inc.
© 2013 Orexo US, Inc. All rights reserved.
MEDICATION GUIDE
buprenorphine® (Zub-solve)
(buprenorphine and naloxone)
Sublingual Tablet (CIII)
IMPORTANT
  • Keep buprenorphine in a secure place away from children. If a child accidentally takes buprenorphine, this is a medical emergency and can result in death. Get emergency help right away.
  • Read this Medication Guide before you start taking buprenorphine and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor. Talk to your doctor or pharmacist if you have questions about buprenorphine.
  • nShare the important information in this Medication Guide with members of your household.
What is the most important information I should know about buprenorphine?
  • Buprenorphine can cause serious and life-threatening breathing problems. Call your doctor right away or get emergency help if:
  • You feel faint, dizzy, or confused
  • Your breathing gets much slower than is normal for you
  • These can be signs of an overdose or other serious problems.
  • Do not switch from buprenorphine to other medicines that contain buprenorphine without talking with your doctor. The amount of buprenorphine in a dose of buprenorphine is not the same as the amount of buprenorphine in other medicines that contain buprenorphine. Your doctor will prescribe a starting dose of buprenorphine that may be different than other buprenorphine containing medicines you may have been taking.
  • Buprenorphine contains an opioid that can cause physical dependence.
  • Do not stop taking buprenorphine without talking to your doctor. You could become sick with uncomfortable withdrawal signs and symptoms because your body has become used to this medicine.
  • Physical dependence is not the same as drug addiction.
  • Buprenorphine is not for occasional or "as needed" use.
  • An overdose, and even death, can happen if you take benzodiazepines, sedatives, tranquilizers, or alcohol while using buprenorphine. Ask your doctor what you should do if you are taking one of these.
  • Call a doctor or get emergency help right away if you:
  • Feel sleepy and uncoordinated
  • Have blurred vision
  • Have slurred speech
  • Cannot think well or clearly
  • Have slowed reflexes and breathing
  • Do not inject ("shoot-up") buprenorphine. Injecting buprenorphine may cause life-threatening infections and other serious health problems.
  • Injecting buprenorphine may cause serious withdrawal symptoms such as pain, cramps, vomiting, diarrhea, anxiety, sleep problems, and cravings.
  • In an emergency, have family members tell the emergency department staff that you are physically dependent on an opioid and are being treated with buprenorphine.
What is buprenorphine?
  • Buprenorphine is a prescription medicine used to treat adults who are addicted to opioid drugs (either prescription or illegal); as part of a complete treatment program that also includes counseling and behavioral therapy.
  • Buprenorphine is a controlled substance (CIII) because it contains buprenorphine, which can be a target for people who abuse prescription medicines or street drugs. Keep your buprenorphine in a safe place to protect it from theft. Never give your buprenorphine to anyone else; it can cause death or harm them. Selling or giving away this medicine is against the law.
  • It is not known if buprenorphine is safe or effective in children.
Who should not take buprenorphine?
  • Do not take buprenorphine if you are allergic to buprenorphine or naloxone.
What should I tell my doctor before taking buprenorphine?
  • Buprenorphine may not be right for you. Before taking buprenorphine, tell your doctor if you:
  • Have trouble breathing or lung problems
  • Have an enlarged prostate gland (men)
  • Have a head injury or brain problem
  • Have problems urinating
  • Have a curve in your spine that affects your breathing
  • Have liver or kidney problems
  • Have gallbladder problems
  • Have adrenal gland problems
  • Have Addison's disease
  • Have low thyroid (hypothyroidism)
  • Have a history of alcoholism
  • Have mental problems such as hallucinations (seeing or hearing things that are not there)
  • Have any other medical condition
  • Are pregnant or plan to become pregnant. It is not known if buprenorphine will harm your unborn baby. If you take buprenorphine while pregnant, your baby may have symptoms of withdrawal at birth. Talk to your doctor if you are pregnant or plan to become pregnant.
  • Are breastfeeding or plan to breastfeed. buprenorphine can pass into your breast milk and may harm your baby. Talk to your doctor about the best way to feed your baby if you take buprenorphine. Monitor your baby for increased sleepiness and breathing problems.
  • Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
  • Buprenorphine may affect the way other medicines work and other medicines may affect how buprenorphine works. Some medicines may cause serious or life-threatening medical problems when taken with buprenorphine.
  • Sometimes the doses of certain medicines and buprenorphine may need to be changed if used together. Do not take any medicine while using buprenorphine until you have talked with your doctor. Your doctor will tell you if it is safe to take other medicines while you are using buprenorphine.
  • Be especially careful about taking other medicines that may make you sleepy, such as pain medicines, tranquilizers, sleeping pills, anxiety medicines, or antihistamines.
  • Know the medicines you take. Keep a list of them to show your doctor or pharmacist each time you get a new medicine.
How should I take buprenorphine?
  • Always take buprenorphine 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 more often than prescribed by your doctor.
  • You may be prescribed a dose of 2 or more buprenorphine sublingual tablets at the same time.
  • Take buprenorphine 1 time a day.
  • Do not cut, crush, break, chew or swallow the tablet. Your doctor should show you how to take buprenorphine the right way.
  • Follow the same instructions every time you take a dose of buprenorphine.
  • Buprenorphine comes in a blister pack with 10 blister units. Each blister unit contains a buprenorphine tablet.
  • Take the dose prescribed by your doctor as follows:
This image is provided by the National Library of Medicine.
  • While buprenorphine is dissolving, do not chew or swallow the tablet because the medicine will not work as well.
  • Do not eat or drink anything until the buprenorphine tablet has completely dissolved.
  • Talking while the tablet is dissolving can affect how well the medicine in buprenorphine is absorbed.
  • If you miss a dose of buprenorphine, 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 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 the right way.
  • If you take too much buprenorphine go to the nearest hospital emergency room right away.
What should I avoid while taking buprenorphine?
  • Do not drive, operate heavy machinery, or perform any other dangerous activities until you know how this medication affects you. Buprenorphine can cause drowsiness and slow reaction times. This may happen more often in the first few weeks of treatment when your dose is being changed, but can also happen if you drink alcohol or take other sedative drugs when you take buprenorphine.
  • You should not drink alcohol while taking buprenorphine, as this can lead to loss of consciousness or even death.
What are the possible side effects of buprenorphine?
  • Buprenorphine can cause serious side effects, including:
  • See "What is the most important information I should know about buprenorphine?"
  • Respiratory problems. You have a higher risk of death and coma if you take buprenorphine with other medicines, such as benzodiazepines.
  • Sleepiness, dizziness, and problems with coordination
  • Dependency or abuse
  • Liver problems. Call your doctor right away if you notice any of these signs of liver problems: Your skin or the white part of your eyes turning yellow (jaundice), urine turning dark, stools turning light in color, you have less of an appetite, or you have stomach (abdominal) pain or nausea. Your doctor should do tests before you start taking and while you take buprenorphine.
  • Allergic reaction. You may have a rash, hives, swelling of your face, wheezing, or loss of blood pressure and consciousness. Call a doctor or get emergency help right away.
  • Opioid withdrawal. This can include: shaking, sweating more than normal, feeling hot or cold more than normal, runny nose, watery eyes, goose bumps, diarrhea, vomiting and muscle aches. Tell your doctor if you develop any of these symptoms
  • Decrease in blood pressure. You may feel dizzy if you get up too fast from sitting or lying down.
The most common side effects of buprenorphine include:
  • Tell your doctor about any side effect that bothers you or that does not go away.
  • These are not all the possible side effects of buprenorphine. For more information, ask your doctor or pharmacist.
  • Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
How should I store buprenorphine?
  • Store buprenorphine at room temperature between 68°F to 77°F (20°C to 25°C).
  • Keep buprenorphine in a safe place, out of the sight and reach of children.
How should I dispose of unused buprenorphine?
  • Dispose of unused buprenorphine sublingual tablets as soon as you no longer need them.
  • Flush unused tablets down the toilet.
General information about the safe and effective use of buprenorphine
  • Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use buprenorphine for a condition for which it was not prescribed. Do not give buprenorphine to other people, even if they have the same symptoms you have. It may harm them and it is against the law.
  • This Medication Guide summarizes the most important information about buprenorphine. If you would like more information, talk to your doctor or pharmacist. You can ask your doctor or pharmacist for information that is written for health professionals.
  • For more information, call 1-888-buprenorphine (1-888-982-7658).
What are the ingredients in buprenorphine?
  • Active Ingredients: buprenorphine and naloxone
  • Inactive Ingredients: mannitol, citric acid, sodium citrate, microcrystalline cellulose, croscarmellose sodium, sucralose, silicon dioxide, sodium stearyl fumarate, and menthol flavor.
  • This Medication Guide has been approved by the U.S. Food and Drug Administration.
Manufactured for Orexo US, Inc. by Orexo AB with AAIPharma Wilmington, North Carolina
Distributed by Orexo US, Inc.
New York, New York
ZUBSOLV is a licensed trademark of Orexo US, Inc.
© 2013 Orexo US, Inc. All rights reserved.
Issued: 07/2013
Printed in USA Code # ZUB 01

Precautions with Alcohol

Alcohol-Buprenorphine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Buprenorphine (mucous membrane) Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Buprenorphine (mucous membrane) Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

  1. PMID 2458208 (PMID 2458208)
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  2. PMID 2576057 (PMID 2576057)
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 |Pill Ingred=BUPRENORPHINE HYDROCHLORIDE[BUPRENORPHINE]|+sep=;
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 |Pill Dosage=8 mg
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 |Pill Shape=Round
 |Pill Size (mm)=10
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 |Drug Author=Roxane Laboratories, Inc
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