BUPRENAL

Buprenorphine is a weak partial mu-opioid receptor agonist and a weak kappa-opioid receptor antagonist used for the treatment of severe pain. 12, 15 It is also commonly used as an alternative to methadone for the treatment of severe opioid addiction.

Buprenorphine is commercially available as the brand name product Suboxone which is formulated in a 4:1 fixed-dose along with naloxone, a non-selective competitive opioid receptor antagonist.

Combination with naloxone is intended to reduce the abuse potential of Suboxone, as naloxone is poorly absorbed by the oral route (and has no effect when taken Oral), but would reverse the opioid agonist effects of buprenorphine if injected Intravenous. 14, 22 Buprenorphine has poor gastrointestinal absorption and is therefore formulated as a sublingual tablet.

Buprenorphine has a number of unique pharmacokinetic and pharmacodynamic properties that make it a preferred agent for the treatment of conditions requiring high doses of strong opioids.

For example, buprenorphine dissociates from opioid receptors very slowly, resulting in a long duration of action and relief from pain or withdrawal symptoms for upwards of 24-36 hours.

Use of once-daily buprenorphine may benefit individuals who have developed tolerance to other potent opioids and who require larger and more frequent doses.

Buprenorphine may also be a preferred agent over methadone (which is also commonly used to treat severe pain and opioid use disorder), as it has less effect on Qtc interval prolongation, 9, 10 fewer drug interactions, reduced risk of sexual side effects, 17 and an improved safety profile with a lower risk of overdose and respiratory depression. 6, 7, 8 Buprenorphine acts as a partial mu-opioid receptor agonist with a high affinity for the receptor, but lower intrinsic activity compared to other full mu-opioid agonists such as heroin, oxycodone, or methadone.

This means that buprenorphine preferentially binds the opioid receptor and displaces lower affinity opioids without activating the receptor to a comparable degree.

Clinically, this results in a slow onset of action and a clinical phenomenon known as the "ceiling effect" where once a certain dose is reached, buprenorphine's effects plateau.

This effect can be beneficial, however, as dose-related side effects such as respiratory depression, sedation, and intoxication also plateau at around 32 mg, resulting in a lower risk of overdose compared to methadone and other full agonist opioids. 4, 5 It also means that opioid-dependent patients do not experience sedation or euphoria at the same rate that they might experience with more potent opioids, improving quality of life for patients with severe pain and reducing the reinforcing effects of opioids which can lead to drug-seeking behaviours.

Treatment of opioid addiction with buprenorphine, methadone, or slow-release oral morphine (SROM) is termed Opioid Agonist Treatment (OAT) or Opioid Substitution Therapy (OST).

The intention of substitution of illicit opioids with the long-acting opioids used in OAT is to prevent withdrawal symptomns for 24-36 hours following dosing to ultimately reduce cravings and drug-seeking behaviours.

Use of

OAT is also intended to improved social stabilization including a reduction in crime rates, marginalization, incarceration, and use of illicit substances such as heroin or fentanyl.

Illegally purchased opioids can often be injected and may be laced with other substances that increase the risk of harm or overdose.

Provision of

OAT is often combined with education about harm reduction including use of clean needles and injection supplies in an effort to reduce the risks associated with injection drug use which includes contraction of HIV and Hepatitis C and other complications including skin infections, abscesses, or endocarditis.

Buprenorphine is available in different formulations, such as sublingual tablets, buccal films, transdermal films, and injections, alone or in combination with naloxone.

The buccal film, intramuscular or intravenous injection, and transdermal formulation are indicated for the management of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate. 21, 23, 24 The extended-release subcutaneous injections of buprenorphine are indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a single dose of a transmucosal buprenorphine product or who are already being treated with buprenorphine.

Injections are part of a complete treatment plan that includes counselling and psychosocial support.

Sublingual tablets and buccal films, in combination with naloxone, are indicated for the maintenance treatment of opioid dependence as part of a complete treatment plan that includes counselling and psychosocial support. 19,

Buprenorphine interacts predominately with the opioid mu-receptor.

These mu-binding sites are discretely distributed in the human brain, spinal cord, and other tissues.

In clinical settings, buprenorphine exerts its principal pharmacologic effects on the central nervous system.

Its primary actions of therapeutic value are analgesia and sedation.

In addition to analgesia, alterations in mood, euphoria and dysphoria, and drowsiness commonly occur.

Buprenorphine depresses the respiratory centers, depresses the cough reflex, and constricts the pupils.

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.

Abrupt discontinuation of treatment is not recommended as it may result in an opioid withdrawal syndrome that may be delayed in onset.

Signs and symptoms may include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning.

System (CNS) Depression and Overdose Buprenorphine has been associated with life-threatening respiratory depression and death.

Many, but not all, post-marketing reports regarding coma and death involved misuse by self-injection or were associated with the concomitant use of buprenorphine and benzodiazepines or other CNS depressant, including alcohol.

Use buprenorphine and naloxone sublingual tablets 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).

Naïve Patients There have been reported deaths of opioid-naïve individuals who received a 2 mg dose of buprenorphine as a sublingual tablet for analgesia.

Buprenorphine and naloxone sublingual tablets are not appropriate as an analgesic in opioid-naïve patients.

Precipitation of Opioid Withdrawal Signs and Symptoms If buprenorphine is started in opioid-dependent individuals, it will displace the other opioids and cause a phenomenon known as "precipitated withdrawal" which is characterized by a rapid and intense onset of withdrawal symptoms.

Individuals must therefore be in a state of mild to moderate withdrawal before starting therapy with buprenorphine.

Because it contains naloxone, buprenorphine and naloxone sublingual tablets are also highly likely to produce marked and intense withdrawal signs and symptoms if misused parenterally by individuals dependent on full opioid agonists such as heroin, morphine, or methadone.

Buprenorphine and other morphine-like opioids have been shown to decrease bowel motility and cause constipation.

Buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions and should be administered with caution to patients with dysfunction of the biliary tract.

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans.

They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.

The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date.

Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation.

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.

If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible.

If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids.

Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers.

Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency.

The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Use in Patients With Impaired Hepatic Function Buprenorphine/naloxone products are not recommended in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment.

The doses of buprenorphine and naloxone in this fixed-dose cannot be individually titrated, and hepatic impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine.

Therefore, patients with severe hepatic impairment will be exposed to substantially higher levels of naloxone than patients with normal hepatic function.

This may result in an increased risk of precipitated withdrawal at the beginning of treatment (induction) and may interfere with buprenorphine's efficacy throughout treatment.

In patients with moderate hepatic impairment, the differential reduction of naloxone clearance compared to buprenorphine clearance is not as great as in subjects with severe hepatic impairment.

However, buprenorphine/naloxone products are not recommended for initiation of (treatment induction) in patients with moderate hepatic impairment due to the increased risk of precipitated withdrawal.

Buprenorphine/naloxone products may be used with caution for maintenance treatment in patients with moderate hepatic impairment who have initiated treatment on a buprenorphine product without naloxone.

However, patients should be carefully monitored and consideration given to the possibility of naloxone interfering with buprenorphine's efficacy.

Risk of

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 and naloxone sublingual tablets 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.

Like other opioids, buprenorphine and naloxone sublingual tablets may produce orthostatic hypotension in ambulatory patients.

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.

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.

Kappa-type opioid receptor Antagonist Mu-type opioid receptor Partial agonist.

Bioavailablity of buprenorphine/naloxone is very high following intravenous or subcutaneous administration, lower by the sublingual or buccal route, and very low when administered by the oral route.

It is therefore provided as a sublingual tablet that is absorbed from the oral mucosa directly into systemic circulation.

Clinical pharmacokinetic studies found that 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 in a linear fashion with the increase in dose (in the range of 4-16 mg), although the increase was not directly dose-proportional.

Buprenorphine combination with naloxone (2 mg/0.5 mg) provided in sublingual tablets demonstrated a Cmax of 0.780 ng/mL with a Tmax of 1.50 hr and AUC of 7.651 ng.hr/mL.

Coadministration with naloxone does not effect the pharmacokinetics of buprenorphine.

Buprenorphine is highly lipophilic, and therefore extensively distributed, with rapid penetration through the blood-brain barrier.

The estimated volume of distribution is 188-335 L when given Intravenous.

It is able to cross into the placenta and breast milk.

Buprenorphine is metabolized to norbuprenorphine via Cytochrome P450 3A4/3A5-mediated N-dealkylation.

Buprenorphine and norbuprenorphine both also undergo glucuronidation to the inactive metabolites buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, respectively. 18, 22 While norbuprenorphine has been found to bind to opioid receptors in-vitro, brain concentrations are very low which suggests that it does not contribute to the clinical effects of buprenorphine.

Naloxone undergoes direct glucuronidation to naloxone-3-glucuronide as well as N-dealkylation, and reduction of the 6-oxo group.

Hover over products below to view reaction partners Buprenorphine Norbuprenorphine Hydroxynorbuprenorphine Hydroxybuprenorphine Hydroxynorbuprenorphine Buprenorphine glucuronide.

Buprenorphine, like morphine and other phenolic opioid analgesics, is metabolized by the liver and its clearance is related to hepatic blood flow.

It is primarily eliminated via feces (as free forms of buprenorphine and norbuprenorphine) while 10-30% of the dose is excreted in urine (as conjugated forms of buprenorphine and norbuprenorphine).

The overall mean elimination half-life of buprenorphine in plasma ranges from 31-42 hours, although the levels are very low 10 hours after dosing (majority of AUC of buprenorphine is captured within 10 hours), indicating that the effective half-life may be shorter.

Buprenorphine demonstrates slow dissociation kinetics (~166 min), which contributes to its long duration of action and allows for once-daily or even every-second-day dosing.

In clinical trial studies, the half-life of sublingually administered buprenorphine/naloxone 2 mg/0.5 mg was found to be 30.75 hours.

may be higher in children than in adults.

Plasma clearance rate, Intravenous administration, anaesthetized patients = 901.2 ± 39.7 mL/min Plasma clearance rate, Intravenous administration, healthy subjects = 1042-1280 mL/min.

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Manifestations of acute overdose include pinpoint pupils, sedation, hypotension, respiratory depression and death.

Buprenorphine sublingual tablet is contraindicated in patients with a history of hypersensitivity to buprenorphine, as serious adverse reactions, including anaphylactic shock, have been reported.

Hypersensitivity to buprenorphine.

Administer buprenorphine sublingual tablet sublingually as a single daily dose.

Strongly consider prescribing naloxone at the time buprenorphine sublingual tablet is initiated or renewed because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose.

To avoid precipitating withdrawal, induction with buprenorphine sublingual tablet should be undertaken when objective and clear signs of withdrawal are evident.

Buprenorphine and naloxone sublingual film or buprenorphine and naloxone sublingual tablet is generally initiated after two days of buprenorphine sublingual tablet titration.

Administer buprenorphine sublingual tablets as directed in the Full Prescribing Information.

Buprenorphine sublingual tablet must be administered whole.

Do not cut, chew, or swallow buprenorphine sublingual tablets.

When discontinuing treatment, gradually taper to avoid signs and symptoms of withdrawal. 2.1 Important Dosage and Administration Instructions Buprenorphine sublingual tablet is administered sublingually as a single daily dose.

Buprenorphine sublingual tablet does not contain naloxone and is preferred for use only during induction.

Following induction, buprenorphine and naloxone sublingual film or buprenorphine and naloxone sublingual tablet is preferred due to the presence of naloxone when clinical use includes unsupervised administration.

The use of buprenorphine sublingual tablet for unsupervised administration should be limited to those patients who cannot tolerate buprenorphine and naloxone sublingual film or buprenorphine and naloxone sublingual tablet; for example, those patients who have been shown to be hypersensitive to naloxone.

Medication should be prescribed in consideration of the frequency of visits.

Provision of multiple refills is not advised early in treatment or without appropriate patient follow-up visits. 2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver.

Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with buprenorphine sublingual tablet.

Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose.

Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with buprenorphine sublingual tablet itself.

Higher than normal doses and repeated administration of naloxone may be necessary due to the long duration of action of buprenorphine sublingual tablet and its affinity for the mu-opioid receptor.

Inform patients and caregivers of their options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) . 2.3 Induction Prior to induction, consideration should be given to the type of opioid dependence (i.e., long - or short-acting opioid products), the time since last opioid use, and the degree or level of opioid dependence.

Patients dependent on heroin or other short-acting opioid products: At treatment initiation, the first dose of buprenorphine sublingual tablet should be administered only when objective and clear signs of moderate opioid withdrawal appear, and not less than 4 hours after the patient last used an opioid.

It is recommended that an adequate treatment dose, titrated to clinical effectiveness, should be achieved as rapidly as possible.

The dosing on the initial day of treatment may be given in 2 mg to 4 mg increments if preferred.

In some studies, gradual induction over several days led to a high rate of dropout of buprenorphine patients during the induction period.

In a one-month study, patients received 8 mg of buprenorphine sublingual tablet on Day and 16 mg buprenorphine sublingual tablet on Day 2.

Day 3 onward, patients received either buprenorphine and naloxone sublingual tablet or buprenorphine sublingual tablet at the same buprenorphine dose as Day 2 based on their assigned treatment.

Induction in the studies of buprenorphine solution was accomplished over to 4 days, depending on the target dose.

Patients dependent on methadone or other long-acting opioid products: Patients dependent upon methadone or other long-acting opioid products may be more susceptible to precipitated and prolonged withdrawal during induction than those on short-acting opioid products; therefore, the first dose of buprenorphine sublingual tablet should only be administered when objective and clear signs of moderate opioid withdrawal appear, and generally not less than 24 hours after the patient last used a long-acting opioid product.

There is little controlled experience with the transfer of methadone-maintained patients to buprenorphine.

Available evidence suggests that withdrawal signs and symptoms are possible during induction onto buprenorphine.

Withdrawal appears more likely in patients maintained on higher doses of methadone (>30 mg) and when the first buprenorphine dose is administered shortly after the last methadone dose. 2.4 Maintenance Buprenorphine and naloxone sublingual tablet is preferred for maintenance treatment.

Where buprenorphine sublingual tablet is used in maintenance in patients who cannot tolerate the presence of naloxone, the dosage of buprenorphine sublingual tablets should be progressively adjusted in increments/decrements of 2 mg or 4 mg buprenorphine to a level that holds the patient in treatment and suppresses opioid withdrawal signs and symptoms.

After treatment induction and stabilization, the maintenance dose of buprenorphine sublingual tablet is generally in the range of 4 mg to 24 mg buprenorphine per day depending on the individual patient.

The recommended target dosage of buprenorphine sublingual tablet is 16 mg as a single daily dose.

Dosages higher than 24 mg have not been demonstrated to provide any clinical advantage.

When determining the prescription quantity for unsupervised administration, consider the patient’s level of stability, the security of his or her home situation, and other factors likely to affect the ability to manage supplies of take-home medication.

There is no maximum recommended duration of maintenance treatment.

Patients may require treatment indefinitely and should continue for as long as patients are benefiting and the use of buprenorphine sublingual tablet contributes to the intended treatment goals. 2.5 Method of Administration Buprenorphine sublingual tablet must be administered whole.

Do not cut, chew, or swallow buprenorphine sublingual tablet.

Advise patients not to eat or drink anything until the tablet is completely dissolved.

Buprenorphine sublingual tablet should be placed under the tongue until it is dissolved.

For doses requiring the use of more than two tablets, patients are advised to either place all the tablets at once or alternatively (if they cannot fit in more than two tablets comfortably), place two tablets at a time under the tongue.

Either way, the patients should continue to hold the tablets under the tongue until they dissolve; swallowing the tablets reduces the bioavailability of the drug.

To ensure consistency in bioavailability, patients should follow the same manner of dosing with continued use of the product.

Proper administration technique should be demonstrated to the patient.

Advise patients to do the following after the product has completely dissolved in the oral mucosa: take a sip of water, swish gently around the teeth and gums, and swallow.

Advise patients to wait for at least one hour after taking buprenorphine sublingual tablet before brushing teeth. 2.6 Clinical Supervision Treatment should be initiated with supervised administration, progressing to unsupervised administration as the patient’s clinical stability permits.

The use of buprenorphine sublingual tablets for unsupervised administration should be limited to those patients who cannot tolerate buprenorphine and naloxone sublingual tablet, for example those patients with known hypersensitivity to naloxone.

Buprenorphine and naloxone sublingual tablets and buprenorphine sublingual tablets are both subject to diversion and abuse.

When determining the prescription quantity for unsupervised administration, consider the patient’s level of stability, the security of his or her home situation, and other factors likely to affect the ability of the patient to manage supplies of take-home medication.

Ideally, patients should be seen at reasonable intervals (e.g., at least weekly during the first month of treatment) based upon the individual circumstances of the patient.

Provision of multiple refills is not advised early in treatment or without appropriate patient follow-up visits.

Periodic assessment is necessary to determine compliance with the dosing regimen, effectiveness of the treatment plan, and overall patient progress.

Once a stable dosage has been achieved and patient assessment (e.g., urine drug screening) does not indicate illicit drug use, less frequent follow-up visits may be appropriate.

A once-monthly visit schedule may be reasonable for patients on a stable dosage of medication who are making progress toward their treatment objectives.

Continuation or modification of pharmacotherapy should be based on the healthcare provider’s evaluation of treatment outcomes and objectives such as: 1.

Absence of medication toxicity. 2.

Absence of medical or behavioral adverse effects. 3.

Responsible handling of medications by the patient. 4.

Patient’s compliance with all elements of the treatment plan (including recovery-oriented activities, psychotherapy, and/or other psychosocial modalities). 5.

Abstinence from illicit drug use (including problematic alcohol and/or benzodiazepine use).

If treatment goals are not being achieved, the healthcare provider should re-evaluate the appropriateness of continuing the current treatment. 2.7 Patients With Severe Hepatic Impairment Consider reducing the starting and titration incremental dose by half and monitor for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine. 2.8 Unstable Patients Healthcare providers will need to decide when they cannot appropriately provide further management for particular patients.

For example, some patients may be abusing or dependent on various drugs, or unresponsive to psychosocial intervention such that the healthcare provider does not feel that he/she has the expertise to manage the patient.

In such cases, the healthcare provider may want to assess whether to refer the patient to a specialist or more intensive behavioral treatment environment.

Decisions should be based on a treatment plan established and agreed upon with the patient at the beginning of treatment.

Patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be provided with, or referred to, more intensive and structured treatment. 2.9 Discontinuing Treatment The decision to discontinue therapy with buprenorphine and naloxone sublingual tablets or buprenorphine sublingual tablets after a period of maintenance should be made as part of a comprehensive treatment plan.

Advise patients of the potential to relapse to illici.

Buprenorphine sublingual tablets containing 2 mg buprenorphine (as the free base, equivalent to 2.16 mg buprenorphine hydrochloride USP) are uncoated, round, biconvex, white to off-white, sublingual tablets, debossed with ‘459’ on one side and plain on other side and are supplied as: Bottles of with child-resistant cap…………….NDC 62756-459-83 Unit-Dose blister pack of 30 (3×10) tablets …….

NDC 62756-459-64 Buprenorphine sublingual tablets containing 8 mg buprenorphine (as the free base, equivalent to 8.64 mg buprenorphine hydrochloride USP) are uncoated, round, biconvex, white to off-white, sublingual tablets, debossed with ‘460’ on one side and plain on other side and are supplied as: Bottles of with child-resistant cap…………….NDC 62756-460-83 Unit-Dose blister pack of 30 (3×10) tablets …….

NDC 62756-460-64 Blister Pack of 30………………………………….NDC 58118-0460-8 Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) .

Protect from light.

Store buprenorphine sublingual tablets securely and dispose of properly.

The data on use of buprenorphine, the active ingredient in buprenorphine sublingual tablets, in pregnancy, are limited; however, these data do not indicate an increased risk of major malformations specifically due to buprenorphine exposure.

There are limited data from randomized clinical trials in women maintained on buprenorphine that were not designed appropriately to assess the risk of major malformations.

Observational studies have reported on congenital malformations among buprenorphine‐exposed pregnancies, but were also not designed appropriately to assess the risk of congenital malformations specifically due to buprenorphine exposure.

Reproductive and developmental studies in rats and rabbits identified adverse events at clinically relevant and higher doses.

Embryofetal death was observed in both rats and rabbits administered buprenorphine during the period of organogenesis at doses approximately and 0.3 times, respectively, the human sublingual dose of 16 mg/day of buprenorphine.

• and post-natal development studies in rats demonstrated increased neonatal deaths at 0.3 times and above and dystocia at approximately 3 times the human sublingual dose of 16 mg/day of buprenorphine.

No clear teratogenic effects were seen when buprenorphine was administered during organogenesis with a range of doses equivalent to or greater than the human sublingual dose of 16 mg/day of buprenorphine.

However, increases in skeletal abnormalities were noted in rats and rabbits administered buprenorphine daily during organogenesis at doses approximately 0.6 times and approximately equal to the human sublingual dose of 16 mg/day of buprenorphine, respectively.

In a few studies, some events such as acephalus and omphalocele were also observed but these findings were not clearly treatment-related.

Based on animal data, advice pregnant women of the potential risk to a fetus.

The estimated background risks of major birth defects and miscarriage for the indicated population are unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

Disease-associated maternal and embryo-fetal risk Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death.

In addition, untreated opioid addiction often results in continued or relapsing illicit opioid use.

Dose Adjustment during Pregnancy and the Postpartum Period Dosage adjustments of buprenorphine may be required during pregnancy, even if the patient was maintained on a stable dose prior to pregnancy.

Withdrawal signs and symptoms should be monitored closely and the dose adjusted as necessary.

Fetal/neonatal adverse reactions Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with buprenorphine sublingual tablets.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight.

Signs of neonatal withdrawal usually occur in the first days after birth.

The duration and severity of neonatal opioid withdrawal syndrome may vary.

Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly.

Opioid‐dependent women on buprenorphine maintenance therapy may require additional analgesia during labor.

Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine during pregnancy.

Limited data from trials, observational studies, case series, and case reports on buprenorphine use in pregnancy do not indicate an increased risk of major malformations specifically due to buprenorphine.

Several factors may complicate the interpretation of investigations of the children of women who take buprenorphine during pregnancy, including maternal use of illicit drugs, late presentation for prenatal care, infection, poor compliance, poor nutrition, and psychosocial circumstances.

Interpretation of data is complicated further by the lack of information on untreated opioid‐dependent pregnant women, who would be the most appropriate group for comparison.

Rather, women on another form of opioid medication‐assisted treatment, or women in the general population are generally used as the comparison group.

However, women in these comparison groups may be different from women prescribed buprenorphine‐containing products with respect to maternal factors that may lead to poor pregnancy outcomes.

In a multicenter, double‐blind, randomized, controlled trial [Maternal Opioid Treatment: Human Experimental Research (MOTHER)] designed primarily to assess neonatal opioid withdrawal effects, opioid‐dependent pregnant women were randomized to buprenorphine (n=86) or methadone (n=89) treatment, with enrollment at an average gestational age of 18.7 weeks in both groups.

A total of of the 86 women in the buprenorphine group (33%) and of the 89 women in the methadone group (18%) discontinued treatment before the end of pregnancy.

Among women who remained in treatment until delivery, there was no difference between buprenorphine‐treated and methadone‐treated groups in the number of neonates requiring NOWS treatment or in the peak severity of NOWS.

Buprenorphine‐exposed neonates required less morphine (mean total dose, 1.1 mg vs. 10.4 mg), had shorter hospital stays (10.0 days vs. 17.5 days), and shorter duration of treatment for NOWS (4.1 days vs. 9.9 days) compared to the methadone‐exposed group.

There were no differences between groups in other primary outcomes (neonatal head circumference,) or secondary outcomes (weight and length at birth, preterm birth, gestational age at delivery, and 1‐ minute and 5‐minute Apgar scores), or in the rates of maternal or neonatal adverse events.

The outcomes among mothers who discontinued treatment before delivery and may have relapsed to illicit opioid use are not known.

Because of the imbalance in discontinuation rates between the buprenorphine and methadone groups, the study findings are difficult to interpret.

The exposure margins listed below are based on body surface area comparisons (mg/m2) to the human sublingual dose of 16 mg buprenorphine via buprenorphine sublingual tablets.

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 human sublingual dose of 16 mg).

Maternal toxicity resulting in mortality was noted in these studies in both rats and rabbits.

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.

Maternal toxicity was seen in the high-dose group but not at the lower doses where the findings were observed.

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 human sublingual dose of 16 mg).

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 and 6 times, respectively, the human sublingual dose of 16 mg), after IV doses up to 0.8 mg/kg/day (estimated exposure was approximately 0.5 times and equal to, respectively, the human sublingual dose of 16 mg), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 95 times the human sublingual dose of 16 mg) and 25 mg/kg/day in rabbits (estimated exposure was approximately 30 times the human sublingual dose of 16 mg).

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 human sublingual dose of 16 mg), 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 human sublingual dose of 16 mg) in the absence of maternal toxicity or oral administration of 1 mg/kg/day or greater (estimated exposure was approximately equal to the human sublingual dose of 16 mg) 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 human sublingual dose of 16 mg).

No maternal toxicity was noted at doses causing post-implantation loss in this study.

Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine from Gestation Day 14 through Lactation Day at 5 mg/kg/day (approximately 3 times the human sublingual dose of 16 mg).

Fertility, and pre.

• 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 human sublingual dose of 16 mg), after IM doses of 0.5 mg/kg/day and up (approximately 0.3 times the human sublingual dose of 16 mg), and after SC doses of 0.1 mg/kg/day and up (approximately 0.06 times the human sublingual dose of 16 mg).

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 human sublingual dose of 16 mg).

The safety and effectiveness of buprenorphine sublingual tablet has not been established in pediatric patients.

Clinical studies of buprenorphine sublingual tablet, buprenorphine and naloxone sublingual film, or buprenorphine and naloxone sublingual tablet did not include sufficient numbers of subjects aged 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.

Due to possible decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in geriatric patients, the decision to prescribe buprenorphine sublingual tablets should be made cautiously in individuals 65 years of age or older and these patients should be monitored for signs and symptoms of toxicity or overdose.