Drug Safety-related Labeling Changes (SrLC)

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BUNAVAIL (NDA-205637)

(BUPRENORPHINE HYDROCHLORIDE; NALOXONE HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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06/17/2022 (SUPPL-24)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.13 Dental Adverse Events

Newly added subsection:
Cases of dental caries, some severe (i.e., tooth fracture, tooth loss), have been reported following the use of transmucosal buprenorphine-containing products. Reported events include cavities, tooth decay, dental abscesses/infection, rampant caries, tooth erosion, fillings falling out, and, in some cases, total tooth loss. Treatment for these events included tooth extraction, root canal, dental surgery, as well as other restorative procedures (i.e., fillings, crowns, implants, dentures). Multiple cases were reported in individuals without any prior history of dental problems.

Refer patients to dental care services and encourage them to have regular dental checkups while taking BUNAVAIL. Educate patients to seek dental care and strategies to maintain or improve oral health while being treated with transmucosal buprenorphine-containing products. Strategies include, but are not limited to, gently rinsing the teeth and gums with water and then swallowing after BUNAVAIL has been completely dissolved in the oral mucosa. Advise patients to wait for at least one hour after taking BUNAVAIL before brushing teeth [see Dosing and Administration (2.6), Information for Patients (17), Medication Guide].

5.14 QTc Prolongation

Newly added subsection:

Thorough QT studies with buprenorphine products have demonstrated QT prolongation less than or equal to 15 msec. This QTc prolongation effect does not appear to be mediated by hERG channels. Based on these two findings, buprenorphine is unlikely to be pro-arrhythmic when used alone in patients without risk factors. The risk of combining buprenorphine with other QT-prolonging agents is not known.

Consider these observations in clinical decisions when prescribing Bunavail to patients with risk factors such as hypokalemia, bradycardia, recent conversion from atrial fibrillation, congestive heart failure, digitalis therapy, baseline QT prolongation, subclinical long-QT syndrome, or severe hypomagnesemia.

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…
Local reactions: dental decay (including caries, tooth fracture, and tooth loss), glossodynia, glossitis, oral mucosal erythema, oral hypoesthesia, and stomatitis.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

Before taking BUNAVAIL, tell your healthcare provider about all of your medical conditions, including if you have:

…          

• tooth problems, including a history of cavities

…

How should I take BUNAVAIL?

• After BUNAVAIL is completely dissolved, rinse your mouth with water and swallow. Wait for at least one hour before brushing teeth.

• Report any problems with your teeth immediately to your healthcare provider and schedule an appointment with a dentist. Tell your dentist that you have started taking BUNAVAIL.

…

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Safe Use
Before initiating treatment with BUNAVAIL, explain the points listed below to caregivers and patients. Instruct patients to read the Medication Guide each time BUNAVAIL is dispensed because new information may be available.

…

• Advise patients that, after BUNAVAIL has completely dissolved in the oral mucosa, to take a sip of water, swish it gently around their teeth and gums, and swallow. Advise patients to wait for at least one hour after taking BUNAVAIL before brushing teeth [see Warnings and Precautions (5.13)].

• Refer patients to dental care services and encourage them to have regular dental checkups while taking BUNAVAIL. Instruct patients to inform their dentist that they have started therapy on BUNAVAIL [see Warnings and Precautions (5.13)].

…

03/04/2021 (SUPPL-21)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Risk of Life-Threatening Respiratory Depression and Central Nervous System (CNS) Depression

Additions and/or revisions underlined:

… Use BUNAVAIL 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).

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information (12.3)].

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.9)].

Newly added information:

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 BUNAVAIL. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose [see Dosage and Administration (2.3)].

Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with BUNAVAIL itself. Higher than normal doses and repeated administration of naloxone may be necessary due to the long duration of action of BUNAVAIL and its affinity for the mu receptor [see Overdosage (10)].

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).

Educate patients and caregivers on how to recognize respiratory depression and, if naloxone is prescribed, how to treat with naloxone. Emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information (17)].

5.3 Managing Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Additions and/or revisions underlined:

… Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the patient’s buprenorphine treatment and coordinate care to minimize the risks associated with concomitant use.

If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in buprenorphine treatment for opioid use disorder [see Warnings and Precautions (5.2)].

7 Drug Interactions

Table 3: Clinically Significant Drug Interactions

Benzodiazepines and Other Central Nervous System (CNS) Depressants

Under Intervention, the following language is added:

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in treatment for opioid use disorder [see Warnings and Precautions (5.2)].

Muscle Relaxants

Under Intervention, the following language is added:

Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.3), Warnings and Precautions (5.2, 5.3)]

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

IMPORTANT: Keep BUNAVAIL in a secure place away from children. Accidental use by a child is a medical emergency and can result in death. If a child accidentally uses BUNAVAIL, get emergency help or call 911 right away. Tell your healthcare provider if you are living in a household where there are small children.

What is the most important information I should know about BUNAVAIL?

• BUNAVAIL contains a medicine called buprenorphine. Buprenorphine is an opioid that can cause serious and life-threatening breathing problems, especially if you take or use certain other medicines or drugs.

• Talk to your healthcare provider about naloxone. Naloxone is a medicine that is available to patients for the emergency treatment of an opioid overdose, including accidental use of BUNAVAIL by a child.

PATIENT COUNSELING INFORMATION

Safe Use

Newly added information:

If naloxone is prescribed, also advise patients and caregivers:

• Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions (5.2)].

• Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

  Because patients being treated for opioid use disorder are at risk for relapse, discuss the importance of having access to naloxone with the patient and caregiver. Also discuss the importance of having access to naloxone if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose.

  Inform patients and caregivers of the 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).

  Educate patients and caregivers on how to recognize the signs and symptoms of an opioid overdose.

  Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered. Repeat administration may be necessary, particularly for overdose involving BUNAVAIL, because naloxone is often not effective at the doses available for patient access [see Dosage and Administration (2.3), Warnings and Precautions (5.2), Overdosage (9.2)].

  If naloxone is prescribed, also advise patients and caregivers:

• How to treat with naloxone in the event of an opioid overdose

• To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency

• To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do.

10/07/2019 (SUPPL-20)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.2 Risk of Life-Threatening Respiratory Depression and Central Nervous System (CNS) Depression

Newly added information to end of subsection:

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper.

7 Drug Interactions

Table 3. Clinically Significant Drug Interactions

Serotonergic Drugs

Additions and/or revisions underlined:

Example: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined in bulleted information:

What is the most important information I should know about BUNAVAIL?

• Never give anyone else your BUNAVAIL. They could die from taking it. Selling or giving away BUNAVAIL is against the law.

• Store BUNAVAIL securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.

How should I dispose of unused BUNAVAIL?

• Dispose of expired, unwanted, or unused BUNAVAIL by promptly flushing down the toilet, if a drug take-back option is not readily available. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store BUNAVAIL securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving BUNAVAIL unsecured can pose a deadly risk to others in the home.

Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused BUNAVAIL should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.

02/01/2018 (SUPPL-16)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

BUNAVAIL is contraindicated in patients with a history of hypersensitivity to buprenorphine or naloxone …

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Addiction, Abuse, and Misuse

BUNAVAIL contains buprenorphine, a Schedule III controlled substance that can be abused in a manner …

5.2 Risk of Respiratory and Central Nervous System (CNS) Depression

Buprenorphine has been associated with life-threating respiratory depression and death. Many, but not all, post-marketing reports regarding coma and death involved misuses by self-injection or were associated with the concomitant use of benzodiazepines or other CNS depressants, including alcohol. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with BUNAVAIL.

Use BUNAVAIL with caution in patients …

5.3 Managing Risks from Concomitant Use of Benzodiazepines or Other CNS Depressants

Concomitant use of buprenorphine and benzodiazepines or other CNS depressants increases the risk of adverse reactions including overdose and death. Medication-assisted treatment of opioid use disorder, however, should not be categorically denied to patients taking these drugs. Prohibiting or creating barriers to treatment can pose an even greater risk of morbidity and mortality due to the opioid use disorder alone.

As a routine part of orientation to buprenorphine treatment, educate patients about the risks of concomitant use of benzodiazepines, sedatives, opioid analgesics, and alcohol.

Newly added information:

Develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants at initiation of buprenorphine treatment, or if it emerges as a concern during treatment. Adjustments to induction procedures and additional monitoring may be required. There is no evidence to support dose limitations or arbitrary caps of buprenorphine as a strategy to address benzodiazepine use in buprenorphine-treated patients. However, if a patient is sedated at the time of buprenorphine dosing, delay or omit the buprenorphine dose if appropriate.

Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.

For patients in buprenorphine treatment, benzodiazepines are not the treatment of choice for anxiety or insomnia. Before co-prescribing benzodiazepines, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments to address anxiety or insomnia. Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the patient’s buprenorphine treatment and coordinate care to minimize the risks associated with concomitant use.

In addition, take measures to confirm that patients are taking their medications as prescribed and are not diverting or supplementing with illicit drugs. Toxicology screening should test for

prescribed and illicit benzodiazepines.

5.7 Risk of Opioid Withdrawal with Abrupt Discontinuation

Additions and/or revisions underlined:

The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset. When discontinuing BUNAVAIL, gradually taper the dosage.

5.8 Risk of Hepatitis, Hepatic Events

5.9 Hypersensitivity Reactions

5.11 Risk of Overdose in Opioid Naïve Patients

5.12 Use in Patients With Impaired Hepatic Function

6 Adverse Reactions

Addition of the following:

The following serious adverse reactions are described elsewhere in the labeling:

• Addiction, Abuse, and Misuse
• Respiratory and CNS Depression
• Neonatal Opioid Withdrawal Syndrome
• Adrenal Insufficiency
• Opioid Withdrawal
• Hepatitis, Hepatic Events
• Hypersensitivity Reactions
• Orthostatic Hypotension
• Elevation of Cerebrospinal Fluid Pressure
• Elevation of Intracholedochal Pressure

6.2 Postmarketing Experience

Newly added information:

Local reactions: Glossodynia, glossitis, oral mucosal erythema, oral hypoesthesia, and stomatitis.

8 Use in Specific Populations

Additions and/or revisions underlined:

8.5 Geriatric Use

… 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 BUNAVAIL 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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Safe Use

Additions and/or revisions underlined:

• BUNAVAIL must be administered whole. Advise patients not to cut, chew, or swallow BUNAVAIL.
• Inform patients and caregivers that potentially fatal additive effects may occur if BUNAVAIL is used with benzodiazepines or other CNS depressants, including alcohol. Counsel patients that such medications should not be used concomitantly unless supervised by a health care provider.
• Advise patients that, like other opioids, BUNAVAIL may produce orthostatic hypotension in ambulatory individuals.
• Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible.

04/27/2017 (SUPPL-13)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined)

The data on use of buprenorphine, one of the active ingredients in BUNAVAIL buccal film, 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. The extremely limited data on sublingual naloxone exposure in pregnancy are not sufficient to evaluate a drug-associated risk.

…Embryofetal death was observed in both rats and rabbits administered buprenorphine during the period of organogenesis at doses approximately 6 and 0.3 times, respectively, the human sublingual dose of 16 mg/day of buprenorphine (equivalent to 8.4 mg BUNAVAIL buccal film). Pre-and postnatal 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(equivalent to 8.4 mg/1.4 mg BUNAVAIL buccal film). 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 (equivalent to 8.4 mg/1.4 mg BUNAVAIL buccal film). 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 (equivalent to 8.4 mg/1.4 mg BUNAVAIL buccal film), respectively. In a few studies, some events such as acephalus and omphalocele were also observed but these findings were not clearly treatment- related.

Clinical Considerations

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.

Labor or Delivery

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

Data

Human Data

…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 28 of the 86 women in the buprenorphine group (33%) and 16 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.

Animal Data

…The exposure margins listed below are based on body surface area comparisons (mg/m2) to the recommended human sublingual dose of 16 mg buprenorphine from Suboxone sublingual tablets (equivalent to 8.4 mg/1.4 mg BUNAVAIL buccal film).

…Following oral administration to rats no teratogenic effects were observed at buprenorphine doses up to 250 mg/kg/day (estimated exposure approximately 150 times the human sublingual dose of 16 mg) in the presence of maternal toxicity (mortality).

Following oral administration to rabbits, no teratogenic effects were observed at buprenorphine doses up to 40 mg/kg/day (estimated exposure approximately 50 times the human sublingual dose of 16 mg) in the absence of clear maternal toxicity… Maternal toxicity resulting in mortality was noted in these studies in both rats and rabbits… Maternal toxicity was seen in the high-dose group but not at the lower doses where the findings were observed.

In rabbits, buprenorphine produced statistically significant pre-implantation losses… No maternal toxicity was noted at doses causing post-implantation loss in this study.

8.2 Lactation

(Additions and/or revisions are underlined)

Risk Summary

Based on two studies in 13 lactating women maintained on buprenorphine treatment, buprenorphine and its metabolite norbuprenorphine were present in low levels in human milk 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 limited. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BUNAVAIL buccal film and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

 

Data

Data were consistent from two studies (N=13) of breastfeeding infants whose mothers were maintained on sublingual doses of buprenorphine ranging from 2.4 to 24 mg/day, showing that the infants were exposed to less than 1% of the maternal daily dose.

In a study of six lactating women who were taking a median sublingual buprenorphine dose of 0.29 mg/kg/day 5 to 8 days after delivery, breast milk provided a median infant dose of 0.42 mcg/kg/day of buprenorphine and 0.33 mcg/kg/day of norbuprenorphine, equal to 0.2% and 0.12%, respectively, of the maternal weight-adjusted dose (relative dose/kg (%) of norbuprenorphine was calculated from the assumption that buprenorphine and norbuprenorphine are equipotent).

Data from a study of seven lactating women who were taking a median sublingual buprenorphine dose of 7 mg/day an average of 1.12 months after delivery indicated that the mean milk concentrations (Cavg) of buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L respectively. Based on the study data, and assuming milk consumption of 150 mL/kg/day, an exclusively breastfed infant would receive an estimated mean absolute infant dose (AID) of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of norbuprenorphine, or a mean relative dose (RID) of 0.38% and 0.18%, respectively, of the maternal weight-adjusted dose.

04/27/2017 (SUPPL-7)

Approved Drug Label (PDF)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Additions and/or revisions are underlined)

How should I take BUNAVAIL?

• After induction (your first few days of dosing), take BUNAVAIL 1 time a day.

12/16/2016 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Neonatal Opioid Withdrawal Syndrome

Newly added subsection:

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy, whether that use is medically-authorized or illicit. Unlike opioid withdrawal syndrome in adults, NOWS may be life-threatening if not recognized and treated in the neonate. Healthcare professionals should observe newborns for signs of NOWS and manage accordingly.

Advise pregnant women receiving opioid addiction treatment with BUNAVAIL of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. This risk must be balanced against the risk of untreated opioid addiction which often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes. Therefore, prescribers should discuss the importance and benefits of management of opioid addiction throughout pregnancy.

5.6 Adrenal Insufficiency

Newly added subsection:

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 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.

6 Adverse Reactions

Additions and/or revisions underlined:

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.

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

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.

The safety of BUNAVAIL buccal film is supported by clinical trials using buprenorphine and naloxone sublingual tablets …

6.2 Postmarketing Experience

Newly added subsection:

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.

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

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

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in BUNAVAIL.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids.

7 Drug Interactions

Table 3 Includes clinically significant drug interactions with BUNAVAIL

Information is now in table format; please refer to label.

8 Use in Specific Populations

8.1 Pregnancy

Risk Summary

There are no adequate and well-controlled studies of BUNAVAIL buccal film or buprenorphine/naloxone in pregnant women. Limited published data on use of buprenorphine, the active ingredient in BUNAVAIL, in pregnancy, have not shown an increased risk of major malformations.

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 6 and 0.3 times, respectively, the human sublingual dose of 16 mg/day of buprenorphine. Pre-and postnatal 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.

The estimated background risk of major birth defects and miscarriage for the indicated population is 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 2-4% and 15-20%, respectively.

Clinical Considerations

Females and Males of Reproductive Potential

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known where these effects on fertility are reversible.

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.

Fetal/neonatal adverse reactions

Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with BUNAVAIL.

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 of birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for signs and neonatal opioid withdrawal syndrome and manage accordingly.

Labor or 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

BUNAVAIL has been shown to have differences in bioavailability compared to 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 from Suboxone, which is equivalent to the human buccal dose of 8.4 mg buprenorphine via BUNAVAIL.

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 during the period of organogenesis. Following oral administration to rats no teratogenic effects were observed at buprenorphine doses up to 250 mg/kg/day (estimated exposure approximately 150 times the human sublingual dose of 16 mg).

Following oral administration to rabbits, no teratogenic effects were observed at buprenorphine doses up to 40 mg/kg/day (estimated exposure approximately 50 times the human sublingual dose of 16 mg). 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). 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 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 3 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) 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).

Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine during gestation and lactation at 5 mg/kg/day (approximately 3 times the human sublingual dose of 16 mg). Fertility, 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).

8.2 Lactation

PLLR conversion:

Risk Summary

Based on two studies in 13 lactating women, buprenorphine and its metabolite …

8.3 Females and Males of Reproductive Potential

PLLR conversion; newly added subsection:

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

BUNAVAIL may not be right for you. Before taking BUNAVAIL, tell your doctor if you:

• Are pregnant or plan to become pregnant. If you take BUNAVAIL while pregnant, your baby may have symptoms of opioid withdrawal or respiratory depression at birth. Talk to your doctor if you are pregnant or plan to become pregnant.

PATIENT COUNSELING INFORMATION

See FDA approved patient labeling (Medication Guide).

Safe Use

Addition of the following bullets:

Before initiating treatment with BUNAVAIL buccal film, explain the points listed below to caregivers and patients. Instruct patients to read the Medication Guide each time BUNAVAIL is dispensed because new information may be available.

• Inform patients that BUNAVAIL could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop.  Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications.

• Inform patients that BUNAVAIL could cause adrenal insufficiency, a potentially life- threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms..

• Advise women that if they are pregnant while being treated with BUNAVAIL, the baby may have signs of withdrawal at birth and that appropriate treatment is available.