Drug Safety-related Labeling Changes (SrLC)

Get Email Alerts | Guide

SUBUTEX (NDA-020732)

(BUPRENORPHINE HYDROCHLORIDE)

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

Download Data

Expand all

06/17/2022 (SUPPL-28)

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 patients to have regular dental checkups while taking SUBUTEX. 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 SUBUTEX has been completely dissolved in the oral mucosa. Advise patients to wait for at least one hour after taking SUBUTEX 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 SUBUTEX 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 SUBUTEX, 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 SUBUTEX sublingual tablet?

…

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

…

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

• Advise patients that, after SUBUTEX 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 SUBUTEX 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 SUBUTEX. Instruct patients to inform their dentist that they have started therapy on SUBUTEX [see Warnings and Precautions (5.13)].

...

03/04/2021 (SUPPL-24)

Approved Drug Label (PDF)

5 Warnings and Precautions

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

Additions and/or revisions underlined:

… Use SUBUTEX 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 (17)].

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 (2.10)].

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 SUBUTEX. 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 SUBUTEX itself. Higher than normal doses and repeated administration of naloxone may

be necessary due to the long duration of action of SUBUTEX and its affinity for the mu?opioid 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, 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, strongly 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, strongly consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), 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 SUBUTEX sublingual tablet 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 takes SUBUTEX sublingual tablet, 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 SUBUTEX sublingual tablet?

• SUBUTEX 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. Call your doctor right away or get emergency help if:

  • You feel faint, dizzy, or confused …

• 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 SUBUTEX by a child.

PATIENT COUNSELING INFORMATION

Safe Use

Newly added information:

• 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 SUBOXONE sublingual film, because naloxone is often not effective at the doses available for patient access [Dosage and Administration (2.3), Warnings and Precautions (5.2), Overdosage (10)].

  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.

10/30/2019 (SUPPL-20)

Approved Drug Label (PDF)

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

MEDICATION GUIDE

(changes made to Medication Guide to be consistent with the medicaltion Guide for Sublocade,also additions underlined)

…

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

• Buprenorphine is a medicine in SUBUTEX that can cause serious and life-threatening problems, especially if you take or use certain other medicines or drugs. Call your healthcare provider right away or get emergency help if you:

  
  

  
  

  • feel faint or dizzy   o         cannot think well or clearly

  • have mental changes such as confusion     o         have slowed reflexes

  • have slower breathing than you normally have       o         have a high body temperature

  • have severe sleepiness         o         feel agitated

  • have blurred vision o         have stiff muscles

  • have problems with coordination   o         have trouble walking

  • have slurred speech

     

    …

     

• Do not inject (“shoot-up”) or snort SUBUTEX.

• Injecting SUBUTEX  may cause life-threatening infections and other serious health problems.

• Crushing and/or dissolving SUBUTEX  and then injecting it (“shooting up”) could cause serious precipitated withdrawal (sudden, serious, withdrawal symptoms such as pain, cramps, vomiting and diarrhea) in people who are physically dependent on other opioids.

Snorting SUBUTEX could cause precipitated withdrawal. In an emergency, have family members tell emergency department staff that you are physically dependent on an opioid and are being treated with SUBUTEX.

10/07/2019 (SUPPL-22)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.2 Risk of Life-Threatening Respiratory 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.

Additions and/or revisions underlined:

5.10 Precipitation of Opioid Withdrawal Signs and Symptoms

Because of the partial agonist properties of buprenorphine, SUBUTEX may precipitate opioid withdrawal signs and symptoms in individuals physically dependent on full opioid agonists if administered sublingually or parenterally before the agonist effects of other opioids have subsided.

5.12 Use in Patients with Impaired Hepatic Function

In a pharmacokinetic study, buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment.

For patients with severe hepatic impairment, a dose adjustment is recommended, and patients with moderate or severe hepatic impairment should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine.

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined;

The most frequently reported post-marketing adverse events with SUBUTEX not observed in clinical trials, excluding drug exposure during pregnancy, was drug misuse or abuse.

Local reactions: Glossodynia, glossitis …

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).

8 Use in Specific Populations

8.6 Hepatic Impairment

Additions and/or revisions underlined:

The effects of hepatic impairment on the pharmacokinetics of buprenorphine were evaluated in a pharmacokinetic study. Buprenorphine is extensively metabolized in the liver and buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment.

For patients with severe hepatic impairment, a dose adjustment is recommended, and patients with moderate or severe hepatic impairment should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine.

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

MEDICATION GUIDE

Section has been reformatted; please refer to label for complete information.

Additions and/or revisions underlined in bulleted information:

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

• Store SUBUTEX 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 SUBUTEX?

• Dispose of expired, unwanted, or unused SUBUTEX 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

Storage and Disposal:

Additions and/or revisions underlined:

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store SUBUTEX 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 SUBUTEX 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 SUBUTEX 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-18)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

SUBUTEX is contraindicated in patients with a history of hypersensitivity to buprenorphine …

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Addiction, Abuse, and Misuse

SUBUTEX 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 SUBUTEX.

Use SUBUTEX 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 SUBUTEX, gradually taper the dosage.

5.8 Risk of Hepatitis, Hepatic Events

5.9 Hypersensitivity Reactions

5.11 Risk of Overdose in Opioid Naïve Patients

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

8.1 Pregnancy

Risk Summary

Additions and/or revisions underlined:

… 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, advise 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 …

8.5 Geriatric Use

Additions and/or revisions underlined:

… 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 SUBUTEX 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)

MEDICATION GUIDE

Newly added section; please refer to label for complete information.

PATIENT COUNSELING INFORMATION

Safe Use

Additions and/or revisions underlined:

• Inform patients and caregivers that potentially fatal additive effects may occur if SUBUTEX are used with benzodiazepines or other CNS depressants, including alcohol. Counsel patients that such medications should not be used concomitantly unless supervised by their health care provider.

Addition of the following:

• Advise patients that if they miss a dose of SUBUTEX 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.

• Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible.

09/07/2017 (SUPPL-16)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined)

Risk Summary

The data on use of buprenorphine, the active ingredient in SUBUTEX 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.

…

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 SUBUTEX sublingual tablets.

…

Labor or Delivery

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

Data

Human Data

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 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.

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. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SUBUTEX sublingual tablets and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

Clinical Considerations

Advise breastfeeding women taking buprenorphine products to monitor the infant for increased drowsiness and breathing difficulties.

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 infant dose (RID) of 0.38% and 0.18%, respectively, of the maternal weight-adjusted dose.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Advise patients to read the FDA-approved patient labeling (Medication Guide).

Safe Use

…

• Warn patients that it is extremely dangerous to self-administer non-prescribed benzodiazepines or other CNS depressants (including alcohol) while taking SUBUTEX sublingual tablet. Caution patients prescribed benzodiazepines or other CNS depressants to use them only as directed by their healthcare providers.
• Advise patients that SUBUTEX sublingual tablet contains…
• Instruct patients to keep SUBUTEX sublingual tablet in a secure place… Advise patients to seek medical attention immediately if a child is exposed to SUBUTEX sublingual tablet.
• Advise patients never to give SUBUTEX sublingual tablet to anyone else…
• Advise patients that selling or giving away this medication is against the law.
• Caution patients that SUBUTEX sublingual tablet may impair the mental or physical abilities…
• Advise patients not to change the dosage of SUBUTEX sublingual tablet without consulting their healthcare providers.
• Advise patients to take SUBUTEX sublingual tablet once a day.
• Inform patients that SUBUTEX sublingual tablet can cause drug dependence
• Advise patients seeking to discontinue treatment with buprenorphine for opioid dependence to work closely with their healthcare providers on a tapering schedule and inform them of the potential to relapse to illicit drug use associated with discontinuation of opioid agonist/partial agonist medication-assisted treatment.
• Advise patients that, like other opioids, SUBUTEX sublingual tablet may produce orthostatic hypotension in ambulatory individuals.
• Advise patients to inform their healthcare providers if…
• Advise women who are breastfeeding to monitor the infant for drowsiness and difficulty breathing.
• Advise patients to inform their family members that, in the event of emergency,…
• Advise patients to refer to the Medication Guide for additional information regarding the counseling information.

12/16/2016 (SUPPL-14)

Approved Drug Label (PDF)

5 Warnings and Precautions

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 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.

6 Adverse Reactions

6.2 Postmarketing Experience

Addition of  subsection:

The following adverse reactions have been identified during post approval use of buprenorphine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The most frequently reported post-marketing adverse events with SUBUTEX not observed in clinical trials, excluding drug exposure during pregnancy, was drug misuse or abuse.

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 SUBUTEX.

7 Drug Interactions

Addition of the following:

Serotonergic Drugs

The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.

If concomitant use is warranted, carefully observe the patient, particularly during treatment intitiation and dose adjustment. Discontinue SUBUTEX if serontonin syndrome is suspected.

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

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)

PATIENT COUNSELING INFORMATION

17.1 Safe Use

Addition of the following:

• Inform patients that opioids 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 healthcare providers if they are taking, or plan to take serotonergic medications.

• Inform patients that opioids 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.

   

12/16/2016 (SUPPL-15)

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 SUBUTEX 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.

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…The most frequently reported post-marketing adverse events with SUBUTEX not observed in clinical trials, excluding drug exposure during pregnancy, was drug misuse or abuse.

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

7 Drug Interactions

Table 3 Includes clinically significant drug interactions with SUBUTEX

Information has been converted to table format; please refer to label.

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion: extensive changes; please refer to label.

 

8.2 Lactation

PLLR conversion:

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 SUBUTEX is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SUBUTEX 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 SUBUTEX 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 mcg/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.

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

MEDICATION GUIDE

What is the most important information I should know about SUBOXONE

Addition and/or revisions underlined:

• Do not switch from SUBOXONE to other medicines that contain buprenorphine without talking with your doctor. The amount of buprenorphine in a dose of SUBOXONE may not be the same as the amount of buprenorphine in other medicines that contain buprenorphine. Your doctor will prescribe a starting dose of SUBOXONE that may be different than other buprenorphine containing medicines you may have been taking.

• An overdose, and even death, can happen if you take benzodiazepines, sedatives, tranquilizers, antidepressants, or alcohol while using SUBOXONE …

  What should I tell my doctor before taking SUBOXONE sublingual tablets?

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

• Are pregnant or plan to become pregnant. If you take SUBOXONE 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.

• Are breastfeeding or plan to breastfeed. SUBOXONE can pass into your milk and may harm your baby. Talk to your doctor about the best way to feed your baby if you take SUBOXONE. 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 ...

PATIENT COUNSELING INFORMATION

Healthcare provider replaces physician in all instances in this section.

See FDA-approved patient labeling (Medication Guide)

17.1 Safe Use

Addition of the following:

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