Suboxone

SUBOXONE sublingual film is indicated for treatment of opioid dependence. SUBOXONE sublingual film should be used as part of a complete treatment plan that includes counseling and psychosocial support.

• Administer SUBOXONE sublingual film as a single daily dose. (
  2.1 Important Dosage and Administration Information

  SUBOXONE sublingual film is administered sublingually or buccally as a single daily dose.

  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.
  )
  
• Strongly consider prescribing naloxone at the time SUBOXONE sublingual film is initiated or renewed because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose. (
  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 SUBOXONE sublingual film. 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 Warnings and Precautions ]

  .

  Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with SUBOXONE sublingual film itself. Higher than normal doses and repeated administration of naloxone may be necessary due to the long duration of action of SUBOXONE sublingual film and its affinity for the mu-opioid receptor

  [see Overdosage ]

  .

  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)

  [see Patient Counseling Information ]

  .
  )
  
• To avoid precipitating withdrawal, induction with SUBOXONE sublingual film should be undertaken when objective and clear signs of withdrawal are evident and SUBOXONE sublingual film should be administered in divided doses when used as initial treatment. (
  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

  Patients dependent on heroin or other short‐acting opioid products may be inducted with either SUBOXONE sublingual film or with sublingual buprenorphine monotherapy. At treatment initiation, the first dose of SUBOXONE sublingual film should be administered when objective signs of moderate opioid withdrawal appear, not less than six hours after the patient last used opioids.

  It is recommended that an adequate treatment dose, titrated to clinical effectiveness, be achieved as rapidly as possible. In some studies, a too‐gradual induction over several days led to a high rate of drop‐out of buprenorphine patients during the induction period.

  On Day 1, an induction dosage of up to 8 mg/2 mg SUBOXONE sublingual film is recommended. Clinicians should start with an initial dose of 2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone and may titrate upwards in 2 or 4 mg increments of buprenorphine, at approximately 2‐hour intervals, under supervision, to 8 mg/2 mg buprenorphine/naloxone based on the control of acute withdrawal symptoms.

  On Day 2, a single daily dose of up to 16 mg/4 mg SUBOXONE sublingual film is recommended.

  Because the exposure to naloxone is somewhat higher after buccal than after sublingual administration, it is recommended that the sublingual site of administration be used during induction to minimize exposure to naloxone, to reduce the risk of precipitated withdrawal.

  Patients dependent on methadone or long‐acting opioid products

  Patients dependent upon methadone or long‐acting opioid products may be more susceptible to precipitated and prolonged withdrawal during induction than those on short‐acting opioid products.

  Buprenorphine/naloxone combination products have not been evaluated in adequate and well‐controlled studies for induction in patients who are physically dependent on long‐acting opioid products, and the naloxone in these combination products is absorbed in small amounts by the sublingual route and could cause worse precipitated and prolonged withdrawal. For this reason, buprenorphine monotherapy is recommended in patients taking long‐acting opioids when used according to approved administration instructions. Following induction, the patient may then be transitioned to once‐daily SUBOXONE sublingual film.
  )
  
• For patients dependent on short‐acting opioid products who are in opioid withdrawal; on Day 1, administer up to 8 mg/2 mg SUBOXONE sublingual film (in divided doses). On Day 2, administer up to 16 mg/4 mg of SUBOXONE sublingual film as a single dose. (
  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

  Patients dependent on heroin or other short‐acting opioid products may be inducted with either SUBOXONE sublingual film or with sublingual buprenorphine monotherapy. At treatment initiation, the first dose of SUBOXONE sublingual film should be administered when objective signs of moderate opioid withdrawal appear, not less than six hours after the patient last used opioids.

  It is recommended that an adequate treatment dose, titrated to clinical effectiveness, be achieved as rapidly as possible. In some studies, a too‐gradual induction over several days led to a high rate of drop‐out of buprenorphine patients during the induction period.

  On Day 1, an induction dosage of up to 8 mg/2 mg SUBOXONE sublingual film is recommended. Clinicians should start with an initial dose of 2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone and may titrate upwards in 2 or 4 mg increments of buprenorphine, at approximately 2‐hour intervals, under supervision, to 8 mg/2 mg buprenorphine/naloxone based on the control of acute withdrawal symptoms.

  On Day 2, a single daily dose of up to 16 mg/4 mg SUBOXONE sublingual film is recommended.

  Because the exposure to naloxone is somewhat higher after buccal than after sublingual administration, it is recommended that the sublingual site of administration be used during induction to minimize exposure to naloxone, to reduce the risk of precipitated withdrawal.

  Patients dependent on methadone or long‐acting opioid products

  Patients dependent upon methadone or long‐acting opioid products may be more susceptible to precipitated and prolonged withdrawal during induction than those on short‐acting opioid products.

  Buprenorphine/naloxone combination products have not been evaluated in adequate and well‐controlled studies for induction in patients who are physically dependent on long‐acting opioid products, and the naloxone in these combination products is absorbed in small amounts by the sublingual route and could cause worse precipitated and prolonged withdrawal. For this reason, buprenorphine monotherapy is recommended in patients taking long‐acting opioids when used according to approved administration instructions. Following induction, the patient may then be transitioned to once‐daily SUBOXONE sublingual film.
  )
  
• For patients dependent on methadone or long‐acting opioid products, induction onto sublingual buprenorphine monotherapy is recommended on Days 1 and 2 of treatment. (
  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

  Patients dependent on heroin or other short‐acting opioid products may be inducted with either SUBOXONE sublingual film or with sublingual buprenorphine monotherapy. At treatment initiation, the first dose of SUBOXONE sublingual film should be administered when objective signs of moderate opioid withdrawal appear, not less than six hours after the patient last used opioids.

  It is recommended that an adequate treatment dose, titrated to clinical effectiveness, be achieved as rapidly as possible. In some studies, a too‐gradual induction over several days led to a high rate of drop‐out of buprenorphine patients during the induction period.

  On Day 1, an induction dosage of up to 8 mg/2 mg SUBOXONE sublingual film is recommended. Clinicians should start with an initial dose of 2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone and may titrate upwards in 2 or 4 mg increments of buprenorphine, at approximately 2‐hour intervals, under supervision, to 8 mg/2 mg buprenorphine/naloxone based on the control of acute withdrawal symptoms.

  On Day 2, a single daily dose of up to 16 mg/4 mg SUBOXONE sublingual film is recommended.

  Because the exposure to naloxone is somewhat higher after buccal than after sublingual administration, it is recommended that the sublingual site of administration be used during induction to minimize exposure to naloxone, to reduce the risk of precipitated withdrawal.

  Patients dependent on methadone or long‐acting opioid products

  Patients dependent upon methadone or long‐acting opioid products may be more susceptible to precipitated and prolonged withdrawal during induction than those on short‐acting opioid products.

  Buprenorphine/naloxone combination products have not been evaluated in adequate and well‐controlled studies for induction in patients who are physically dependent on long‐acting opioid products, and the naloxone in these combination products is absorbed in small amounts by the sublingual route and could cause worse precipitated and prolonged withdrawal. For this reason, buprenorphine monotherapy is recommended in patients taking long‐acting opioids when used according to approved administration instructions. Following induction, the patient may then be transitioned to once‐daily SUBOXONE sublingual film.
  )
  
• The maintenance dose of SUBOXONE sublingual film is generally in the range of 4 mg/1 mg to 24 mg/6 mg per day and should be based on clinical response. (
  2.4 Maintenance

  • For maintenance, SUBOXONE sublingual film may be administered buccally or sublingually.
  • The dosage of SUBOXONE sublingual film from Day 3 onwards should be progressively adjusted in increments/decrements of 2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone to a level that holds the patient in treatment and suppresses opioid withdrawal signs and symptoms.
  • After treatment induction to the recommended dose of 16 mg/4 mg buprenorphine/naloxone per day, dosing should be further adjusted based on the individual patient and clinical response. The maintenance dose of SUBOXONE sublingual film is generally in the range of 4 mg/1 mg buprenorphine/naloxone to 24 mg/6 mg buprenorphine/naloxone per day. Dosages higher than 24 mg/6 mg daily have not been investigated in randomized clinical trials but may be appropriate for some patients.
  • 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 SUBOXONE sublingual film contributes to the intended treatment goals.
  )
  
• Sublingual Administration: Place one film under the tongue, close to the base on the left or right side, and allow to completely dissolve. Buccal Administration: Place one film on the inside of the left or right cheek and allow to completely dissolve. (
  2.5 Method of Administration

  SUBOXONE sublingual film must be administered whole. Do not cut, chew, or swallow SUBOXONE sublingual film. Advise patients not to eat or drink anything until the film is completely dissolved.

  Sublingual Administration

  Place one film under the tongue, close to the base on the left or right side. If an additional film is necessary to achieve the prescribed dose, place an additional film sublingually on the opposite side from the first film. Place the film in a manner to minimize overlapping as much as possible. The film must be kept under the tongue until the film is completely dissolved. If a third film is necessary to achieve the prescribed dose, place it under the tongue on either side after the first 2 films have dissolved.

  Buccal Administration

  Place one film on the inside of the right or left cheek. If an additional film is necessary to achieve the prescribed dose, place an additional film on the inside of the opposite cheek. The film must be kept on the inside of the cheek until the film is completely dissolved. If a third film is necessary to achieve the prescribed dose, place it on the inside of the right or left cheek after the first two films have dissolved.

  SUBOXONE sublingual film should NOT be moved after placement.

  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 SUBOXONE before brushing teeth

  [see Warnings and Precautions , Postmarketing Experience , Information for Patients , and the Medication Guide]

  .
  )
  
• SUBOXONE sublingual film must be administered whole. Do not cut, chew, or swallow SUBOXONE sublingual film (
  2.5 Method of Administration

  SUBOXONE sublingual film must be administered whole. Do not cut, chew, or swallow SUBOXONE sublingual film. Advise patients not to eat or drink anything until the film is completely dissolved.

  Sublingual Administration

  Place one film under the tongue, close to the base on the left or right side. If an additional film is necessary to achieve the prescribed dose, place an additional film sublingually on the opposite side from the first film. Place the film in a manner to minimize overlapping as much as possible. The film must be kept under the tongue until the film is completely dissolved. If a third film is necessary to achieve the prescribed dose, place it under the tongue on either side after the first 2 films have dissolved.

  Buccal Administration

  Place one film on the inside of the right or left cheek. If an additional film is necessary to achieve the prescribed dose, place an additional film on the inside of the opposite cheek. The film must be kept on the inside of the cheek until the film is completely dissolved. If a third film is necessary to achieve the prescribed dose, place it on the inside of the right or left cheek after the first two films have dissolved.

  SUBOXONE sublingual film should NOT be moved after placement.

  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 SUBOXONE before brushing teeth

  [see Warnings and Precautions , Postmarketing Experience , Information for Patients , and the Medication Guide]

  .
  )
  
• When discontinuing treatment, gradually taper to avoid signs and symptoms of withdrawal. (
  2.8 Discontinuing Treatment

  The decision to discontinue therapy with SUBOXONE sublingual film after a period of maintenance should be made as part of a comprehensive treatment plan. Advise patients of the potential to relapse to illicit drug use following discontinuation of opioid agonist/partial agonist medication‐assisted treatment. Taper patients to reduce the occurrence of opioid withdrawal signs and symptoms

  [See Warnings and Precautions ]

  .
  )
  

SUBOXONE sublingual film is supplied as an orange rectangular film with a white printed logo in four dosage strengths:

• Buprenorphine 2 mg/naloxone 0.5 mg,
• Buprenorphine 4 mg/naloxone 1 mg,
• Buprenorphine 8 mg/naloxone 2 mg and
• Buprenorphine 12 mg/naloxone 3 mg

• Lactation: Buprenorphine passes into mother's milk. (
  8.2 Lactation

  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 infant urine.

  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 SUBOXONE sublingual film 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 (C_avg) 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.
  )
  
• Geriatric Patients: Monitor for sedation and respiratory depression. (
  8.5 Geriatric Use

  Clinical studies of SUBOXONE sublingual film, SUBOXONE sublingual tablets, or SUBUTEX sublingual tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Due to possible decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in geriatric patients, the decision to prescribe SUBOXONE sublingual film 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.
  )
  
• Moderate or Severe Hepatic Impairment: Buprenorphine/naloxone products are not recommended in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment. (
  8.6 Hepatic Impairment

  The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone has been evaluated in a pharmacokinetic study. Both drugs are extensively metabolized in the liver. While no clinically significant changes have been observed in subjects with mild hepatic impairment; the plasma levels have been shown to be higher and half-life values have been shown to be longer for both buprenorphine and naloxone in subjects with moderate and severe hepatic impairment. The magnitude of the effects on naloxone are greater than that on buprenorphine in both moderately and severely impaired subjects. The difference in magnitude of the effects on naloxone and buprenorphine are greater in subjects with severe hepatic impairment than in subjects with moderate hepatic impairment, and therefore the clinical impact of these effects is likely to be greater in patients with severe hepatic impairment than in patients with moderate hepatic impairment.

  Buprenorphine/naloxone products should be avoided in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment

  [see Warnings and Precautions , Clinical Pharmacology ].
  )
  

• Addiction, Abuse, and Misuse:
  Buprenorphine can be abused in a similar manner to other opioids. Monitor patients for conditions indicative of diversion or progression of opioid dependence and addictive behaviors. Multiple refills should not be prescribed early in treatment or without appropriate patient follow-up visits. (
  5.1 Addiction, Abuse, and Misuse

  SUBOXONE sublingual film contains buprenorphine, a schedule III controlled substance that can be abused in a manner similar to other opioids, legal or illicit. Prescribe and dispense buprenorphine with appropriate precautions to minimize risk of misuse, abuse, or diversion, and ensure appropriate protection from theft, including in the home. Clinical monitoring appropriate to the patient's level of stability is essential. Multiple refills should not be prescribed early in treatment or without appropriate patient follow‐up visits

  [see Drug Abuse and Dependence ]

  .
  )
  
• Respiratory Depression:
  Life-threatening respiratory depression and death have occurred in association with buprenorphine use. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with SUBOXONE sublingual film. (
  5.2 Risk of Life-Threatening Respiratory and Central Nervous System (CNS) Depression

  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 depressants, including alcohol. Warn patients of the potential danger of self‐administration of benzodiazepines or other CNS depressants while under treatment with SUBOXONE sublingual film

  [see Warnings and Precautions , Drug Interactions ].

  Use SUBOXONE sublingual film 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 ]

  .

  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 ]

  .

  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 SUBOXONE sublingual film. 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 ]

  .

  Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with SUBOXONE sublingual film itself. Higher than normal doses and repeated administration of naloxone may be necessary due to the long duration of action of SUBOXONE sublingual film and its affinity for the mu-opioid receptor

  [see Overdosage ]

  .

  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 ]

  .
  , 
  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.

  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.

  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 ].

  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

  [see Drug Interactions ].
  )
  
• Unintentional Pediatric Exposure:
  Store SUBOXONE sublingual film safely out of the sight and reach of children. Buprenorphine can cause severe, possibly fatal, respiratory depression in children. (
  5.4 Unintentional Pediatric Exposure

  Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally exposed to it. Store buprenorphine‐containing medications safely out of the sight and reach of children and destroy any unused medication appropriately [see

  Patient Counseling Information

  ].
  )
  
• Neonatal Opioid Withdrawal Syndrome:
  Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy (
  5.5 Neonatal Opioid Withdrawal Syndrome

  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

  [see Use in Specific Populations ]

  .

  Advise pregnant women receiving opioid addiction treatment with SUBOXONE sublingual film of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available

  [see Use in Specific Populations ]

  . 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.
  )
  
• Adrenal Insufficiency:
  If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (
  5.6 Adrenal Insufficiency

  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.
  )
  
• Risk of Opioid Withdrawal with Abrupt Discontinuation:
  If treatment is temporarily interrupted or discontinued, monitor patients for withdrawal and treat appropriately. (
  5.7 Risk of Opioid Withdrawal with Abrupt Discontinuation

  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

  [see Drug Abuse and Dependence ]

  . When discontinuing SUBOXONE sublingual film, gradually taper the dosage

  [see Dosage and Administration ]

  .
  )
  
• Risk of Hepatitis, Hepatic Events:
  Monitor liver function tests prior to initiation and during treatment and evaluate suspected hepatic events. (
  5.8 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, are 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, SUBOXONE sublingual film 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.
  )
  
• Precipitation of Opioid Withdrawal Signs and Symptoms:
  An opioid withdrawal syndrome is likely to occur with parenteral misuse of SUBOXONE sublingual film by individuals physically dependent on full opioid agonists, or by sublingual or buccal administration before the agonist effects of other opioids have subsided. (
  5.10 Precipitation of Opioid Withdrawal Signs and Symptoms

  Because it contains naloxone, SUBOXONE sublingual film is likely to produce withdrawal signs and symptoms if misused parenterally by individuals dependent on full opioid agonists such as heroin, morphine, or methadone. Because of the partial agonist properties of buprenorphine, SUBOXONE sublingual film may precipitate opioid withdrawal signs and symptoms in such persons if administered before the agonist effects of the opioid have subsided.
  )
  
• Risk of Overdose in Opioid‐Naïve Patients
  : SUBOXONE sublingual film is not appropriate as an analgesic. There have been reported deaths of opioid naïve individuals who received a 2 mg sublingual dose. (
  5.11 Risk of Overdose in Opioid 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. SUBOXONE sublingual film is not appropriate as an analgesic.
  )