Table 4. Clinically Significant Drug Interactions
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention:	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. Before co-prescribing benzodiazepines for anxiety or insomnia, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments [see Warnings and Precautions (5.2,5.3)] . 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)] .
Examples:	Alcohol, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids.
Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of SUBOXONE sublingual film is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see Clinical Pharmacology (12.3)] , potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.
Intervention:	If concomitant use is necessary, consider dosage reduction of SUBOXONE sublingual film until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the SUBOXONE sublingual film dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see Clinical Pharmacology (12.3)] , potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see Clinical Pharmacology (12.3)] , which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the SUBOXONE sublingual film dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider SUBOXONE sublingual film dosage reduction and monitor for signs of respiratory depression.
Examples:	Rifampin, carbamazepine, phenytoin
Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Clinical Impact:	Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delavirdine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.
Intervention:	Patients who are on chronic SUBOXONE sublingual film treatment should have their dose monitored if NNRTIs are added to their treatment regimen.
Examples:	efavirenz, nevirapine, etravirine, delavirdine
Antiretrovirals: Protease inhibitors (PIs)
Clinical Impact:	Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.
Intervention:	Monitor patients taking SUBOXONE sublingual film and atazanavir with and without ritonavir, and reduce dose of SUBOXONE sublingual film if warranted.
Examples:	atazanavir, ritonavir
Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)
Clinical Impact:	Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.
Intervention:	None
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue SUBOXONE sublingual film sublingual film if serotonin syndrome is suspected.
Examples:	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).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).
Intervention:	The use of SUBOXONE sublingual film is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Muscle Relaxants
Clinical Impact:	Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients receiving muscle relaxants and SUBOXONE sublingual film for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of SUBOXONE sublingual film and/or the muscle relaxant as necessary. 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)] .
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when SUBOXONE sublingual film is used concomitantly with anticholinergic drugs.

Includes clinically significant drug interactions with SUBOXONE.

Benzodiazepines and Other Central Nervous System (CNS) Depressants

Clinical Impact:

Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.

Intervention:

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.

Before co-prescribing benzodiazepines for anxiety or insomnia, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments

[see Warnings and Precautions (

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 (5.3), Drug Interactions (7)].

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 (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 (2.8)]

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 (2.2)]

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 (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 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.

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 (5.2)].

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 (7)].

)]

.

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

[see Warnings and Precautions (5.3), Drug Interactions (7)].

[see Patient Counseling Information (17)]

[see Dosage and Administration (2.8)]

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.

[see Dosage and Administration (2.2)]

[see Overdosage (10)]

[see Patient Counseling Information (17)]

)]

Examples:

Alcohol, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids.

Inhibitors of CYP3A4

Clinical Impact:

The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of SUBOXONE sublingual film is achieved.

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease

[see Clinical Pharmacology (

12.3 Pharmacokinetics

Absorption

In several pharmacokinetic studies following the administration of different dosages, a dose of one or two of the 2 mg/0.5 mg SUBOXONE sublingual films administered sublingually or buccally showed comparable relative bioavailability to the same total dose of SUBOXONE sublingual tablets. In contrast, one 8 mg/2 mg and one 12 mg/3 mg SUBOXONE sublingual films administered sublingually or buccally showed higher relative bioavailability for both buprenorphine and naloxone compared to the same total dose of SUBOXONE sublingual tablets. A combination of one 8 mg/2 mg and two 2 mg/0.5 mg SUBOXONE sublingual films (total dose of 12 mg/3 mg) administered sublingually showed comparable relative bioavailability to the same total dose of SUBOXONE sublingual tablets, while buccally administered SUBOXONE sublingual films showed higher relative bioavailability.Table 5, below, illustrates the relative increase in exposure to buprenorphine and naloxone associated with SUBOXONE sublingual films compared to SUBOXONE sublingual tablets, and shows the effect of route of administration [

see Dosage and Administration (2.9,2.10)

Across relevant pharmacokinetic studies, the pharmacokinetic parameters and exposures derived from the buccal and sublingual administrations of SUBOXONE sublingual film were comparable to one another.

Table 5. Changes in Pharmacokinetic Parameters for SUBOXONE Sublingual Film Administered Sublingually or Buccally in Comparison to SUBOXONE Sublingual Tablet
Note: 1. the 16 mg/4 mg strength film is not marketed; it is compositionally proportional to the 8 mg/2 mg strength film and has the same size of 2 x 8 mg/2 mg film. 2. – represents no change when the 90% confidence intervals for the geometric mean ratios of the Cmax and AUC0-last values are within the 80% to 125% limit. 3. There are no data for the 4 mg/1 mg strength film; it is compositionally proportional to 2 mg/0.5 mg strength film and has the same size of 2 x 2 mg/0.5 mg film strength.
Dosage	PK Parameter	Increase in Buprenorphine			PK Parameter	Increase in Naloxone
Dosage	PK Parameter	Film Sublingual Compared to Tablet Sublingual	Film Buccal Compared to Tablet Sublingual	Film Buccal Compared to Film Sublingual	PK Parameter	Film Sublingual Compared to Tablet Sublingual	Film Buccal Compared to Tablet Sublingual	Film Buccal Compared to Film Sublingual
1 x 2 mg/0.5 mg	C_max	22%	25%	-	C_max	-	-	-
1 x 2 mg/0.5 mg	AUC_0-last	-	19%	-	AUC_0-last	-	-	-
2 x 2 mg/0.5 mg	C_max	-	21%	21%	C_max	-	17%	21%
2 x 2 mg/0.5 mg	AUC_0-last	-	23%	16%	AUC_0-last	-	22%	24%
1 x 8 mg/2 mg	C_max	28%	34%	-	C_max	41%	54%	-
1 x 8 mg/2 mg	AUC_0-last	20%	25%	-	AUC_0-last	30%	43%	-
1 x 12 mg/3 mg	C_max	37%	47%	-	C_max	57%	72%	9%
1 x 12 mg/3 mg	AUC_0-last	21%	29%	-	AUC_0-last	45%	57%	-
1 x 8 mg/2 mg plus 2 x 2 mg/0.5 mg	C_max	-	27%	13%	C_max	17%	38%	19%
1 x 8 mg/2 mg plus 2 x 2 mg/0.5 mg	AUC_0-last	-	23%	-	AUC_0-last	-	30%	19%
1 x 16 mg/4 mg film	C_max	34%	29%	7%	C_max	44%	46%	9%
1 x 16 mg/4 mg film	AUC_0-last	32%	-	-	AUC_0-last	49%	36%	3%

Distribution

Buprenorphine is approximately 96% protein bound, primarily to alpha and beta globulin. Naloxone is approximately 45% protein bound, primarily to albumin.

Elimination

Buprenorphine is metabolized and eliminated in urine and feces. Naloxone undergoes metabolism as well. When SUBOXONE sublingual film is administered sublingually or buccally, buprenorphine has a mean elimination half-life ranging from 24 to 42 hours and naloxone has a mean elimination half-life ranging from 2 to 12 hours.

Metabolism

Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation. The N-dealkylation pathway is mediated primarily by the CYP3A4. Norbuprenorphine, the major metabolite, can further undergo glucuronidation. Norbuprenorphine has been found to bind opioid receptors

in vitro

; however, it has not been studied clinically for opioid-like activity. Naloxone undergoes direct glucuronidation to naloxone-3-glucuronide as well as N-dealkylation, and reduction of the 6-oxo group.

Excretion

A mass balance study of buprenorphine showed complete recovery of radiolabel in urine (30%) and feces (69%) collected up to 11 days after dosing. Almost all of the dose was accounted for in terms of buprenorphine, norbuprenorphine, and two unidentified buprenorphine metabolites. In urine, most of buprenorphine and norbuprenorphine was conjugated (buprenorphine, 1% free and 9.4% conjugated; norbuprenorphine, 2.7% free and 11% conjugated). In feces, almost all of the buprenorphine and norbuprenorphine were free (buprenorphine, 33% free and 5% conjugated; norbuprenorphine, 21% free and 2% conjugated). Based on all studies performed with sublingually and buccally administered SUBOXONE sublingual film, buprenorphine has a mean elimination half-life from plasma ranging from 24 to 42 hours and naloxone has a mean elimination half-life from plasma ranging from 2 to 12 hours.

Drug Interactions Studies

CYP3A4 Inhibitors and Inducers

Buprenorphine has been found to be a CYP2D6 and CYP3A4 inhibitor and its major metabolite, norbuprenorphine, has been found to be a moderate CYP2D6 inhibitor in

in vitro

studies employing human liver microsomes. However, the relatively low plasma concentrations of buprenorphine and norbuprenorphine resulting from therapeutic doses are not expected to raise significant drug-drug interaction concerns

[see Drug Interactions (7)]

Specific Populations

Hepatic Impairment

In a pharmacokinetic study, the disposition of buprenorphine and naloxone were determined after administering a 2.0/0.5 mg SUBOXONE sublingual tablet in subjects with varied degrees of hepatic impairment as indicated by Child-Pugh criteria. The disposition of buprenorphine and naloxone in patients with hepatic impairment were compared to disposition in subjects with normal hepatic function.

In subjects with mild hepatic impairment, the changes in mean C_max, AUC_0-last, and half-life values of both buprenorphine and naloxone were not clinically significant. No dosing adjustment is needed in patients with mild hepatic impairment.

For subjects with moderate and severe hepatic impairment, mean C_max, AUC_0-last, and half-life values of both buprenorphine and naloxone were increased; the effects on naloxone are greater than that on buprenorphine (Table 6).

Table 6. Changes in Pharmacokinetic Parameters in Subjects With Moderate and Severe Hepatic Impairment
Hepatic Impairment	PK Parameters	Increase in buprenorphine compared to healthy subjects	Increase in naloxone compared to healthy subjects
Moderate	C_max	8%	170%
	AUC_0-last	64%	218%
	Half-life	35%	165%
Severe	C_max	72%	1030%
	AUC_0-last	181%	1302%
	Half-life	57%	122%

The difference in magnitude of the effects on naloxone and buprenorphine are greater in subjects with severe hepatic impairment than subjects with moderate hepatic impairment

[see Warnings and Precautions (5.12), Use in Specific Populations (8.6)].

HCV infection

In subjects with HCV infection but no sign of hepatic impairment, the changes in the mean C_max, AUC_0-last, and half-life values of buprenorphine and naloxone were not clinically significant in comparison to healthy subjects without HCV infection.

)]

, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.

Intervention:

If concomitant use is necessary, consider dosage reduction of SUBOXONE sublingual film until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.

If a CYP3A4 inhibitor is discontinued, consider increasing the SUBOXONE sublingual film dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.

Examples:

Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)

CYP3A4 Inducers

Clinical Impact:

The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine

[see Clinical Pharmacology (

12.3 Pharmacokinetics

Absorption

see Dosage and Administration (2.9,2.10)

Table 5. Changes in Pharmacokinetic Parameters for SUBOXONE Sublingual Film Administered Sublingually or Buccally in Comparison to SUBOXONE Sublingual Tablet
Note: 1. the 16 mg/4 mg strength film is not marketed; it is compositionally proportional to the 8 mg/2 mg strength film and has the same size of 2 x 8 mg/2 mg film. 2. – represents no change when the 90% confidence intervals for the geometric mean ratios of the Cmax and AUC0-last values are within the 80% to 125% limit. 3. There are no data for the 4 mg/1 mg strength film; it is compositionally proportional to 2 mg/0.5 mg strength film and has the same size of 2 x 2 mg/0.5 mg film strength.
Dosage	PK Parameter	Increase in Buprenorphine			PK Parameter	Increase in Naloxone
Dosage	PK Parameter	Film Sublingual Compared to Tablet Sublingual	Film Buccal Compared to Tablet Sublingual	Film Buccal Compared to Film Sublingual	PK Parameter	Film Sublingual Compared to Tablet Sublingual	Film Buccal Compared to Tablet Sublingual	Film Buccal Compared to Film Sublingual
1 x 2 mg/0.5 mg	C_max	22%	25%	-	C_max	-	-	-
1 x 2 mg/0.5 mg	AUC_0-last	-	19%	-	AUC_0-last	-	-	-
2 x 2 mg/0.5 mg	C_max	-	21%	21%	C_max	-	17%	21%
2 x 2 mg/0.5 mg	AUC_0-last	-	23%	16%	AUC_0-last	-	22%	24%
1 x 8 mg/2 mg	C_max	28%	34%	-	C_max	41%	54%	-
1 x 8 mg/2 mg	AUC_0-last	20%	25%	-	AUC_0-last	30%	43%	-
1 x 12 mg/3 mg	C_max	37%	47%	-	C_max	57%	72%	9%
1 x 12 mg/3 mg	AUC_0-last	21%	29%	-	AUC_0-last	45%	57%	-
1 x 8 mg/2 mg plus 2 x 2 mg/0.5 mg	C_max	-	27%	13%	C_max	17%	38%	19%
1 x 8 mg/2 mg plus 2 x 2 mg/0.5 mg	AUC_0-last	-	23%	-	AUC_0-last	-	30%	19%
1 x 16 mg/4 mg film	C_max	34%	29%	7%	C_max	44%	46%	9%
1 x 16 mg/4 mg film	AUC_0-last	32%	-	-	AUC_0-last	49%	36%	3%

Distribution

Buprenorphine is approximately 96% protein bound, primarily to alpha and beta globulin. Naloxone is approximately 45% protein bound, primarily to albumin.

Elimination

Metabolism

in vitro

Excretion

Drug Interactions Studies

CYP3A4 Inhibitors and Inducers

Buprenorphine has been found to be a CYP2D6 and CYP3A4 inhibitor and its major metabolite, norbuprenorphine, has been found to be a moderate CYP2D6 inhibitor in

in vitro

[see Drug Interactions (7)]

Specific Populations

Hepatic Impairment

Table 6. Changes in Pharmacokinetic Parameters in Subjects With Moderate and Severe Hepatic Impairment
Hepatic Impairment	PK Parameters	Increase in buprenorphine compared to healthy subjects	Increase in naloxone compared to healthy subjects
Moderate	C_max	8%	170%
	AUC_0-last	64%	218%
	Half-life	35%	165%
Severe	C_max	72%	1030%
	AUC_0-last	181%	1302%
	Half-life	57%	122%

The difference in magnitude of the effects on naloxone and buprenorphine are greater in subjects with severe hepatic impairment than subjects with moderate hepatic impairment

[see Warnings and Precautions (5.12), Use in Specific Populations (8.6)].

HCV infection

)]

, potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine.

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase

[see Clinical Pharmacology (

12.3 Pharmacokinetics

Absorption

see Dosage and Administration (2.9,2.10)

Table 5. Changes in Pharmacokinetic Parameters for SUBOXONE Sublingual Film Administered Sublingually or Buccally in Comparison to SUBOXONE Sublingual Tablet
Note: 1. the 16 mg/4 mg strength film is not marketed; it is compositionally proportional to the 8 mg/2 mg strength film and has the same size of 2 x 8 mg/2 mg film. 2. – represents no change when the 90% confidence intervals for the geometric mean ratios of the Cmax and AUC0-last values are within the 80% to 125% limit. 3. There are no data for the 4 mg/1 mg strength film; it is compositionally proportional to 2 mg/0.5 mg strength film and has the same size of 2 x 2 mg/0.5 mg film strength.
Dosage	PK Parameter	Increase in Buprenorphine			PK Parameter	Increase in Naloxone
Dosage	PK Parameter	Film Sublingual Compared to Tablet Sublingual	Film Buccal Compared to Tablet Sublingual	Film Buccal Compared to Film Sublingual	PK Parameter	Film Sublingual Compared to Tablet Sublingual	Film Buccal Compared to Tablet Sublingual	Film Buccal Compared to Film Sublingual
1 x 2 mg/0.5 mg	C_max	22%	25%	-	C_max	-	-	-
1 x 2 mg/0.5 mg	AUC_0-last	-	19%	-	AUC_0-last	-	-	-
2 x 2 mg/0.5 mg	C_max	-	21%	21%	C_max	-	17%	21%
2 x 2 mg/0.5 mg	AUC_0-last	-	23%	16%	AUC_0-last	-	22%	24%
1 x 8 mg/2 mg	C_max	28%	34%	-	C_max	41%	54%	-
1 x 8 mg/2 mg	AUC_0-last	20%	25%	-	AUC_0-last	30%	43%	-
1 x 12 mg/3 mg	C_max	37%	47%	-	C_max	57%	72%	9%
1 x 12 mg/3 mg	AUC_0-last	21%	29%	-	AUC_0-last	45%	57%	-
1 x 8 mg/2 mg plus 2 x 2 mg/0.5 mg	C_max	-	27%	13%	C_max	17%	38%	19%
1 x 8 mg/2 mg plus 2 x 2 mg/0.5 mg	AUC_0-last	-	23%	-	AUC_0-last	-	30%	19%
1 x 16 mg/4 mg film	C_max	34%	29%	7%	C_max	44%	46%	9%
1 x 16 mg/4 mg film	AUC_0-last	32%	-	-	AUC_0-last	49%	36%	3%

Distribution

Buprenorphine is approximately 96% protein bound, primarily to alpha and beta globulin. Naloxone is approximately 45% protein bound, primarily to albumin.

Elimination

Metabolism

in vitro

Excretion

Drug Interactions Studies

CYP3A4 Inhibitors and Inducers

Buprenorphine has been found to be a CYP2D6 and CYP3A4 inhibitor and its major metabolite, norbuprenorphine, has been found to be a moderate CYP2D6 inhibitor in

in vitro

[see Drug Interactions (7)]

Specific Populations

Hepatic Impairment

Table 6. Changes in Pharmacokinetic Parameters in Subjects With Moderate and Severe Hepatic Impairment
Hepatic Impairment	PK Parameters	Increase in buprenorphine compared to healthy subjects	Increase in naloxone compared to healthy subjects
Moderate	C_max	8%	170%
	AUC_0-last	64%	218%
	Half-life	35%	165%
Severe	C_max	72%	1030%
	AUC_0-last	181%	1302%
	Half-life	57%	122%

The difference in magnitude of the effects on naloxone and buprenorphine are greater in subjects with severe hepatic impairment than subjects with moderate hepatic impairment

[see Warnings and Precautions (5.12), Use in Specific Populations (8.6)].

HCV infection

)]

, which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression.

Intervention:

If concomitant use is necessary, consider increasing the SUBOXONE sublingual film dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.

If a CYP3A4 inducer is discontinued, consider SUBOXONE sublingual film dosage reduction and monitor for signs of respiratory depression.

Examples:

Rifampin, carbamazepine, phenytoin

Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Clinical Impact:

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delavirdine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.

Intervention:

Patients who are on chronic SUBOXONE sublingual film treatment should have their dose monitored if NNRTIs are added to their treatment regimen.

Examples:

efavirenz, nevirapine, etravirine, delavirdine

Antiretrovirals: Protease inhibitors (PIs)

Clinical Impact:

Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.

Intervention:

Monitor patients taking SUBOXONE sublingual film and atazanavir with and without ritonavir, and reduce dose of SUBOXONE sublingual film if warranted.

Examples:

atazanavir, ritonavir

Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)

Clinical Impact:

Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.

Intervention:

None

Serotonergic Drugs

Clinical Impact:

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

Intervention:

If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue SUBOXONE sublingual film sublingual film if serotonin syndrome is suspected.

Examples:

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).

Monoamine Oxidase Inhibitors (MAOIs)

Clinical Impact:

MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).

Intervention:

The use of SUBOXONE sublingual film is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.

Examples:

phenelzine, tranylcypromine, linezolid

Muscle Relaxants

Clinical Impact:

Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Intervention:

Monitor patients receiving muscle relaxants and SUBOXONE sublingual film for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of SUBOXONE sublingual film and/or the muscle relaxant as necessary. 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 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 (5.2)]

[see Overdosage (10)]

[see Patient Counseling Information (17)]

), Warnings and Precautions (

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

[see Warnings and Precautions (5.3), Drug Interactions (7)].

[see Patient Counseling Information (17)]

[see Dosage and Administration (2.8)]

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.

[see Dosage and Administration (2.2)]

[see Overdosage (10)]

[see Patient Counseling Information (17)]

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

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

[see Drug Interactions (7)].

)]

Diuretics

Clinical Impact:

Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

Intervention:

Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs

Clinical Impact:

The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Intervention:

Monitor patients for signs of urinary retention or reduced gastric motility when SUBOXONE sublingual film is used concomitantly with anticholinergic drugs.

Coverage for Suboxone