Buprenorphine and Naloxone Sublingual Film

Drug Addiction and Treatment Act

Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this product in the treatment of opioid dependence is limited to healthcare providers who meet certain qualifying requirements, and who have notified the Secretary of Health and Human Services (HHS) of their intent to prescribe this product for the treatment of opioid dependence and have been assigned a unique identification number that must be included on every prescription.

Important Dosage and Administration Information

Buprenorphine and Naloxone 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.

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 Buprenorphine and Naloxone Sublingual Film or with sublingual buprenorphine monotherapy. At treatment initiation, the first dose of Buprenorphine and Naloxone 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 Buprenorphine and Naloxone Sublingual Film is recommended. Clinicians should start with an initial dose of 2 mg/0.5 mg or 4 mg/1 mg buprenorphine and 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 and naloxone based on the control of acute withdrawal symptoms.

On Day 2, a single daily dose of up to 16 mg/4 mg Buprenorphine and Naloxone 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 and 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 Buprenorphine and Naloxone Sublingual Film.

Maintenance

• For maintenance, Buprenorphine and Naloxone Sublingual Film may be administered buccally or sublingually. • The dosage of Buprenorphine and Naloxone 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 and naloxone to a level that holds the patient in treatment and suppresses opioid withdrawal signs and symptoms. • After treatment induction and stabilization, the maintenance dose of Buprenorphine and Naloxone Sublingual Film is generally in the range of 4 mg/1 mg buprenorphine and naloxone to 24 mg/6 mg buprenorphine and naloxone per day depending on the individual patient and clinical response. The recommended target dosage of Buprenorphine and Naloxone Sublingual Film during maintenance is 16 mg/4 mg buprenorphine and naloxone/day as a single daily dose. Dosages higher than 24 mg/6 mg daily have not been demonstrated to provide a clinical advantage. • When determining the prescription quantity for unsupervised administration, consider the patient’s level of stability, the security of his or her home situation, and other factors likely to affect the ability to manage supplies of take-home medication. • There is no maximum recommended duration of maintenance treatment. Patients may require treatment indefinitely and should continue for as long as patients are benefiting and the use of Buprenorphine and Naloxone Sublingual Film contributes to the intended treatment goals.

Method of Administration

Buprenorphine and Naloxone Sublingual Film must be administered whole. Do not cut, chew, or swallow Buprenorphine and Naloxone 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.

Buprenorphine and Naloxone 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.

Clinical Supervision

Treatment should be initiated with supervised administration, progressing to unsupervised administration as the patient’s clinical stability permits. Buprenorphine and Naloxone Sublingual Film is subject to diversion and abuse. When determining the prescription quantity for unsupervised administration, consider the patient’s level of stability, the security of his or her home situation, and other factors likely to affect the ability to manage supplies of take-home medication.

Ideally patients should be seen at reasonable intervals (e.g., at least weekly during the first month of treatment) based upon the individual circumstances of the patient. 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. Periodic assessment is necessary to determine compliance with the dosing regimen, effectiveness of the treatment plan, and overall patient progress.

Once a stable dosage has been achieved and patient assessment (e.g., urine drug screening) does not indicate illicit drug use, less frequent follow-up visits may be appropriate. A once-monthly visit schedule may be reasonable for patients on a stable dosage of medication who are making progress toward their treatment objectives. Continuation or modification of pharmacotherapy should be based on the healthcare provider’s evaluation of treatment outcomes and objectives such as:

1. Absence of medication toxicity. 2. Absence of medical or behavioral adverse effects. 3. Responsible handling of medications by the patient. 4. Patient’s compliance with all elements of the treatment plan (including recovery-oriented activities, psychotherapy, and/or other psychosocial modalities). 5. Abstinence from illicit drug use (including problematic alcohol and/or benzodiazepine use).

If treatment goals are not being achieved, the healthcare provider should re-evaluate the appropriateness of continuing the current treatment.

Unstable Patients

Healthcare providers will need to decide when they cannot appropriately provide further management for particular patients. For example, some patients may be abusing or dependent on various drugs, or unresponsive to psychosocial intervention such that the healthcare provider does not feel that he/she has the expertise to manage the patient. In such cases, the healthcare provider may want to assess whether to refer the patient to a specialist or more intensive behavioral treatment environment. Decisions should be based on a treatment plan established and agreed upon with the patient at the beginning of treatment.

Patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be provided with, or referred to, more intensive and structured treatment.

Discontinuing Treatment

The decision to discontinue therapy with Buprenorphine and Naloxone 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 (5.7)].

Switching Between Buprenorphine or Buprenorphine and Naloxone Sublingual Tablets and Buprenorphine and Naloxone Sublingual Film

Patients being switched between buprenorphine and naloxone or buprenorphine only sublingual tablets and Buprenorphine and Naloxone Sublingual Film should be started on the same dosage of the previously administered product. However, dosage adjustments may be necessary when switching between buprenorphine products. Not all strengths and combinations of the Buprenorphine and Naloxone Sublingual Films are bioequivalent to buprenorphine and naloxone sublingual tablets as observed in pharmacokinetic studies [see Clinical Pharmacology (12.3)]. Therefore, systemic exposures of buprenorphine and naloxone may be different when patients are switched from tablets to film or vice-versa. Patients should be monitored for symptoms related to over-dosing or under-dosing.

Switching Between Buprenorphine and Naloxone Sublingual Film Strengths

As indicated in Table 1, the sizes and the compositions of the two units of Buprenorphine and Naloxone Sublingual Films, i.e., 8 mg/2 mg and the 12 mg/3 mg units, are different from one another. If patients switch between various combinations of lower and higher strength units of Buprenorphine and Naloxone Sublingual Films to obtain the same total dose, (e.g., from three 4 mg/1 mg units to a single 12 mg/3 mg unit, or vice-versa), systemic exposures of buprenorphine and naloxone may be different and patients should be monitored for over-dosing or under-dosing. For this reason, pharmacist should not substitute one or more film strengths for another without approval of the prescriber.

Table 1. Comparison of Available Buprenorphine and Naloxone Sublingual Film Strengths by Dimensions and Drug Concentrations.

Buprenorphine and Naloxone Sublingual Film unit strength (buprenorphine/naloxone)	Buprenorphine and Naloxone Sublingual Film unit dimensions	Buprenorphine Concentration % (w/w)	Naloxone Concentration % (w/w)
8 mg/2 mg	22.0 mm x 12.8 mm	17.2	4.88
12 mg/3 mg (1.5 times the length of the 8 mg/2 mg unit)	22.0 mm x 19.2 mm	17.2	4.88

Switching Between Sublingual and Buccal Sites of Administration

The systemic exposure of buprenorphine between buccal and sublingual administration of Buprenorphine and Naloxone Sublingual Film is similar. Therefore, once induction is complete, patients can switch between buccal and sublingual administration without significant risk of under or overdosing.

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

• Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)] • Respiratory and CNS Depression [see Warnings and Precautions (5.2), (5.3)] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.5)] • Adrenal Insufficiency [see Warnings and Precautions (5.6)] • Opioid Withdrawal [see Warnings and Precautions (5.7, 5.10)] • Hepatitis, Hepatic Events [see Warnings and Precautions (5.8)] • Hypersensitivity Reactions [see Warnings and Precautions (5.9)] • Orthostatic Hypotension [see Warnings and Precautions (5.14)] • Elevation of Cerebrospinal Fluid Pressure [see Warnings and Precautions (5.15)] • Elevation of Intracholedochal Pressure [see Warnings and Precautions (5.16)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of Buprenorphine and Naloxone Sublingual Film is supported by clinical trials using buprenorphine sublingual tablets and buprenorphine and naloxone sublingual tablets, and other trials using buprenorphine sublingual solutions, as well as an open-label study in 194 patients treated with Buprenorphine and Naloxone Sublingual Film administered sublingually and 188 patients treated with the film administered buccally. In total, safety data from clinical studies are available from over 3000 opioid-dependent subjects exposed to buprenorphine at doses in the range used in the treatment of opioid dependence. Few differences in the adverse event profile were noted with regard to sublingually and buccally administered Buprenorphine and Naloxone Sublingual Film, buprenorphine and naloxone sublingual tablets, buprenorphine sublingual tablets and a buprenorphine ethanolic sublingual solution.

The most common adverse event (> 1%) associated with the sublingual administration of the Buprenorphine and Naloxone Sublingual Film was oral hypoesthesia. Other adverse events were constipation, glossodynia, oral mucosal erythema, vomiting, intoxication, disturbance in attention, palpitations, insomnia, withdrawal syndrome, hyperhidrosis, and blurred vision.

The most common adverse events associated with the buccal administration were similar to those observed with sublingual administration of the film.

Other adverse event data were derived from larger, controlled studies of buprenorphine and naloxone sublingual tablets and buprenorphine sublingual tablets and of buprenorphine sublingual solution. In a comparative study of buprenorphine and naloxone sublingual tablets and buprenorphine sublingual tablets, adverse event profiles were similar for subjects treated with 16 mg/4 mg buprenorphine and naloxone sublingual tablets or 16 mg buprenorphine sublingual tablets. The following adverse events were reported to occur by at least 5% of patients in a 4 week study of buprenorphine and naloxone sublingual tablets and buprenorphine sublingual tablets.

Table 2. Adverse Events (≥ 5%) by Body System and Treatment Group in a 4 Week Study

Abbreviations: COSTART = Coding Symbols for Thesaurus of Adverse Reaction Terms.
Body System/ Adverse Event (COSTART Terminology)	Buprenorphine and Naloxone Sublingual Tablets 16 mg/4 mg/day N = 107 n (%)	Buprenorphine Sublingual Tablets 16 mg/day N = 103 n (%)	Placebo N = 107 n (%)
Body as a Whole
Asthenia	7 (6.5%)	5 (4.9%)	7 (6.5%)
Chills	8 (7.5%)	8 (7.8%)	8 (7.5%)
Headache	39 (36.4%)	30 (29.1%)	24 (22.4%)
Infection	6 (5.6%)	12 (11.7%)	7 (6.5%)
Pain	24 (22.4%)	19 (18.4%)	20 (18.7%)
Pain abdomen	12 (11.2%)	12 (11.7%)	7 (6.5%)
Pain back	4 (3.7%)	8 (7.8%)	12 (11.2%)
Withdrawal syndrome	27 (25.2%)	19 (18.4%)	40 (37.4%)
Cardiovascular System
Vasodilation	10 (9.3%)	4 (3.9%)	7 (6.5%)
Digestive System
Constipation	13 (12.1%)	8 (7.8%)	3 (2.8%)
Diarrhea	4 (3.7%)	5 (4.9%)	16 (15.0%)
Nausea	16 (15.0%)	14 (13.6%)	12 (11.2%)
Vomiting	8 (7.5%)	8 (7.8%)	5 (4.7%)
Nervous System
Insomnia	15 (14.0%)	22 (21.4%)	17 (15.9%)
Respiratory System
Rhinitis	5 (4.7%)	10 (9.7%)	14 (13.1%)
Skin And Appendages
Sweating	15 (14.0%)	13 (12.6%)	11 (10.3%)

The adverse event profile of buprenorphine was also characterized in the dose-controlled study of a buprenorphine ethanolic solution, over a range of doses in four months of treatment. Table 3 shows adverse events reported by at least 5% of subjects in any dose group in the dose-controlled trial.

Table 3. Adverse Events (≥ 5%) by Body System and Treatment Group in a 16 Week Study

* Sublingual solution. Doses in this table cannot necessarily be delivered in tablet form, but for comparison purposes: “Very low” dose (1 mg solution) would be less than a tablet dose of 2 mg “Low” dose (4 mg solution) approximates a 6 mg tablet dose “Moderate” dose (8 mg solution) approximates a 12 mg tablet dose “High” dose (16 mg solution) approximates a 24 mg tablet dose
Body System/ Adverse Event (COSTART Terminology)	Buprenorphine Dose
	Very Low* N = 184 n (%)	Low* N = 180 n (%)	Moderate* N = 186 n (%)	High* N = 181 n (%)	Total* N = 731 n (%)
Body as a Whole
Abscess	9 (5%)	2 (1%)	3 (2%)	2 (1%)	16 (2%)
Asthenia	26 (14%)	28 (16%)	26 (14%)	24 (13%)	104 (14%)
Chills	11 (6%)	12 (7%)	9 (5%)	10 (6%)	42 (6%)
Fever	7 (4%)	2 (1%)	2 (1%)	10 (6%)	21 (3%)
Flu syndrome	4 (2%)	13 (7%)	19 (10%)	8 (4%)	44 (6%)
Headache	51 (28%)	62 (34%)	54 (29%)	53 (29%)	220 (30%)
Infection	32 (17%)	39 (22%)	38 (20%)	40 (22%)	149 (20%)
Injury accidental	5 (3%)	10 (6%)	5 (3%)	5 (3%)	25 (3%)
Pain	47 (26%)	37 (21%)	49 (26%)	44 (24%)	177 (24%)
Pain back	18 (10%)	29 (16%)	28 (15%)	27 (15%)	102 (14%)
Withdrawal syndrome	45 (24%)	40 (22%)	41 (22%)	36 (20%)	162 (22%)
Digestive System
Constipation	10 (5%)	23 (13%)	23 (12%)	26 (14%)	82 (11%)
Diarrhea	19 (10%)	8 (4%)	9 (5%)	4 (2%)	40 (5%)
Dyspepsia	6 (3%)	10 (6%)	4 (2%)	4 (2%)	24 (3%)
Nausea	12 (7%)	22 (12%)	23 (12%)	18 (10%)	75 (10%)
Vomiting	8 (4%)	6 (3%)	10 (5%)	14 (8%)	38 (5%)
Nervous System
Anxiety	22 (12%)	24 (13%)	20 (11%)	25 (14%)	91 (12%)
Depression	24 (13%)	16 (9%)	25 (13%)	18 (10%)	83 (11%)
Dizziness	4 (2%)	9 (5%)	7 (4%)	11 (6%)	31 (4%)
Insomnia	42 (23%)	50 (28%)	43 (23%)	51 (28%)	186 (25%)
Nervousness	12 (7%)	11 (6%)	10 (5%)	13 (7%)	46 (6%)
Somnolence	5 (3%)	13 (7%)	9 (5%)	11 (6%)	38 (5%)
Respiratory System
Cough increase	5 (3%)	11 (6%)	6 (3%)	4 (2%)	26 (4%)
Pharyngitis	6 (3%)	7 (4%)	6 (3%)	9 (5%)	28 (4%)
Rhinitis	27 (15%)	16 (9%)	15 (8%)	21 (12%)	79 (11%)
Skin and Appendages
Sweat	23 (13%)	21 (12%)	20 (11%)	23 (13%)	87 (12%)
Special Senses
Runny eyes	13 (7%)	9 (5%)	6 (3%)	6 (3%)	34 (5%)

The safety of Buprenorphine and Naloxone Sublingual Film during treatment induction is supported by a clinical trial using 16 patients treated with Buprenorphine and Naloxone Sublingual Film and 18 treated with a buprenorphine-only sublingual film. Few differences in the adverse event profiles were noted between Buprenorphine and Naloxone Sublingual Film and the buprenorphine-only sublingual film.

The most common adverse event occurring during treatment induction and the 3 days following induction using Buprenorphine and Naloxone Sublingual Film was restlessness. Other adverse events were anxiety, piloerection, stomach discomfort, irritability, headache, rhinorrhea, cold sweat, arthralgia, and lacrimation increased.

Four subjects left the study early on the first day of sublingual film administration. However, there was no evidence to suggest that any of the four subjects experienced precipitated withdrawal secondary to the administration of buprenorphine or Buprenorphine and Naloxone Sublingual Films.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Buprenorphine and Naloxone Sublingual Film. 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 postmarketing adverse events were peripheral edema, stomatitis, glossitis, and blistering and ulceration of the mouth or tongue.

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 Buprenorphine and Naloxone Sublingual Film.

Androgen Deficiency

Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].

Local Reactions

glossodynia, glossitis, oral mucosal erythema, oral hypoesthesia, and stomatitis

Clinical Presentation: The manifestations of acute overdose include pinpoint pupils, sedation, hypotension, respiratory depression, and death.

Treatment of Overdose: In the event of overdose, the respiratory and cardiac status of the patient should be monitored carefully. When respiratory or cardiac functions are depressed, primary attention should be given to the re-establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Oxygen, IV fluids, vasopressors, and other supportive measures should be employed as indicated.

In the case of overdose, the primary management should be the re-establishment of adequate ventilation with mechanical assistance of respiration, if required. Naloxone may be of value for the management of buprenorphine overdose. Higher than normal doses and repeated administration may be necessary. The long duration of action of Buprenorphine and Naloxone Sublingual Film should be taken into consideration when determining the length of treatment and medical surveillance needed to reverse the effects of an overdose. Insufficient duration of monitoring may put patients at risk.

Mechanism of Action

Buprenorphine and Naloxone Sublingual Film contains buprenorphine and naloxone. Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor. Naloxone is a potent antagonist at mu-opioid receptors and produces opioid withdrawal signs and symptoms in individuals physically dependent on full opioid agonists when administered parenterally.

Pharmacodynamics

Subjective Effects

Comparisons of buprenorphine to full opioid agonists such as methadone and hydromorphone suggest that sublingual buprenorphine produces typical opioid agonist effects which are limited by a ceiling effect.

In opioid-experienced subjects who were not physically dependent, acute sublingual doses of buprenorphine and naloxone tablets produced opioid agonist effects which reached a maximum between doses of 8 mg/2 mg and 16 mg/4 mg buprenorphine and naloxone.

Opioid agonist ceiling-effects were also observed in a double-blind, parallel group, dose-ranging comparison of single doses of buprenorphine sublingual solution (1, 2, 4, 8, 16, or 32 mg), placebo and a full agonist control at various doses. The treatments were given in ascending dose order at intervals of at least one week to 16 opioid-experienced subjects who were not physically dependent. Both active drugs produced typical opioid agonist effects. For all measures for which the drugs produced an effect, buprenorphine produced a dose-related response. However, in each case, there was a dose that produced no further effect. In contrast, the highest dose of the full agonist control always produced the greatest effects. Agonist objective rating scores remained elevated for the higher doses of buprenorphine (8 mg to 32 mg) longer than for the lower doses and did not return to baseline until 48 hours after drug administration. The onset of effects appeared more rapidly with buprenorphine than with the full agonist control, with most doses nearing peak effect after 100 minutes for buprenorphine compared to 150 minutes for the full agonist control.

Physiologic Effects

Buprenorphine in IV (2, 4, 8, 12 and 16 mg) and sublingual (12 mg) doses has been administered to opioid-experienced subjects who were not physically dependent to examine cardiovascular, respiratory, and subjective effects at doses comparable to those used for treatment of opioid dependence. Compared to placebo, there were no statistically significant differences among any of the treatment conditions for blood pressure, heart rate, respiratory rate, O2 saturation, or skin temperature across time. Systolic BP was higher in the 8 mg group than placebo (3 hour AUC values). Minimum and maximum effects were similar across all treatments. Subjects remained responsive to low voice and responded to computer prompts. Some subjects showed irritability, but no other changes were observed.

The respiratory effects of sublingual buprenorphine were compared with the effects of methadone in a double-blind, parallel group, dose ranging comparison of single doses of buprenorphine sublingual solution (1, 2, 4, 8, 16, or 32 mg) and oral methadone (15, 30, 45, or 60 mg) in non-dependent, opioid-experienced volunteers. In this study, hypoventilation not requiring medical intervention was reported more frequently after buprenorphine doses of 4 mg and higher than after methadone. Both drugs decreased O2 saturation to the same degree.

Effect of Naloxone

Physiologic and subjective effects following acute sublingual administration of buprenorphine tablets and buprenorphine and naloxone tablets were similar at equivalent dose levels of buprenorphine. Naloxone had no clinically significant effect when administered by the sublingual route, although blood levels of the drug were measurable. Buprenorphine and naloxone, when administered sublingually to an opioid-dependent cohort, was recognized as an opioid agonist, whereas when administered intramuscularly, combinations of buprenorphine with naloxone produced opioid antagonist actions similar to naloxone. This finding suggests that the naloxone in buprenorphine and naloxone tablets may deter injection of buprenorphine and naloxone tablets by persons with active substantial heroin or other full mu-opioid dependence. However, clinicians should be aware that some opioid-dependent persons, particularly those with a low level of full mu-opioid physical dependence or those whose opioid physical dependence is predominantly to buprenorphine, abuse buprenorphine and naloxone combinations by the intravenous or intranasal route. In methadone-maintained patients and heroin-dependent subjects, IV administration of buprenorphine and naloxone combinations precipitated opioid withdrawal signs and symptoms and was perceived as unpleasant and dysphoric. In morphine-stabilized subjects, intravenously administered combinations of buprenorphine with naloxone produced opioid antagonist and withdrawal signs and symptoms that were ratio-dependent; the most intense withdrawal signs and symptoms were produced by 2:1 and 4:1 ratios, less intense by an 8:1 ratio.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6.2)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation.

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 Buprenorphine and Naloxone Sublingual Films administered sublingually or buccally showed comparable relative bioavailability to the same total dose of buprenorphine and naloxone sublingual tablets. In contrast, one 8 mg/2 mg and one 12 mg/3 mg Buprenorphine and Naloxone Sublingual Films administered sublingually or buccally showed higher relative bioavailability for both buprenorphine and naloxone compared to the same total dose of buprenorphine and naloxone sublingual tablets. A combination of one 8 mg/2 mg and two 2 mg/0.5 mg Buprenorphine and Naloxone Sublingual Films (total dose of 12 mg/3 mg) administered sublingually showed comparable relative bioavailability to the same total dose of buprenorphine and naloxone sublingual tablets, while buccally administered Buprenorphine and Naloxone Sublingual Films showed higher relative bioavailability. Table 5, below, illustrates the relative increase in exposure to buprenorphine and naloxone associated with Buprenorphine and Naloxone Sublingual Films compared to buprenorphine and naloxone 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 Buprenorphine and Naloxone Sublingual Film were comparable to one another.

Table 5. Changes in Pharmacokinetic Parameters for Buprenorphine and Naloxone Sublingual Film Administered Sublingually or Buccally in Comparison to Buprenorphine and Naloxone 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
		Film Sublingual Compared to Tablet Sublingual	Film Buccal Compared to Tablet Sublingual	Film Buccal Compared to Film Sublingual		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	Cmax	22%	25%	-	Cmax	-	-	-
	AUC0-last	-	19%	-	AUC0-last	-	-	-
2 x 2 mg/0.5 mg	Cmax	-	21%	21%	Cmax	-	17%	21%
	AUC0-last	-	23%	16%	AUC0-last	-	22%	24%
1 x 8 mg/2 mg	Cmax	28%	34%	-	Cmax	41%	54%	-
	AUC0-last	20%	25%	-	AUC0-last	30%	43%	-
1 x 12 mg/3 mg	Cmax	37%	47%	-	Cmax	57%	72%	9%
	AUC0-last	21%	29%	-	AUC0-last	45%	57%	-
1 x 8 mg/2 mg plus 2 x 2 mg/0.5 mg	Cmax	-	27%	13%	Cmax	17%	38%	19%
	AUC0-last	-	23%	-	AUC0-last	-	30%	19%
1 x 16 mg/4 mg film	Cmax	34%	29%	7%	Cmax	44%	46%	9%
	AUC0-last	32%	-	-	AUC0-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 Buprenorphine and Naloxone 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 Buprenorphine and Naloxone 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 Interaction 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 mg/0.5 mg buprenorphine and naloxone 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 Cmax, AUC0-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 Cmax, AUC0-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	Cmax	8%	170%
	AUC0-last	64%	218%
	Half-life	35%	165%
Severe	Cmax	72%	1030%
	AUC0-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 Cmax, AUC0-last, and half-life values of buprenorphine and naloxone were not clinically significant in comparison to healthy subjects without HCV infection.

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

Safe Use

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

• Buprenorphine and Naloxone Sublingual Film must be administered whole. Advise patients not to cut, chew, or swallow Buprenorphine and Naloxone Sublingual Film. • Inform patients and caregivers that potentially fatal additive effects may occur if Buprenorphine and Naloxone Sublingual Film is used with benzodiazepines or other CNS depressants, including alcohol. Counsel patients that such medications should not be used concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.2, 5.3), Drug Interactions (7)]. • Advise patients that Buprenorphine and Naloxone Sublingual Film contains an opioid that can be a target for people who abuse prescription medications or street drugs. Caution patients to keep their films in a safe place, and to protect them from theft. • Instruct patients to keep Buprenorphine and Naloxone Sublingual Film in a secure place, out of the sight and reach of children. Accidental or deliberate ingestion by a child may cause respiratory depression that can result in death. Advise patients to seek medical attention immediately if a child is exposed to Buprenorphine and Naloxone Sublingual Film. • 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 [see Drug Interactions (7)]. • 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 [see Warnings and Precautions (5.6)]. • Advise patients to never give Buprenorphine and Naloxone Sublingual Film to anyone else, even if he or she has the same signs and symptoms. It may cause harm or death. • Advise patients that selling or giving away this medication is against the law. • Caution patients that Buprenorphine and Naloxone Sublingual Film may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving or operating machinery. Caution should be taken especially during drug induction and dose adjustment and until individuals are reasonably certain that buprenorphine therapy does not adversely affect their ability to engage in such activities [see Warnings and Precautions (5.13)]. • Advise patients not to change the dosage of Buprenorphine and Naloxone Sublingual Film without consulting their healthcare provider. • Advise patients to take Buprenorphine and Naloxone Sublingual Film once a day. • Advise patients that if they miss a dose of Buprenorphine and Naloxone Sublingual Film 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 Buprenorphine and Naloxone Sublingual Film can cause drug dependence and that withdrawal signs and symptoms may occur when the medication is discontinued. • Advise patients seeking to discontinue treatment with buprenorphine for opioid dependence to work closely with their healthcare provider 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, Buprenorphine and Naloxone Sublingual Film may produce orthostatic hypotension in ambulatory individuals [see Warnings and Precautions (5.14)]. • Advise patients to inform their healthcare provider if any other prescription medications, over-the-counter medications, or herbal preparations are prescribed or currently being used [see Drug Interactions (7)]. • Advise women that if they are pregnant while being treated with Buprenorphine and Naloxone Sublingual Film, the baby may have signs of withdrawal at birth and that withdrawal is treatable [see Warnings and Precautions (5.5), Use in Specific Populations (8.1)]. • Advise women who are breastfeeding to monitor the infant for drowsiness and difficulty breathing [see Use in Specific Populations (8.2)]. • Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)]. • Advise patients to inform their family members that, in the event of emergency, the treating healthcare provider or emergency room staff should be informed that the patient is physically dependent on an opioid and that the patient is being treated with Buprenorphine and Naloxone Sublingual Film.

Disposal of Unused Buprenorphine and Naloxone Sublingual Films

Unused Buprenorphine and Naloxone Sublingual Films should be disposed of as soon as they are no longer needed. Unused films should be flushed down the toilet.

Buprenorphine and Naloxone Sublingual Film   (CIII)
for sublingual or buccal administration
(bue″ pre nor′ feen nal ox′ one)

IMPORTANT: Keep Buprenorphine and Naloxone Sublingual Film in a secure place away from children. Accidental use by a child is a medical emergency and can result in death. If a child accidentally uses Buprenorphine and Naloxone Sublingual Film, get emergency help right away.

Read this Medication Guide that comes with Buprenorphine and Naloxone Sublingual Film before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor. Talk to your doctor or pharmacist if you have questions about Buprenorphine and Naloxone Sublingual Film.

Share the important information in this Medication Guide with members of your household.

What is the most important information I should know about Buprenorphine and Naloxone Sublingual Film?

• Buprenorphine and Naloxone Sublingual Film can cause serious and life-threatening breathing problems. Call your doctor right away or get emergency help if: o You feel faint, dizzy, or confused o Your breathing gets much slower than is normal for you   These can be signs of an overdose or other serious problems. • Do not switch from Buprenorphine and Naloxone Sublingual Film to other medicines that contain buprenorphine without talking with your doctor. The amount of buprenorphine in a dose of Buprenorphine and Naloxone Sublingual Film is not the same as the amount of buprenorphine in other medicines that contain buprenorphine. Your doctor will prescribe a starting dose of Buprenorphine and Naloxone Sublingual Film that may be different than other buprenorphine containing medicines you may have been taking. • Buprenorphine and Naloxone Sublingual Film contains an opioid that can cause physical dependence. o Do not stop taking Buprenorphine and Naloxone Sublingual Film without talking to your doctor. You could become sick with uncomfortable withdrawal signs and symptoms because your body has become used to this medicine. o Physical dependence is not the same as drug addiction. o Buprenorphine and Naloxone Sublingual Film is not for occasional or “as needed” use. • An overdose and even death can happen if you take benzodiazepines, sedatives, tranquilizers, antidepressants, or alcohol while using Buprenorphine and Naloxone Sublingual Film. Ask your doctor what you should do if you are taking one of these. • Call a doctor or get emergency help right away if you: o Feel sleepy and uncoordinated o Have blurred vision o Have slurred speech o Cannot think well or clearly o Have slowed reflexes and breathing • Do not inject (“shoot-up”) Buprenorphine and Naloxone Sublingual Film. o Injecting Buprenorphine and Naloxone Sublingual Film may cause life-threatening infections and other serious health problems. o Injecting Buprenorphine and Naloxone Sublingual Film may cause serious withdrawal symptoms such as pain, cramps, vomiting, diarrhea, anxiety, sleep problems, and cravings. • In an emergency, have family members tell emergency department staff that you are physically dependent on an opioid and are being treated with Buprenorphine and Naloxone Sublingual Film.

What is Buprenorphine and Naloxone Sublingual Film?

• Buprenorphine and Naloxone Sublingual Film is a prescription medicine used to treat adults who are addicted to (dependent on) opioid drugs (either prescription or illegal) as part of a complete treatment program that also includes counseling and behavioral therapy.

Buprenorphine and Naloxone Sublingual Film is a controlled substance (CIII) because it contains buprenorphine, which can be a target for people who abuse prescription medicines or street drugs. Keep your Buprenorphine and Naloxone Sublingual Film in a safe place to protect it from theft. Never give your Buprenorphine and Naloxone Sublingual Film to anyone else; it can cause death or harm them. Selling or giving away this medicine is against the law.

• It is not known if Buprenorphine and Naloxone Sublingual Film is safe or effective in children.

Who should not take Buprenorphine and Naloxone Sublingual Film?

Do not take Buprenorphine and Naloxone Sublingual Film if you are allergic to buprenorphine or naloxone.

What should I tell my doctor before taking Buprenorphine and Naloxone Sublingual Film?

Buprenorphine and Naloxone Sublingual Film may not be right for you. Before taking Buprenorphine and Naloxone Sublingual Film, tell your doctor if you:

• Have liver or kidney problems • Have trouble breathing or lung problems • Have an enlarged prostate gland (men) • Have a head injury or brain problem • Have problems urinating • Have a curve in your spine that affects your breathing • Have gallbladder problems • Have adrenal gland problems • Have Addison’s disease • Have low thyroid (hypothyroidism) • Have a history of alcoholism • Have mental problems such as hallucinations (seeing or hearing things that are not there) • Have any other medical condition • Are pregnant or plan to become pregnant. If you take Buprenorphine and Naloxone Sublingual Film while pregnant, your baby may have signs of opioid withdrawal at birth. Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy. Talk to your doctor if you are pregnant or plan to become pregnant. • Are breastfeeding or plan to breastfeed. Buprenorphine and naloxone 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 Buprenorphine and Naloxone Sublingual Film. 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. Buprenorphine and Naloxone Sublingual Film may affect the way other medicines work, and other medicines may affect how Buprenorphine and Naloxone Sublingual Film works. Some medicines may cause serious or life-threatening medical problems when taken with Buprenorphine and Naloxone Sublingual Film.

Sometimes the doses of certain medicines and Buprenorphine and Naloxone Sublingual Film may need to be changed if used together. Do not take any medicine while using Buprenorphine and Naloxone Sublingual Film until you have talked with your doctor. Your doctor will tell you if it is safe to take other medicines while you are taking Buprenorphine and Naloxone Sublingual Film.

Be especially careful about taking other medicines that may make you sleepy, such as pain medicines, tranquilizers, antidepressant medicines, sleeping pills, anxiety medicines or antihistamines.

Know the medicines you take. Keep a list of them to show your doctor or pharmacist each time you get a new medicine.

How should I take Buprenorphine and Naloxone Sublingual Film?

• Always take Buprenorphine and Naloxone Sublingual Film exactly as your doctor tells you. Your doctor may change your dose after seeing how it affects you. Do not change your dose unless your doctor tells you to change it. • Do not take Buprenorphine and Naloxone Sublingual Film more often than prescribed by your doctor. • Take Buprenorphine and Naloxone Sublingual Film 1 time a day. • When you are beginning treatment, take Buprenorphine and Naloxone Sublingual Film only under the tongue (sublingual administration). • After a few days, you can choose whether you will take Buprenorphine and Naloxone Sublingual Film on the inside of your cheek (buccal administration) or by sublingual administration. • Buprenorphine and Naloxone Sublingual Film must be taken whole. Do not cut, chew, or swallow Buprenorphine and Naloxone Sublingual Film. • Your doctor should show you how to take Buprenorphine and Naloxone Sublingual Film the right way. • Each Buprenorphine and Naloxone Sublingual Film comes in a sealed child-resistant foil pouch. Do not open the foil pouch until you are ready to use it.

Taking Buprenorphine and Naloxone Sublingual Film:

• To open your Buprenorphine and Naloxone Sublingual Film foil pouch, cut with scissors along the dotted line (see Figure 1).

Figure 1

• Before taking Buprenorphine and Naloxone Sublingual Film, drink water to moisten your mouth. This helps the film dissolve more easily.

To take Buprenorphine and Naloxone Sublingual Film under your tongue (sublingual administration):

• Hold the film between two fingers by the outside edges. • Place the Buprenorphine and Naloxone Sublingual Film under your tongue, close to the base either to the left or right of the center (see Figure 2).

Figure 2

o If your doctor tells you to take 2 films at a time, place the second film under your tongue on the opposite side. Avoid letting the films touch. o Keep the films in place until they have completely dissolved. o If your doctor tells you to take a third film, place it under your tongue on either side after the first 2 films have dissolved.

To take Buprenorphine and Naloxone Sublingual Film on the inside of your cheek (buccal administration):

• Hold the film between two fingers by the outside edges. • Place one film on the inside of your right or left cheek (see Figure 3).

Figure 3

o If your doctor tells you to take 2 films at a time, place the other film on the inside of the opposite cheek. o Keep the films in place until they have completely dissolved. o If your doctor tells you to take a third film, place it on the inside of your right or left cheek after the first 2 films have dissolved.

  

• While Buprenorphine and Naloxone Sublingual Film is dissolving, do not chew or swallow the film because the medicine will not work as well. • Talking while the film is dissolving can affect how well the medicine in Buprenorphine and Naloxone Sublingual Film is absorbed. • If you miss a dose of Buprenorphine and Naloxone Sublingual Film, take your medicine when you remember. If it is almost time for your next dose, skip the missed dose and take the next dose at your regular time. Do not take 2 doses at the same time unless your doctor tells you to. If you are not sure about your dosing, call your doctor. • Do not stop taking Buprenorphine and Naloxone Sublingual Film suddenly. You could become sick and have withdrawal symptoms because your body has become used to the medicine. Physical dependence is not the same as drug addiction. Your doctor can tell you more about the differences between physical dependence and drug addiction. To have fewer withdrawal symptoms, ask your doctor how to stop using Buprenorphine and Naloxone Sublingual Film the right way. • If you take too many Buprenorphine and Naloxone Sublingual Films or overdose, call Poison Control or get emergency medical help right away.

What should I avoid while taking Buprenorphine and Naloxone Sublingual Film?

• Do not drive, operate heavy machinery, or perform any other dangerous activities until you know how this medication affects you. Buprenorphine can cause drowsiness and slow reaction times. This may happen more often in the first few weeks of treatment when your dose is being changed, but can also happen if you drink alcohol or take other sedative drugs when you take Buprenorphine and Naloxone Sublingual Film. • You should not drink alcohol while using Buprenorphine and Naloxone Sublingual Film, as this can lead to loss of consciousness or even death.

What are the possible side effects of Buprenorphine and Naloxone Sublingual Film?

Buprenorphine and Naloxone Sublingual Film can cause serious side effects, including:

• See “What is the most important information I should know about Buprenorphine and Naloxone Sublingual Film?” • Respiratory problems. You have a higher risk of death and coma if you take Buprenorphine and Naloxone Sublingual Film with other medicines, such as benzodiazepines. • Sleepiness, dizziness, and problems with coordination • Dependency or abuse • Liver problems. Call your doctor right away if you notice any of these signs of liver problems: Your skin or the white part of your eyes turning yellow (jaundice), urine turning dark, stools turning light in color, you have less of an appetite, or you have stomach (abdominal) pain or nausea. Your doctor should do tests before you start taking and while you take Buprenorphine and Naloxone Sublingual Film. • Allergic reaction. You may have a rash, hives, swelling of the face, wheezing, or a loss of blood pressure and consciousness. Call a doctor or get emergency help right away. • Opioid withdrawal. This can include: shaking, sweating more than normal, feeling hot or cold more than normal, runny nose, watery eyes, goose bumps, diarrhea, vomiting, and muscle aches. Tell your doctor if you develop any of these symptoms. • Decrease in blood pressure. You may feel dizzy if you get up too fast from sitting or lying down.

Common side effects of Buprenorphine and Naloxone Sublingual Film include:

• Nausea • Vomiting • Drug withdrawal syndrome • Headache • Sweating • Numb mouth • Constipation • Swollen and/or painful tongue • The inside of your mouth is more red than normal • Intoxication (feeling lightheaded or drunk) • Disturbance in attention • Irregular heart beat (palpitations) • Decrease in sleep (insomnia) • Blurred vision • Back pain • Fainting • Dizziness • Sleepiness

Tell your doctor about any side effect that bothers you or that does not go away.

These are not all the possible side effects of Buprenorphine and Naloxone Sublingual Film. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Buprenorphine and Naloxone Sublingual Film?

• Store Buprenorphine and Naloxone Sublingual Film at room temperature between 20° to 25°C (68° to 77°F). • Keep Buprenorphine and Naloxone Sublingual Film in a safe place, out of the sight and reach of children.

How should I dispose of unused Buprenorphine and Naloxone Sublingual Film?

• Dispose of unused Buprenorphine and Naloxone Sublingual Film as soon as you no longer need them. • Unused films should be removed from the foil pouch and flushed down the toilet. • Do not flush the Buprenorphine and Naloxone Sublingual Film foil pouch down the toilet.

If you need help with disposal of Buprenorphine and Naloxone Sublingual Film, call 1-877-446-3679 (1-877-4-INFO-RX).

General information about the safe and effective use of Buprenorphine and Naloxone Sublingual Film.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not take Buprenorphine and Naloxone Sublingual Film for a condition for which it was not prescribed. Do not give Buprenorphine and Naloxone Sublingual Film to other people, even if they have the same symptoms you have. It may harm them and it is against the law.

This Medication Guide summarizes the most important information about Buprenorphine and Naloxone Sublingual Film. If you would like more information, talk to your doctor or pharmacist. You can ask your doctor or pharmacist for information that is written for health professionals.

For more information, call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).

What are the ingredients in Buprenorphine and Naloxone Sublingual Film?

Active ingredients: buprenorphine and naloxone.

Inactive ingredients: polyethylene oxide, polyethylene glycol, hypromellose, maltitol, acesulfame potassium, lemon-lime flavor, citric acid anhydrous, trisodium citrate dihydrate, FD&C Yellow No. 6, and white ink. In addition, the white imprinting ink contains titanium dioxide and hypromellose.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured for:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Revised: 5/2018
BNSF:R3

Dosage Forms And Strengths

CASSIPA®, 16 mg/4 mg, is a flexible, rectangular film with uniformly distributed orange color, imprinted with “16” in blue ink as a strength identifier (“16” may appear to be green in color). CASSIPA® is available in the following dosage strength:

• Buprenorphine 16 mg/naloxone 4 mg

Storage And Handling

CASSIPA® (buprenorphine and naloxone) sublingual film, 16 mg/4 mg, is a flexible rectangular film with uniformly distributed orange color, imprinted with “16” in blue ink as a strength identifier (“16” may appear to be green in color), in child-resistant polyester/foil laminated pouches, 30 films per carton. The film can be removed from the pouch as an intact piece.

NDC 0093-2155-33 (buprenorphine and naloxone) 16 mg/4 mg per sublingual film; content expressed in terms of free base, equivalent to 17.25 mg buprenorphine hydrochloride and 4.89 mg of naloxone hydrochloride dihydrate – 30 films per carton.

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F).

Advise patients to store buprenorphine-containing medications safely and out of sight and reach of children and to destroy any unused medication appropriately [see Patient Counseling Information].

Manufactured By: Lohmann Therapy Systems, Corporation (LTS), West Caldwell, NJ 07006. Manufactured For: TEVA PHARMACEUTICALS USA, INC., North Wales, PA 19454. Revised: Sep 2018