Suboxone 2/0.5 Sublingual Tablet

Generic Name: BUPRENORPHINE AND NALOXONE
Brand Name: Suboxone
  • Substance Name(s):
  • NALOXONE HYDROCHLORIDE
  • BUPRENORPHINE HYDROCHLORIDE

DRUG INTERACTIONS

7 Monitor patients starting or ending CYP3A4 inhibitors or inducers for potential over or under dosing.

(7.1) Use caution in prescribing SUBOXONE sublingual film for patients receiving benzodiazepines or other CNS depressants and warn patients against concomitant self-administration/misuse.

(7.3) 7.1 Cytochrome P-450 3A4 (CYP3A4) Inhibitors and Inducers Buprenorphine is metabolized to norbuprenorphine primarily by cytochrome CYP3A4; therefore, potential interactions may occur when SUBOXONE sublingual film is given concurrently with agents that affect CYP3A4 activity.

The concomitant use of SUBOXONE sublingual film with CYP3A4 inhibitors (e.g., azole antifungals such as ketoconazole, macrolide antibiotics such as erythromycin, and HIV protease inhibitors) should be monitored and may require dose-reduction of one or both agents.

The interaction of buprenorphine with CYP3A4 inducers has not been studied; therefore, it is recommended that patients receiving SUBOXONE sublingual film be monitored for signs and symptoms of opioid withdrawal if inducers of CYP3A4 (e.g., efavirenz, phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered [see Clinical Pharmacology (12.3)].

7.2 Antiretrovirals Three classes of antiretroviral agents have been evaluated for CYP3A4 interactions with buprenorphine.

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

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4.

Efavirenz, nevirapine and etravirine are known CYP3A inducers whereas delaviridine 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.

It is recommended that patients who are on chronic buprenorphine treatment have their dose monitored if NNRTIs are added to their treatment regimen.

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.

Monitoring of patients taking buprenorphine and atazanavir with and without ritonavir is recommended, and dose reduction of buprenorphine may be warranted.

7.3 Benzodiazepines There have been a number of post-marketing reports regarding coma and death associated with the concomitant use of buprenorphine and benzodiazepines.

In many, but not all, of these cases, buprenorphine was misused by self-injection.

Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists.

SUBOXONE sublingual film should be prescribed with caution to patients taking benzodiazepines or other drugs that act on the CNS, regardless of whether these drugs are taken on the advice of a physician or are being abused/misused.

Patients should be warned that it is extremely dangerous to self-administer non-prescribed benzodiazepines while taking SUBOXONE sublingual film, and should also be cautioned to use benzodiazepines concurrently with SUBOXONE sublingual film only as directed by their physician.

OVERDOSAGE

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

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.

DESCRIPTION

11 SUBOXONE (buprenorphine and naloxone) sublingual film is an orange film, imprinted with a logo identifying the product and strength in white ink.

It contains buprenorphine HCl, a mu-opioid receptor partial agonist and a kappa-opioid receptor antagonist, and naloxone HCl dihydrate, an opioid receptor antagonist, at a ratio of 4:1 (ratio of free bases).

It is intended for sublingual administration and is available in two dosage strengths, 2 mg buprenorphine with 0.5 mg naloxone and 8 mg buprenorphine with 2 mg naloxone.

Each sublingual film also contains polyethylene oxide, hydroxypropyl methylcellulose, maltitol, acesulfame potassium, lime flavor, citric acid, sodium citrate, FD&C yellow #6, and white ink.

Chemically, buprenorphine HCl is (2S)-2-[17-Cyclopropylmethyl-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol hydrochloride.

It has the following chemical structure: Buprenorphine HCl has the molecular formula C29 H41 NO4 • HCl and the molecular weight is 504.10.

It is a white or off-white crystalline powder, sparingly soluble in water, freely soluble in methanol, soluble in alcohol, and practically insoluble in cyclohexane.

Chemically, naloxone HCl dihydrate is 17-Allyl-4,5 α -epoxy-3, 14-dihydroxymorphinan-6-one hydrochloride dihydrate.

It has the following chemical structure: Naloxone hydrochloride dihydrate has the molecular formula C19H21NO4 • HCl • 2H20 and the molecular weight is 399.87.

It is a white to slightly off-white powder and is freely soluble in water, soluble in alcohol, and practically insoluble in toluene and ether.

GERIATRIC USE

8.5 Geriatric Use Clinical studies of SUBOXONE sublingual film, SUBOXONE (buprenorphine and naloxone) sublingual tablets, or SUBUTEX (buprenorphine) sublingual tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently than younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

DOSAGE FORMS AND STRENGTHS

3 SUBOXONE sublingual film is supplied as an orange rectangular sublingual film with a white printed logo in two dosage strengths: buprenorphine/naloxone 2 mg/0.5 mg, and buprenorphine/naloxone 8 mg/2 mg.

Sublingual film: 2 mg buprenorphine with 0.5 mg naloxone and 8 mg buprenorphine with 2 mg naloxone.

(3)

MECHANISM OF ACTION

12.1 Mechanism of Action SUBOXONE 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.

INDICATIONS AND USAGE

1 SUBOXONE sublingual film is indicated for maintenance treatment of opioid dependence and should be used as part of a complete treatment plan to include counseling and psychosocial support.

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 physicians 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.

SUBOXONE sublingual film is indicated for maintenance treatment of opioid dependence.

Prescription use of this product is limited under the Drug Addiction Treatment Act.

(1)

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of SUBOXONE sublingual film have not been established in pediatric patients.

PREGNANCY

8.1 Pregnancy Pregnancy Category C.

There are no adequate and well-controlled studies of SUBOXONE sublingual film or buprenorphine/naloxone in pregnant women.

SUBOXONE sublingual film should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Teratogenic Effects: Effects on embryo-fetal development were studied in Sprague-Dawley rats and Russian white rabbits following oral (1:1) and intramuscular (IM) (3:2) administration of mixtures of buprenorphine and naloxone.

Following oral administration to rats and rabbits, no teratogenic effects were observed at buprenorphine doses up to 250 mg/kg/day and 40 mg/kg/day, respectively (estimated exposure approximately 150 times and 50 times, respectively, the recommended human daily sublingual dose of 16 mg on a mg/m2 basis).

No definitive drug-related teratogenic effects were observed in rats and rabbits at IM doses up to 30 mg/kg/day (estimated exposure approximately 20 times and 35 times, respectively, the recommended human daily dose of 16 mg on a mg/m2 basis).

Acephalus was observed in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group.

Following oral administration of buprenorphine to rats, dose-related post-implantation losses, evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure approximately 6 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis).

In the rabbit, increased post-implantation losses occurred at an oral dose of 40 mg/kg/day.

Following IM administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live fetuses and increases in resorptions, occurred at 30 mg/kg/day.

Buprenorphine was not teratogenic in rats or rabbits after IM or subcutaneous (SC) doses up to 5 mg/kg/day (estimated exposure was approximately 3 and 6 times, respectively, the recommended human daily sublingual dose of 16 mg on a mg/m2 basis), after IV doses up to 0.8 mg/kg/day (estimated exposure was approximately 0.5 times and equal to, respectively, the recommended human daily sublingual dose of 16 mg on a mg/m2 basis), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 95 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis) and 25 mg/kg/day in rabbits (estimated exposure was approximately 30 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis).

Significant increases in skeletal abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC administration of 1 mg/kg/day and up (estimated exposure was approximately 0.6 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis), but were not observed at oral doses up to 160 mg/kg/day.

Increases in skeletal abnormalities in rabbits after IM administration of 5 mg/kg/day (estimated exposure was approximately 6 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis) or oral administration of 1 mg/kg/day or greater (estimated exposure was approximately equal to the recommended human daily sublingual dose of 16 mg on a mg/m2 basis) were not statistically significant.

In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 mg/kg/day or greater and post-implantation losses that were statistically significant at IV doses of 0.2 mg/kg/day or greater (estimated exposure approximately 0.3 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis).

Non-teratogenic Effects: Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine 5 mg/kg/day (approximately 3 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis).

Fertility, peri-, and post-natal development studies with buprenorphine in rats indicated increases in neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 0.5 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis), after IM doses of 0.5 mg/kg/day and up (approximately 0.3 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis), and after SC doses of 0.1 mg/kg/day and up (approximately 0.06 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis).

Delays in the occurrence of righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day (approximately 50 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis).

NUSRING MOTHERS

8.3 Nursing Mothers Buprenorphine passes into breast milk.

Breast-feeding is not advised in mothers treated with buprenorphine products.

An apparent lack of milk production during general reproduction studies with buprenorphine in rats caused decreased viability and lactation indices.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Buprenorphine can be abused in a similar manner to other opioids.

Clinical monitoring appropriate to the patient’s level of stability is essential.

Multiple refills should not be prescribed early in treatment or without appropriate patient follow-up visits.

(5.1) Significant respiratory depression and death have occurred in association with buprenorphine, particularly when taken by the intravenous (IV) route in combination with benzodiazepines or other CNS depressants (including alcohol).

(5.2) Consider dose reduction of CNS depressants, SUBOXONE sublingual film or both in situations of concomitant prescription.

(5.3) Store SUBOXONE sublingual film safely out of the sight and reach of children.

Buprenorphine can cause severe, possibly fatal, respiratory depression in children.

(5.4) Chronic administration produces opioid-type physical dependence.

Abrupt discontinuation or rapid dose taper may result in opioid withdrawal syndrome.

(5.5) Monitor liver function tests prior to initiation and during treatment and evaluate suspected hepatic events.

(5.6) Do not administer SUBOXONE sublingual film to patients with known hypersensitivity to buprenorphine or naloxone.

(5.7) A marked and intense opioid withdrawal syndrome is highly likely to occur with parenteral misuse of SUBOXONE sublingual film by individuals physically dependent on full opioid agonists or by sublingual administration before the agonist effects of other opioids have subsided.

(5.8) Neonatal withdrawal has been reported following use of buprenorphine by the mother during pregnancy.

(5.9) SUBOXONE sublingual film is not appropriate as an analgesic.

There have been reported deaths of opioid naïve individuals who received a 2 mg sublingual dose.

(5.10) Caution patients about the risk of driving or operating hazardous machinery.

(5.11) 5.1 Abuse Potential Buprenorphine can be abused in a manner similar to other opioids, legal or illicit.

Prescribe and dispense buprenorphine with appropriate precautions to minimize risk of misuse, abuse, or diversion, and ensure appropriate protection from theft, including in the home.

Clinical monitoring appropriate to the patient’s level of stability is essential.

Multiple refills should not be prescribed early in treatment or without appropriate patient follow-up visits.

[see Drug Abuse and Dependence (9.2)].

5.2 Respiratory Depression Buprenorphine, particularly when taken by the IV route, in combination with benzodiazepines or other CNS depressants (including alcohol), has been associated with significant respiratory depression and death.

Many, but not all post-marketing reports regarding coma and death associated with the concomitant use of buprenorphine and benzodiazepines, involved misuse by self-injection.

Deaths have also been reported in association with concomitant administration of buprenorphine with other depressants such as alcohol or other CNS depressant drugs.

Patients should be warned of the potential danger of self-administration of benzodiazepines or other depressants while under treatment with SUBOXONE sublingual film.

[see Drug Interactions (7.3)] 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.

SUBOXONE sublingual film should be used 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).

5.3 CNS Depression Patients receiving buprenorphine in the presence of opioid analgesics, general anesthetics, benzodiazepines, phenothiazines, other tranquilizers, sedative/hypnotics or other CNS depressants (including alcohol) may exhibit increased CNS depression.

Consider dose reduction of CNS depressants, SUBOXONE sublingual film, or both in situations of concomitant prescription.

[see Drug Interactions (7.3)].

5.4 Unintentional Pediatric Exposure Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally exposed to it.

Store buprenorphine-containing medications safely out of the sight and reach of children and destroy any unused medication appropriately [see Disposal of Unused SUBOXONE Sublingual Film (17.2)].

5.5 Dependence Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation or rapid taper.

The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset.

Buprenorphine can be abused in a manner similar to other opioids.

This should be considered when prescribing or dispensing buprenorphine in situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion.

[see Drug Abuse and Dependence (9.3)] 5.6 Hepatitis, Hepatic Events Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine in clinical trials and through post-marketing adverse event reports.

The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy.

In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injecting drug use may have played a causative or contributory role.

In other cases, insufficient data were available to determine the etiology of the abnormality.

Withdrawal of buprenorphine has resulted in amelioration of acute hepatitis in some cases; however, in other cases no dose reduction was necessary.

The possibility exists that buprenorphine had a causative or contributory role in the development of the hepatic abnormality in some cases.

Liver function tests, prior to initiation of treatment is recommended to establish a baseline.

Periodic monitoring of liver function during treatment is also recommended.

A biological and etiological evaluation is recommended when a hepatic event is suspected.

Depending on the case, SUBOXONE sublingual film may need to be carefully discontinued to prevent withdrawal signs and symptoms and a return by the patient to illicit drug use, and strict monitoring of the patient should be initiated.

5.7 Allergic Reactions Cases of hypersensitivity to buprenorphine and naloxone containing products have been reported both in clinical trials and in the post-marketing experience.

Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported.

The most common signs and symptoms include rashes, hives, and pruritus.

A history of hypersensitivity to buprenorphine or naloxone is a contraindication to the use of SUBOXONE sublingual film.

5.8 Precipitation of Opioid Withdrawal Signs and Symptoms Because it contains naloxone, SUBOXONE sublingual film is highly likely to produce marked and intense withdrawal signs and symptoms if misused parenterally by individuals dependent on full opioid agonists such as heroin, morphine, or methadone.

Because of the partial agonist properties of buprenorphine, SUBOXONE sublingual film may precipitate opioid withdrawal signs and symptoms in such persons if administered sublingually before the agonist effects of the opioid have subsided.

5.9 Neonatal Withdrawal Neonatal withdrawal has been reported in the infants of women treated with buprenorphine during pregnancy.

From post-marketing reports, the time to onset of neonatal withdrawal signs ranged from Day 1 to Day 8 of life with most cases occurring on Day 1.

Adverse events associated with the neonatal withdrawal syndrome included hypertonia, neonatal tremor, neonatal agitation, and myoclonus, and there have been reports of convulsions, apnea, respiratory depression, and bradycardia.

5.10 Use in Opioid Naïve Patients There have been reported deaths of opioid naive individuals who received a 2 mg dose of buprenorphine as a sublingual tablet for analgesia.

SUBOXONE sublingual film is not appropriate as an analgesic.

5.11 Impairment of Ability to Drive or Operate Machinery SUBOXONE sublingual film may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery, especially during treatment induction and dose adjustment.

Patients should be cautioned about driving or operating hazardous machinery until they are reasonably certain that SUBOXONE sublingual film therapy does not adversely affect his or her ability to engage in such activities.

5.12 Orthostatic Hypotension Like other opioids, SUBOXONE sublingual film may produce orthostatic hypotension in ambulatory patients.

5.13 Elevation of Cerebrospinal Fluid Pressure Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions and other circumstances when cerebrospinal pressure may be increased.

Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation.

5.14 Elevation of Intracholedochal Pressure Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract.

5.15 Effects in Acute Abdominal Conditions As with other opioids, buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

5.16 General Precautions SUBOXONE sublingual film should be administered with caution in debilitated patients and those with myxedema or hypothyroidism, adrenal cortical insufficiency (e.g., Addison’s disease); CNS depression or coma; toxic psychoses; prostatic hypertrophy or urethral stricture; acute alcoholism; delirium tremens; or kyphoscoliosis.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION 17.1 Safe Use Before initiating treatment with Suboxone, explain the points listed below to caregivers and patients.

Instruct patients to read the Medication Guide each time Suboxone is dispensed because new information may be available.

Patients should be warned that it is extremely dangerous to self-administer non-prescribed benzodiazepines or other CNS depressants (including alcohol) while taking SUBOXONE sublingual film.

Patients prescribed benzodiazepines or other CNS depressants should be cautioned to use them only as directed by their physician.

[see Warnings and Precautions (5.2), Drug Interactions (7.3)] Patients should be advised that SUBOXONE sublingual film contains an opioid that can be a target for people who abuse prescription medications or street drugs.

Patients should be cautioned to keep their films in a safe place, and to protect them from theft.

Patients should be instructed to keep SUBOXONE 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.

Patients should be advised that if a child is exposed to SUBOXONE sublingual film, medical attention should be sought immediately.

Patients should be advised never to give SUBOXONE sublingual film to anyone else, even if he or she has the same signs and symptoms.

It may cause harm or death.

Patients should be advised that selling or giving away this medication is against the law.

Patients should be cautioned that SUBOXONE 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 (5.11)] Patients should be advised not to change the dosage of SUBOXONE sublingual film without consulting their physician.

Patients should be advised to take SUBOXONE sublingual film once a day.

Patients should be informed that SUBOXONE sublingual film can cause drug dependence and that withdrawal signs and symptoms may occur when the medication is discontinued.

Patients seeking to discontinue treatment with buprenorphine for opioid dependence should be advised to work closely with their physician on a tapering schedule and should be apprised of the potential to relapse to illicit drug use associated with discontinuation of opioid agonist/partial agonist medication-assisted treatment.

Patients should be cautioned that, like other opioids, SUBOXONE sublingual film may produce orthostatic hypotension in ambulatory individuals.

[see Warnings and Precautions.

(5.12)] Patients should inform their physician if any other prescription medications, over-the-counter medications, or herbal preparations are prescribed or currently being used.

[see Drug Interactions (7.1, 7.2 and 7.3)] Women of childbearing potential who become pregnant or are planning to become pregnant, should be advised to consult their physician regarding the possible effects of using SUBOXONE sublingual film during pregnancy.

[see Use in Specific Populations (8.1)] Patients should be warned that buprenorphine passes into breast milk.

Breast-feeding is not advised in mothers treated with buprenorphine products.

[see Use in Specific Populations (8.3)].

Patients should inform their family members that, in the event of emergency, the treating physician or emergency room staff should be informed that the patient is physically dependent on an opioid and that the patient is being treated with SUBOXONE sublingual film.

Refer to the Medication Guide for additional information regarding the counseling information.

17.2 Disposal of Unused SUBOXONE Sublingual Film Unopened SUBOXONE sublingual films should be disposed of as soon as they are no longer needed: Remove the SUBOXONE film from its foil pouch.

Drop the SUBOXONE film into the toilet.

Repeat steps 1 and 2 for each SUBOXONE film.

Flush the toilet after all unneeded films have been put into the toilet.

Foil pouches or cartons should not be flushed down the toilet.

RA016 09/2010 Revised 9/7/2010 Manufactured for Reckitt Benckiser Pharmaceuticals Inc., Richmond, VA 23235 by: MonoSol Rx, LLC, Warren, NJ 07059 Distributed by: Reckitt Benckiser Pharmaceuticals Inc.

Richmond, VA 23235

DOSAGE AND ADMINISTRATION

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

SUBOXONE sublingual film should be used in patients who have been initially inducted using SUBUTEX® (buprenorphine) sublingual tablets.

Administer SUBOXONE sublingual film sublingually as a single daily dose.

(2) The recommended daily dose for maintenance is 16/4 mg.

2.1 Maintenance SUBOXONE sublingual film is indicated for maintenance treatment.

The recommended target dosage of SUBOXONE sublingual film is 16/4 mg buprenorphine/naloxone/day, as a single daily dose.

The dosage of SUBOXONE sublingual film should be progressively adjusted in increments/decrements of 2/0.5 mg or 4/1 mg buprenorphine/naloxone to a level that holds the patient in treatment and suppresses opioid withdrawal signs and symptoms.

The maintenance dose of SUBOXONE sublingual film is generally in the range of 4/1 mg buprenorphine/naloxone to 24/6 mg buprenorphine/naloxone per day depending on the individual patient.

Dosages higher than this have not been demonstrated to provide any clinical advantage.

2.2 Method of Administration Place the SUBOXONE sublingual film under the tongue.

If an additional SUBOXONE sublingual film is necessary to achieve the prescribed dose, place the additional sublingual film sublingually on the opposite side from the first film.

Place the sublingual film in a manner to minimize overlapping as much as possible.

The sublingual film must be kept under the tongue until the film is completely dissolved.

SUBOXONE sublingual film should NOT be chewed, swallowed, or moved after placement.

Proper administration technique should be demonstrated to the patient.

2.3 Clinical Supervision Treatment should be initiated with supervised administration, progressing to unsupervised administration as the patient’s clinical stability permits.

SUBOXONE 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 physician’s evaluation of treatment outcomes and objectives such as: Absence of medication toxicity.

Absence of medical or behavioral adverse effects.

Responsible handling of medications by the patient.

Patient’s compliance with all elements of the treatment plan (including recovery-oriented activities, psychotherapy, and/or other psychosocial modalities).

Abstinence from illicit drug use (including problematic alcohol and/or benzodiazepine use).

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

2.4 Unstable Patients Physicians 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 physician does not feel that he/she has the expertise to manage the patient.

In such cases, the physician 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.

2.5 Stopping Treatment The decision to discontinue therapy with SUBOXONE sublingual film after a period of maintenance should be made as part of a comprehensive treatment plan.

Both gradual and abrupt discontinuation of buprenorphine has been used, but the data are insufficient to determine the best method of dose taper at the end of treatment.

2.6 Switching between SUBOXONE (buprenorphine and naloxone) Sublingual Tablets and SUBOXONE Sublingual film Patients being switched between SUBOXONE (buprenorphine and naloxone) sublingual tablets and SUBOXONE sublingual film should be started on the same dosage as the previously administered product.

However, dosage adjustments may be necessary when switching between products.

Because of the potentially greater relative bioavailability of SUBOXONE sublingual film compared to SUBOXONE (buprenorphine and naloxone) sublingual tablets, patients switching from SUBOXONE (buprenorphine and naloxone) sublingual tablets to SUBOXONE sublingual film should be monitored for over-medication.

Those switching from SUBOXONE sublingual film to SUBOXONE (buprenorphine and naloxone) sublingual tablets should be monitored for withdrawal or other indications of under-dosing.

In clinical studies, pharmacokinetics of SUBOXONE sublingual film was similar to the respective dosage strengths of SUBOXONE (buprenorphine and naloxone) sublingual tablets, although not all doses and dose combinations met bioequivalence criteria.