Bunavail oral / sublingual

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Like other narcotic medicines, buprenorphine and naloxone can slow your breathing. Death may occur if breathing becomes too weak.

Call your doctor at once or seek emergency medical attention if you have:

• weak or shallow breathing, feeling like you might pass out;

• confusion, loss of coordination, extreme weakness;

• blurred vision, slurred speech;

• adrenal gland problems--nausea, vomiting, loss of appetite, dizziness, feeling weak or tired;

• high levels of serotonin in the body--agitation, hallucinations, fever, fast heart rate, overactive reflexes, nausea, vomiting, diarrhea, loss of coordination, fainting;

• liver problems--nausea, upper stomach pain, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or

• withdrawal symptoms--diarrhea, vomiting, shaking or shivering, runny nose, watery eyes, muscle pain, and feeling very hot or cold.

Common side effects may include:

• dizziness, drowsiness, blurred vision, feeling drunk;

• tongue pain, redness or numbness inside your mouth;

• constipation, mild nausea, vomiting;

• headache, back pain, swelling in your hands or feet;

• fast or pounding heartbeats, increased sweating; or

• sleep problems (insomnia).

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

The U.S. Food and Drug Administration (FDA) has approved Bunavail (buprenorphine and naloxone) buccal film (CIII) for the maintenance treatment of opioid dependence as part of a complete treatment plan with counselling and psychosocial support.

Buprenorphine is a narcotic analgesic similar to morphine, and has the potential for being abused and misused. Always keep opioid medicines in a safe place to protect from theft, and out of the sight and reach of children. Naloxone is an opioid antagonist (marketed as Narcan and Evzio) used for the emergency treatment of known or suspected opioid overdose.

There are a number of buprenorphine/naloxone formulations currently available including Suboxone (tablets and sublingual film) and Zubsolv (sublingual tablets). Bunavail is a buccal formulation which sticks to the inside of the cheek, and unlike sublingual formulations which need to be kept in place until dissolved, patients can talk, swallow and go about normal daily activities while the medication is being consistently absorbed.

Bunavail can cause serious life‐threatening breathing problems, overdose and death, particularly when misused and administered via the intravenous (IV) route, or in combination with benzodiazepines, sedatives, tranquilizers or alcohol. Injecting this medicine may also cause serious withdrawal symptoms such as pain, cramps, vomiting, diarrhea, anxiety, sleep problems, and cravings.

Common side effects of Bunavail include headache, drug withdrawal syndrome, lethargy (lack of energy), sweating, constipation, decrease in sleep (insomnia), fatigue and sleepiness.

Bunavail is manufactured for BioDelivery Sciences International, Inc. in Raleigh, North Carolina.

IMPORTANT: Keep Bunavail in a secure place away from children. Accidental use by a child is a medical emergency and can result in death. If a child accidently uses this medicine, get emergency help right away.

Read this Medication Guide before you start using this medicine 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 any questions. Share the important information in this Medication Guide with members of your household.

• 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 Bunavail.
• You should not drink alcohol during treatment, as this can lead to loss of consciousness or even death.

Applies to buprenorphine / naloxone: buccal film, sublingual film, sublingual tablet

General

The most commonly observed adverse events included headache, nausea, vomiting, hyperhidrosis, constipation, signs and symptoms of withdrawal, insomnia, pain and peripheral edema. Additionally, oral hypoesthesia was reported with the sublingual film.[Ref]

Other

Very common (10% or more): Pain (22.4%)
Common (1% to 10%): Asthenia, chills, pyrexia, malaise, injury, ear pain
Uncommon (0.1% to 1%): Hypothermia, heat stroke
Postmarketing reports: Vertigo[Ref]

Nervous system

Very common (10% or more): Headache (36.4%)
Common (1% to 10%): Migraine, dizziness, hypertonia, paraesthesia, somnolence
Uncommon (0.1% to 1%): Amnesia, convulsion, hyperkinesia, speech disorder, tremor

Buprenorphine:
Postmarketing reports: Neonatal withdrawal syndrome including symptoms of hypertonia, neonatal tremor, neonatal agitation, and myoclonus; reports of neonatal convulsions, apnea, respiratory depression, and bradycardia[Ref]

Respiratory

Buprenorphine-naloxone:
Common (1% to 10%): Pharyngitis, rhinitis, cough, sinusitis, upper respiratory infection, asthma, bronchitis, dyspnea, pneumonia, increased sputum
Uncommon (0.1% to 1%): Yawning
Frequency not reported: Rhinorrhea

Buprenorphine:
Frequency not reported: Significant respiratory depression, coma, death[Ref]

There have been postmarketing reports coma and death associated with concomitant use of buprenorphine and benzodiazepines; many of these reports have involved misuse by self-injection.[Ref]

Gastrointestinal

Very common (10% or more): Constipation (12.1%), nausea (15%), abdominal pain (11.2%)
Common (1% to 10%): Vomiting, diarrhea, dyspepsia, flatulence, oral hypoesthesia
Uncommon (0.1% to 1%): Mouth ulceration, tongue discoloration, tooth abscess, glossodynia, mucosal erythema (oral), toothache
Frequency not reported: Stomach discomfort,
Postmarketing reports: Stomatitis, glossitis, tongue disorder, pancreatitis[Ref]

Endocrine

Common (1% to 10%): Erectile dysfunction, decreased libido
Uncommon (0.1% to 1%): Amenorrhea, ejaculation disorder, menorrhagia, metrorrhagia
Postmarketing reports: Disorders of pregnancy[Ref]

Hypersensitivity

Buprenorphine:
Frequency not reported: Hypersensitivity reactions including bronchospasm, angioneurotic edema, and anaphylactic shock; more commonly reported as rash hives, and pruritus

Naloxone:
Frequency not reported: Hypersensitivity reactions including bronchospasm, angioneurotic edema, and anaphylactic shock; more commonly reported as rash hives, and pruritus[Ref]

Cardiovascular

Common (1% to 10%): Vasodilation, hypertension
Uncommon (0.1% to 1%): Angina pectoris, bradycardia, myocardial infarction, palpitations, tachycardia, hypotension, chest pain
Postmarketing reports: Peripheral edema, syncope, orthostatic hypotension, heart rate and rhythm disorders[Ref]

Ocular

Common (1% to 10%): Amblyopia, lacrimal disorder
Uncommon (0.1% to 1%): Conjunctivitis, miosis[Ref]

Hepatic

Buprenorphine-naloxone:
Common (1% to 10%): Abnormal liver function tests

Buprenorphine:
Frequency not reported: Cytolytic hepatitis, hepatitis with jaundice, transient asymptomatic elevations of hepatic transaminases, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy.[Ref]

In clinical trials and in postmarketing reports, cases of cytolytic hepatitis and hepatitis with jaundice have been reported in association with buprenorphine use. The spectrum of abnormalities has ranged from transient asymptomatic elevations of hepatic transaminases to hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. The presence of preexisting liver enzyme abnormalities, viral hepatitis, concomitant hepatotoxic drug use, and ongoing IV drug abuse may have played a causative or contributory role.[Ref]

Psychiatric

Common (1% to 10%): Anxiety, depression, nervousness, abnormal thinking
Uncommon (0.1% to 1%): Abnormal dreams, agitation, apathy, depersonalization, drug dependence, euphoric mood, hostility
Frequency not reported: Restlessness, irritability
Postmarketing reports: Hallucination, attempted suicide, insomnia[Ref]

Dermatologic

Very common (10% or more): Sweating (14%)
Common (1% to 10%): Pruritus, rash, urticaria, ecchymosis
Uncommon (0.1% to 1%): Acne, alopecia, dermatitis exfoliative, dry skin, skin mass, herpes simplex, skin nodule
Frequency not reported: Piloerection, cold sweat[Ref]

Genitourinary

Common (1% to 10%): Urine abnormality
Uncommon (0.1% to 1%): Urinary tract infection, vaginal infection, albuminuria, dysuria, hematuria, urinary retention[Ref]

Hematologic

Uncommon (0.1% to 1%): Anemia, leucocytosis, leukopenia, lymphadenopathy, thrombocytopenia[Ref]

Immunologic

Common (1% to 10%): Influenza, infection[Ref]

Metabolic

Uncommon (0.1% to 1%): Decreased appetite, hyperglycemia, hyperlipidemia, hypoglycemia, decreased weight[Ref]

Musculoskeletal

Common (1% to 10%): Back pain, arthralgia, muscle spasms, myalgia, rigid neck, leg cramps, joint disorder
Uncommon (0.1% to 1%): Arthritis
Frequency not reported: Arthralgia[Ref]

Renal

Uncommon (0.1% to 1%): Nephrolithiasis, blood creatinine increased[Ref]

Some side effects of Bunavail may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Severe Hepatic impairment: Use not recommended
Moderate Hepatic Impairment: Not recommended for induction due to increased risk of precipitated withdrawal; may be used cautiously for maintenance treatment; monitor for opioid withdrawal.
Mild hepatic impairment: Use with caution.

Administration advice:
-Proper administration technique should be demonstrated to the patient
-Do not cut, chew, or swallow products
-Do not eat or drink anything until the dose is completely dissolved
-Do not move product after placement
-To ensure consistency, follow the same manner of dosing with continued use
-If a dose is missed, take it as soon as remembered; if it is almost time for the next dose, skip the missed dose and take the next dose at the regular time

-SUBLINGUAL TABLET:
-Place under tongue until dissolved
-For doses requiring multiple tablets, place all tablets in different locations under tongue, minimize overlapping; alternatively, divide into multiple portions, taking second and subsequent portions directly after previous portion has dissolved
-Median dissolution time for Zubsolv(R) was 5 minutes

SUBLINGUAL FILM:
-Before administration, drink water to moisten mouth
-Place film under tongue close to the base on the left or right side; keep under tongue until completely dissolved; on average dissolution takes 4 to 8 minutes
-For doses requiring multiple films, place additional film on the opposite side minimizing overlap as much as possible; alternatively, divide into multiple portions, taking second and subsequent portions directly after previous portion has dissolved

BUCCAL FILM:
-Use tongue to wet inside of the cheek or rinse mouth with water to moisten application area
-Apply to inside of the cheek; press and hold for 5 seconds
-Allow film to completely dissolve; avoid manipulating film with tongue or fingers
-If multiple films are needed, immediately apply the next film in the same manner to the opposite cheek; up to 2 films can be applied to one cheek at a time

Preparation techniques:
-FILM: Wait to open foil pack until ready to use; protect from freezing and moisture
-TABLET: Wait to open blister until ready for use: do not push tablet through blister pack as it may break

General:
-Treatment should be under the supervision of a physician experienced in the management of opiate dependence/addiction.
-Medication treatment should be used as part of a complete treatment plan to include counseling and psychosocial support.
-To avoid precipitating withdrawal, buprenorphine monotherapy is generally used for induction, especially when there is doubt about the level of dependence or previous drug use.
-Multiple refills should not be provided early in treatment or without appropriate follow-up.
-The decision to discontinue treatment should be made as part of a comprehensive treatment plan; abrupt discontinuation is not recommended.

Monitoring:
-Monitor for under and over dosing.
-Hepatic: Regular monitoring of liver function tests is recommended.
-If treatment goals are not being achieved, patients should be re-evaluated to determine the appropriateness of treatment or need for more intensive and structured treatment.

Patient advice:
-Advise patients to store this drug safely out of the sight and reach of children; accidental use by children is a medical emergency and can result in death.
-Advise patients that abusing this product by injecting it may cause serious withdrawal symptoms due to the presence of naloxone.
-Patients should understand the risk of life-threatening respiratory depression, and be informed as to when this risk is greatest.
-This drug may cause drowsiness, dizziness, or impair thinking, or motor skills; patients should avoid driving or operating machinery until adverse effects are determined.
-Women of child bearing potential should understand that prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome and that prompt recognition and treatment will be necessary.
-Patients should be instructed in proper disposal.

Bunavail is a combination tablet containing buprenorphine and naloxone.

Buprenorphine is an opioid (narcotic) that has a unique and complex mechanism of action, which includes incomplete binding to mu opioid receptors and complete binding to kappa opioid receptors. Opioid receptors have three main effects: reducing breathing (respiratory depression), producing euphoria (feelings of intense happiness or excitement), and decreasing pain. The way buprenorphine binds means it can satisfy opioid cravings without producing strong feelings of euphoria or causing significant respiratory depression. In addition, while it is bound to opioid receptors, other opioids (such as heroin or oxycodone) cannot bind. It also stays on the receptors for longer - about three days; which makes it a good choice for use in opioid addiction treatment programs.

Naloxone is present in this combination tablet to discourage misuse. Naloxone is a very strong blocker of mu opioid receptors and will precipitate people into opioid withdrawal if drug misusers attempt to convert the tablet into an injectable form. Naloxone has poor absorption when taken sublingually.