BUNAVAIL® (buprenorphine and naloxone buccal film)

BUNAVAIL® (buprenorphine and naloxone buccal film)

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BUNAVAIL® (buprenorphine and naloxone buccal film)

BUNAVAIL (buprenorphine and naloxone buccal film) is a citrus flavored oral transmucosal form of buprenorphine, an opioid partial agonist, and naloxone, an opioid antagonist, intended for application to the buccal mucosa. Each dose unit is a yellow rectangular film, with ink marking on the mucoadhesive side. The film adheres upon contact with the moist buccal mucosa. BUNAVAIL contains buprenorphine HCl, a muopioid receptor partial agonist and a kappa-opioid receptor antagonist, and naloxone HCl dihydrate, an opioid receptor antagonist, at a ratio of ~6:1 (ratio of free bases). It is available in three strengths: 2.1 mg buprenorphine with 0.3 mg naloxone in a 2.2 cm2 film; 4.2 mg buprenorphine with 0.7 mg naloxone in a 4.4 cm2 film; and 6.3 mg buprenorphine with 1 mg naloxone in a 6.5 cm2 film.

Each film also contains carboxymethylcellulose sodium, citric acid, citrus blend flavor, dibasic sodium phosphate, blue ink, hydroxyethyl cellulose, hydroxypropyl cellulose, methylparaben, monobasic sodium phosphate, polycarbophil, propylene glycol, propylparaben, yellow iron oxide, sodium benzoate, sodium hydroxide, sodium saccharin, vitamin E acetate, and purified water. The blue ink contains FD&C Blue No.1, ethanol, purified shellac, acetone, ammonium hydroxide and water.

Chemically, buprenorphine HCl, USP is 6,14-Ethenomorphinan-7-methanol, 17-(cyclopropyl-methyl)-α-(1,1- dimethylethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-α-methyl-, hydrochloride, [5α, 7α (S)].

Buprenorphine HCl has the molecular formula C29H41NO4 ∙ 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, USP is morphinan-6-one, 4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)-, hydrochloride, (5α)-, dihydrate.

Naloxone hydrochloride dihydrate has the molecular formula C19H21NO4 ∙ HCl ∙ 2H2O 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.

Indications and usage

BUNAVAIL contains buprenorphine, a partial opioid agonist, and naloxone, an opioid antagonist, and is indicated for the treatment of opioid dependence. BUNAVAIL should be used as part of a complete treatment plan that includes counseling and psychosocial support.

Mechanism of Action

BUNAVAIL 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, if administered parenterally, in individuals physically dependent on full opioid agonists.

Dosage and administration

  • Prescription use of this product is limited under the Drug Addiction Treatment Act.
  • BUNAVAIL is administered buccally as a single daily dose.
  • Strongly consider prescribing naloxone at the time BUNAVAIL is initiated or renewed because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose
  • To avoid precipitating withdrawal, induction with BUNAVAIL buccal film should be undertaken when objective and clear signs of withdrawal are evident and BUNAVAIL should be administered in divided doses when used as initial treatment
  • For patients dependent on short-acting opioid products who are in opioid withdrawal; on Day 1, administer up to 4.2 mg/0.7 mg BUNAVAIL (in divided doses). On Day 2, administer up to 8.4 mg/1.4 mg of BUNAVAIL as a single dose.
  • For patients dependent on methadone or long-acting opioid products, induction onto sublingual buprenorphine monotherapy is recommended.
  • For maintenance treatment, the recommended target dosage of BUNAVAIL is 8.4 mg/1.4 mg as a single daily dose.
  • Apply BUNAVAIL as directed in the Full Prescribing Information. Do not cut, tear, chew, or swallow BUNAVAIL.
  • When discontinuing treatment, gradually taper to avoid signs and symptoms of withdrawal.

Contraindications

BUNAVAIL is contraindicated in patients with a history of hypersensitivity to buprenorphine or naloxone as serious adverse reactions, including anaphylactic shock, have been reported

Warnings and precautions

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

Risk of Life-Threatening Respiratory Depression and Central Nervous System (CNS) Depression: Buprenorphine has been associated with life-threatening respiratory depression and death. Many, but not all, post-marketing reports regarding coma and death involved misuse by self-injection or were associated with the concomitant use of buprenorphine and benzodiazepines or other CNS depressants including alcohol. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with BUNAVAIL.

Use BUNAVAIL 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).

Neonatal Opioid Withdrawal Syndrome: Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy, whether that use is medically-authorized or illicit. Unlike opioid withdrawal syndrome in adults, NOWS may be life-threatening if not recognized and treated in the neonate. Healthcare professionals should observe newborns for signs of NOWS and manage accordingly. .

Risk of Opioid Withdrawal with Abrupt Discontinuation: Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation or rapid taper. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset. When discontinuing BUNAVAIL, gradually taper the dosage.

Hypersensitivity Reactions: Cases of hypersensitivity to buprenorphine and naloxone containing products have been reported both in clinical trials and in 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 BUNAVAIL.

Risk of Overdose in Opioid Naïve Patients: There have been reported deaths of opioid naïve individuals who received a 2 mg dose of buprenorphine, smaller than the lowest strength of BUNAVAIL, for analgesia. BUNAVAIL is not appropriate as an analgesic.

Impairment of Ability to Drive or Operate Machinery: BUNAVAIL 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. Caution patients about driving or operating hazardous machinery until they are reasonably certain that BUNAVAIL therapy does not adversely affect their ability to engage in such activities.

Orthostatic Hypotension: Like other opioids, BUNAVAIL may produce orthostatic hypotension in ambulatory patients.

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.

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.

Adverse reactions

Adverse events commonly observed with buccal administration of BUNAVAIL are headache, nausea, vomiting, hyperhidrosis, constipation, signs and symptoms of withdrawal, insomnia, pain, and peripheral edema

Drug interactions

Benzodiazepine and other Central Nervous System (CNS) Depressants: Due to additive pharmacologic effects, the concomitant use of benzodiazepines and other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death. Examples: Alcohol, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids.

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

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir)

CYP3A4 Inducers: The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine, potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine.

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase, which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression. Examples: Rifampin, carbamazepine, phenytoin

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

Antiretrovirals: Protease inhibitors (PIs): Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetics 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. Examples: atazanavir, ritonavir

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

Serotonergic Drugs: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Monoamine Oxidase Inhibitors (MAOIs): MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma). Examples: phenelzine, tranylcypromine, linezolid

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

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

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

Use in specific populations

Pregnancy: The data on use of buprenorphine, one of the active ingredients in BUNAVAIL, in pregnancy, are limited; however, these data do not indicate an increased risk of major malformations specifically due to buprenorphine exposure. There are limited data from randomized clinical trials in women maintained on buprenorphine that were not designed appropriately to assess the risk of major malformations.

Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. In addition, untreated opioid addiction often results in continued or relapsing illicit opioid use.

Dosage adjustments of buprenorphine may be required during pregnancy, even if the patient was maintained on a stable dose prior to pregnancy. Withdrawal signs and symptoms should be monitored closely and the dose adjusted as necessary.

Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with BUNAVAIL.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal usually occur in the first days of birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly.

Lactation: Based on two studies in 13 lactating women maintained on buprenorphine treatment, buprenorphine and its metabolite norbuprenorphine were present in low levels in human milk and available data have not shown adverse reactions in breastfed infants. There are no data on the combination product buprenorphine/naloxone in breastfeeding, however oral absorption of naloxone is limited. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BUNAVAIL and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

Infertility: Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible

Pediatric Use: The safety and effectiveness of BUNAVAIL have not been established in pediatric patients. This product is not appropriate for the treatment of neonatal abstinence syndrome in neonates, because it contains naloxone, an opioid antagonist.

Drug abuse and dependence

Controlled Substance: BUNAVAIL contains buprenorphine, a Schedule III substance under the Controlled Substances Act.

Abuse

Buprenorphine, like morphine and other opioids, has the potential for being abused and is subject to criminal diversion. 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. Healthcare professionals should contact their state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Abuse of buprenorphine poses a risk of overdose and death. This risk is increased with the abuse of buprenorphine and alcohol and other substances, especially benzodiazepines.

Dependence

Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by moderate 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

Overdosage

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.

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