SUBOXONE sublingual tablet is an uncoated hexagonal orange tablet, debossed with an alphanumeric word identifying the product and strength. It contains buprenorphine HCl, a partial agonist at the mu‐opioid receptor, 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 tablet also contains lactose, mannitol, cornstarch, povidone K30, citric acid, sodium citrate, FD&C Yellow No.6 color, magnesium stearate, acesulfame K sweetener and a lemon / lime flavor.
Chemically, buprenorphine HCl is (2S)‐2‐[17‐Cyclopropylmethyl‐4,5α‐epoxy‐3‐hydroxy‐6‐methoxy‐6α,14ethano‐14α‐morphinan‐7α‐yl]‐3,3‐dimethylbutan‐2‐ol hydrochloride.
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.
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.
INDICATIONS AND USAGE
SUBOXONE sublingual tablet is indicated for the maintenance treatment of opioid dependence. SUBOXONE sublingual tablet should be used as part of a complete treatment plan that includes counseling and psychosocial support.
Mechanism of Action
SUBOXONE sublingual tablet contains buprenorphine and naloxone. Buprenorphine is a partial agonist at the mu‐opioid receptor and an antagonist at the kappa‐opioid receptor. Naloxone is an opioid antagonist and produces opioid withdrawal signs and symptoms in individuals physically dependent on full opioid agonists when administered parenterally.
DOSAGE AND ADMINISTRATION
SUBOXONE sublingual tablet is administered sublingually as a single daily dose. SUBOXONE sublingual tablets should be used in patients who have been initially inducted using SUBUTEX® (buprenorphine) sublingual tablets.
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.
Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose
Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver. Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with SUBOXONE sublingual tablet. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose.
- The dosage of SUBOXONE sublingual tablet should be progressively adjusted in increments/decrements of 2 mg/0.5 mg or 4 mg/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 tablet is generally in the range of 4 mg/1 mg buprenorphine/naloxone to 24 mg/6 mg buprenorphine/naloxone per day depending on the individual patient. The recommended target dosage of SUBOXONE sublingual tablet is 16 mg/4 mg buprenorphine/naloxone/day as a single daily dose. Dosages higher than 24 mg/6 mg have not been demonstrated to provide any 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 SUBOXONE sublingual tablets contributes to the intended treatment goals.
Method of Administration
SUBOXONE sublingual tablets must be administered whole. Do not cut, chew, or swallow SUBOXONE sublingual tablets. Advise patients not to eat or drink anything until the tablet is completely dissolved.
SUBOXONE sublingual tablet should be placed under the tongue until it is dissolved. For doses requiring the use of more than two tablets, patients are advised to either place all the tablets at once or alternatively (if they cannot fit in more than two tablets comfortably), place two tablets at a time under the tongue. Either way, the patients should continue to hold the tablets under the tongue until they dissolve; swallowing the tablets reduces the bioavailability of the drug. 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.
The decision to discontinue therapy with SUBOXONE sublingual tablets 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 withdrawal signs and symptoms.
SUBOXONE sublingual tablet 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: SUBOXONE sublingual tablets contain 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 of Respiratory and Central Nervous System (CNS) Depression: Buprenorphine has been associated with life‐threatening respiratory depression and death. Many, but not all, post‐marketing reports regarding coma and death involved misuse by self‐injection or were associated with the concomitant use of buprenorphine and benzodiazepines or other CNS depressant, including alcohol. Warn patients of the potential danger of self‐administration of benzodiazepines or other CNS depressants while under treatment with SUBOXONE sublingual tablets.
Managing Risks from Concomitant Use of Benzodiazepine or Other CNS Depressants: Concomitant use of buprenorphine and benzodiazepines or other CNS depressants increases the risk of adverse reactions including overdose and death. Medication‐assisted treatment of opioid use disorder, however, should not be categorically denied to patients taking these drugs. Prohibiting or creating barriers to treatment can pose an even greater risk of morbidity and mortality due to the opioid use disorder alone.
As a routine part of orientation to buprenorphine treatment, educate patients about the risks of concomitant use of benzodiazepines, sedatives, opioid analgesics, and alcohol.
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.
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.
Adrenal Insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non‐specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.
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 SUBOXONE sublingual tablet, gradually taper the dosage
Hypersensitivity 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 tablet.
Precipitation of Opioid Withdrawal Signs and Symptoms: Because it contains naloxone, SUBOXONE sublingual tablet is highly likely to produce marked and intense withdrawal signs and symptoms if misused parenterally by individual dependent on full opioid agonists such as heroin, morphine, or methadone. Because of the partial agonist properties of buprenorphine, SUBOXONE sublingual tablet may precipitate opioid withdrawal signs and symptoms in such persons if administered sublingually before the agonist effects of the opioid have subsided.
Risk of Overdose in Opioid Naïve Patients: There have been reported deaths of opioid naïve individuals who received a 2 mg dose of buprenorphine as a sublingual tablet for analgesia. SUBOXONE sublingual tablet is not appropriate as an analgesic.
Impairment of Ability to Drive or Operate Machinery: SUBOXONE sublingual tablet 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 SUBOXONE sublingual tablet therapy does not adversely affect his or her ability to engage in such activities.
Orthostatic Hypotension: Like other opioids, SUBOXONE sublingual tablets 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.
Effects in Acute Abdominal Conditions: As with other opioids, buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.
Adverse events commonly observed with administration of buprenorphine/naloxone are oral hypoesthesia, glossodynia, oral mucosal erythema, headache, nausea, vomiting, hyperhidrosis, constipation, signs and symptoms of withdrawal, insomnia, pain, and peripheral edema.
|Benzodiazepines or other Central Nervous System (CNS) Depressants|
|Clinical Impact:||Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.|
|Intervention:||Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate. Before co‐prescribing benzodiazepines for anxiety or insomnia, ensure that patients are appropriately diagnosed and consider alternative medications and non‐pharmacologic treatments. If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in treatment for opioid use disorder.|
|Examples:||Alcohol, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids.|
|Inhibitors of CYP3A4|
|Clinical Impact:||The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of SUBOXONE sublingual tablet 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.|
|Intervention:||If concomitant use is necessary, consider dosage reduction of SUBOXONE sublingual tablet until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the SUBOXONE sublingual tablet dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.|
|Examples:||Macrolide antibiotics (e.g., erythromycin), azole‐antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir)|
|Clinical Impact:||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.|
|Intervention:||If concomitant use is necessary, consider increasing the SUBOXONE sublingual tablet dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider SUBOXONE sublingual tablet dosage reduction and monitor for signs of respiratory depression.|
|Examples:||Rifampin, carbamazepine, phenytoin|
|Antiretrovirals: Non‐nucleoside reverse transcriptase inhibitors (NNRTIs)|
|Clinical Impact:||Non‐nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delavirdine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.|
|Intervention:||Patients who are on chronic SUBOXONE sublingual tablet treatment should have their dose monitored if NNRTIs are added to their treatment regimen.|
|Examples:||efavirenz, nevirapine, etravirine, delavirdine|
|Antiretrovirals: Protease inhibitors (PIs)|
|Clinical Impact:||Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post‐marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.|
|Intervention:||Monitor patients taking SUBOXONE sublingual tablet and atazanavir with and without ritonavir, and reduce dose of SUBOXONE sublingual tablet if warranted.|
|Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)|
|Clinical Impact:||Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.|
|Clinical Impact:||The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.|
|Intervention:||If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue SUBOXONE sublingual tablet if serotonin syndrome is suspected.|
|Examples:||Selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants (TCAs), triptans, 5‐HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).|
|Monoamine Oxidase Inhibitors (MAOIs)|
|Clinical Impact:||MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).|
|Intervention:||The use of SUBOXONE sublingual tablet is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.|
|Examples:||phenelzine, tranylcypromine, linezolid|
|Clinical Impact:||Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.|
|Intervention:||Monitor patients receiving muscle relaxants and SUBOXONE sublingual tablet for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of SUBOXONE sublingual tablet and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, strongly consider prescribing naloxone for the emergency treatment of opioid overdose|
|Clinical Impact:||Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.|
|Intervention:||Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.|
|Clinical Impact:||The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.|
|Intervention:||Monitor patients for signs of urinary retention or reduced gastric motility when SUBOXONE sublingual tablet is used concomitantly with anticholinergic drugs.|
USE IN SPECIFIC POPULATIONS
Pregnancy: The data on use of buprenorphine, one of the active ingredients in SUBOXONE sublingual tablets, in pregnancy, are limited; however, these data do not indicate an increased risk of major malformations specifically due to buprenorphine exposure. The extremely limited data on sublingual naloxone exposure in pregnancy are not sufficient to evaluate a drug‐associated risk.
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.
Fetal/neonatal adverse reactions: Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with SUBOXONE sublingual tablets.
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 after 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 SUBOXONE sublingual tablet and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.
Advise breastfeeding women taking buprenorphine products to monitor the infant for increased drowsiness and breathing difficulties.
Pediatric Use: The safety and effectiveness of SUBOXONE sublingual tablets 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
SUBOXONE sublingual tablets contain buprenorphine, a Schedule III controlled substance under the Controlled Substances 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.