Buprenorphine Hydrochloride, Naloxone Hydrochloride
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];
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Overview
Buprenorphine Hydrochloride, Naloxone Hydrochloride is a opioid agonist/antagonist that is FDA approved for the treatment of opioid dependence and should be used as part of a complete treatment plan to include counseling and psychosocial support.. Common adverse reactions include hyperhidrosis, abdominal pain, constipation, nausea, vomiting, headache, insomnia, drug withdrawal, pain.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
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. To avoid precipitating an opioid withdrawal syndrome, the first dose of buprenorphine/naloxone should be started only when objective signs of moderate withdrawal appear.
On Day 1, an induction dosage of up to 8 mg /2 mg buprenorphine/naloxone sublingual film is recommended. Clinicians should start with an initial dose of 2 mg/ 0.5 mg or 4 mg/1 mg buprenorphine/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/naloxone based on the control of acute withdrawal symptoms.
On Day 2, a single daily dose of up to 16 mg/4 mg buprenorphine/naloxone sublingual film is recommended.
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.
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/naloxone combination products have not been evaluated in adequate and well-controlled studies for induction in patients on long-acting opioid products, and contain naloxone, which 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/naloxone sublingual film.
Patients dependent on heroin or other short-acting opioid products
Patients dependent on heroin or short-acting opioid products may be inducted with either buprenorphine/naloxone sublingual film or with sublingual buprenorphine monotherapy. The first dose of buprenorphine/naloxone sublingual film or buprenorphine should be administered when objective signs of moderate opioid withdrawal appear, and not less than 6 hours after the patient last used an opioid.
It is recommended that an adequate maintenance 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.
Maintenance
The dosage of buprenorphine/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/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/naloxone sublingual film 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 and clinical response. The recommended target dosage of buprenorphine/naloxone sublingual film during maintenance is 16 mg/4 mg buprenorphine/naloxone/day as a single daily dose. Dosages higher than 24 mg/6 mg daily have not been demonstrated to provide a clinical advantage.
Method of Administration
Do not cut, chew, or swallow buprenorphine/naloxone sublingual film. Place the buprenorphine/naloxone sublingual film under the tongue, close to the base on the left or right side. If an additional 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. Buprenorphine/naloxone sublingual film should NOT be moved after placement. 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/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 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.
Patients With Hepatic Impairment
Because the doses of this fixed combination product cannot be individually titrated, severe hepatic impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine, and moderate hepatic impairment also results in a reduced clearance of naloxone to a greater extent than buprenorphine, the combination product should generally be avoided in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment.
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.
Stopping Treatment
The decision to discontinue therapy with buprenorphine/naloxone sublingual film after a period of maintenance should be made as part of a comprehensive treatment plan. Taper patients to avoid opioid withdrawal signs and symptoms.
Switching Between Buprenorphine or Buprenorphine and Naloxone Sublingual Tablets and Sublingual Film
Patients being switched between buprenorphine/naloxone or buprenorphine only sublingual tablets and buprenorphine/naloxone sublingual film should be started on the corresponding dosage of the previously administered product. However, dosage adjustments may be necessary when switching between products. Not all strengths and combinations of the buprenorphine/naloxone sublingual films are bioequivalent to the buprenorphine/naloxone sublingual tablets as observed in pharmacokinetic studies. Therefore, systemic exposures of buprenorphine/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/Naloxone Sublingual Film Strengths
2 mg/0.5 mg, 4 mg/1 mg, 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/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/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.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Buprenorphine Hydrochloride, Naloxone Hydrochloride in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Buprenorphine Hydrochloride, Naloxone Hydrochloride in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Buprenorphine Hydrochloride, Naloxone Hydrochloride FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Buprenorphine Hydrochloride, Naloxone Hydrochloride in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Buprenorphine Hydrochloride, Naloxone Hydrochloride in pediatric patients.
Contraindications
Buprenorphine/naloxone sublingual film should not be administered to patients who have been shown to be hypersensitive to buprenorphine or naloxone as serious adverse reactions, including anaphylactic shock, have been reported.
Warnings
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.
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 buprenorphine/naloxone sublingual film.
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.
Buprenorphine/naloxone 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).
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, buprenorphine/naloxone sublingual film, or both in situations of concomitant prescription.
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.
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.
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 are 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, buprenorphine/naloxone 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.
Allergic Reactions
Cases of hypersensitivity to buprenorphine/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 buprenorphine/naloxone sublingual film.
Precipitation of Opioid Withdrawal Signs and Symptoms
Because it contains naloxone, buprenorphine/naloxone sublingual film is likely to produce 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, buprenorphine/naloxone sublingual film may precipitate opioid withdrawal signs and symptoms in such persons if administered sublingually before the agonist effects of the opioid have subsided.
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.
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. Buprenorphine/naloxone sublingual film is not appropriate as an analgesic.
Use in Patients With Impaired Hepatic Function
buprenorphine/naloxone products are not recommended in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment. Because hepatic impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine, the doses of buprenorphine and naloxone in this fixed-dose combination product cannot be individually titrated. Therefore, patients with severe hepatic impairment will be exposed to substantially higher levels of naloxone than patients with normal hepatic function. This may result in an increased risk of precipitated withdrawal at the beginning of treatment (induction) and may interfere with buprenorphine's efficacy throughout treatment. In patients with moderate hepatic impairment, the differential reduction of naloxone clearance compared to buprenorphine clearance is not as great as in subjects with severe hepatic impairment. Therefore, buprenorphine/naloxone products are not recommended for initiation of treatment (induction) in patients with moderate hepatic impairment due to the increased risk of precipitated withdrawal. However, buprenorphine/naloxone products may be used with caution for maintenance treatment in patients with moderate hepatic impairment who have initiated treatment on a buprenorphine product without naloxone. However, patients should be carefully monitored and consideration given to the possibility of naloxone interfering with buprenorphine's efficacy.
Impairment of Ability to Drive or Operate Machinery
Buprenorphine/naloxone 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 buprenorphine/naloxone sublingual film therapy does not adversely affect his or her ability to engage in such activities.
Orthostatic Hypotension
Like other opioids, buprenorphine/naloxone sublingual film 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.
General Precautions
Buprenorphine/naloxone 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.
Adverse Reactions
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.
Clinical Trials Experience
The safety of buprenorphine/naloxone sublingual film is supported by clinical trials using buprenorphine sublingual tablets and buprenorphine/naloxone sublingual tablets, and other trials using buprenorphine sublingual solutions, as well as an open-label study in 194 patients treated with buprenorphine/naloxone sublingual film. 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 among buprenorphine/naloxone sublingual film, buprenorphine/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/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.
Other adverse event data were derived from larger, controlled studies of buprenorphine/naloxone and buprenorphine tablets and of buprenorphine sublingual solution. In a comparative study of buprenorphine/naloxone and buprenorphine sublingual tablets, adverse event profiles were similar for subjects treated with 16 mg/4 mg buprenorphine/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/naloxone sublingual tablets and buprenorphine sublingual tablets.
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.
The safety of buprenorphine/naloxone sublingual film during treatment induction is supported by a clinical trial using 16 patients treated with buprenorphine/naloxone sublingual film and 18 treated with a buprenorphine-only sublingual film. Few differences in the adverse event profiles were noted between buprenorphine/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/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 not evidence to suggest that any of the four subjects experienced precipitated withdrawal secondary to the administration of buprenorphine or buprenorphine/naloxone sublingual films.
Postmarketing Experience
The most frequently reported postmarketing adverse events were peripheral edema, stomatitis, glossitis, and tongue disorder.
Drug Interactions
Cytochrome P-450 3A4 (CYP3A4) Inhibitors and Inducers
Buprenorphine is metabolized to norbuprenorphine primarily by cytochrome CYP3A4; therefore, potential interactions may occur when buprenorphine/naloxone sublingual film is given concurrently with agents that affect CYP3A4 activity. The concomitant use of buprenorphine/naloxone 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 buprenorphine/naloxone 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.
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.
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. Buprenorphine/naloxone 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 buprenorphine/naloxone sublingual film, and should also be cautioned to use benzodiazepines concurrently with buprenorphine/naloxone sublingual film only as directed by their physician.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): C There are no adequate and well-controlled studies of buprenorphine/naloxone in pregnant women. Limited published data on use of buprenorphine, the active ingredient in buprenorphine/naloxone, in pregnancy, have not shown an increased risk of major malformations. All pregnancies, regardless of drug exposure, have a background risk of 2-4% for major birth defects, and 15-20% for pregnancy loss. Reproductive and developmental studies in rats and rabbits identified adverse events at clinically relevant doses. Pre-and postnatal development studies in rats demonstrated dystocia, increased neonatal deaths, and developmental delays. No clear teratogenic effects were seen with a range of doses equivalent to or greater than the human dose. However, in a few studies, some events such as acephalus, omphalocele, and skeletal abnormalities were observed but these findings were not clearly treatment-related. Embryofetal death was also observed in both rats and rabbits.
Buprenorphine/naloxone sublingual film should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Clinical Considerations
Disease-associated maternal and embryo-fetal risk
Opioid dependence in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death.
Fetal/neonatal adverse reactions
Neonatal abstinence syndrome may occur in newborn infants of mothers who were on buprenorphine maintenance treatment. Observe newborns for poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly.
Data
Human Data
Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine during pregnancy. Limited published data on malformations from trials, observational studies, case series, and case reports on buprenorphine use in pregnancy have not shown an increased risk of major malformations. Based on these studies the incidence of neonatal abstinence syndrome is not clear and there does not appear to be a dose-response relationship.
Animal Data
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).
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). An apparent lack of milk production during these studies likely contributed to the decreased pup viability and lactation indices. 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).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Buprenorphine Hydrochloride, Naloxone Hydrochloride in women who are pregnant.
Labor and Delivery
As with all opioids, use of buprenorphine prior to delivery may result in respiratory depression in the newborn. Closely monitor neonates for signs of respiratory depression. An opioid antagonist such as naloxone should be available for reversal of opioid induced respiratory depression in the neonate.
Nursing Mothers
Based on two studies in 13 lactating women, buprenorphine and its metabolite norbuprenorphine are present in low levels in human milk and infant urine, 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 minimal. Caution should be exercised when buprenorphine/naloxone is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for buprenorphine/naloxone and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.
Clinical Considerations
Advise the nursing mother taking buprenorphine/naloxone to monitor the infant for increased drowsiness and breathing difficulties.
Data
Based on limited data from a study of 6 lactating women who were taking a median oral dose of buprenorphine of 0.29 mg/kg/day 5-8 days after delivery, breast milk contained a median infant dose of 0.42 mcg/kg/day of buprenorphine and 0.33 mcg/kg/day of norbuprenorphine, which are equal to 0.2% and 0.12% of the maternal weight-adjusted dose.
Based on limited data from a study of 7 lactating women who were taking a median oral dose of buprenorphine of 7 mg/day an average of 1.12 months after delivery, the mean milk concentrations of buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L respectively. Based on the limited data from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively breastfed infant would receive an estimated mean of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of norbuprenorphine, which are 0.38% and 0.18% of the maternal weight-adjusted dose.
No adverse reactions were observed in the infants in these two studies.
Pediatric Use
The safety and effectiveness of buprenorphine/naloxone sublingual film 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.
Geriatic Use
Clinical studies of buprenorphine/naloxone sublingual film, buprenorphine/naloxone sublingual tablets, or 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.
Gender
There is no FDA guidance on the use of Buprenorphine Hydrochloride, Naloxone Hydrochloride with respect to specific gender populations.
Race
There is no FDA guidance on the use of Buprenorphine Hydrochloride, Naloxone Hydrochloride with respect to specific racial populations.
Renal Impairment
No differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent and 6 normal patients following IV administration of 0.3 mg buprenorphine. The effects of renal failure on naloxone pharmacokinetics are unknown.
Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone has been evaluated in a pharmacokinetic study. Both drugs are extensively metabolized in the liver. While no clinically significant changes have been observed in subjects with mild hepatic impairment; the plasma levels have been shown to be higher and half-life values have been shown to be longer for both buprenorphine and naloxone in subjects with moderate and severe hepatic impairment. The magnitude of the effects on naloxone are greater than that on buprenorphine in both moderately and severely impaired subjects. The difference in magnitude of the effects on naloxone and buprenorphine are greater in subjects with severe hepatic impairment than in subjects with moderate hepatic impairment, and therefore the clinical impact of these effects is likely to be greater in patients with severe hepatic impairment than in patients with moderate hepatic impairment. Buprenorphine/naloxone products should be avoided in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Buprenorphine Hydrochloride, Naloxone Hydrochloride in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Buprenorphine Hydrochloride, Naloxone Hydrochloride in patients who are immunocompromised.
Administration and Monitoring
Administration
Oral
Monitoring
Patients should be monitored for symptoms related to over-dosing or under-dosing when switching between buprenorphine or buprenorphine and naloxone sublingual tablets and buprenorphine/naloxone sublingual film and between buprenorphine/naloxone sublingual film strengths.
IV Compatibility
There is limited information regarding the compatibility of Buprenorphine Hydrochloride, Naloxone Hydrochloride and IV administrations.
Overdosage
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.
Pharmacology
Buprenorphine Hydrochloride, Naloxone Hydrochloride
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Mechanism of Action
(Description)
Structure
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 four dosage strengths, 2 mg buprenorphine with 0.5 mg naloxone, 4 mg buprenorphine with 1 mg naloxone, 8 mg buprenorphine with 2 mg naloxone and 12 mg buprenorphine with 3 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 • 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.
Pharmacodynamics
(Description)
Pharmacokinetics
(Description)
Nonclinical Toxicology
(Description)
Clinical Studies
Condition 1
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Condition 2
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Condition 3
(Description)
How Supplied
(Description)
Storage
There is limited information regarding Buprenorphine Hydrochloride, Naloxone Hydrochloride Storage in the drug label.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
(Patient Counseling Information)
Precautions with Alcohol
Alcohol-Buprenorphine Hydrochloride, Naloxone Hydrochloride interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Buprenorphine Hydrochloride, Naloxone Hydrochloride Brand Names in the drug label.
Look-Alike Drug Names
- (Paired Confused Name 1a) — (Paired Confused Name 1b)
- (Paired Confused Name 2a) — (Paired Confused Name 2b)
- (Paired Confused Name 3a) — (Paired Confused Name 3b)
Drug Shortage Status
Drug Shortage
Price
References
The contents of this FDA label are provided by the National Library of Medicine.