buprenorphine HCl 2 MG / naloxone HCl 0.5 MG Sublingual Tablet
DRUG INTERACTIONS
7 Table 4 Includes clinically significant drug interactions with SUBOXONE.
Table 4.
Clinically Significant Drug Interactions Benzodiazepines and 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 [see Warnings and Precautions ( 5.2 , 5.3 )] .
Examples: Alcohol, non-benzodiazepine 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 film is achieved.
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see Clinical Pharmacology ( 12.3 )] , 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 film 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 film 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) CYP3A4 Inducers Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see Clinical Pharmacology ( 12.3 )] , 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 [see Clinical Pharmacology ( 12.3 )] , 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 film dosage until stable drug effects are achieved.
Monitor for signs of opioid withdrawal.
If a CYP3A4 inducer is discontinued, consider SUBOXONE sublingual film 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 film 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 film and atazanavir with and without ritonavir, and reduce dose of SUBOXONE sublingual film if warranted.
Examples: atazanavir, ritonavir 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.
Intervention: None Serotonergic Drugs 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 film sublingual film if serotonin syndrome is suspected.
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), 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 film is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid Muscle Relaxants 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 film for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of SUBOXONE sublingual film and/or the muscle relaxant as necessary.
Diuretics 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.
Anticholinergic Drugs 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 film is used concomitantly with anticholinergic drugs.
Benzodiazepines: Use caution in prescribing SUBOXONE sublingual film for patients receiving benzodiazepines or other CNS depressants and warn patients against concomitant self-administration/misuse.
( 7 ) CYP3A4Inhibitors and Inducers: Monitor patients starting or ending CYP3A4 inhibitors or inducers for potential over- or under- dosing.
( 7 ) Antiretrovirals: Patients who are on chronic buprenorphine treatment should have their dose monitored if NNRTIs are added to their treatment regimen.
Monitor patients taking buprenorphine and atazanavir with and without ritonavir.
Dose reduction of buprenorphine may be warranted ( 7 ).
Serotonergic Drugs: Concomitant use may result in serotonin syndrome.
Discontinue SUBOXONE sublingual film if serotonin syndrome is suspected.
( 7 )
OVERDOSAGE
10 Clinical Presentation 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.
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.
The long duration of action of SUBOXONE sublingual film should be taken into consideration when determining the length of treatment and medical surveillance needed to reverse the effects of an overdose.
Insufficient duration of monitoring may put patients at risk.
DESCRIPTION
11 SUBOXONE® (buprenorphine and naloxone) sublingual film is an orange film, imprinted with a logo identifying the product and strength in white ink.
It contains buprenorphine HCl, a mu-opioid receptor partial agonist, and a kappa- opioid receptor antagonist, and naloxone HCl dihydrate, an opioid antagonist, at a ratio of 4:1 (ratio of free bases).
It is intended for sublingual or buccal 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 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 C 29 H 41 NO 4 • 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 C 19 H 21 NO 4 • HCl • 2H 2 O 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.
Figure Figure
HOW SUPPLIED
16 / STORAGE AND HANDLING Product: 63629-4028
RECENT MAJOR CHANGES
Dosage and Administration ( 2.2 , 2.3 , 2.5 , 2.8 ) 09/2017 Warnings and Precautions ( 5.2 , 5.3 ) 02/2018
GERIATRIC USE
8.5 Geriatric Use Clinical studies of SUBOXONE sublingual film, SUBOXONE sublingual tablets, or SUBUTEX 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.
Due to possible decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in geriatric patients, the decision to prescribe SUBOXONE sublingual film should be made cautiously in individuals 65 years of age or older and these patients should be monitored for signs and symptoms of toxicity or overdose.
DOSAGE FORMS AND STRENGTHS
3 SUBOXONE sublingual film is supplied as an orange rectangular film with a white printed logo in four dosage strengths: Buprenorphine 2 mg/naloxone 0.5 mg, Buprenorphine 4 mg/naloxone 1 mg, Buprenorphine 8 mg/naloxone 2 mg and Buprenorphine 12 mg/naloxone 3 mg Sublingual film: buprenorphine 2 mg/ naloxone, 4 0.5 mg , buprenorphine 4 mg/ naloxone, 8 1 mg , buprenorphine 8 mg/ naloxone 2 mg and buprenorphine 12 mg/ naloxone 3 mg.
( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action SUBOXONE sublingual film contains buprenorphine and naloxone.
Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor.
Naloxone is a potent antagonist at mu opioid receptors and produces opioid withdrawal signs and symptoms in individuals physically dependent on full opioid agonists when administered parenterally.
INDICATIONS AND USAGE
1 SUBOXONE sublingual film is indicated for treatment of opioid dependence .
SUBOXONE sublingual film should be used as part of a complete treatment plan that includes counseling and psychosocial support.
SUBOXONE® sublingual film contains buprenorphine, a partial‐opioid agonist, and naloxone, an opioid antagonist, and is indicated for treatment of opioid dependence.
( 1 ) SUBOXONE sublingual film should be used as part of a complete treatment plan that includes counseling and psychosocial support.
( 1 )
PEDIATRIC USE
8.4 Pediatric Use The safety and effectiveness of SUBOXONE 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.
PREGNANCY
8.1 Pregnancy Risk Summary The data on use of buprenorphine, one of the active ingredients in SUBOXONE sublingual film, 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 [see Data ].
Observational studies have reported on congenital malformations among buprenorphine-exposed pregnancies, but were also not designed appropriately to assess the risk of congenital malformations specifically due to buprenorphine exposure [ see Data ].
The extremely limited data on sublingual naloxone exposure in pregnancy are not sufficient to evaluate a drug-associated risk.
Reproductive and developmental studies in rats and rabbits identified adverse events at clinically relevant and higher doses.
Embryofetal death was observed in both rats and rabbits administered buprenorphine during the period of organogenesis at doses approximately 6 and 0.3 times, respectively, the human sublingual dose of 16 mg/day of buprenorphine.
Pre-and postnatal development studies in rats demonstrated increased neonatal deaths at 0.3 times and above and dystocia at approximately 3 times the human sublingual dose of 16 mg/day of buprenorphine.
No clear teratogenic effects were seen when buprenorphine was administered during organogenesis with a range of doses equivalent to or greater than the human sublingual dose of 16 mg/day of buprenorphine.
However, increases in skeletal abnormalities were noted in rats and rabbits administered buprenorphine daily during organogenesis at doses approximately 0.6 and approximately equal to the human sublingual dose of 16 mg/day of buprenorphine, respectively.
In a few studies, some events such as acephalus and omphalocele were also observed but these findings were not clearly treatment-related [see Data ].
Based on animal data, advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population are unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations Disease – associated maternal and embryo – fetal 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.
Dose Adjustment during Pregnancy and the Postpartum Period 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 film.
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 [see Warnings and Precautions ( 5.5 )] .
Labor or Delivery Opioid-dependent women on buprenorphine maintenance therapy may require additional analgesia during labor.
Data Human Data Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine during pregnancy.
Limited data on malformations from trials, observational studies, case series, and case reports on buprenorphine use in pregnancy do not indicate an increased risk of major malformations specifically due to buprenorphine.
Several factors may complicate the interpretation of investigations of the children of women who take buprenorphine during pregnancy, including maternal use of illicit drugs, late presentation for prenatal care, infection, poor compliance, poor nutrition, and psychosocial circumstances.
Interpretation of data is complicated further by the lack of information on untreated opioid-dependent pregnant women, who would be the most appropriate group for comparison.
Rather, women on another form of opioid medication- assisted treatment, or women in the general population are generally used as the comparison group.
However, women in these comparison groups may be different from women prescribed buprenorphine-containing products with respect to maternal factors that may lead to poor pregnancy outcomes.
In a multicenter, double-blind, randomized, controlled trial [Maternal Opioid Treatment: Human Experimental Research (MOTHER)] designed primarily to assess neonatal opioid withdrawal effects, opioid-dependent pregnant women were randomized to buprenorphine (n=86) or methadone (n=89) treatment, with enrollment at an average gestational age of 18.7 weeks in both groups.
A total of 28 of the 86 women in the buprenorphine group (33%) and 16 of the 89 women in the methadone group (18%) discontinued treatment before the end of pregnancy.
Among women who remained in treatment until delivery, there was no difference between buprenorphine- treated and methadone-treated groups in the number of neonates requiring NOWS treatment or in the peak severity of NOWS.
Buprenorphine-exposed neonates required less morphine (mean total dose, 1.1 mg vs.
10.4 mg), had shorter hospital stays (10.0 days vs.
17.5 days), and shorter duration of treatment for NOWS (4.1 days vs.
9.9 days) compared to the methadone-exposed group.
There were no differences between groups in other primary outcomes (neonatal head circumference,) or secondary outcomes (weight and length at birth, preterm birth, gestational age at delivery, and 1-minute and 5-minute Apgar scores), or in the rates of maternal or neonatal adverse events.
The outcomes among mothers who discontinued treatment before delivery and may have relapsed to illicit opioid use are not known.
Because of the imbalance in discontinuation rates between the buprenorphine and methadone groups, the study findings are difficult to interpret.
Animal Data The exposure margins listed below are based on body surface area comparisons (mg/m 2 ) to the human sublingual dose of 16 mg buprenorphine via SUBOXONE sublingual tablets.
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 during the period of organogenesis.
Following oral administration to rats no teratogenic effects were observed at buprenorphine doses up to 250 mg/kg/day (estimated exposure approximately 150 times the human sublingual dose of 16 mg) in the presence of maternal toxicity (mortality).
Following oral administration to rabbits, no teratogenic effects were observed at buprenorphine doses up to 40 mg/kg/day (estimated exposure approximately 50 times, the human sublingual dose of 16 mg) in the absence of clear maternal toxicity.
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 human sublingual dose of 16 mg).
Maternal toxicity resulting in mortality was noted in these studies in both rats and rabbits.
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.
Maternal toxicity was seen in the high-dose group but not at the lower doses where the findings were observed.
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 human sublingual dose of 16 mg).
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 human sublingual dose of 16 mg), after IV doses up to 0.8 mg/kg/day (estimated exposure was approximately 0.5 times and equal to, respectively, the human sublingual dose of 16 mg), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 95 times the human sublingual dose of 16 mg) and 25 mg/kg/day in rabbits (estimated exposure was approximately 30 times the human daily sublingual dose of 16 mg).
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 human sublingual dose of 16 mg), 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 human daily sublingual dose of 16 mg) in the absence of maternal toxicity or oral administration of 1 mg/kg/day or greater (estimated exposure was approximately equal to the human sublingual dose of 16 mg) 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 human daily sublingual dose of 16 mg).
No maternal toxicity was noted at doses causing post-implantation loss in this study.
Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine from Gestation Day 14 through Lactation Day 21 at 5 mg/kg/day (approximately 3 times the human sublingual dose of 16 mg).
Fertility, pre- 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 human daily sublingual dose of 16 mg), after IM doses of 0.5 mg/kg/day and up (approximately 0.3 times the human sublingual dose of 16 mg), and after SC doses of 0.1 mg/kg/day and up (approximately 0.06 times the human sublingual dose of 16 mg).
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 human sublingual dose of 16 mg).
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse: Buprenorphine can be abused in a similar manner to other opioids.
l Monitor patients for conditions indicative of ldiversion or progression of opioid dependence and addictive behaviors.
Multiple refills should not be prescribed early in treatment or without appropriate patient follow‐up visits.
( 5.1 ) Respiratory Depression: Life‐threatening respiratory depression and death have occurred in association with buprenorphine, use.
Warn patients of the potential danger of self‐administration of benzodiazepines or other CNS depressants while under treatment with SUBOXONE sublingual film, or both in situations of concomitant.
( 5.2 , 5.3 ) Unintentional Pediatric Exposure: Store SUBOXONE sublingual film safely out of the sight and reach of children.
Buprenorphine can cause severe, possibly fatal, respiratory depression in children.
( 5.4 ) Neonatal Opioid Withdrawal Syndrome: Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy ( 5.5 ) Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid.
( 5.6 ) Risk of Opioid Withdrawal with Abrupt Discontinuation: If treatment is temporarily interrupted or discontinued, monitor patients for withdrawal and treat appropriately.
( 5.7 ) Risk of Hepatitis, Hepatic Events: Monitor liver function tests prior to initiation and during treatment and evaluate suspected hepatic events.
( 5.8 ) Precipitation of Opioid Withdrawal Signs and Symptoms: An opioid withdrawal syndrome is likely to occur with parenteral misuse of SUBOXONE sublingual film by individuals physically dependent on full opioid agonists, or by sublingual or buccal administration before the agonist effects of other opioids have subsided.
( 5.10 ) Risk of Overdose in Opioid‐Naïve Patients: SUBOXONE sublingual film is not appropriate as an analgesic.
There have been reported deaths of opioid naïve individuals who received a 2 mg sublingual dose.
( 5.11 ) 5.1 Addiction, Abuse , and Misuse SUBOXONE sublingual film 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 [see Drug Abuse and Dependence ( 9.2 )] .
5.2 Risk 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 depressants, including alcohol.
Warn patients of the potential danger of self‐administration of benzodiazepines or other CNS depressants while under treatment with SUBOXONE sublingual film [see Warnings and Precautions ( 5.3 ), Drug Interactions ( 7 )].
Use SUBOXONE sublingual film with caution in patients with compromised respiratory function (e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or pre‐existing respiratory depression).
5.3 Managing Risks from Concomitant Use of Benzodiazepines 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.
Develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants at initiation of buprenorphine treatment, or if it emerges as a concern during treatment.
Adjustments to induction procedures and additional monitoring may be required.
There is no evidence to support dose limitations or arbitrary caps of buprenorphine as a strategy to address benzodiazepine use in buprenorphine‐treated patients.
However, if a patient is sedated at the time of buprenorphine dosing, delay or omit the buprenorphine dose if appropriate.
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.
For patients in buprenorphine treatment, benzodiazepines are not the treatment of choice for anxiety or insomnia.
Before co‐prescribing benzodiazepines, ensure that patients are appropriately diagnosed and consider alternative medications and non‐pharmacologic treatments to address anxiety or insomnia.
Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the patient’s buprenorphine treatment and coordinate care to minimize the risks associated with concomitant use.
In addition, take measures to confirm that patients are taking their medications as prescribed and are not diverting or supplementing with illicit drugs.
Toxicology screening should test for prescribed and illicit benzodiazepines [see Drug Interactions ( 7 )].
5.4 Unintentional Pediatric Exposure Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally exposed to it.
Store buprenorphine‐containing medications safely out of the sight and reach of children.
and destroy any unused medication appropriately [see Patient Counseling Information ( 17 ) ].
5.5 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 [see Use in Specific Populations ( 8.1 )] .
Advise pregnant women receiving opioid addiction treatment with SUBOXONE sublingual film of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations ( 8.1 )] .
This risk must be balanced against the risk of untreated opioid addiction which often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes.
Therefore, prescribers should discuss the importance and benefits of management of opioid addiction throughout pregnancy.
5.6 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.
5.7 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 [see Drug Abuse and Dependence ( 9.3 )] .
When discontinuing SUBOXONE sublingual film, gradually taper the dosage [see Dosage and Administration ( 2.8 )] .
5.8 Risk of 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, SUBOXONE sublingual film may need to be carefully discontinued to prevent withdrawal signs and symptoms and a return by the patient to illicit drug use, and strict monitoring of the patient should be initiated.
5.9 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 film.
5.10 Precipitation of Opioid Withdrawal Signs and Symptoms Because it contains naloxone, SUBOXONE 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, SUBOXONE sublingual film may precipitate opioid withdrawal signs and symptoms in such persons if administered before the agonist effects of the opioid have subsided.
5.11 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 film is not appropriate as an analgesic.
5.12 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.
The doses of buprenorphine and naloxone in this fixed‐dose combination product cannot be individually titrated., and hepatic impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine.
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.
However, 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.
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 [see Use in Specific Populations ( 8.6 )].
5.13 Impairment of Ability to Drive or Operate Machinery SUBOXONE sublingual film may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery, especially during treatment induction and dose adjustment.
Caution patients about driving or operating hazardous machinery until they are reasonably certain that SUBOXONE sublingual film therapy does not adversely affect his or her ability to engage in such activities.
5.14 Orthostatic Hypotension Like other opioids, SUBOXONE sublingual film may produce orthostatic hypotension in ambulatory patients.
5.15 Elevation of Cerebrospinal Fluid Pressure Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal pressure may be increased.
Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation.
5.16 Elevation of Intracholedochal Pressure Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract.
5.17 Effects in Acute Abdominal Conditions As with other opioids, buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling ( Medication Guide ).
Safe Use Before initiating treatment with SUBOXONE sublingual film, explain the points listed below to caregivers and patients.
Instruct patients to read the Medication Guide each time SUBOXONE sublingual film is dispensed because new information may be available.
SUBOXONE sublingual film must be administered whole.
Advise patients not to cut, chew, or swallow SUBOXONE sublingual film.
Inform patients and caregivers that potentially fatal additive effects may occur if SUBOXONE sublingual film is used with benzodiazepines or other CNS depressants , including alcohol.
Counsel patients that such medications should not be used concomitantly unless supervised bya health care provider [see Warnings and Precautions ( 5.2 , 5.3 ), Drug Interactions ( 7 )].
Advise patients that SUBOXONE sublingual film contains an opioid that can be a target for people who abuse prescription medications or street drugs.
Caution patients to keep their films in a safe place, and to protect them from theft.
Instruct patients to keep SUBOXONE sublingual film in a secure place, out of the sight and reach of children.
Accidental or deliberate ingestion by a child may cause respiratory depression that can result in death.
Advise patients to seek medical attention immediately if a child is exposed to SUBOXONE sublingual film.
Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs.
Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop.
Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see Drug Interactions ( 7 )] .
Inform patients that opioids could cause adrenal insufficiency, a potentially life- threatening condition.
Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.
Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions ( 5.6 )] .
Advise patients to never give SUBOXONE sublingual film to anyone else, even if he or she has the same signs and symptoms.
It may cause harm or death.
Advise patients that selling or giving away this medication is against the law.
Caution patients that SUBOXONE sublingual film may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving or operating machinery.
Caution should be taken especially during drug induction and dose adjustment and until individuals are reasonably certain that buprenorphine therapy does not adversely affect their ability to engage in such activities [see Warnings and Precautions ( 5.13 )].
Advise patients not to change the dosage of SUBOXONE sublingual film without consulting their healthcare provider.
Advise patients to take SUBOXONE sublingual film once a day.
Advise patients that if they miss a dose of SUBOXONE sublingual film they should take it as soon as they remember.
If it is almost time for the next dose, they should skip the missed dose and take the next dose at the regular time.
Inform patients that SUBOXONE sublingual film can cause drug dependence and that withdrawal signs and symptoms may occur when the medication is discontinued.
Advise patients seeking to discontinue treatment with buprenorphine for opioid dependence to work closely with their healthcare provider on a tapering schedule and inform them of the potential to relapse to illicit drug use associated with discontinuation of opioid agonist/partial agonist medication-assisted treatment.
Advise patients that, like other opioids, SUBOXONE sublingual film may produce orthostatic hypotension in ambulatory individuals [see Warnings and Precautions ( 5.14 )].
Advise patients to inform their healthcare provider if any other prescription medications, over-the-counter medications, or herbal preparations are prescribed or currently being used [see Drug Interactions ( 7 )].
Advise women that if they are pregnant while being treated with SUBOXONE sublingual film, the baby may have signs of withdrawal at birth and that withdrawal is treatable [see Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.1 )].
Advise women who are breastfeeding to monitor the infant for drowsiness and difficulty breathing [see Use in Specific Populations ( 8.2 )].
Inform patients that chronic use of opioids may cause reduced fertility.
It is not known whether these effects on fertility are reversible [see Use in Specific Populations ( 8.3 )].
Advise patients to inform their family members that, in the event of emergency, the treating healthcare provider or emergency room staff should be informed that the patient is physically dependent on an opioid and that the patient is being treated with SUBOXONE sublingual film.
Disposal of Unused SUBOXONE Sublingual Films Unused SUBOXONE sublingual films should be disposed of as soon as they are no longer needed.
Unused films should be flushed down the toilet.
Manufactured for Indivior Inc.
North Chesterfield, VA 23235 by: Aquestive Therapeutics, Warren, NJ 07059 Distributed by: Indivior Inc.
North Chesterfield, VA 23235 SUBOXONE ® and SUBUTEX ® are registered trademarks of Indivior UK Ltd.
DOSAGE AND ADMINISTRATION
2 Prescription use of this product is limited under the Drug Addiction Treatment Act.
( 2.1 ) Administer SUBOXONE sublingual film as a single daily dose.
( 2.2 ) To avoid precipitating withdrawal, induction with SUBOXONE sublingual film should be undertaken when objective and clear signs of withdrawal are evident and SUBOXONE sublingual film should be administered in divided doses when used as initial treatment.
( 2.3 ) For patients dependent on short‐acting opioid products who are in opioid withdrawal; on Day 1, administer up to 8 mg/2 mg SUBOXONE sublingual film (in divided doses).
On Day 2, administer up to 16 mg/4 mg of SUBOXONE sublingual film as a single dose.
( 2.3 ) For patients dependent on methadone or long‐acting opioid products, induction onto sublingual buprenorphine monotherapy is recommended on Days 1 and 2 of treatment.
( 2.3 ) For maintenance treatment, the target dosage of SUBOXONE sublingual film is usually 16 mg/4 mg as a single daily dose.
( 2.4 ) Sublingual Administration: Place one film under the tongue, close to the base on the left or right side, and allow to completely dissolve.
Buccal Administration: Place one film on the inside of the left or right cheek and allow to completely dissolve.
( 2.5 ) SUBOXONE sublingual film must be administered whole.
Do not cut, chew, or swallow SUBOXONE sublingual film ( 2.5 ) When discontinuing treatment, gradually taper to avoid signs and symptoms of withdrawal.
( 2.8 ) 2.1 Drug Addiction and Treatment 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.
2.2 Important Dosage and Administration Information SUBOXONE sublingual film is administered sublingually or buccally as a single daily dose.
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.
2.3 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.
Patients dependent on heroin or other short‐acting opioid products Patients dependent on heroin or other short‐acting opioid products may be inducted with either SUBOXONE sublingual film or with sublingual buprenorphine monotherapy.
At treatment initiation, the first dose of SUBOXONE sublingual film should be administered when objective signs of moderate opioid withdrawal appear, not less than six hours after the patient last used opioids.
It is recommended that an adequate treatment 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.
On Day 1, an induction dosage of up to 8 mg/2 mg SUBOXONE 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 SUBOXONE sublingual film is recommended.
Because the exposure to naloxone is somewhat higher after buccal than after sublingual administration, it is recommended that the sublingual site of administration be used during induction to minimize exposure to naloxone, to reduce the risk of precipitated withdrawal.
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 who are physically dependent on long‐acting opioid products, and the naloxone in these combination products 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 SUBOXONE sublingual film.
2.4 Maintenance For maintenance, SUBOXONE sublingual film may be administered buccally or sublingually.
The dosage of SUBOXONE 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 SUBOXONE 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 SUBOXONE 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.
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 film contributes to the intended treatment goals.
2.5 Method of Administration SUBOXONE sublingual film must be administered whole.
Do not cut, chew, or swallow SUBOXONE sublingual film.
Advise patients not to eat or drink anything until the film is completely dissolved.
Sublingual Administration Place one film under the tongue, close to the base on the left or right side.
If an additional film is necessary to achieve the prescribed dose, place an additional film sublingually on the opposite side from the first film.
Place the film in a manner to minimize overlapping as much as possible.
The film must be kept under the tongue until the film is completely dissolved.
If a third film is necessary to achieve the prescribed dose, place it under the tongue on either side after the first 2 films have dissolved.
Buccal Administration Place one film on the inside of the right or left cheek.
If an additional film is necessary to achieve the prescribed dose, place an additional film on the inside of the opposite cheek.
The film must be kept on the inside of the cheek until the film is completely dissolved.
If a third film is necessary to achieve the prescribed dose, place it on the inside of the right or left cheek after the first two films have dissolved.
SUBOXONE sublingual film should NOT be moved after placement.
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.
2.6 Clinical Supervision Treatment should be initiated with supervised administration, progressing to unsupervised administration as the patient’s clinical stability permits.
SUBOXONE sublingual film is subject to diversion and abuse.
When determining the prescription quantity for unsupervised administration, consider the patient’s level of stability, the security of his or her home situation, and other factors likely to affect the ability to manage supplies of take‐home medication.
Ideally patients should be seen at reasonable intervals (e.g., at least weekly during the first month of treatment) based upon the individual circumstances of the patient.
Medication should be prescribed in consideration of the frequency of visits.
Provision of multiple refills is not advised early in treatment or without appropriate patient follow‐up visits.
Periodic assessment is necessary to determine compliance with the dosing regimen, effectiveness of the treatment plan, and overall patient progress.
Once a stable dosage has been achieved and patient assessment (e.g., urine drug screening) does not indicate illicit drug use, less frequent follow‐up visits may be appropriate.
A once‐monthly visit schedule may be reasonable for patients on a stable dosage of medication who are making progress toward their treatment objectives.
Continuation or modification of pharmacotherapy should be based on the healthcare provider’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 healthcare provider should re‐evaluate the appropriateness of continuing the current treatment.
2.7 Unstable Patients Healthcare providers 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 healthcare provider does not feel that he/she has the expertise to manage the patient.
In such cases, the healthcare provider may want to assess whether to refer the patient to a specialist or more intensive behavioral treatment environment.
Decisions should be based on a treatment plan established and agreed upon with the patient at the beginning of treatment.
Patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be provided with, or referred to, more intensive and structured treatment.
2.8 Discontinuing Treatment The decision to discontinue therapy with SUBOXONE sublingual film after a period of maintenance should be made as part of a comprehensive treatment plan.
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 opioid withdrawal signs and symptoms.
[See Warnings and Precautions ( 5.7 )] .
2.9 Switching Between Buprenorphine or Buprenorphine and Naloxone Sublingual Tablets and SUBOXONE Sublingual Film Patients being switched between buprenorphine and naloxone or buprenorphine only sublingual tablets and SUBOXONE sublingual film should be started on the same dosage of the previously administered product.
However, dosage adjustments may be necessary when switching between buprenorphine products.
Not all strengths and combinations of the SUBOXONE sublingual films are bioequivalent to SUBOXONE® sublingual tablets as observed in pharmacokinetic studies [see Clinical Pharmacology ( 12.3 )] .
Therefore, systemic exposures of buprenorphine and 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.
2.10 Switching Between SUBOXONE Sublingual Film Strengths As indicated in Table 1 , the sizes and the compositions of the four units of SUBOXONE sublingual films, i.e., 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 SUBOXONE 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 and 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.
Table 1.
Comparison of Available SUBOXONE Sublingual Film Strengths by Dimensions and Drug Concentrations.
SUBOXONE sublingual film unit strength (buprenorphine/naloxone) SUBOXONE sublingual film unit dimensions Buprenorphine Concentration % (w/w) Naloxone Concentration % (w/w) 2 mg/0.5 mg 22.0 mm x 12.8 mm 5.4 1.53 4 mg/1 mg (2 times the length of the 2 mg/0.5 mg unit) 22.0 mm x 25.6 mm 5.4 1.53 8 mg/2 mg 22.0 mm x 12.8 mm 17.2 4.88 12 mg/3 mg (1.5 times the length of the 8 mg/2 mg unit) 22.0 mm X 19.2 mm 17.2 4.88 2.11 Switching Between Sublingual and Buccal Sites of Administration The systemic exposure of buprenorphine between buccal and sublingual administration of SUBOXONE sublingual film is similar.
Therefore, once induction is complete, patients can switch between buccal and sublingual administration without significant risk of under or overdosing.