Buprenorphine 8 MG Sublingual Tablet
Generic Name: BUPRENORPHINE HYDROCHLORIDE
Brand Name: Buprenorphine
- Substance Name(s):
- BUPRENORPHINE HYDROCHLORIDE
DRUG INTERACTIONS
7 Monitor patients starting or ending CYP3A4 inhibitors or inducers for potential over or under dosing.
(7.1) Use caution in prescribing Buprenorphine Sublingual Tablets for patients receiving benzodiazepines or other CNS depressants and warn patients against concomitant self-administration/misuse.
(7.3) Serotonergic Drugs: Concomitant use may result in serotonin syndrome.
Discontinue Buprenorphine Sublingual Tablets if serotonin syndrome is suspected.
(7.4) 7.1 Cytochrome P-450 3A4 (CYP3A4) Inhibitors and Inducers Buprenorphine is metabolized to norbuprenorphine primarily by cytochrome CYP3A4; therefore, potential interactions may occur when Buprenorphine Sublingual Tablets are given concurrently with agents that affect CYP3A4 activity.
The concomitant use of Buprenorphine Sublingual Tablets 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 many CYP3A4 inducers has not been studied; therefore, it is recommended that patients receiving Buprenorphine Sublingual Tablets be monitored for signs and symptoms of opioid withdrawal if inducers of CYP3A4 (e.g., phenobarbital, carbamazepine, phenytoin, rifampicin) are coadministered [s e e C lini c al P h arma c ology ( 12.3 ) ] .
7.2 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 postmarketing 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.
7.3 Benzodiazepines There have been a number of postmarketing 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 Sublingual Tablets 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 Sublingual Tablets, and should also be cautioned to use benzodiazepines concurrently with Buprenorphine Sublingual Tablets only as directed by their physician.
7.4 Serotonergic Drugs The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system, such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue), has resulted in serotonin syndrome.
If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment.
Discontinue SUBUTEX sublingual tablets if serotonin syndrome is suspected.
OVERDOSAGE
10 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 t h e c ase of ov er d os e , t h e p r i m a r y m a n ag e m en t s h o u l d b e t h e re-e s t a b lis h m e n t of a d e qu a t e v e n t ila t ion w i t h mec h a n i c al assis t a n c e of re s p i r a t io n , if re qu i re d .
Naloxo n e m ay b e of val u e f or t h e m a n ag e m e n t of bup re n o r p h i n e ov er d os e .
Hig h e r t h an n o r m al d os e s a n d re p e a te d a d m i n is t r a t ion m ay b e n e c e ssa r y.
Th e lo n g d u r a t ion of a ct ion of bup re n o r ph i n e s h o u l d b e t a k e n i n t o c o n si d er a t ion w h e n d ete r m i n i n g t h e l e n g t h of tre a t me n t a n d m e d i c al s u r v e illa n c e n ee d e d t o r e v er se t h e e ff ect s of an ov er d os e.
I n s u f f i c i e n t du r a t ion of m o n i t o r i n g m ay pu t p a t i e n t s at r is k.
DESCRIPTION
11 Buprenorphine Sublingual Tablets are an uncoated oval orange tablet, imprinted with a logo on one side and a numeric imprint on the other side.
The tablets contain buprenorphine HCl and are available in two dosage strengths, 2 mg buprenorphine and 8 mg buprenorphine (as free base).
Each tablet also contains citric acid anhydrous, crospovidone, FD&C yellow #6 HT aluminum lake, lactose monohydrate, magnesium stearate, mannitol, pregelatinized starch (maize), povidone, sodium citrate dihydrate.
Chemically, buprenorphine HCl, USP 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, USP has the molecular formula C2 9H4 1NO4• 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.
The following chemical structure for Buprenorphine HCl, USP 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.
CLINICAL STUDIES
6.1 Adverse Events in Clinical Trials The safety of Buprenorphine Sublingual Tablets was supported by clinical trials using Buprenorphine Sublingual Tablets, buprenorphine and naloxone sublingual tablet and other trials using buprenorphine sublingual solutions.
In total, safety data were available from 3214 opioid-dependent subjects exposed to buprenorphine at doses in the range used in treatment of opioid addiction.
Few differences in adverse event profile were noted between Buprenorphine Sublingual Tablets or buprenorphine administered as a sublingual solution.
The following adverse events were reported to occur by at least 5% of patients in a 4-week study (Table 1).
Table 1.
Adverse Events ≥5% by Body System and Treatment Group in a 4-week Study N (%) N (%) Body System /Adverse Event (COSTART Terminology) Buprenorphine Sublingual Tablets 16 mg/day N=103 Placebo N=107 Body as a Whole Asthenia 5 (4.9%) 7 (6.5%) Chills 8 (7.8%) 8 (7.5%) Headache 30 (29.1%) 24 (22.4%) Infection 12 (11.7%) 7 (6.5%) Pain 19 (18.4%) 20 (18.7%) Pain Abdomen 12 (11.7%) 7 (6.5%) Pain Back 8 (7.8%) 12 (11.2%) Withdrawal Syndrome 19 (18.4%) 40 (37.4%) Cardiovascular System Vasodilation 4 (3.9%) 7 (6.5%) Digestive System Constipation 8 (7.8%) 3 (2.8%) Diarrhea 5 (4.9%) 16 (15.0%) Nausea 14 (13.6%) 12 (11.2%) Vomiting 8 (7.8%) 5 (4.7%) Nervous System Insomnia 22 (21.4%) 17 (15.9%) Respiratory System Rhinitis 10 (9.7%) 14 (13.1%) Skin And Appendages Sweating 13 (12.6%) 11 (10.3%) The adverse event profile of buprenorphine was also characterized in the dose-controlled study of buprenorphine solution, over a range of doses in four months of treatment.
Table 2 shows adverse events reported by at least 5% of subjects in any dose group in the dose-controlled study.
Table 2.
Adverse Events (≥5%) by Body System and Treatment Group in a 16-week Study Body System /Adverse Event (COSTART Terminology) Buprenorphine Dose* Very Low* (N=184) Low* (N=180) Moderate* (N=186) High* (N=181) Total* (N=731) N (%) N (%) N (%) N (%) N (%) Body as a Whole Abscess 9 (5%) 2 (1%) 3 (2%) 2 (1%) 16 (2%) Asthenia 26 (14%) 28 (16%) 26 (14%) 24 (13%) 104 (14%) Chills 11 (6%) 12 (7%) 9 (5%) 10 (6%) 42 (6%) Fever 7 (4%) 2 (1%) 2 (1%) 10 (6%) 21 (3%) Flu Syndrome 4 (2%) 13 (7%) 19 (10%) 8 (4%) 44 (6%) Headache 51 (28%) 62 (34%) 54 (29%) 53 (29%) 220 (30%) Infection 32 (17%) 39 (22%) 38 (20%) 40 (22%) 149 (20%) Injury Accidental 5 (3%) 10 (6%) 5 (3%) 5 (3%) 25 (3%) Pain 47 (26%) 37 (21%) 49 (26%) 44 (24%) 177 (24%) Pain Back 18 (10%) 29 (16%) 28 (15%) 27 (15%) 102 (14%) Withdrawal Syndrome 45 (24%) 40 (22%) 41 (22%) 36 (20%) 162 (22%) Digestive System Constipation 10 (5%) 23 (13%) 23 (12%) 26 (14%) 82 (11%) Diarrhea 19 (10%) 8 (4%) 9 (5%) 4 (2%) 40 (5%) Dyspepsia 6 (3%) 10 (6%) 4 (2%) 4 (2%) 24 (3%) Nausea 12 (7%) 22 (12%) 23 (12%) 18 (10%) 75 (10%) Vomiting 8 (4%) 6 (3%) 10 (5%) 14 (8%) 38 (5%) Nervous System Anxiety 22 (12%) 24 (13%) 20 (11%) 25 (14%) 91 (12%) Depression 24 (13%) 16 (9%) 25 (13%) 18 (10%) 83 (11%) Dizziness 4 (2%) 9 (5%) 7 (4%) 11 (6%) 31 (4%) Insomnia 42 (23%) 50 (28%) 43 (23%) 51 (28%) 186 (25%) Nervousness 12 (7%) 11 (6%) 10 (5%) 13 (7%) 46 (6%) Somnolence 5 (3%) 13 (7%) 9 (5%) 11 (6%) 38 (5%) Respiratory System Cough Increase 5 (3%) 11 (6%) 6 (3%) 4 (2%) 26 (4%) Pharyngitis 6 (3%) 7 (4%) 6 (3%) 9 (5%) 28 (4%) Rhinitis 27 (15%) 16 (9%) 15 (8%) 21 (12%) 79 (11%) Skin and Appendages Sweat 23 (13%) 21 (12%) 20 (11%) 23 (13%) 87 (12%) Special Senses Runny Eyes 13 (7%) 9 (5%) 6 (3%) 6 (3%) 34 (5%) *Sublingual solution.
Doses in this table cannot necessarily be delivered in tablet form, but for comparison purposes: “Very low” dose (1 mg solution) would be less than a tablet dose of 2 mg “Low” dose (4 mg solution) approximates a 6 mg tablet dose “Moderate” dose (8 mg solution) approximates a 12 mg tablet dose “High” dose (16 mg solution) approximates a 24 mg tablet dose
HOW SUPPLIED
16 / STORAGE AND HANDLING Buprenorphine Sublingual Tablets are available as follows: 2 mg – Oval, orange tablets debossed with on one side and 156 on the other side.
Tablets are supplied in bottles of 30 (NDC 0228-3156-03), 90 (NDC 0228-3156-09) and a blister pack of 30 (NDC 0228-3156-73).
8 mg – Oval, orange tablets debossed with on one side and 153 on the other side.
Tablets are supplied in bottles of 30 (NDC 0228-3153-03), 90 (NDC 0228-3153-09) and a blister pack of 30 (NDC 0228-3153-73).
Store at 25°C (77°F), excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature].
Dispense in a tight, light-resistant container as defined in USP.
CAU T ION: D E A O r de r F o r m R e qu i re d .
P a t i e n t s s h o u ld b e a d vi s e d t o s t o r e bup re n o r p h i n e-c o n t ai n i n g m e d i c a t io n s sa f e ly a n d o u t of sig h t a n d re a c h of ch il d re n .
Destroy any unused medication appropriately [s e e Pati e nt C ouns e ling ( 17 ) ] .
tablets debossed tablets debossed
RECENT MAJOR CHANGES
Warnings and Precautions Neonatal Opioid Withdrawal Syndrome (5.5) 11/2016 Adrenal Insufficiency (5.6) 11/2016
GERIATRIC USE
8.5 Geriatric Use Clinical studies of Buprenorphine Sublingual Tablets, buprenorphine and naloxone sublingual film, or buprenorphine and naloxone sublingual tablet 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.
DOSAGE FORMS AND STRENGTHS
3 Buprenorphine Sublingual Tablets are supplied as an uncoated oval orange tablet in two dosage strengths: buprenorphine 2 mg, and buprenorphine 8 mg Sublingual tablet: 2 mg buprenorphine and 8 mg buprenorphine.
(3)
MECHANISM OF ACTION
12.1 Mechanism of Action Buprenorphine Sublingual Tablets contain buprenorphine.
Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor.
INDICATIONS AND USAGE
1 Buprenorphine Sublingual Tablets are indicated for the treatment of opioid dependence and is preferred for induction.
Buprenorphine Sublingual Tablets should be used as part of a complete treatment plan to include counseling and psychosocial support.
U nd e r t h e D r u g A dd i ct i on T re a t m e n t A c t ( DA T A) c o d i f i e d at 21 U.
S .
C.
823 ( g ) , p re s cr i p t ion u se of t h is p r o du c t in t h e tre a t me n t of o p ioid d e p e nd e n c e is li m i te d t o ph ysi c i a n s w h o m e e t c ert ain qu al i f yi n g re q u i reme n t s, a n d w h o h ave n o t i f i e d t h e S ecret a r y of H e al t h a n d H u m an S er vi ce s ( HH S ) of t h e ir i n te n t t o p re s cr i b e t h is p r o du c t f or t h e tre a t me n t of o p ioid d e p e nd e n c e a n d h a ve b ee n assig n e d a u n i qu e i d e n t i f i c a t ion nu m b e r t h at m u st b e i n c l ud e d on e v er y pr e s cr i p t io n.
Buprenorphine Sublingual Tablets are indicated for the treatment of opioid dependence and is preferred for induction.
Prescription use of this product is limited under the Drug Addiction Treatment Act.
(1)
PEDIATRIC USE
8.4 Pediatric Use The safety and effectiveness of Buprenorphine Sublingual Tablets has not been established in pediatric patients.
PREGNANCY
8.1 Pregnancy Pregnancy Category C.
R i sk S u mm ary There are no adequate and well-controlled studies of Buprenorphine Sublingual Tablets or buprenorphine in pregnant women.
Limited published data on use of buprenorphine, the active ingredient in Buprenorphine Sublingual Tablets, in pregnancy, have not shown an increased risk of major malformations.
All pregnancies, regardless of drug exposure, have a background risk of 2% to 4% for major birth defects, and 15% to 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 Sublingual Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Clinical Considerations Dis e as e- asso c iat e d ma t e rnal and e mbr y o – f e tal 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.
F e tal/n e onatal ad ve rse r e a c tions Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with Buprenorphine Sublingual Tablets.
Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight.
Signs of neonatal withdrawal usually occur in the first days after birth.
The duration and severity of neonatal opioid withdrawal syndrome may vary.
Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly [ s e e W arnings and Pr e c autions ( 5.5 ) ].
L abor or D e li ve ry 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.
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.
An i m al Data 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/m2basis), 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/m2basis) 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/m2basis).
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/m2basis), 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/m2basis) 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/m2basis) 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 was approximately 0.3 times the recommended human daily sublingual dose of 16 mg on a mg/m2basis).
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).
NUSRING MOTHERS
8.3 Nursing Mothers Risk Summary 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 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 and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.
C lini c al C onsid e ratio n s Advise the nursing mother taking buprenorphine 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 to 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.
F e m al e s a n d M al e s of R e p r o du ct ive P o te n t ial Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential.
It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2)].
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Buprenorphine can be abused in a similar manner to other opioids.
Significant respiratory depression and death have occurred in association with buprenorphine, particularly when taken by the intravenous (IV) route in combination with benzodiazepines or other CNS depressants (including alcohol).
(5.2) Consider dose reduction of CNS depressants, Buprenorphine Sublingual Tablets, or both in situations of concomitant prescription.
(5.3) Store Buprenorphine Sublingual Tablets 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 (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) Chronic administration produces opioid-type physical dependence.
Abrupt discontinuation or rapid dose taper may result in opioid withdrawal syndrome.
(5.7) Monitor liver function tests prior to initiation and during treatment and evaluate suspected hepatic events.
(5.8) Do not administer Buprenorphine Sublingual Tablets to patients with known hypersensitivity to buprenorphine.
(5.9) Buprenorphine Sublingual Tablets may precipitate opioid withdrawal signs and symptoms in individuals physically dependent on full opioid agonists if administered sublingually or parenterally before the agonist effects of other opioids have subsided.
(5.10) Buprenorphine Sublingual Tablets are NOT appropriate as an analgesic.
There have been reported deaths of opioid naïve individuals who received a 2 mg sublingual dose of buprenorphine.
(5.11) Buprenorphine Sublingual Tablets should be used with caution in patients with moderate to severe hepatic impairment and a dose adjustment is recommended for patients with severe hepatic impairment (5.12).
Caution patients about the risk of driving or operating hazardous machinery.
(5.13) 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.
(5.1) 5.1 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 [s e e Drug Abuse and D e p e nd e n c e ( 9.2 ) ] .
5.2 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 postmarketing 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 Sublingual Tablets [ s e e Drug I nt e ra c tions ( 7.3 ) ] .
In t h e c ase of ov er d os e , t h e p r i m a r y m a n ag e m en t s h o u l d b e t h e re-e s t a b lis h m e n t of a d e qu a t e v e n t ila t ion w i t h mec h a n i c al assis t a n c e of re s p i r a t io n , if re qu i re d .
Naloxo n e m ay b e of val u e f or t h e m a n ag e m e n t of bup re n o r p h i n e ov er d os e .
Hig h e r t h an n o r m al d os e s a n d re p e a te d a d m i n is tr a t i o n m ay b e n e c e ssa r y.
Buprenorphine Sublingual Tablets 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).
5.3 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 Sublingual Tablets, or both in situations of concomitant prescription [s e e Drug I n t e ra c tions ( 7.3 ) ] .
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 [s e e Pati e nt C ouns e ling ( 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 [s e e Use in Sp e c ific Populations ( 8.1 ) ].
Advise pregnant women receiving opioid addiction treatment with Buprenorphine Sublingual Tablets of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [s e e U s e in Sp ec ific 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 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 [s e e Drug Abuse and D e p e nd e n c e ( 9.3 ) ] .
5.8 Hepatitis, Hepatic Events Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine in clinical trials and through postmarketing 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 is 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 Sublingual Tablets 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 Allergic Reactions Cases of hypersensitivity to buprenorphine products have been reported both in clinical trials and in the postmarketing experience.
Cases of bronchospasm, angioneutrotic edema, and anaphylactic shock have been reported.
The most common signs and symptoms include rashes, hives, and pruritus.
A history of hypersensitivity to buprenorphine is a contraindication to the use of Buprenorphine Sublingual Tablets.
5.10 Precipitation of Opioid Withdrawal Signs and Symptoms Because of the partial agonist properties of buprenorphine, Buprenorphine Sublingual Tablets may precipitate opioid withdrawal signs and symptoms in individuals physically dependent on full opioid agonists if administered sublingually or parenterally before the agonist effects of other opioids have subsided.
5.11 Use 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.
Buprenorphine Sublingual Tablets are not appropriate as an analgesic.
5.12 Use in Patients w ith Impaired Hepatic Function In a pharmacokinetic study, buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment.
For patients with severe hepatic impairment, a dose adjustment is recommended, and patients with moderate or severe hepatic impairment should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine [see Dosage and Administration (2.5) and Use in Specific Populations (8.6)].
5.13 Impairment of Ability to Drive or Operate Machinery Buprenorphine Sublingual Tablets 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 therapy does not adversely affect his or her ability to engage in such activities.
5.14 Orthostatic Hypotension Like other opioids, Buprenorphine Sublingual Tablets 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.
5.18 General Precautions Buprenorphine Sublingual Tablets 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.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide) S a f e Use B e f o r e i n i t ia t i n g tre a t me n t w i t h B u p re n o r ph i n e Sub l i n g u al T a b l et s, e x p lain t h e p o i n t s lis te d b e low t o c a re giv er s a n d p a t i e n t s.
I n s tr u c t p a t i e n t s t o re ad t h e M e d i c a t ion G u i de e a c h t i m e Bup re n o r ph i n e Sub l i n g u a l T a b l et s are d is p e n s e d b ec a u se n e w i n f o r m a t ion m ay b e availa b l e .
Patients should be warned that it is extremely dangerous to self-administer non-prescribed benzodiazepines or other CNS depressants (including alcohol) while taking Buprenorphine Sublingual Tablets.
Patients prescribed benzodiazepines or other CNS depressants should be cautioned to use them only as directed by their physicians [s e e W arnings a nd Pr ec autions ( 5.2 ) , Drug I nt e r a c tions ( 7.3 ) ] .
Patients should be advised that Buprenorphine Sublingual Tablets contain an opioid that can be a target for people who abuse prescription medications or street drugs.
Patients should be cautioned to keep their tablets in a safe place, and to protect them from theft.
Patients should be instructed to keep Buprenorphine Sublingual Tablets 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.
Patients should be advised that if a child is exposed to Buprenorphine Sublingual Tablets, medical attention should be sought immediately.
Inform patients that Buprenorphine Sublingual Tablets 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 physicians if they are taking, or plan to take serotonergic medications [s e e Drug I nt e ra c t i ons 7.4 ].
Inform patients that Buprenorphine Sublingual Tablets 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 [s e e W arnings a nd Pr ec autions ( 5.6 ) ].
Patients should be advised never to give Buprenorphine Sublingual Tablets to anyone else, even if he or she has the same signs and symptoms.
It may cause harm or death.
Patients should be advised that selling or giving away this medication is against the law.
Patients should be cautioned that Buprenorphine Sublingual Tablets may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving or operating hazardous 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 [s ee W arnings and Pr e c autions ( 5.13 ) ] .
Patients should be advised not to change the dosage of Buprenorphine Sublingual Tablets without consulting their physicians.
Patients should be advised to take Buprenorphine Sublingual Tablets once a day.
Patients should be informed that Buprenorphine Sublingual Tablets can cause drug dependence and that withdrawal signs and symptoms may occur when the medication is discontinued.
Patients seeking to discontinue treatment with buprenorphine for opioid dependence should be advised to work closely with their physicians on a tapering schedule and should be apprised of the potential to relapse to illicit drug use associated with discontinuation of opioid agonist/partial agonist medication-assisted treatment.
Patients should be cautioned that, like other opioids, Buprenorphine Sublingual Tablets may produce orthostatic hypotension in ambulatory individuals [s e e W arnings and Pr ec autions ( 5.12 ) ] .
Patients should inform their physicians if any other prescription medications, over-the-counter medications, or herbal preparations are prescribed or currently being used [ s e e Drug I nt e ra c tions ( 7.1 , 7.2 and 7.3 ) ] .
Advise women that if they are pregnant while being treated with Buprenorphine Sublingual Tablets, the baby may have signs of withdrawal at birth and that withdrawal is treatable [s ee W arnings and Pr e c autions ( 5.5 ) , Sp ec ific Popula t ions ( 8.1 ) ].
Patients should be warned that buprenorphine passes into breast milk.
Breast feeding is therefore not advised in mothers treated with buprenorphine products.
[s e e Sp ec ific Populations ( 8.3 ) ] .
Patients should inform their family members that, in the event of emergency, the treating physician or emergency room staff should be informed that the patient is physically dependent on an opioid and that the patient is being treated with Buprenorphine Sublingual Tablets.
Refer to the Medication Guide for additional information regarding the counseling information.
Dis p osal of U nu s e d B u pre n o r ph i n e Su b li n g u al T a b l et s Unused Buprenorphine Sublingual Tablets should be disposed of as soon as they are no longer needed.
Flush unused tablets down the toilet.
Manufactured by: Actavis Elizabeth LLC Elizabeth, NJ 07207 USA Distributed by: Actavis Pharma, Inc.
Parsippany, NJ 07054 USA 40-9095 Revised – November 2016
DOSAGE AND ADMINISTRATION
2 Buprenorphine Sublingual Tablets are administered sublingually as a single daily dose.
Buprenorphine Sublingual Tablets contain no naloxone HCl and is preferred for use only during induction.
Following induction, Buprenorphine and Naloxone Sublingual Film or Buprenorphine and Naloxone Sublingual Tablet is preferred due to the presence of naloxone when clinical use includes unsupervised administration.
The use of Buprenorphine Sublingual Tablets for unsupervised administration should be limited to those patients who cannot tolerate Buprenorphine and Naloxone Sublingual Film or Buprenorphine and Naloxone Sublingual Tablet; for example, those patients who have been shown to be hypersensitive to naloxone.
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.
Administer Buprenorphine Sublingual Tablets sublingually as a single daily dose.
(2) To avoid precipitating withdrawal, induction with Buprenorphine Sublingual Tablets should be undertaken when objective and clear signs of withdrawal are evident.
(2.1).
Buprenorphine and naloxone sublingual film CIII or buprenorphine and naloxone sublingual tablet CIII is generally initiated after two days of Buprenorphine Sublingual Tablets titration.
2.1 Induction Prior to induction, consideration should be given to the type of opioid dependence (i.e., long- or short-acting opioid), the time since last opioid use, and the degree or level of opioid dependence.
To avoid precipitating withdrawal, induction with Buprenorphine Sublingual Tablets should be undertaken when objective and clear signs of withdrawal are evident.
It is recommended that an adequate treatment dose, titrated to clinical effectiveness, should be achieved as rapidly as possible.
In a one-month study, patients received 8 mg of Buprenorphine Sublingual Tablets on Day 1 and 16 mg Buprenorphine Sublingual Tablets on Day 2.
From Day 3 onward, patients received either buprenorphine and naloxone sublingual tablet or Buprenorphine Sublingual Tablets at the same buprenorphine dose as Day 2 based on their assigned treatment.
Induction in the studies of buprenorphine solution was accomplished over 3 to 4 days, depending on the target dose.
In some studies, gradual induction over several days led to a high rate of drop-out of buprenorphine patients during the induction period.
Pati e n ts taki n g h e roin o r ot h e r s h ort – a c ti n g opi o ids: At treatment initiation, the dose of Buprenorphine Sublingual Tablets should be administered at least 4 hours after the patient last used opioids or preferably when moderate objective signs of opioid withdrawal appear.
Pati e n ts on m e t h ad o n e or ot h e r lo n g – a c ti n g opio i ds: There is little controlled experience with the transfer of methadone-maintained patients to buprenorphine.
Available evidence suggests that withdrawal signs and symptoms are possible during induction onto buprenorphine.
Withdrawal appears more likely in patients maintained on higher doses of methadone (greater than 30 mg) and when the first buprenorphine dose is administered shortly after the last methadone dose.
Buprenorphine Sublingual Tablets dosing should be initiated preferably when moderate objective signs of opioid withdrawal appear.
2.2 Maintenance Buprenorphine and naloxone is preferred for maintenance treatment.
Where buprenorphine is used in maintenance in patients who cannot tolerate the presence of naloxone, the dosage of buprenorphine should be progressively adjusted in increments / decrements of 2 mg or 4 mg buprenorphine to a level that holds the patient in treatment and suppresses opioid withdrawal signs and symptoms.
The maintenance dose is generally in the range of 4 mg to 24 mg buprenorphine per day depending on the individual patient.
Doses higher than this have not been demonstrated to provide any clinical advantage.
2.3 Method of Administration Buprenorphine Sublingual Tablets should be placed under the tongue until it is dissolved.
For doses requiring the use of more than two tablets, patients are advised to either place all the tablets at once or alternatively (if they cannot fit in more than two tablets comfortably), place two tablets at a time under the tongue.
Either way, the patients should continue to hold the tablets under the tongue until they dissolve; swallowing the tablets reduces the bioavailability of the drug.
To ensure consistency in bioavailability, patients should follow the same manner of dosing with continued use of the product.
P r o pe r a d m i n is tr a t ion t ec hn i qu e s h o u ld b e d em o n s t r a te d t o t h e p a t i en t .
2.4 Clinical Supervision Treatment should be initiated with supervised administration, progressing to unsupervised administration as the patient’s clinical stability permits.
The use of buprenorphine for unsupervised administration should be limited to those patients who cannot tolerate buprenorphine and naloxone, for example those patients with known hypersensitivity to naloxone.
Buprenorphine and naloxone and buprenorphine are both subject to diversion and abuse.
When determining the size of 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 of the patient 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.
2.5 Patients w ith Hepatic Impairment Severe hepatic impairment: Consider reducing the starting and titration incremental dose by half compared to patients with normal liver function, and monitor for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine.
Moderate hepatic impairment: Although no dose adjustment is necessary for patients with moderate hepatic impairment, Buprenorphine Sublingual Tablets should be used with caution in these patients and prescribers should monitor patients for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine.
Mild hepatic impairment: No clinically significant differences in pharmacokinetic parameters were observed in subjects with mild hepatic impairment.
No dose adjustment is needed in patients with mild hepatic impairment [see Warnings and Precautions (5.11)].
2.6 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.
2.7 Stopping Treatment The decision to discontinue therapy with buprenorphine and naloxone or buprenorphine after a period of maintenance should be made as part of a comprehensive treatment plan.
Both gradual and abrupt discontinuation of buprenorphine has been used, but the data are insufficient to determine the best method of dose taper at the end of treatment.