SUBOXONE 8-2 mg Tablet

DESCRIPTION

id: f040580e-2e35-4356-9eba-022f285e790a
displayName: DESCRIPTION SECTION
FDA Article Code: 34089-3

Rx only Under the Drug Addiction Treatment Act of 2000 (DATA) codified at 21 U.S.C.
823(g), prescription use of this product in the treatment of opioid dependence
is limited to physicians who meet certain qualifying requirements, and have
notified the Secretary of Health and Human Services (HHS) of their intent to
prescribe this product for the treatment of opioid dependence. DESCRIPTIONSUBOXONE sublingual tablets contain buprenorphine HCl and
naloxone HCl dihydrate at a ratio of 4:1 buprenorphine: naloxone (ratio of free
bases). SUBUTEX sublingual tablets contain buprenorphine HCl. Buprenorphine is a partial agonist at the mu-opioid receptor and an
antagonist at the kappa-opioid receptor. Naloxone is an antagonist at the
mu-opioid receptor. Buprenorphine is a Schedule III narcotic under the Controlled Substances
Act. Buprenorphine hydrochloride is a white powder, weakly acidic with limited
solubility in water (17mg/mL). Chemically, buprenorphine is
17-(cyclopropylmethyl)-α-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-
α-methyl-6,14-ethenomorphinan-7-methanol, hydrochloride [5α, 7α(S)]-. Buprenorphine hydrochloride has the molecular formula C₂₉
H₄₁N0₄ HCl and the molecular
weight is 504.10. Naloxone hydrochloride is a white to slightly off-white powder and is soluble in
water, in dilute acids and in strong alkali. Chemically, naloxone is
17-Allyl-4,5 α -epoxy-3,14-dihydroxymorphinan-6-one hydrochloride. Naloxone
Hydrochloride has the molecular formula C₁₉ H₂₁ N0₄ HCl .2H₂ 0
and the molecular weight is 399.87. SUBOXONE is an uncoated hexagonal orange tablet intended
for sublingual administration. It is available in two dosage strengths, 2mg
buprenorphine with 0.5mg naloxone, and 8mg buprenorphine with 2mg naloxone free
bases. Each tablet also contains lactose, mannitol, cornstarch, povidone K30,
citric acid, sodium citrate, FD and C Yellow No.6 color, magnesium stearate, and
the tablets also contain Acesulfame K sweetener and a lemon / lime flavor. SUBUTEX is an uncoated oval white tablet intended for
sublingual administration. It is available in two dosage strengths, 2mg
buprenorphine and 8mg buprenorphine free base. Each tablet also contains
lactose, mannitol, cornstarch, povidone K30, citric acid, sodium citrate and
magnesium stearate.

CLINICAL PHARMACOLOGY

id: b43bb95b-dba9-4b9b-88c6-142ce2706019
displayName: CLINICAL PHARMACOLOGY SECTION
FDA Article Code: 34090-1

Subjective Effects:Comparisons of buprenorphine with full agonists such as methadone
and hydromorphone suggest that sublingual buprenorphine produces typical opioid
agonist effects which are limited by a ceiling effect. In non-dependent subjects, acute sublingual doses of SUBOXONE tablets
produced opioid agonist effects, which reached a maximum between doses of 8 mg
and 16mg of SUBUTEX. The effects of 16mg SUBOXONE were similar to those produced
by 16mg SUBUTEX (buprenorphine alone). Opioid agonist ceiling effects were also observed in a double-blind, parallel
group, dose ranging comparison of single doses of buprenorphine sublingual
solution (1, 2, 4, 8, 16, or 32 mg), placebo, and a full agonist control at
various doses. The treatments were given in ascending dose order at intervals of
at least one week to 16 opioid-experienced, non-dependent subjects. Both drugs
produced typical opioid agonist effects. For all the measures for which the
drugs produced an effect, buprenorphine produced a dose-related response but, in
each case, there was a dose that produced no further effect. In contrast, the
highest dose of the full agonist control always produced the greatest effects.
Agonist objective rating scores remained elevated for the higher doses of
buprenorphine (8-32 mg) longer than for the lower doses and did not return to
baseline until 48 hours after drug administrations. The onset of effects
appeared more rapidly with buprenorphine than with the full agonist control,
with most doses nearing peak effect after 100 minutes for buprenorphine compared
to 150 minutes for the full agonist control. Physiologic Effects:Buprenorphine in intravenous (2mg, 4mg, 8mg, 12mg and 16 mg) and
sublingual (12mg) doses has been administered to non-dependent subjects to
examine cardiovascular, respiratory and subjective effects at doses comparable
to those used for treatment of opioid dependence. Compared with placebo, there
were no statistically significant differences among any of the treatment
conditions for blood pressure, heart rate, respiratory rate, O₂ saturation or skin temperature across time. Systolic BP was
higher in the 8 mg group than placebo (3 hour AUC values). Minimum and maximum
effects were similar across all treatments. Subjects remained responsive to low
voice and responded to computer prompts. Some subjects showed irritability, but
no other changes were observed. The respiratory effects of sublingual buprenorphine were compared with the
effects of methadone in a double-blind, parallel group, dose ranging comparison
of single doses of buprenorphine sublingual solution (1, 2, 4, 8, 16, or 32 mg)
and oral methadone (15, 30, 45, or 60 mg) in non-dependent, opioid-experienced
volunteers. In this study, hypoventilation not requiring medical intervention
was reported more frequently after buprenorphine doses of 4 mg and higher than
after methadone. Both drugs decreased O₂ saturation to
the same degree. Effect of Naloxone:Physiologic and subjective effects following acute sublingual
administration of SUBOXONE and SUBUTEX tablets were similar at equivalent dose
levels of buprenorphine. Naloxone, in the SUBOXONE formulation, had no
clinically significant effect when administered by the sublingual route,
although blood levels of the drug were measurable. SUBOXONE, when administered
sublingually even to an opioid-dependent population, was recognized as an opioid
agonist, whereas when administered intramuscularly, combinations of
buprenorphine with naloxone produced opioid antagonist actions similar to
naloxone. In methadone-maintained patients and heroin-dependent subjects,
intravenous administration of buprenorphine/naloxone combinations precipitated
opioid withdrawal and was perceived as unpleasant and dysphoric. In
morphine-stabilized subjects, intravenously administered combinations of
buprenorphine with naloxone produced opioid antagonist and withdrawal effects
that were ratio-dependent; the most intense withdrawal effects were produced by
2:1 and 4:1 ratios, less intense by an 8:1 ratio. SUBOXONE tablets contain
buprenorphine with naloxone at a ratio of 4:1. Pharmacokinetics: Absorption:Plasma levels of buprenorphine increased with the sublingual dose
of SUBUTEX and SUBOXONE, and plasma levels of naloxone increased with the
sublingual dose of SUBOXONE (Table 1). There was a wide
inter-patient variability in the sublingual absorption of buprenorphine and
naloxone, but within subjects the variability was low. Both C_max and AUC of buprenorphine increased in a linear fashion with
the increase in dose (in the range of 4 to 16 mg), although the increase was not
directly dose-proportional. Naloxone did not affect the pharmacokinetics of buprenorphine and both
SUBUTEX and SUBOXONE deliver similar plasma concentrations of buprenorphine. The
levels of naloxone were too low to assess dose-proportionality. At the three
naloxone doses of 1 mg, 2 mg, and 4 mg, levels above the limit of quantitation
(0.05 ng/mL) were not detected beyond 2 hours in seven of eight subjects. In one
individual, at the 4mg dose, the last measurable concentration was at 8 hours.
Within each subject (for most of the subjects), across the doses there was a
trend toward an increase in naloxone concentrations with increase in dose. Mean
peak naloxone levels ranged from 0.11 to 0.28ng/mL in the dsose range of 1-4
mg.

CLINICAL STUDIES

id: 1bbad314-d342-4e03-bedc-085f6f750cb7
displayName: CLINICAL STUDIES SECTION
FDA Article Code: 34092-7

Clinical data on the safety and efficacy of SUBOXONE and SUBUTEX
are derived from studies of buprenorphine sublingual tablet formulations, with
and without naloxone, and from studies of sublingual administration of a more
bioavailable ethanolic solution of buprenorphine. SUBOXONE tablets have been studied in 575 patients, SUBUTEX tablets in 1834
patients and buprenorphine sublingual solutions in 2470 patients. A total of
1270 females have received buprenorphine in clinical trials. Dosing
recommendations are based on data from one trial of both tablet formulations and
two trials of the ethanolic solution. All trials used buprenorphine in
conjunction with psychosocial counseling as part of a comprehensive addiction
treatment program. There have been no clinical studies conducted to assess the
efficacy of buprenorphine as the only component of treatment. In a double blind placebo- and active controlled study, 326 heroin-addicted
subjects were randomly assigned to either SUBOXONE 16 mg per day, 16 mg SUBUTEX
per day or placebo tablets. For subjects randomized to either active treatment,
dosing began with one 8 mg tablet of SUBUTEX on Day 1, followed by 16 mg (two 8
mg tablets) of SUBUTEX on Day 2. On Day 3, those randomized to receive SUBOXONE
were switched to the combination tablet. Subjects randomized to placebo received
one placebo tablet on Day 1 and two placebo tablets per day thereafter for four
weeks. Subjects were seen daily in the clinic (Monday through Friday) for dosing
and efficacy assessments. Take-home doses were provided for weekends. Subjects
were instructed to hold the medication under the tongue for approximately 5 to
10 minutes until completely dissolved. Subjects received one hour of individual
counseling per week and a single session of HIV education. The primary study
comparison was to assess the efficacy of SUBUTEX and SUBOXONE individually
against placebo. The percentage of thrice-weekly urine samples that were
negative for non-study opioids was statistically higher for both SUBUTEX and
SUBOXONE, than for placebo. In a double-blind, double-dummy, parallel-group study comparing buprenorphine
ethanolic solution to a full agonist active control, 162 subjects were
randomized to receive the ethanolic sublingual solution of buprenorphine at 8
mg/day (a dose which is roughly comparable to a dose of 12 mg/day of SUBUTEX or
SUBOXONE), or two relatively low doses of active control, one of which was low
enough to serve as an alternative to placebo, during a 3-10 day induction phase,
a 16-week maintenance phase and a 7-week detoxification phase. Buprenorphine was
titrated to maintenance dose by Day 3; active control doses were titrated more
gradually. Maintenance dosing continued through Week 17, and then medications were
tapered by approximately 20-30% per week over Weeks 18-24, with placebo dosing
for the last two weeks. Subjects received individual and/or group counseling
weekly. Based on retention in treatment and the percentage of thrice-weekly urine
samples negative for non-study opioids, buprenorphine was more effective than
the low dose of the control, in keeping heroin addicts in treatment and in
reducing their use of opioids while in treatment. The effectiveness of
buprenorphine, 8 mg per day was similar to that of the moderate active control
dose, but equivalence was not demonstrated. In a dose-controlled, double-blind, parallel-group, 16-week study, 731
subjects were randomized to receive one of four doses of buprenorphine ethanolic
solution. Buprenorphine was titrated to maintenance doses over 1-4 days ( Table 2) and continued for 16 weeks. Subjects received at least
one session of AIDS education and additional counseling ranging from one hour
per month to one hour per week, depending on site.

INDICATIONS & USAGE

id: ea565047-85e2-4870-85df-782b97899ff3
displayName: INDICATIONS & USAGE SECTION
FDA Article Code: 34067-9

SUBOXONE and SUBUTEX are indicated for the treatment of opioid dependence.

CONTRAINDICATIONS

id: 9d95003a-e7a5-4498-8d65-e1edb82a1600
displayName: CONTRAINDICATIONS SECTION
FDA Article Code: 34070-3

SUBOXONE and SUBUTEX should not be administered to patients who have been shown
to be hypersensitive to buprenorphine, and SUBOXONE should not be administered
to patients who have been shown to be hypersensitive to naloxone.

Warnings

id: 47b01d02-3748-4c6a-950f-252554f3945d
displayName: WARNINGS SECTION
FDA Article Code: 34071-1

Respiratory Depression:Significant respiratory depression has been associated with
buprenorphine, particularly by the intravenous route. A number of deaths have
occurred when addicts have intravenously misused buprenorphine, usually with
benzodiazepines concomitantly. Deaths have also been reported in association
with concomitant administration of buprenorphine with other depressants such as
alcohol or other opioids. Patients should be warned of the potential danger of
the self-administration of benzodiazepines or other depressants while under
treatment with SUBUTEX or SUBOXONE. 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 NOT BE EFFECTIVE IN REVERSING ANY
RESPIRATORY DEPRESSION PRODUCED BY BUPRENORPHINE. SUBOXONE and SUBUTEX should be used with caution in patients with compromised
respiratory function (e.g., chronic obstructive pulmonary disease, cor
pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing
respiratory depression). CNS Depression:Patients receiving buprenorphine in the presence of other
narcotic analgesics, general anesthetics, benzodiazepines, phenothiazines, other
tranquilizers, sedative/hypnotics or other CNS depressants (including alcohol)
may exhibit increased CNS depression. When such combined therapy is
contemplated, reduction of the dose of one or both agents should be
considered. Dependence:Buprenorphine is a partial agonist at the mu-opiate receptor and
chronic administration produces dependence of the opioid type, characterized by
withdrawal upon abrupt discontinuation or rapid taper. The withdrawal syndrome
is milder than seen with full agonists, and may be delayed in onset. Hepatitis, hepatic events:Cases of cytolytic hepatitis and hepatitis with jaundice have
been observed in the addict population receiving buprenorphine both in clinical
trials and in post-marketing adverse event reports. The spectrum of
abnormalities ranges from transient asymptomatic elevations in hepatic
transaminases to case reports of hepatic failure, hepatic necrosis, hepatorenal
syndrome, and hepatic encephalopathy. In many cases, the presence of preexisting
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.
The possibility exists that buprenorphine had a causative or contributory role
in the development of the hepatic abnormality in some cases. Measurements of
liver function tests prior to initiation of treatment is recommended to
establish a baseline. Periodic monitoring of liver function tests during
treatment is also recommended. A biological and etiological evaluation is
recommended when a hepatic event is suspected. Depending on the case, the drug
should be carefully discontinued to prevent withdrawal symptoms and a return to
illicit drug use, and strict monitoring of the patient should be
initiated. Allergic Reactions:Cases of acute and chronic hypersensitivity to buprenorphine have
been reported both in clinical trials and in the post-marketing experience. The
most common signs and symptoms include rashes, hives, and pruritus. Cases of
bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. A
history of hypersensitivity to buprenorphine is a contraindication to Subutex or
Suboxone use. A history of hypersensitivity to naloxone is a contraindication to
Suboxone use. Use in Ambulatory Patients:SUBOXONE and SUBUTEX 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 drug induction and dose
adjustment. Patients should be cautioned about operating hazardous machinery,
including automobiles, until they are reasonably certain that buprenorphine
therapy does not adversely affect their ability to engage in such activities.
Like other opioids, SUBOXONE and SUBUTEX may produce orthostatic hypotension in
ambulatory patients. Head Injury and Increased Intracranial Pressure:SUBOXONE and SUBUTEX, like other potent opioids, may elevate
cerebrospinal fluid pressure and should be used with caution in patients with
head injury, intracranial lesions and other circumstances where cerebrospinal
pressure may be increased. SUBOXONE and SUBUTEX can produce miosis and changes
in the level of consciousness that may interfere with patient evaluation. Opioid withdrawal effects:Because it contains naloxone, SUBOXONE is highly likely to
produce marked and intense withdrawal symptoms if misused parenterally by
individuals dependent on opioid agonists such as heroin, morphine, or methadone.
Sublingually, SUBOXONE may cause opioid withdrawal symptoms in such persons if
administered before the agonist effects of the opioid have subsided.

PRECAUTIONS

id: 944b2115-e0f5-42e6-9bec-f747a434c52a
displayName: PRECAUTIONS SECTION
FDA Article Code: 42232-9

General:SUBOXONE and SUBUTEX should be administered with caution in
elderly or debilitated patients and those with severe impairment of hepatic,
pulmonary, or renal function; 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. The effect of hepatic impairment on the pharmacokinetics of buprenorphine and
naloxone is unknown. Since both drugs are extensively metabolized, the plasma
levels will be expected to be higher in patients with moderate and severe
hepatic impairment. However, it is not known whether both drugs are affected to
the same degree. Therefore, dosage should be adjusted and patients should be
watched for symptoms of precipitated opioid withdrawal. 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. As with other mu-opioid receptor agonists, the administration of SUBOXONE or
SUBUTEX may obscure the diagnosis or clinical course of patients with acute
abdominal conditions. Drug Interactions:Buprenorphine is metabolized to norbuprenorphine by cytochrome
CYP 3A4. Because CYP 3A4 inhibitors may increase plasma concentrations of
buprenorphine, patients already on CYP 3A4 inhibitors such as azole antifungals
(e.g. ketoconazole), macrolide antibiotics (e.g. erythromycin), and HIV protease
inhibitors (e.g. ritonavir, indinavir and saquinavir) should have their dose of
SUBUTEX or SUBOXONE adjusted. Based on anecdotal reports, there may be an interaction between buprenorphine
and benzodiazepines. There have been a number of reports in the post-marketing
experience of coma and death associated with the concomitant intravenous misuse
of buprenorphine and benzodiazepines by addicts. In many of these cases,
buprenorphine was misused by self-injection of crushed SUBUTEX tablets. SUBUTEX
and SUBOXONE should be prescribed with caution to patients on benzodiazepines or
other drugs that act on the central nervous system, regardless of whether these
drugs are taken on the advice of a physician or are taken as drugs of abuse.
Patients should be warned of the potential danger of the intravenous
self-administration of benzodiazepines while under treatment with SUBOXONE or
SUBUTEX. Information for Patients: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 narcotics and that the patient is
being treated with SUBOXONE or SUBUTEX. Patients should be cautioned that a serious overdose and death may occur if
benzodiazepines, sedatives, tranquilizers, antidepressants, or alcohol are taken
at the same time as SUBOXONE or SUBUTEX. SUBOXONE and SUBUTEX 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 drug induction and dose adjustment.
Patients should be cautioned about operating hazardous machinery, including
automobiles, until they are reasonably certain that buprenorphine therapy does
not adversely affect their ability to engage in such activities. Like other
opioids, SUBOXONE and SUBUTEX may produce orthostatic hypotension in ambulatory
patients. Patients should consult their physician if other prescription medications are
currently being used or are prescribed for future use. Carcinogenesis, Mutagenesis and Impairment of
Fertility: Carcinogenicity: Carcinogenicity data
on SUBOXONE are not available. Carcinogenicity studies of buprenorphine were
conducted in Sprague-Dawley rats and CD-1 mice. Buprenorphine was administered
in the diet to rats at doses of 0.6, 5.5, and 56 mg/kg/day (estimated exposure
was approximately 0.4, 3 and 35 times the recommended human daily sublingual
dose of 16 mg on a mg/m² basis) for 27 months.
Statistically significant dose-related increases in testicular interstitial
(Leydig’s) cell tumors occurred, according to the trend test adjusted for
survival. Pair-wise comparison of the high dose against control failed to show
statistical significance. In an 86-week study in CD-1 mice, buprenorphine was
not carcinogenic at dietary doses up to 100 mg/kg/day (estimated exposure was
approximately 30 times the recommended human daily sublingual dose of 16 mg on a
mg/m² basis). Mutagenicity: SUBOXONE: The 4:1 combination of buprenorphine and naloxone was
not mutagenic in a bacterial mutation assay (Ames test) using four strains of
S. typhimurium and two strains of E coli. The combination was not clastogenic in an in vitro cytogenetic assay in human lymphocytes, or in an
intravenous micronucleus test in the rat. SUBUTEX: Buprenorphine was studied in a series of tests utilizing
gene, chromosome, and DNA interactions in both prokaryotic and eukaryotic
systems. Results were negative in yeast (Saccharomyces
cerevisiae) for recombinant, gene convertant, or forward mutations;
negative in Bacillus subtilis “rec”assay, negative
for clastogenicity in CHO cells, Chinese hamster bone marrow and spermatogonia
cells, and negative in the mouse lymphoma L5178Y assay. Results were equivocal
in the Ames test: negative in studies in two laboratories, but positive for
frame shift mutation at a high dose (5mg/plate) in a third study. Results were
positive in the Green-Tweets (E. coli) survival test,
positive in a DNA synthesis inhibition (DSI) test with testicular tissue from
mice, for both in vivo and in
vitro incorporation of [³H]thymidine, and positive
in unscheduled DNA synthesis (UDS) test using testicular cells from mice. Impairment of Fertility: SUBOXONE: Dietary administration of SUBOXONE in the rat at dose
levels of 500 ppm or greater (equivalent to approximately 4/mg/kg/day or
greater; estimated exposure was approximately 28 times the recommended human
daily sublingual dose of 16 mg on a mg/m² basis) produced
a reduction in fertility demonstrated by reduced female conception rates. A
dietary dose of 100 ppm (equivalent to approximately 10 mg/kg/day; estimated
exposure was approximately 6 times the recommended human daily sublingual dose
of 16 mg on a mg/m² basis) had no adverse effect on
fertility. SUBUTEX: Reproduction studies of buprenorphine in rats
demonstrated no evidence of impaired fertility at daily oral doses up to
80mg/kg/day (estimated exposure was approximately 50 times the recommended human
daily sublingual dose of 16 mg on a mg/m² basis) or up to
5mg/kg/day im or sc
(estimated exposure was approximately 3 times the recommended human daily
sublingual dose of 16 mg on a mg/m² basis). Pregnancy; Pregnancy Category C: Teratogenic effects:SUBOXONE: Effects on embryo-fetal development were studied in
Sprague-Dawley rats and Russian white rabbits following oral (1:1) and
intramuscular (3:2) administration of mixtures of buprenorphine and naloxone.
Following oral administration to rats and rabbits, no teratogenic effects were
observed at doses up to 250 mg/kg/day and 40 mg/kg/day, respectively (estimated
exposure was approximately 150 times and 50 times, respectively, the recommended
human daily sublingual dose of 16 mg on a mg/m² basis).
No definitive drug-related teratogenic effects were observed in rats and rabbits
at intramuscular doses up to 30 mg/kg/day (estimated exposure was approximately
20 times and 35 times, respectively, the recommended human daily dose of 16 mg
on a mg/m² basis). Acephalus was observed in one rabbit
fetus from the low-dose group and omphacele was observed in two rabbit fetuses
from the same litter in the mid-dose group; no findings were observed in fetuses
from the high-dose group. Following oral administration to the rat, 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 was approximately 6
times the recommended human daily sublingual dose of 16 mg on a mg/m² basis). In the rabbit, increased post-implantation losses
occurred at an oral dose of 40 mg/kg/day. Following intramuscular 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. SUBUTEX: Buprenorphine was not teratogenic in rats or rabbits after im or sc doses up to 5 mg/kg/day
(estimated exposure was approximately 3 and 6 times, respectively, the
recommended human daily sublingual dose of 16 mg on a mg/m² basis), after iv doses up to 0.8
mg/kg/day (estimated exposure was approximately 0.5 times and equal to,
respectively, the recommended human daily sublingual dose of 16 mg on a
mg/m² basis), or after oral doses up to 160 mg/kg/day in
rats (estimated exposure was approximately 95 times the recommended human daily
sublingual dose of 16 mg on a mg/m² basis) and 25
mg/kg/day in rabbits (estimated exposure was approximately 30 times the
recommended human daily sublingual dose of 16 mg on a mg/m² basis). Significant increases in skeletal abnormalities
(e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after
sc administration of 1 mg/kg/day and up (estimated
exposure was approximately 0.6 times the recommended human daily sublingual dose
of 16 mg on a mg/m² basis), but were not observed at oral
doses up to 160 mg/kg/day. Increases in skeletal abnormalities in rabbits after
im administration of 5 mg/kg/day (estimated exposure
was approximately 6 times the recommended human daily sublingual dose of 16 mg
on a mg/m² basis) or oral administration of 1 mg/kg/day
or greater (estimated exposure was approximately equal to the recommended human
daily sublingual dose of 16 mg on a mg/m² basis) were not
statistically significant. In rabbits, buprenorphine produced statistically significant pre-implantation
losses at oral doses of 1 mg/kg/day or greater and post-implantation losses that
were statistically significant at iv doses of 0.2
mg/kg/day or greater (estimated exposure was approximately 0.3 times the
recommended human daily sublingual dose of 16 mg on a mg/m² basis). There are no adequate and well-controlled studies of SUBOXONE or SUBUTEX in
pregnant women. SUBOXONE or SUBUTEX should only be used during pregnancy if the
potential benefit justifies the potential risk to the fetus. Non-teratogenic effects.Dystocia was noted in pregnant rats treated im with buprenorphine 5 mg/kg/day (approximately 3 times
the recommended human daily sublingual dose of 16 mg on a mg/m² basis). Both fertility and peri- and postnatal 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). 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). Neonatal Withdrawal:Neonatal withdrawal has been reported in the infants of women
treated with SUBUTEX during pregnancy. From post-marketing reports, the time to
onset of neonatal withdrawal symptoms ranged from Day 1 to Day 8 of life with
most occurring on Day 1. Adverse events associated with neonatal withdrawal
syndrome included hypertonia, neonatal tremor, neonatal agitation, and
myoclonus. There have been rare reports of convulsions and in one case, apnea
and bradycardia were also reported. Nursing Mothers:An apparent lack of milk production during general reproduction
studies with buprenorphine in rats caused decreased viability and lactation
indices. Use of high doses of sublingual buprenorphine in pregnant women showed
that buprenorphine passes into the mother’s milk. Breast-feeding is therefore
not advised in mothers treated with SUBUTEX or SUBOXONE. Pediatric Use:SUBOXONE and SUBUTEX are not recommended for use in pediatric
patients. The safety and effectiveness of SUBOXONE and SUBUTEX in patients below
the age of 16 have not been established.

DRUG ABUSE AND DEPENDENCE

id: d50a0dc9-21df-464f-8673-4c681967273f
displayName: DRUG ABUSE AND DEPENDENCE SECTION
FDA Article Code: 42227-9

SUBOXONE and SUBUTEX are controlled as Schedule III narcotics
under the Controlled Substances Act. Buprenorphine is a partial agonist at the mu-opioid receptor and chronic
administration produces dependence of the opioid type, characterized by moderate
withdrawal upon abrupt discontinuation or rapid taper. The withdrawal syndrome
is milder than seen with full agonists, and may be delayed in onset (SEE WARNINGS)   Neonatal withdrawal has been reported in the infants of women treated with
SUBUTEX during pregnancy (See PRECAUTIONS)  SUBOXONE contains naloxone and if misused parenterally, is highly likely to
produce marked and intense withdrawal symptoms in subjects dependent on other
opioid agonists.

OVERDOSAGE

id: d7ff0db5-245a-41ac-abf0-4d2f35dbb4f8
displayName: OVERDOSAGE SECTION
FDA Article Code: 34088-5

Manifestations:Manifestations of acute overdose include pinpoint pupils,
sedation, hypotension, respiratory depression and death. Treatment:The respiratory and cardiac status of the patient should be
monitored carefully. In the event of depression of respiratory or cardiac
function, 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, intravenous 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 WlTH MECHANICAL ASSISTANCE OF
RESPIRATION IF REQUIRED. NALOXONE MAY NOT BE EFFECTIVE IN REVERSING ANY
RESPIRATORY DEPRESSION PRODUCED BY BUPRENORPHINE. High doses of naloxone hydrochloride. 10-35 mg/70 kg may be of limited value
in the management of buprenorphine overdose.. Doxapram (a respiratory stimulant)
also has been used.

DOSAGE & ADMINISTRATION

id: d1d7ee6d-5524-425e-a481-ca0a71bd3587
displayName: DOSAGE & ADMINISTRATION SECTION
FDA Article Code: 34068-7

SUBUTEX or SUBOXONE is administered sublingually as a single
daily dose in the range of 12 to 16mg/ day. When taken sublingually, SUBOXONE
and SUBUTEX have similar clinical effects and are interchangeable. There are no
adequate and well-controlled studies using SUBOXONE as initial medication.
SUBUTEX contains no naloxone and is preferred for use during induction.
Following induction, SUBOXONE, due to the presence of naloxone, is preferred
when clinical use includes unsupervised administration. The use of SUBUTEX for
unsupervised administration should be limited to those patients who cannot
tolerate SUBOXONE, for example those patients who have been shown to be
hypersensitive to naloxone. Method of administration:SUBOXONE and SUBUTEX tablets should be placed under the tongue
until they are 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. 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 SUBUTEX should be undertaken when objective and clear
signs of withdrawal are evident. In a one-month study of SUBOXONE tablets induction was conducted with SUBUTEX
tablets. Patients received 8mg of SUBUTEX on day 1 and 16mg SUBUTEX on day 2.
From day 3 onward, patients received SUBOXONE tablets at the same buprenorphine
dose as day 2. Induction in the studies of buprenorphine solution was
accomplished over 3-4 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. Therefore it is recommended
that an adequate maintenance dose, titrated to clinical effectiveness, should be
achieved as rapidly as possible to prevent undue opioid withdrawal
symptoms. Patients taking heroin or other short-acting
opioids:At treatment initiation, the dose of SUBUTEX should be
administered at least 4 hours after the patient last used opioids or preferably
when early signs of opioid withdrawal appear. Patients on methadone or other long-acting
opioids:There is little controlled experience with the transfer of
methadone-maintained patients to buprenorphine. Available evidence suggests that
withdrawal symptoms are possible during induction to buprenorphine treatment.
Withdrawal appears more likely in patients maintained on higher doses of
methadone (>30mg) and when the first buprenorphine dose is administered
shortly after the last methadone dose. Maintenance:SUBOXONE is the preferred medication for maintenance treatment
due to the presence of naloxone in the formulation. Adjusting the dose until the maintenance dose is
achieved:The recommended target dose of SUBOXONE is 16 mg/day. Clinical
studies have shown that 16mg of SUBUTEX or SUBOXONE is a clinically effective
dose compared with placebo and indicate that doses as low as 12 mg may be
effective in some patients. The dosage of SUBOXONE should be progressively
adjusted in increments / decrements of 2mg or 4mg to a level that holds the
patient in treatment and suppresses opioid withdrawal effects. This is likely to
be in the range of 4mg to 24mg per day depending on the individual. Reducing dosage and stopping treatment:The decision to discontinue therapy with SUBOXONE or SUBUTEX
after a period of maintenance or brief stabilization should be made as part of a
comprehensive treatment plan. Both gradual and abrupt discontinuation have been
used, but no controlled trials have been undertaken to determine the best method
of dose taper at the end of treatment.

ADVERSE REACTIONS

id: 79bcafc6-465d-44ed-b0d8-50a2c7d7383a
displayName: ADVERSE REACTIONS SECTION
FDA Article Code: 34084-4

The safety of SUBOXONE has been evaluated in 497 opioid-dependent
subjects. The prospective evaluation of SUBOXONE was supported by clinical
trials using SUBUTEX (buprenorphine tablets without naloxone) and other trials
using buprenorphine sublingual solutions. In total, safety data are 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 SUBOXONE and
SUBUTEX or buprenorphine administered as a sublingual solution.

In a comparative study, adverse event profiles were similar for subjects
treated with 16 mg SUBOXONE or 16mg SUBUTEX. The following adverse events were
reported to occur by at least 5% of patients in a 4-week study (Table 3).  
 
Table 3. Adverse Events ( GE 5%) by Body System and Treatment Group in a
4-week Study
    N(%)    N(%)    N(%)
Body
System / Adverse Event (COSTART Terminology)    SUBOXONE
16mg/day N=107    SUBUTEX
16mg/day N=103    Placebo
N=107
Body as a
Whole    
    
    
Asthenia    7 (6.5%)    5 (4.9%)    7 (6.5%)
Chills    8 (7.5%)    8 (7.8%)    8 (7.5%)
Headache    39 (36.4%)    30(29.1%)    24 (22.4%)
Infection    6 (5.6%)    12(11.7%)    7 (6.5%)
Pain    24 (22.4%)    19(18.4%)    20(18.7%)
Pain Abdomen    12(11.2%)    12(11.7%)    7 (6.5%)
Pain Back    4 (3.7%)    8 (7.8%)    12(11.2%)
Withdrawal Syndrome    27 (25.2%)    19(18.4%)    40 (37.4%)
Cardiovascular System    
    
    
Vasodilation    10(9.3%)    4 (3.9%)    7 (6.5%)
Digestive
System    
    
    
Constipation    13(12.1%)    8 (7.8%)    3 (2.8%)
Diarrhea    4 (3.7%)    5 (4.9%)    16(15.0%)
Nausea    16(15.0%)    14(13.6%)    12(11.2%)
Vomiting    8 (7.5%)    8 (7.8%)    5 (4.7%)
Nervous
System    
    
    
Insomnia    15(14.0%)    22(21.4%)    17(15.9%)
Respiratory System    
    
    
Rhinitis    5 (4.7%)    10(9.7%)    14(13.1%)
Skin And
Appendages    
    
    
Sweating    15(14.0%)    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 4  shows adverse events reported by
at least 5% of subjects in any dose group in the dose-controlled study.

HOW SUPPLIED

id: cf577704-7ba5-4026-8d41-5db32e2dba53
displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5

SUBOXONE is supplied as sublingual tablets.

Hexagonal orange tablets containing 8mg buprenorphine with 2mg naloxone.
Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP
Controlled Room Temperature].

Manufactured by:

Reckitt Benckiser Healthcare (UK) Ltd

Hull, UK, HU8 7DS

Distributed By:

 Bryant Ranch Prepack
 12623 Sherman Way
 North Hollywood, CA 91605
 Voice (877) 885-0882   Fax (877) 277-7552