Included as part of the PRECAUTIONS section.
Risk Of Serious Harm Or Death With Intravenous
Intravenous injection presents significant risk of
serious harm or death as SUBLOCADE forms a solid mass upon contact with body
fluids. Occlusion, local tissue damage, and thrombo-embolic events, including
life threatening pulmonary emboli, could result if administered intravenously [see
SUBLOCADE Risk Evaluation and Mitigation Strategy (REMS) Program, and Drug Abuse And Dependence]. Do not
administer intravenously or intramuscularly.
SUBLOCADE Risk Evaluation And Mitigation Strategy (REMS)
SUBLOCADE is available only through a restricted program
called the SUBLOCADE REMS Program because of the risk of serious harm or death
that could result from intravenous self-administration. The goal of the REMS is
to mitigate serious harm or death that could result from intravenous
selfadministration by ensuring that healthcare settings and pharmacies are
certified and only dispense SUBLOCADE directly to a healthcare provider for
administration by a healthcare provider.
Notable requirements of the SUBLOCADE REMS Program
include the following:
- Healthcare Settings and Pharmacies that order and
dispense SUBLOCADE must be certified in the SUBLOCADE REMS Program.
- Certified Healthcare Settings and Pharmacies must
establish processes and procedures to verify SUBLOCADE is provided directly to
a healthcare provider for administration by a healthcare provider, and the drug
is not dispensed to the patient.
- Certified Healthcare Settings and Pharmacies must not
distribute, transfer, loan, or sell SUBLOCADE.
Further information is available at www.SublocadeREMS.com
or call 1-866-258-3905.
Addiction, Abuse, And Misuse
SUBLOCADE contains buprenorphine, a Schedule III
controlled substance that can be abused in a manner similar to other opioids.
Buprenorphine is sought by people with opioid use disorder and is subject to
criminal diversion. Monitor all patients for progression of opioid use disorder
and addictive behaviors [see Drug Abuse And Dependence].
Risk Of Life-Threatening Respiratory And Central Nervous
System (CNS) Depression
Buprenorphine has been associated with life-threatening
respiratory depression and death. Many, but not all, postmarketing 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 SUBLOCADE [see Risks From Concomitant Use of Benzodiazepines Or Other CNS Depressants With
INTERACTIONS, PATIENT INFORMATION].
Use SUBLOCADE with caution in patients with compromised
respiratory function (e.g., chronic obstructive pulmonary disease, cor
pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing
Due to its extended-release characteristics, if SUBLOCADE
is discontinued as a result of compromised respiratory function, monitor
patients for ongoing buprenorphine effects for several months.
Opioids can cause sleep-related breathing disorders
including central sleep apnea (CSA) and sleeprelated hypoxemia. Opioid use
increases the risk of CSA in a dose-dependent fashion. In patients who present
with CSA, consider decreasing the opioid dosage using best practices for opioid
taper [see DOSAGE AND ADMINISTRATION].
Managing Risks From Concomitant Use Of Benzodiazepines Or
Other CNS Depressants With Buprenorphine
Concomitant use of buprenorphine and benzodiazepines or
other CNS depressants increases the risk of adverse reactions including
overdose, respiratory depression, 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
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 with buprenorphine. 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 patientÃ¢â¬™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].
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].
Advise pregnant women receiving opioid addiction
treatment with SUBLOCADE of the risk of neonatal opioid withdrawal syndrome and
ensure that appropriate treatment will be available [see Use In Specific Populations].
This risk should 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 of
management of opioid addiction throughout pregnancy.
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
the opioid to allow adrenal function to recover and continue corticosteroid
treatment until adrenal function recovers. Other opioids may be tried as some
cases reported use of a different opioid without recurrence of adrenal insufficiency.
The information available does not identify any particular opioids as being
more likely to be associated with adrenal insufficiency.
Risk Of Opioid Withdrawal With Abrupt Discontinuation Of SUBLOCADE
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.
The withdrawal syndrome is milder than that seen with full agonists and may be delayed
in onset [see Drug Abuse And Dependence].
Withdrawal signs and symptoms were not observed in the
month following discontinuation of SUBLOCADE. Considering the long half-life,
any withdrawal signs and symptoms that may occur would be expected to be
delayed [see CLINICAL PHARMACOLOGY]. Model simulations indicate that
steady- state buprenorphine plasma concentrations decreased slowly over time
following the last injection and remained at therapeutic levels for 2 to 5
months on average, depending on the dosage administered (100 or 300 mg,
Patients who elect to discontinue treatment with
SUBLOCADE should be monitored for withdrawal signs and symptoms. Consider
transmucosal buprenorphine if needed to treat withdrawal after discontinuing SUBLOCADE.
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 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. In one subject in the
SUBLOCADE clinical program, surgical removal was followed by improvement in
Liver function tests, prior to initiation of treatment,
are recommended to establish a baseline. Monthly monitoring of liver function
during treatment, particularly with 300 mg maintenance dose, is also recommended.
An etiological evaluation is recommended when a hepatic adverse event is
Cases of hypersensitivity to buprenorphine-containing
products have been reported both in clinical trials and in the postmarketing
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 is a
contraindication to the use of SUBLOCADE [see CONTRAINDICATIONS].
Precipitation Of Opioid Withdrawal In Patients Dependent On
Full Agonist Opioids
Because of the partial opioid agonist properties of
buprenorphine, buprenorphine may precipitate opioid withdrawal signs and
symptoms in persons who are currently physically dependent on full opioid agonists
such as heroin, morphine, or methadone before the effects of the full opioid
agonist have subsided. Verify that patients have tolerated and are dose
adjusted on transmucosal buprenorphine before subcutaneously injecting
Risks Associated With Treatment Of Emergent Acute Pain
While on SUBLOCADE, situations may arise where patients
need acute pain management, or may require anesthesia. Treat patients receiving
SUBLOCADE with a non-opioid analgesic whenever possible. Patients requiring
opioid therapy for analgesia may be treated with a high-affinity full opioid
analgesic under the supervision of a physician, with particular attention to
respiratory function. Higher doses may be required for analgesic effect.
Therefore, a higher potential for toxicity exists with opioid administration.
If opioid therapy is required as part of anesthesia, patients should be
continuously monitored in an anesthesia care setting by persons not involved in
the conduct of the surgical or diagnostic procedure. The opioid therapy should
be provided by individuals specifically trained in the use of anesthetic drugs
and the management of the respiratory effects of potent opioids, specifically
the establishment and maintenance of a patent airway and assisted ventilation.
Advise patients of the importance of instructing their
family members, in the event of emergency, to inform the treating healthcare
provider or emergency room staff that the patient is physically dependent on an
opioid and that the patient is being treated with SUBLOCADE [see PATIENT INFORMATION].
The above guidance should also be considered for any
patient who has been treated with SUBLOCADE within the last 6 months.
Use In Opioid NaÃÂ¯ve Patients
There have been reported deaths of opioid naÃÂ¯ve
individuals who received a 2 mg dose of buprenorphine as a sublingual tablet.
SUBLOCADE is not appropriate for use in opioid naÃÂ¯ve patients.
Use In Patients With Impaired Hepatic Function
In a pharmacokinetic study with transmucosal
buprenorphine, 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. The effect of hepatic
impairment on the pharmacokinetics of SUBLOCADE has not been studied.
Because of the long-acting nature of the product,
adjustments to dosages of SUBLOCADE are not rapidly reflected in plasma
buprenorphine levels. Because buprenorphine levels cannot be rapidly decreased,
patients with pre-existing moderate to severe hepatic impairment are not
candidates for treatment with SUBLOCADE.
Patients who develop moderate to severe hepatic
impairment while being treated with SUBLOCADE should be monitored for several
months for signs and symptoms of toxicity or overdose caused by increased
levels of buprenorphine [see Use In Specific Populations, CLINICAL
Use In Patients At Risk For Arrhythmia
Buprenorphine has been observed to prolong the QTc
interval in some patients participating in clinical trials. Consider these
observations in clinical decisions when prescribing buprenorphine to patients
with hypokalemia, hypomagnesemia, or clinically unstable cardiac disease,
including unstable atrial fibrillation, symptomatic bradycardia, unstable
congestive heart failure, or active myocardial ischemia.ÃÂ Periodic
electrocardiographic (ECG) monitoring is recommended in these patients. Avoid
the use of buprenorphine in patients with a history of Long QT Syndrome or an
immediate family member with this condition or those taking Class IA
antiarrhythmic medications (e.g., quinidine, procainamide, disopyramide) or
Class III antiarrhythmic medications (e.g., sotalol, amiodarone, dofetilide),
or other medications that prolong the QT interval [see CLINICAL PHARMACOLOGY].
Impairment Of Ability To Drive Or Operate Machinery
SUBLOCADE 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 the first few days following
treatment and dose adjustment. Buprenorphine plasma levels accumulate during
the first two months and are maintained with the 100 mg maintenance dose;
further accumulation occurs with the 300 mg maintenance dose, which achieves
steady-state after the fourth monthly injection. Caution patients about driving
or operating hazardous machinery until they are reasonably certain that SUBLOCADE
does not adversely affect their ability to engage in such activities.
Buprenorphine may produce orthostatic hypotension in
Elevation Of Cerebrospinal Fluid Pressure
Buprenorphine may elevate cerebrospinal fluid pressure
and should be used with caution in patients with head injury, intracranial
lesions, and other circumstances when cerebrospinal pressure may be increased.
Buprenorphine can produce miosis and changes in the level of consciousness that
may interfere with patient evaluation.
Elevation Of Intracholedochal Pressure
Buprenorphine has been shown to increase intracholedochal
pressure, as do other opioids, and thus should be administered with caution to
patients with dysfunction of the biliary tract.
Effects In Acute Abdominal Conditions
Buprenorphine may obscure the diagnosis or clinical
course of patients with acute abdominal conditions.
Unintentional Pediatric Exposure
Buprenorphine can cause severe, possibly fatal,
respiratory depression in children who are accidentally exposed to it.
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Medication Guide).
SUBLOCADE Risk Evaluation And Mitigation Strategy (REMS)
Advise patients that because of the risk of serious harm
or death due to intravenous self-administration, SUBLOCADE is available only through
a restricted program called the SUBLOCADE REMS Program. Healthcare settings and
pharmacies are certified and only dispense SUBLOCADE directly to a healthcare provider
for administration by healthcare providers [see WARNINGS AND PRECAUTIONS].
Interaction With Benzodiazepines And Other CNS
Inform patients and caregivers that potentially fatal
additive effects may occur if SUBLOCADE is used with benzodiazepines or other
CNS depressants, including alcohol. Counsel patients that such medications
should not be used concomitantly unless supervised by a healthcare provider [see
WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].
Inform patients that SUBLOCADE 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].
Inform patients that SUBLOCADE 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].
Inform patients that anaphylaxis has been reported with
buprenorphine. Advise patients how to recognize such a reaction and when to
seek medical attention [see WARNINGS AND PRECAUTIONS].
Driving Or Operating Heavy Machinery
Caution patients that SUBLOCADE may impair the mental or
physical abilities required for the performance of potentially dangerous tasks
such as driving or operating hazardous machinery. Instruct patients not to
drive or operate hazardous machinery until they are reasonably certain that
SUBLOCADE does not adversely affect their ability to engage in such activities [see
WARNINGS AND PRECAUTIONS].
Dependence And Withdrawal
Inform patients that SUBLOCADE can cause drug dependence
and that withdrawal signs and symptoms may occur when the medication is
discontinued [see WARNINGS AND PRECAUTIONS].
Inform patients that, like other opioids, SUBLOCADE may
produce orthostatic hypotension in ambulatory individuals [see WARNINGS AND
Long Duration Of Action
Inform patients that they may have detectable levels of
buprenorphine for a prolonged period of time after treatment with SUBLOCADE.
Considerations of drug-drug interactions, buprenorphine effects, and analgesia
may continue to be relevant for several months after the last injection [see CLINICAL
Instruct patients to inform their healthcare providers of
any other prescription medications, over thecounter medications, or herbal
preparations that are prescribed or currently being used [see DRUG
Neonatal Opioid Withdrawal Syndrome
Advise women that if they are pregnant while being
treated with SUBLOCADE, the baby may have signs of withdrawal at birth and that
withdrawal is treatable [see WARNINGS AND PRECAUTIONS, Use In Specific
Advise women of childbearing potential who become
pregnant or are planning to become pregnant to consult their healthcare
provider regarding the possible effects of using SUBLOCADE during pregnancy [see
Use In Specific Populations].
Warn patients that buprenorphine passes into breast milk.
Advise the nursing mother taking buprenorphine to monitor the infant for
increased drowsiness and breathing difficulties [see Use In Specific
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, CLINICAL PHARMACOLOGY].
Patients should be advised to instruct their family
members to, in the event of emergency, inform the treating healthcare provider
or emergency room staff that the patient is physically dependent on an opioid
and that the patient is being treated with SUBLOCADE [see WARNINGS AND
Tell your patients to seek emergency attention if they
have signs or symptoms of respiratory or CNS depression or overdose [see WARNINGS
Tell your patients not to tamper with or try to remove
their depot [see DOSAGE AND ADMINISTRATION].
Impairment Of Fertility
Long-term studies in animals performed
to evaluate carcinogenic potential of SUBLOCADE have not been conducted.
However, the carcinogenic potential of the active drug substance in SUBLOCADE, buprenorphine,
has been evaluated in Sprague-Dawley rats and CD-1 mice.
In the carcinogenicity study
conducted in Sprague-Dawley rats, buprenorphine was administered in the diet at
doses of 0.6, 5.5, and 56 mg/kg/day (approximately 0.5, 5, and 50 times the
recommended human monthly SC dose of 300 mg of buprenorphine) for 27 months. A
statistically significant doserelated increase in Leydig cell tumors occurred.
In an 86 week study in CD-1 mice, buprenorphine was not carcinogenic at dietary
doses up to 100 mg/kg/day (approximately 45 times the recommended human monthly
SC dose of 300 mg of buprenorphine).
NMP, an excipient in SUBLOCADE,
produced an increase in hepatocellular adenomas and carcinomas in male and
female mice at 6 and 8 times the maximum daily dose (MDD) of NMP via SUBLOCADE.
The clinical significance of these findings is unclear. No tumors were noted at
1 and 1.3 times the MDD. In 2-year inhalation and dietary studies in rats, NMP
did not result in evidence of carcinogenicity.
No evidence of mutagenic
potential for subcutaneous SUBLOCADE was found in in vivo subcutaneous micronucleus
test using ratsÃ¢â¬™ marrow.
Mutagenic potential for
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 (S. 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 (5 mg/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
In a fertility study in rats,
female mating, fertility, and fecundity indices were unaffected by the SC administration
of SUBLOCADE up to 900 mg/kg buprenorphine (approximately 38 times the maximum recommended
human dose [MRHD] of 300 mg on an AUC basis). However, higher mean postimplantation
loss was observed with SUBLOCADE at 900 mg/kg buprenorphine and at an
equivalent level of ATRIGEL® alone, which correlated with higher mean number of
resorptions and reduced mean number of viable fetuses/litter size. Mean gravid
uterine weight and mean final body weight were lower with SUBLOCADE at 900
mg/kg buprenorphine and an equivalent level of ATRIGEL® alone, and correlated
with higher mean number of resorptions and lower fetal body weights. The NOAEL
for female fertility was 900 mg/kg and the NOAEL for female-mediated
developmental parameters was 600 mg/kg (approximately 25 times the MRHD on an
Male fertility and reproduction
indices were lower as evidenced by abnormal sperm parameters (low motility, low
mean number of sperm, and higher percentage of abnormal sperm) with SUBLOCADE
at 600 mg/kg and with an equivalent level of ATRIGEL®. The NOAEL for male
fertility parameters, including sperm analysis, and male-mediated developmental
parameters was 300 mg/kg (approximately 32 times the MRHD on an AUC basis).
Adverse effects on testes and
male fertility were noted in published study in which rats were treated for 10
weeks with daily oral doses of NMP, an excipient in SUBLOCADE at greater than
11.6 times the MDD and resulted in male-mediated adverse effects on offspring
(decreased pup weight and survival) at daily doses 3.5 times the MDD of NMP
delivered by SUBLOCADE. No adverse effects were noted at oral doses equivalent
to the dose of NMP delivered by SUBLOCADE.
Use In Specific Populations
The data on use of
buprenorphine, the active ingredient in SUBLOCADE, 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 Human
Observational studies have
reported 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 Human Data].
In published animal
reproduction studies with NMP, an excipient in SUBLOCADE, preimplantation
losses, delayed ossification, reduced fetal weight, developmental delays and
reduced cognitive function were reported at doses equivalent to the doses of
NMP via SUBLOCADE. Decreased pup survival at 2 times the dose of NMP and
malformation and postimplantation losses were reported at 3 times the dose of
NMP via SUBLOCADE. In animal reproduction studies with SUBLOCADE, SUBLOCADE
administered subcutaneously to pregnant rats and rabbits during the period of
organogenesis at a buprenorphine dose equivalent to 38 and 15 times,
respectively, the maximum recommended human dose (MRHD) of 300 mg caused
embryolethality, which appeared to be attributable primarily to the SUBLOCADE
vehicle. In addition, reduced fetal body weights, increased visceral
malformations and skeletal malformations were observed in rats and rabbits at a
buprenorphine dose equivalent to 38 and 15 times, respectively, the MRHD. These
effects were also observed with the SUBLOCADE vehicle alone, but the skeletal
and visceral malformations in rat appear at least partially attributable to
buprenorphine [see Animal 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 is 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
to 4% and 15 to 20%, respectively. SUBLOCADE should be used during pregnancy
only if the potential benefit justifies the potential risk to the fetus.
Disease-Associated Maternal And
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.
Neonatal opioid withdrawal
syndrome may occur in newborn infants of mothers who are receiving treatment
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].
Labor Or Delivery
Opioid-dependent women on
buprenorphine maintenance therapy may require additional analgesia during
labor. 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.
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. Pregnancy in an
opioid dependent woman poses challenges to treating physicians and potential
hazards for the fetus including control of illicit drug, nicotine and alcohol
use, infections, premature birth, abortion, low birth weight, toxaemia, third trimester
bleeding, malpresentation, puerperal morbidity, fetal distress, meconium
aspiration, narcotic withdrawal, postnatal growth deficiency, microcephaly,
(neuro-) developmental disorders and increased neonatal mortality.
A multicenter, double-blind,
double-dummy, flexible-dose study in 175 pregnant women [Maternal Opioid
Treatment: Human Experimental Research (MOTHER)] was conducted to study
outcomes in neonates born to mothers using methadone or buprenorphine,
including the number of neonates requiring treatment for NOWS, the Peak NOWS
score, the total amount of morphine needed to treat NOWS, the length of
hospital stay for neonates, and neonatal head circumference. The authors found that
18% of pregnant women in the methadone group and 33% in the buprenorphine group
discontinued treatment over the course of the pregnancy. They reported no
significant difference in the incidence of NOWS, but in the prenatally
buprenorphine-exposed condition, the duration of treatment for NOWS was
shorter, duration of hospital stays were shorter and the amount of morphine
required was significantly less; however, methodological concerns limit the
conclusions that may be made.
Preimplantation losses, delayed ossification and reduced
fetal body weights were reported in published studies following treatment of
pregnant rats during organogenesis with NMP, an excipient in SUBLOCADE, via inhalation at approximately equivalent doses
of NMP delivered by SUBLOCADE. Fetal malformations and resorptions have also
been reported following oral administration of 3 times the MDD of NMP delivered
by SUBLOCADE at the MDD based on a body surface area comparison.
Post-implantation loss and
increased cardiovascular and skull malformations were demonstrated in pregnant
rabbits administered oral NMP, an excipient in SUBLOCADE, at doses 3.2 times
the human MDD of NMP via SUBLOCADE in the absence of maternal toxicity. No
adverse effects were reported at an oral dose equivalent to the MDD via
SUBLOCADE based on a body surface area comparison.
Decreased pup survival was
noted following oral treatment of pregnant rats prior to and during gestation
and lactation with NMP, an excipient in SUBLOCADE at doses 1.8 times the MDD. Developmental
delays and impaired cognitive function were reported in pups born to pregnant
rats treated with NMP via inhalation during gestation at doses equivalent to
the MDD of NMP via SUBLOCADE based on a body surface area comparison.
In an embryofetal development
study in rats, SUBLOCADE administered subcutaneously to pregnant animals before
mating and again on GD 7 during the period of organogenesis resulted in
increased postimplantation loss, which correlated with higher mean number of
resorptions and decreased number of viable fetuses per litter, and decreased
mean fetal body weights at 900 mg/kg (approximately 38 times the maximum
recommended human dose [MRHD] of 300 mg of SUBLOCADE on an AUC basis); however,
similar effects were observed with an equivalent level of ATRIGEL® delivery
system alone, indicating they may be attributable to the vehicle. Dose-related
increases in incidences of skeletal malformations of the head and visceral malformations
were observed with SUBLOCADE with significant changes at 900 mg/kg
(approximately 38 times the MRHD on an AUC basis). Although similar effects
were observed with equivalent levels of ATRIGEL® delivery system, the incidence
of skeletal malformations, primarily skull malformations, was higher in the
SUBLOCADE groups suggesting that buprenorphine contributed to the increased
incidence. Based on these results, the NOAEL for developmental toxicity was 300
mg/kg (approximately 15 times the MRHD on an AUC basis).
In an embryofetal development
study in rabbits, administration of a single subcutaneous injection of SUBLOCADE
to pregnant animals on Gestation Day 7 during the period of organogenesis
resulted an increased litter incidence of skeletal malformations at 155 mg/kg
(approximately 7 times the MRHD on an AUC basis), which appear to be
buprenorphine-related adverse effects. There was also an increased litter
incidence of external malformations, visceral, and skeletal malformations and
variations at 390 mg/kg SUBLOCADE (approximately 15 times the MRHD on an AUC
basis); however, similar effects were observed with an equivalent level of the
ATRIGEL® delivery system, indicating they may be attributable to the vehicle.
In addition, increased post-implantation loss, which correlated with increased
mean number of resorptions and decreased mean number of viable fetuses, and
decreased fetal body weights were observed at 390 mg/kg (approximately 15 times
the MRHD on an AUC basis); however, similar findings were also observed with an
equivalent level of the ATRIGEL® delivery system alone. Based on these results,
the NOAEL for developmental toxicity for SUBLOCADE was 78 mg/kg (approximately
3 times the MRHD on an AUC basis).
In a pre- and postnatal
development study in rats, SUBLOCADE was administered subcutaneously to pregnant
animals once during implantation (on Gestation Day 7) and once during weaning
(on Lactation Day 7). There were no adverse effects on offspring survival,
sexual maturation, behavioral assessment, or reproductive performance at up to
300 mg/kg (approximately 10 times the MRHD on an mg/m² basis).
Based on two studies in 13
lactating women maintained on buprenorphine treatment, buprenorphine and its
metabolite norbuprenorphine are present in low levels in human milk and infant
urine. Available data have not shown adverse reactions in breastfed infants.
Caution should be exercised when SUBLOCADE is administered to a nursing woman.
The developmental and health benefits of breastfeeding should be considered
along with the motherÃ¢â¬™s clinical need for SUBLOCADE and any potential adverse
effects on the breastfed child from the drug or from the underlying maternal condition.
Advise breastfeeding women
taking buprenorphine products to monitor the infant for increased drowsiness
and breathing difficulties.
Data were consistent from two
studies (N=13) of breastfeeding infants whose mothers were maintained on
sublingual doses of buprenorphine ranging from 2.4 to 24 mg/day, showing that
the infants were exposed to less than 1% of the maternal daily dose. In a study
of six lactating women who were taking a median sublingual buprenorphine dose
of 0.29 mg/kg/day 5 to 8 days after delivery, breast milk provided a median
infant dose of 0.42 mcg/kg/day of buprenorphine and 0.33 mcg/kg/day of
norbuprenorphine, equal to 0.2% and 0.12%, respectively, of the maternal
weight-adjusted dose (relative dose/kg (%) of norbuprenorphine was calculated
from the assumption that buprenorphine and norbuprenorphine are equipotent).
Data from a study of seven
lactating women who were taking a median sublingual buprenorphine dose of 7
mg/day an average of 1.12 months after delivery indicated that the mean milk
concentrations (Cavg) of buprenorphine and norbuprenorphine were 3.65 mcg/L and
1.94 mcg/L respectively. Based on the study data, and assuming milk consumption
of 150 mL/kg/day, an exclusively breastfed infant would receive an estimated
mean absolute infant dose (AID) of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day
of norbuprenorphine, or a mean relative infant dose (RID) of 0.38% and 0.18%,
respectively, of the maternal weight-adjusted dose.
Females And Males Of Reproductive
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
Male fertility may be reduced
based on animal data demonstrating adverse effects of SUBLOCADE on sperm
parameters [see Nonclinical Toxicology].
The safety and effectiveness of
SUBLOCADE have not been established in pediatric patients.
Clinical studies of SUBLOCADE
did not include sufficient numbers of subjects aged 65 and over to determine
whether they responded differently than younger subjects. Other reported
clinical experience with buprenorphine has not identified differences in
responses between geriatric 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 SUBLOCADE 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.
The effect of hepatic
impairment on the pharmacokinetics of SUBLOCADE has not been studied.
The effect of hepatic
impairment on the pharmacokinetics of sublingual buprenorphine has been evaluated
in a pharmacokinetic study. While no clinically significant changes have been
observed in subjects with mild hepatic impairment, the plasma levels have been
shown to be higher and half-life values have been shown to be longer for
buprenorphine in subjects with moderate and severe hepatic impairment.
Because of the long-acting
nature of the product, adjustments to dosages of SUBLOCADE are not rapidly reflected
in plasma buprenorphine levels. Because buprenorphine levels cannot be rapidly
adjusted, patients with pre-existing moderate to severe hepatic impairment are
not candidates for treatment with SUBLOCADE.
Patients who develop moderate
to severe hepatic impairment while being treated with SUBLOCADE should be
monitored for signs and symptoms of toxicity or overdose caused by increased
levels of buprenorphine. If signs and symptoms of toxicity or overdose occur
within 2 weeks of SUBLOCADE administration, removal of the depot may be
required [see DOSAGE AND ADMINISTRATION, WARNINGS AND
PRECAUTIONS, CLINICAL PHARMACOLOGY].
Clinical studies of SUBLOCADE
did not include subjects with renal impairment. No differences in buprenorphine
pharmacokinetics were observed between 9 dialysis-dependent and 6 normal
patients following IV administration of 0.3 mg buprenorphine.