Included as part of the "PRECAUTIONS" Section
Serious Complications From Insertion And Removal Of PROBUPHINE
Rare but serious complications including nerve damage and migration resulting in embolism and
death may result from improper insertion of drug implants inserted in the upper arm. Additional
complications may include local migration, protrusion, and expulsion.
Insert PROBUPHINE in accordance with the instructions. [see INDICATIONS, DOSAGE AND ADMINISTRATION]. It is essential to insert PROBUPHINE subdermally so that each
implant is palpable after insertion. It is also essential to confirm proper placement by palpation
immediately after insertion. If PROBUPHINE is inserted too deeply (intramuscular or in the
fascia), neural or vascular injury may occur.
Incomplete insertions or infections may lead to protrusion or expulsion. [see DOSAGE AND ADMINISTRATION]. Accidental exposures to PROBUPHINE can result from protrusion or
expulsion of the implants. [see Unintentional Pediatric Exposure].
Improper insertion may lead to complicated removal if the implant is inserted too deeply, is not
palpable, or has migrated. Deep insertions may lead to difficulty localizing the implant; additional
surgical procedures may be required in order to remove the implant [see DOSAGE AND ADMINISTRATION]. Injury to deeper neural or vascular structures in the arm may occur when
removing deeply inserted implants.
All Healthcare Providers must successfully complete a live training program on the insertion and
removal procedures and become certified in the PROBUPHINE REMS program, prior to
performing insertions or prescribing PROBUPHINE implants. There are additional requirements
and prerequisites that must be met to become certified to insert PROBUPHINE implants. Only
Healthcare Providers who have performed a surgical procedure in the last 3 months and demonstrate
competency in the PROBUPHINE procedures at the live training can become certified to perform
insertions. Patients must be monitored to ensure that PROBUPHINE is removed by a healthcare
provider certified to insert PROBUPHINE implants. [see PROBUPHINE REMS Program].
PROBUPHINE REMS Program
PROBUPHINE is available only through a restricted program under a REMS, called the
PROBUPHINE REMS Program, because of the risk of complications of migration, protrusion and
expulsion, and nerve damage associated with the insertion and removal of PROBUPHINE [see Serious Complications From Insertion And Removal Of PROBUPHINE].
Notable requirements of the PROBUPHINE REMS Program include the following:
- Healthcare Providers who Prescribe PROBUPHINE must be certified with the program
by enrolling and completing live training
- Healthcare Providers who Insert PROBUPHINE must
- meet the prerequisite requirements [see DOSAGE AND ADMINISTRATION and Serious Complications From Insertion And Removal Of PROBUPHINE]
- be certified with the program by enrolling and completing live training, including
demonstrating competency in PROBUPHINE procedures
- Patients must be monitored to ensure that PROBUPHINE is removed by a healthcare
provider certified to insert PROBUPHINE implants
- PROBUPHINE will only be distributed to certified prescribers through a restricted
Further information is available at www.PROBUPHINEREMS.com or 1-844-859-6341.
Addiction, Abuse, And Misuse
PROBUPHINE 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 disorders and is
subject to criminal diversion. Consider these risks and the patient’s stability in treatment for opioid
dependence when determining whether PROBUPHINE is appropriate for the patient. Monitor all
patients receiving PROBUPHINE for conditions indicative of diversion or progression of opioid
dependence and addictive behaviors.
Risk Of Respiratory And Central Nervous System (CNS) Depression
Buprenorphine, has been associated with life-threatening respiratory depression and death. Many,
but not all, post-marketing reports regarding coma and death involved misuse by self-injection or
were associated with the concomitant use of buprenorphine and benzodiazepines or other CNS
depressants, including alcohol.
Warn patients of the potential danger of self-administration of benzodiazepines or other CNS
depressants while under treatment with PROBUPHINE [see Managing Risks From Concomitant Use Of Benzodiazepines Or Other CNS Depressants With Buprenorphine , DRUG INTERACTIONS, PATIENT INFORMATION].
Use PROBUPHINE 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).
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 and death. Medication-assisted treatment of opioid use
disorder, however, should not be categorically denied to patients taking these drugs. Prohibiting or
creating barriers to treatment can pose an even greater risk of morbidity and mortality due to the
opioid use disorder alone.
As a routine part of orientation to buprenorphine treatment, educate patients about the risks of
concomitant use of benzodiazepines, sedatives, opioid analgesics, and alcohol.
Develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants
at initiation of buprenorphine treatment, or if it emerges as a concern during treatment. Adjustments
to induction procedures and additional monitoring may be required. There is no evidence to support
dose limitations or arbitrary caps of buprenorphine as a strategy to address benzodiazepines use in
buprenorphine-treated patients. However, if a patient is sedated at the time of buprenorphine dosing,
delay or omit the buprenorphine dose if appropriate.
Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant
use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others,
gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or
decreasing to the lowest effective dose may be appropriate.
For patients in buprenorphine treatment, benzodiazepines are not the treatment of choice for anxiety
or insomnia. Before co-prescribing benzodiazepines, ensure that patients are appropriately diagnosed
and consider alternative medications and non-pharmacologic treatments to address anxiety or
insomnia. Ensure that other healthcare providers prescribing benzodiazepines or other CNS
depressants are aware of the patient’s buprenorphine treatment and coordinate care to minimize the
risks associated with concomitant use.
In addition, take measures to confirm that patients are taking their medications as prescribed and are
not diverting or supplementing with illicit drugs. Toxicology screening should test for prescribed
and illicit benzodiazepines [see DRUG INTERACTIONS].
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 PROBUPHINE of the risk of
neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use In Specific Populations]. 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.
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
Unintentional Pediatric Exposure
Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are
accidentally exposed to it. Instruct patients to keep the expelled implant(s) away from
others, especially children.
Risk Of Opioid Withdrawal With Abrupt Discontinuation
Of PROBUPHINE Treatment
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 milder than that seen with full
agonists, and may be delayed in onset [see Drug Abuse And Dependence]. If
PROBUPHINE implants are not to be immediately replaced upon removal, maintain patients on
their previous dosage of sublingual buprenorphine until PROBUPHINE treatment is resumed [see DOSAGE AND ADMINISTRATION]. Patients who elect to discontinue PROBUPHINE treatment
should be monitored for withdrawal with consideration given to use of a tapering dose of
Risk Of Hepatitis, Hepatic Events
Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving
sublingual buprenorphine for the treatment of opioid dependence, both in clinical trials and through
post-marketing adverse event reports.
The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic
transaminases to case reports of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and
hepatic encephalopathy. In many cases, the presence of pre-existing liver enzyme abnormalities,
infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic
drugs, and ongoing injection drug abuse 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. Liver function tests are recommended prior to initiation of treatment 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. Monitor
patients with declining hepatic function for side effects resulting from increased exposure to
buprenorphine. Patients may require removal of PROBUPHINE implants.
Allergic reactions to buprenorphine and/or EVA are possible. Cases of hypersensitivity to
sublingual buprenorphine have been reported both in clinical trials and in the post-marketing
experience. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been
reported. The most common signs and symptoms include rashes, hives, and pruritus. A history of
hypersensitivity to buprenorphine or EVA is a contraindication to PROBUPHINE use.
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 are clinically stable on transmucosal buprenorphine and
not dependent on full agonists before inserting PROBUPHINE.
Risks Associated With Treatment Of Emergent Acute Pain
While on PROBUPHINE, situations may arise where patients need acute pain management, or
may require anesthesia. Treat patients receiving PROBUPHINE with a non-opioid analgesic
whenever possible. Patients requiring opioid therapy for analgesia may be treated with a highaffinity
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 must 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.
Use In Patients With Impaired Hepatic Function
In a pharmacokinetic study with sublingual 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 implanted buprenorphine, such as PROBUPHINE, has not been studied.
Because PROBUPHINE cannot be titrated, patients with pre-existing moderate to severe hepatic
impairment are not candidates for treatment with PROBUPHINE. Patients who develop moderate
to severe hepatic impairment while being treated with PROBUPHINE should be monitored for
signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine, and
patients may require removal of PROBUPHINE implants [see Use In Specific Populations, CLINICAL PHARMACOLOGY].
Impairment Of Ability To Drive And OperateMachinery
PROBUPHINE may impair the mental or physical abilities required for the performance of
potentially dangerous tasks such as driving a car or operating machinery, especially for the first
24- 48 hours following initial insertion. Caution patients about driving or operating hazardous
machinery until they are reasonably certain that PROBUPHINE does not adversely affect their
ability to engage in such activities.
PROBUPHINE may produce orthostatic hypotension in ambulatory patients.
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 where 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
Infection At Implant Site
Infection may occur at the site of the insertion or removal. Excessive palpation shortly after
insertion of the implants may increase the chance of infection. Improper removal carries risk of
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Instruct patients to read the Medication Guide each time PROBUPHINE is implanted because new
information may be available.
Risks Relating To The Insertion And Removal Procedure [see WARNINGS AND PRECAUTIONS],
Accidental Overdose, Misuse And Abuse If An Implant Comes Out Or Protrudes From The Skin
[see WARNINGS AND PRECAUTIONS].
- Inform patients that there are risks associated with the insertion and removal of
- Migration with potential for embolism or nerve damage
- Expulsion or protrusion
- Injury to nerves or blood vessels
- Infection at the insertion or removal site
- Removal complications
- Implants may be difficult to locate if they were inserted too deeply, or if
patients manipulate them, or have gained significant weight since insertion.
- Special procedures, tests, or a referral to a specialist may be needed to
remove the implants if they are difficult to locate.
- Inform patients that there is a risk to others of accidental overdose, misuse, and abuse if
the implant comes out of the arm.
- Inform patients that appropriate care of their incision is important to reduce the risk of
complications associated with the insertion of PROBUPHINE.
- Inform patients to call a Healthcare Provider immediately if they experience any of the
- The implant protrudes or is expelled.
- Bleeding or symptoms of infection, such as excessive or worsening itching,
pain, irritation or redness, or swelling at the insertion site.
- Symptoms suggesting the implant has migrated, such as numbness or weakness,
or shortness of breath.
- Symptoms of numbness or weakness in the arm after insertion or removal procedure.
- Inform patients that if the PROBUPHINE implants protrude or are expelled, they should:
- Wash their hands if they have touched the PROBUPHINEimplants.
- Cover the area where the implants were inserted with a cleanbandage.
- Not allow others to touch or use the PROBUPHINE implants, since this could be very
- Put the implants in a plastic bag and take the implants to a Healthcare Provider
- Keep the implants away from others, especially children.
- Protect the implants from theft until they can take them to their doctor.
- Inform patients that improper removal by a non-Healthcare Provider carries the risk of
implant-site infection and premature removal may induce opioid withdrawal symptoms.
- Inform patients that there are risks associated with minor surgical procedures, such as:
- Itching, pain, irritation or redness, swelling, bleeding, or bruising at the insertion
or removal site.
- Scarring around the incision site.
Interaction With Benzodiazepines And Other CNS Depressants
Inform patients and caregivers that potentially fatal additive effects may occur if PROBUPHINE is
used with benzodiazepines or other CNS depressants, including alcohol, and not to use these
concomitantly unless supervised by a health care provider. [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].
Inform patients that PROBUPHINE 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 [see DRUG INTERACTIONS].
Inform patients that PROBUPHINE could cause adrenal insufficiency, a potentially lifethreatening
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 ingredients contained in PROBUPHINE.
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 PROBUPHINE may impair the mental or physical abilities required for
the performance of potentially dangerous tasks such as driving or operating hazardous
Instruct patients not to drive or operate hazardous machinery until they are reasonably certain
that PROBUPHINE therapy does not adversely affect their ability to engage in such activities
[see WARNINGS AND PRECAUTIONS].
Dependence And Withdrawal
Inform patients that PROBUPHINE 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, PROBUPHINE may produce orthostatic hypotension
in ambulatory individuals [see WARNINGS AND PRECAUTIONS].
Instruct patients to inform their healthcare providers of any other prescription medications,
over- the-counter medications, or herbal preparations that are prescribed or currently being used
[see DRUG INTERACTIONS].
Neonatal Opioid Withdrawal Syndrome
Advise women that if they are pregnant while being treated with PROBUPHINE, the baby
may have signs of withdrawal at birth and that withdrawal is treatable [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].
Embryo Fetal Toxicity
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 PROBUPHINE 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 Populations].
Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether
these effects on fertility are reversible [see ADVERSE REACTIONS].
Advise patients to instruct their family members to, in the event of emergency, inform the treating
physician or emergency room staff that the patient is physically dependent on an opioid and that the
patient is being treated with PROBUPHINE [see WARNINGS AND PRECAUTIONS].
PROBUPHINE REMS Program
PROBUPHINE is available only through a restricted program called the PROBUPHINE REMS
Program [see WARNINGS AND PRECAUTIONS]. Inform the patient of the following notable
- PROBUPHINE is not available in retail pharmacies.
- PROBUPHINE must be inserted or removed only in the facility of a certified prescriber.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenicity studies testing PROBUPHINE have not been completed.
Carcinogenicity studies of buprenorphine were conducted in Sprague-Dawley rats and CD-1 mice.
Buprenorphine was administered in the diet for 27 months to rats at equivalent doses of 0.6, 5.5, and
56 mg/kg body weight/day (approximately 2, 13, and 99 times the steady state exposure from
PROBUPHINE on an AUC basis). A statistically significant dose-related increase in Leydig cell
tumors occurred. In an 86-week study in CD-1 mice, buprenorphine was not carcinogenic when
administered in the diet at equivalent doses up to 100 mg/kg body weight/day (approximately 53
times the steady state exposure from PROBUPHINE on an AUC basis).
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 Chinese hamster ovary, 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-Tweats (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 test using testicular cells from mice.
Impairment Of Fertility
Dietary administration of buprenorphine in the rat at dose levels of 500 ppm or greater (equivalent
to approximately 47 mg/kg/day or greater; estimated exposure approximately 22 times the highest
human daily dose from PROBUPHINE on an AUC 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 approximately 18 times the recommended human
daily dose from PROBUPHINE on an AUC basis) had no adverse effect on fertility.
Reproduction studies of buprenorphine in rats demonstrated no evidence of impaired fertility at
daily oral doses up to 80 mg/kg/day (estimated exposure approximately 100 times the human daily
SL dose of 8 mg on a mg/m2 basis) or up to 5 mg/kg/day IM or SC (estimated exposure was
approximately 12 times the human daily SL dose of 8 mg on a mg/m2 basis for IM dosing and 18
times the steady state exposure from PROBUPHINE on an AUC basis for SC dosing).
Use In Specific Populations
The data on use of buprenorphine, the active ingredient in PROBUPHINE implant, 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 Data].
Observational studies have reported on congenital malformations among buprenorphine-exposed
pregnancies, but were also not designed appropriately to assess the risk of congenital
malformations specifically due to buprenorphine exposure [see Human Data]. Adequate and wellcontrolled
studies have not been conducted with PROBUPHINE or buprenorphine in pregnant
women. Neonatal opioid withdrawal syndrome has been reported in the infants of women treated
with buprenorphine sublingual tablets during pregnancy [see Clinical Considerations].
Reproductive and developmental studies in rats and rabbits identified adverse events at clinically
relevant and higher doses. Embryo Fetal death was observed in both rats and rabbits administered
buprenorphine during the period of organogenesis at doses approximately 6 and 0.3-times,
respectively, the human sublingual dose of 16 mg/day of buprenorphine. Pre- and post-natal
development studies in rats demonstrated increased neonatal deaths at 0.3-times and above and
dystocia at approximately 3-times the human sublingual dose of 16 mg/day of buprenorphine. No
clear teratogenic effects were seen when buprenorphine was administered during organogenesis
with a range of doses equivalent to or greater than the human sublingual dose of 16 mg/day of
buprenorphine. However, increases in skeletal abnormalities were noted in rats administered
buprenorphine daily during organogenesis at a dose approximately 0.6- and approximately equal to
the human sublingual dose of 16 mg/day of buprenorphine, respectively. In a few studies, some
events such as acephalous and omphalocele were also observed but these findings were not clearly
treatment-related [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
are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse
outcomes. In the U.S. general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Disease-associated Maternal and Embryo-fetal Risk
Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low
birth weight, preterm birth, and fetal death. In addition, untreated opioid addiction often results in
continued or relapsing illicit opioid use.
Dose Adjustment during Pregnancy and the Postpartum Period
Dose adjustments of buprenorphine may be required during pregnancy, even if the patient was
maintained on a stable dose prior to pregnancy. Withdrawal signs and symptoms should be
monitored closely and the dose adjusted as necessary.
Fetal/neonatal Adverse Reactions
Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving
treatment with PROBUPHINE implant.
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.
Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine
during pregnancy. Limited data from trials, observational studies, case series, and case reports on
buprenorphine use in pregnancy do not indicate an increased risk of major malformations
specifically due to buprenorphine. Several factors may complicate the interpretation of
investigations of the children of women who take buprenorphine during pregnancy, including
maternal use of illicit drugs, late presentation for prenatal care, infection, poor compliance, poor
nutrition, and psychosocial circumstances. Interpretation of data is complicated further by the lack
of information on untreated opioid-dependent pregnant women, who would be the most
appropriate group for comparison. Rather, women on another form of opioid medication-assisted
treatment, or women in the general population are generally used as the comparison group.
However, women in these comparison groups may be different from women prescribed
buprenorphine-containing products with respect to maternal factors that may lead to poor
In a multicenter, double-blind, randomized, controlled trial [Maternal Opioid Treatment: Human
Experimental Research (MOTHER)] designed primarily to assess neonatal opioid withdrawal
effects, opioid-dependent pregnant women were randomized to buprenorphine (n=86) or
methadone (n=89) treatment, with enrollment at an average gestational age of 18.7 weeks in both
groups. A total of 28 of the 86 women in the buprenorphine group (33%) and 16 of the 89 women
in the methadone group (18%) discontinued treatment before the end of pregnancy.
Among women who remained in treatment until delivery, there was no difference between
buprenorphine-treated and methadone-treated groups in the number of neonates requiring NOWS
treatment or in the peak severity of NOWS. Buprenorphine-exposed neonates required less
morphine (mean total dose, 1.1 mg vs 10.4 mg), had shorter hospital stays (10.0 days vs 17.5
days), and shorter duration of treatment for NOWS (4.1 days vs 9.9 days) compared to the
methadone-exposed group. There were no differences between groups in other primary outcomes
(neonatal head circumference,) or secondary outcomes (weight and length at birth, preterm birth,
gestational age at delivery, and 1-minute and 5-minute Apgar scores), or in the rates of maternal or
neonatal adverse events. The outcomes among mothers who discontinued treatment before
delivery and may have relapsed to illicit opioid use are not known. Because of the imbalance in
discontinuation rates between the buprenorphine and methadone groups, the study findings are
difficult to interpret.
The exposure margins listed below are based on body surface area comparisons (mg/m2) to the
human sublingual dose of 16 mg buprenorphine via SUBOXONE sublingual tablet.
Effects on embryo-fetal development were studied in Sprague-Dawley rats and Russian white
rabbits following oral (1:1) and intramuscular (IM; 3:2) administration of mixtures of
buprenorphine and naloxone during the period of organogenesis. Following oral administration to
rats, no teratogenic effects were observed at buprenorphine doses up to 250 mg/kg/day (estimated
exposure approximately 150 times the human sublingual dose of 16 mg) in the presence of maternal
toxicity (mortality). Following oral administration to rabbits, no teratogenic effects were observed
at buprenorphine doses up to 40 mg/kg/day (estimated exposure approximately 50 times the human
sublingual dose of 16 mg) in the absence of clear maternal toxicity. No definitive drug-related
teratogenic effects were observed in rats and rabbits at IM doses up to 30 mg/kg/day (estimated
exposure approximately 20 times and 35 times, respectively, the human sublingual does of 16 mg).
Maternal toxicity resulting in mortality was noted in these studies in both rats and rabbits.
Acephalous was observed in one rabbit fetus from the low-dose group and omphalocele was
observed in two rabbit fetuses from the same litter in the mid-dose group; no findings were
observed in fetuses from the high-dose group. Maternal toxicity was seen in the high-dose group but
not at the lower doses where the findings were observed. Following oral administration of
buprenorphine to rats, dose-related post-implantation losses, evidenced by increases in the numbers
of early resorptions with consequent reductions in the numbers of fetuses, were observed at doses of
10 mg/kg/day or greater (estimated exposure approximately 6 times the human sublingual dose of
16 mg). In the rabbit, increased post-implantation losses occurred at an oral dose of 40 mg/kg/day.
Following IM administration in the rat and rabbit, post-implantation losses, as evidenced by
decreases in live fetuses and increases in resorptions, occurred at 30 mg/kg/day.
Buprenorphine was not teratogenic in rats and rabbits after IM or subcutaneous (SC) doses of up to
5 mg/kg/day (estimated exposure was approximately 3 and 6 times, respectively, the human
sublingual dose of 16 mg), after IV doses up to 0.8 mg/kg/day (estimated exposure was
approximately 0.5 times and equal to, respectively, the human sublingual dose of 16 mg), or after
oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 95 times the human
daily sublingual dose of 16 mg) and 25 mg/kg/day in rabbits (estimated exposure was
approximately 30 times the human daily sublingual dose of 16 mg). Significant increases in
skeletal abnormalities (e.g., extra thoracic vertebra or thoracolumbar ribs) were noted in rats after
SC administration of 1 mg/kg/day and up (estimated exposure was approximately 0.6 times the
human sublingual does of 16 mg), but were not observed at oral doses up to 160 mg/kg/day.
Increases in skeletal abnormalities in rabbits after IM administration of 5 mg/kg/day (estimated
exposure was approximately 6 times the human daily sublingual dose of 16 mg) in the absence of
maternal toxicity or oral administration of 1 mg/kg/day or greater (estimated exposure was
approximately equal to the human sublingual dose of 16 mg) were not statistically significant.
In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1
mg/kg/day or greater and post-implantation losses that were statistically significant at IV doses of
0.2 mg/kg/day or greater (estimated exposure approximately 0.3 times the human daily sublingual
dose of 16 mg. No maternal toxicity was noted at doses causing post-implantation loss in this study.
Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine from Gestation Day
14 through Lactation Day 21 at 5 mg/kg/day (approximately 3 times the human sublingual does of
16 mg). Fertility, pre-, and post-natal development studies with buprenorphine in rats indicated
increases in neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 0.5 times
the human daily sublingual dose of 16 mg), after IM doses of 0.5 mg/kg/day and up (approximately
0.3 times the human sublingual dose of 16 mg), and after SC doses of 0.1 mg/kg/day and up
(approximately 0.06 times the human sublingual dose of 16 mg). An apparent lack of milk
production during these studies likely contributed to the decreased pup viability and lactation
indices. Delays in the occurrence of righting reflex and startle response were noted in rat pups at an
oral dose of 80 mg/kg/day (approximately 50 times the human sublingual dose of 16 mg).
Based on two studies in 13 lactating women maintained on sublingual buprenorphine treatment,
buprenorphine and its metabolite norbuprenorphine were present in low levels in human milk
and available data have not shown adverse reactions in breastfed infants. The development and
health benefits of breastfeeding should be considered along with the mother’s clinical need for
buprenorphine treatment 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
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 Potential
Dietary administration of buprenorphine in the rat at dose levels of 500 ppm or greater (equivalent
to approximately 47 mg/kg/day or greater; estimated exposure approximately 22 times the highest
daily exposure from PROBUPHINE on an AUC basis) produced a reduction in fertility
demonstrated by reduced female conception rates [see Nonclinical Toxicology]
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, CLINICAL PHARMACOLOGY].
The safety and effectiveness of PROBUPHINE have not been established in children or adolescents
younger than 16 years of age.
Clinical studies of PROBUPHINE did not include subjects over the age of 65. Other reported
clinical experience with buprenorphine has not identified differences in responses between the
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
PROBUPHINE 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 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
The effect of hepatic impairment on the pharmacokinetics of implanted buprenorphine, such as
PROBUPHINE, has not been studied. Since the drug is extensively metabolized, the plasma levels
can be expected to be higher in patients with moderate and severe hepatic impairment. Because
PROBUPHINE cannot be titrated, patients with pre-existing moderate to severe hepatic impairment
are not candidates for treatment with PROBUPHINE. Monitor patients who develop moderate or
severe hepatic impairment while being treated with PROBUPHINE for signs and symptoms of
toxicity or overdose caused by increased levels of buprenorphine. If signs and symptoms of toxicity
or overdose are observed, removal of PROBUPHINE implants may be required [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].
Clinical studies of PROBUPHINE 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.