BUPRENORPHINE AND NALOXONE SUBLINGUAL FILM- buprenorphine and naloxone film

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

BUPRENORPHINE HYDROCHLORIDE (UNII: 56W8MW3EN1) (BUPRENORPHINE - UNII:40D3SCR4GZ), NALOXONE HYDROCHLORIDE DIHYDRATE (UNII: 5Q187997EE) (NALOXONE - UNII:36B82AMQ7N)

Available from:

Alvogen Inc.

Administration route:

SUBLINGUAL

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

Buprenorphine and naloxone sublingual film is indicated for treatment of opioid dependence. Buprenorphine and naloxone sublingual film should be used as part of a complete treatment plan that includes counseling and psychosocial support. Buprenorphine and naloxone sublingual film is contraindicated in patients with a history of hypersensitivity to buprenorphine or naloxone as serious adverse reactions, including anaphylactic shock, have been reported [see Warnings and Precautions (5.9) ] . The data on use of buprenorphine, one of the active ingredients in buprenorphine and naloxone sublingual film, in pregnancy, are limited; however, these data do not indicate an increased risk of major malformations specifically due to buprenorphine exposure. There are limited data from randomized clinical trials in women maintained on buprenorphine that were not designed appropriately to assess the risk of major malformations [see Data] . Observational studies have reported on congenital malformations among buprenorphine-exposed pregnancies, but were also not designed appropriately to assess the risk of congenital malformations specifically due to buprenorphine exposure [see Data] . The extremely limited data on sublingual naloxone exposure in pregnancy are not sufficient to evaluate a drug-associated risk. Reproductive and developmental studies in rats and rabbits identified adverse events at clinically relevant and higher doses. Embryofetal death was observed in both rats and rabbits administered buprenorphine during the period of organogenesis at doses approximately 6‐times and 0.3‐times, respectively, the human sublingual dose of 16 mg per day of buprenorphine. Pre‐and postnatal development studies in rats demonstrated increased neonatal deaths at 0.3‐times and above and dystocia at approximately 3‐times the human sublingual dose of 16 mg per 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 per day of buprenorphine. However, increases in skeletal abnormalities were noted in rats and rabbits administered buprenorphine daily during organogenesis at doses approximately 0.6‐times and approximately equal to the human sublingual dose of 16 mg per day of buprenorphine, respectively. In a few studies, some events such as acephalus and omphalocele were also observed but these findings were not clearly treatment‐related [see Data] . Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 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. Dosage adjustments of buprenorphine may be required during pregnancy, even if the patient was maintained on a stable dose prior to pregnancy. Withdrawal signs and symptoms should be monitored closely and the dose adjusted as necessary. Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with buprenorphine and naloxone sublingual film. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal usually occur in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.5)] . 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 on malformations from trials, observational studies, case series, and case reports on buprenorphine use in pregnancy do not indicate an increased risk of major malformations specifically due to buprenorphine. Several factors may complicate the interpretation of investigations of the children of women who take buprenorphine during pregnancy, including maternal use of illicit drugs, late presentation for prenatal care, infection, poor compliance, poor nutrition, and psychosocial circumstances. Interpretation of data is complicated further by the lack of information on untreated opioid-dependent pregnant women, who would be the most appropriate group for comparison. Rather, women on another form of opioid medication-assisted treatment, or women in the general population are generally used as the comparison group. However, women in these comparison groups may be different from women prescribed buprenorphine-containing products with respect to maternal factors that may lead to poor pregnancy outcomes. In a multicenter, double-blind, randomized, controlled trial [Maternal Opioid Treatment: Human Experimental Research (MOTHER)] designed primarily to assess neonatal opioid withdrawal effects, opioid-dependent pregnant women were randomized to buprenorphine (n=86) or methadone (n=89) treatment, with enrollment at an average gestational age of 18.7 weeks in both groups. A total of 28 of the 86 women in the buprenorphine group (33%) and 16 of the 89 women in the methadone group (18%) discontinued treatment before the end of pregnancy. Among women who remained in treatment until delivery, there was no difference between buprenorphine-treated and methadone-treated groups in the number of neonates requiring NOWS treatment or in the peak severity of NOWS. Buprenorphine-exposed neonates required less morphine (mean total dose, 1.1 mg vs. 10.4 mg), had shorter hospital stays (10 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 buprenorphine and naloxone sublingual tablets. Effects on embryo‐fetal development were studied in Sprague‐Dawley rats and Russian white rabbits following oral (1:1) and intramuscular (IM) (3:2) administration of mixtures of buprenorphine and naloxone during the period of organogenesis. Following oral administration to rats, no teratogenic effects were observed at buprenorphine doses up to 250 mg/kg per 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 per 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 intramuscular doses up to 30 mg/kg per day (estimated exposure approximately 20 times and 35 times, respectively, the human sublingual dose of 16 mg). Maternal toxicity resulting in mortality was noted in these studies in both rats and rabbits. Acephalus was observed in one rabbit fetus from the low‐dose group and omphalocele was observed in two rabbit fetuses from the same litter in the mid‐dose group; no findings were observed in fetuses from the high‐dose group. Maternal toxicity was seen in the high‐dose group but not at the lower doses where the findings were observed. Following oral administration of buprenorphine to rats, dose‐related post‐implantation losses, evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers of fetuses, were observed at doses of 10 mg/kg per 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 per 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 per day. Buprenorphine was not teratogenic in rats or rabbits after intramuscular or subcutaneous doses up to 5 mg/kg per day (estimated exposure was approximately 3 times and 6 times, respectively, the human sublingual dose of 16 mg), after intravenous doses up to 0.8 mg/kg per 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 per day in rats (estimated exposure was approximately 95 times the human sublingual dose of 16 mg) and 25 mg/kg per day in rabbits (estimated exposure was approximately 30 times the human daily sublingual dose of 16 mg). Significant increases in skeletal abnormalities (e.g., extra thoracic vertebra or thoraco‐lumbar ribs) were noted in rats after subcutaneous administration of 1 mg/kg per day and up (estimated exposure was approximately 0.6 times the human sublingual dose of 16 mg), but were not observed at oral doses up to 160 mg/kg per day. Increases in skeletal abnormalities in rabbits after intramuscular administration of 5 mg/kg per 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 per 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 per day or greater and post‐implantation losses that were statistically significant at intravenous doses of 0.2 mg/kg per 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 per day (approximately 3 times the human sublingual dose of 16 mg). Fertility, pre‐, and post‐natal development studies with buprenorphine in rats indicated increases in neonatal mortality after oral doses of 0.8 mg/kg per day and up (approximately 0.5 times the human daily sublingual dose of 16 mg), after intramuscular doses of 0.5 mg/kg per day and up (approximately 0.3 times the human sublingual dose of 16 mg), and after subcutaneous doses of 0.1 mg/kg per 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 per day (approximately 50 times the human sublingual dose of 16 mg). Based on two studies in 13 lactating women maintained on buprenorphine treatment, buprenorphine and its metabolite norbuprenorphine were present in low levels in human milk and infant urine. Available data have not shown adverse reactions in breastfed infants. There are no data on the combination product buprenorphine and naloxone in breastfeeding, however oral absorption of naloxone is limited. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for buprenorphine and naloxone sublingual film 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 mg per day to 24 mg per 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 per day 5 days to 8 days after delivery, breast milk provided a median infant dose of 0.42 mcg/kg per day of buprenorphine and 0.33 mcg/kg per 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 per 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 per day, an exclusively breastfed infant would receive an estimated mean absolute infant dose (AID) of 0.55 mcg/kg per day of buprenorphine and 0.29 mcg/kg per day of norbuprenorphine, or a mean relative infant dose (RID) of 0.38% and 0.18%, respectively, of the maternal weight‐adjusted dose. Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2) , Clinical Pharmacology (12.2) , Nonclinical Toxicology (13.1)] . The safety and effectiveness of buprenorphine and naloxone sublingual film have not been established in pediatric patients. This product is not appropriate for the treatment of neonatal abstinence syndrome in neonates, because it contains naloxone, an opioid antagonist. Clinical studies of buprenorphine and naloxone sublingual film, buprenorphine and naloxone sublingual tablets, or buprenorphine sublingual tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Due to possible decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in geriatric patients, the decision to prescribe buprenorphine and naloxone sublingual film should be made cautiously in individuals 65 years of age or older and these patients should be monitored for signs and symptoms of toxicity or overdose. The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone has been evaluated in a pharmacokinetic study. Both drugs are extensively metabolized in the liver. 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 both buprenorphine and naloxone in subjects with moderate and severe hepatic impairment. The magnitude of the effects on naloxone are greater than that on buprenorphine in both moderately and severely impaired subjects. The difference in magnitude of the effects on naloxone and buprenorphine are greater in subjects with severe hepatic impairment than in subjects with moderate hepatic impairment, and therefore the clinical impact of these effects is likely to be greater in patients with severe hepatic impairment than in patients with moderate hepatic impairment. Buprenorphine and naloxone products should be avoided in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment [see Warnings and Precautions (5.12) , Clinical Pharmacology (12.3)] . No differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent and 6 normal patients following intravenous administration of 0.3 mg buprenorphine. The effects of renal failure on naloxone pharmacokinetics are unknown. Buprenorphine and naloxone sublingual film contains buprenorphine, a Schedule III controlled substance under the Controlled Substances Act. Buprenorphine, like morphine and other opioids, has the potential for being abused and is subject to criminal diversion. This should be considered when prescribing or dispensing buprenorphine in situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion. Healthcare professionals should contact their state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. Patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be provided with or referred for more intensive and structured treatment. Abuse of buprenorphine poses a risk of overdose and death. This risk is increased with the abuse of buprenorphine and alcohol and other substances, especially benzodiazepines. The healthcare provider may be able to more easily detect misuse or diversion by maintaining records of medication prescribed including date, dose, quantity, frequency of refills, and renewal requests of medication prescribed. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper handling and storage of the medication are appropriate measures that help to limit abuse of opioid drugs. Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by moderate withdrawal signs and symptoms upon abrupt discontinuation or rapid taper. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset [see Warnings and Precautions (5.7) ] . Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy [see Warnings and Precautions (5.5)] .

Product summary:

Buprenorphine and naloxone sublingual film is supplied as an orange rectangular film with white printing in child-resistant polyester/foil laminated pouches: Store at 25°C (77°F), excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Store buprenorphine and naloxone sublingual film securely and dispose of properly [see Patient Counseling Information (17)] . 

Authorization status:

Abbreviated New Drug Application

Patient Information leaflet

Alvogen Inc.
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This Medication Guide has been approved by the U.S. Food and
Drug Administration.
Revised: 03/2023
PL355-05
MEDICATION GUIDE
Buprenorphine and Naloxone
(bue'' pre nor' feen and nal ox' one)
Sublingual Film, CIII
IMPORTANT: Keep buprenorphine and naloxone sublingual film in a secure
place away from children.
Accidental use by a child is a medical emergency and can result in
death. If a child accidentally takes
buprenorphine and naloxone sublingual film, get emergency help or call
911 right away. Tell your
healthcare provider if you are living in a household where there are
small children.
What is the most important information I should know about
buprenorphine and naloxone sublingual
film?
•
Buprenorphine and naloxone sublingual film contains a medicine called
buprenorphine.
Buprenorphine is an opioid that can cause serious and life-threatening
breathing problems,
especially if you take or use certain other medicines or drugs.
•
Talk to your healthcare provider about naloxone. Naloxone is a
medicine that is available to
patients for the emergency treatment of an opioid overdose, including
accidental use of
buprenorphine and naloxone sublingual film by a child. If naloxone is
given, you must call 911 or
get emergency medical help right away to treat an overdose or
accidental use of an opioid.
•
Buprenorphine and naloxone sublingual film may cause serious and
life-threatening breathing
problems. Get emergency help right away if you:
•
feel faint
•
feel dizzy
•
are confused
•
feel sleepy or uncoordinated
•
have blurred vision
•
have slurred speech
•
are breathing slower than
normal
•
cannot think well or clearly
•
Do not take buprenorphine and naloxone sublingual film with certain
medicines. Taking
buprenorphine and naloxone sublingual film with other opioid
medicines, benzodiazepines,
alcohol, or other central nervous system depressants (including street
drugs) can cause severe
drowsiness, decreased awareness, breathing problems, coma, and death.
•
Do not inject (“

Summary of Product characteristics

BUPRENORPHINE AND NALOXONE SUBLINGUAL FILM- BUPRENORPHINE AND
NALOXONE FILM
ALVOGEN INC.
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HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
BUPRENORPHINE AND
NALOXONE SUBLINGUAL FILM SAFELY AND EFFECTIVELY. SEE FULL PRESCRIBING
INFORMATION FOR
BUPRENORPHINE AND NALOXONE SUBLINGUAL FILM.
BUPRENORPHINE AND NALOXONE SUBLINGUAL FILM, FOR SUBLINGUAL OR BUCCAL
USE, CIII.
INITIAL U.S. APPROVAL: 2002
INDICATIONS AND USAGE
Buprenorphine and naloxone sublingual film contains buprenorphine, a
partial-opioid agonist, and
naloxone, an opioid antagonist, and is indicated for treatment of
opioid dependence. (1)
Buprenorphine and naloxone sublingual film should be used as a part of
a complete treatment plan that
includes counseling and psychosocial support. (1)
DOSAGE AND ADMINISTRATION
Administer buprenorphine and naloxone sublingual film as a single
daily dose. (2.1)
Strongly consider prescribing naloxone at the time buprenorphine and
naloxone sublingual film is
initiated or renewed because patients being treated for opioid use
disorder have the potential for
relapse, putting them at risk for opioid overdose. (2.2)
To avoid precipitating withdrawal, induction with buprenorphine and
naloxone sublingual film should be
undertaken when objective and clear signs of withdrawal are evident
and buprenorphine and naloxone
sublingual film should be administered in divided doses when used as
initial treatment. (2.3)
For patients dependent on short-acting opioid products who are in
opioid withdrawal; on Day 1,
administer up to 8 mg/2 mg buprenorphine and naloxone sublingual film
(in divided doses). On Day 2,
administer up to 16 mg/4 mg of buprenorphine and naloxone sublingual
film as a single dose. (2.3)
For patients dependent on methadone or long-acting opioid products,
induction onto sublingual
buprenorphine monotherapy is recommended on Days 1 and 2 of treatment.
(2.3)
For maintenance treatment, the target dosage of buprenorphine and
naloxone sublingual film is usually
16