BUPRENORPHINE HCL AND NALOXONE HCL- buprenorphine and naloxone tablet

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:

REMEDYREPACK INC.

INN (International Name):

BUPRENORPHINE HYDROCHLORIDE

Composition:

BUPRENORPHINE 2 mg

Administration route:

SUBLINGUAL

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

Buprenorphine and Naloxone Sublingual Tablets are indicated for the maintenance treatment of opioid dependence. Buprenorphine and Naloxone Sublingual Tablets should be used as part of a complete treatment plan that includes counseling and psychosocial support. Buprenorphine and Naloxone Sublingual Tablets are 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)] . Risk Summary The data on use of buprenorphine, one of the active ingredients in Buprenorphine and Naloxone Sublingual Tablets, 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. 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 and rabbits administered buprenorphine daily during organogenesis at doses approximately 0.6 times and approximately equal to the human sublingual dose of 16 mg/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 risks 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. Clinical Considerations 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 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. Fetal/neonatal adverse reactions Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with Buprenorphine and Naloxone Sublingual Tablets. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal usually occur in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.5)] . Labor or Delivery Opioid-dependent women on buprenorphine maintenance therapy may require additional analgesia during labor. Data Human Data 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 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. Animal Data The exposure margins listed below are based on body surface area comparisons (mg/m 2 ) 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/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 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/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 the 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 or rabbits after IM or subcutaneous (SC) doses 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 sublingual dose of 16 mg) and 25 mg/kg/day in rabbits (estimated exposure was approximately 30 times the human sublingual dose of 16 mg). Significant increases in skeletal abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC administration of 1 mg/kg/day and up (estimated exposure was approximately 0.6 times the human sublingual dose 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 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 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 dose of 16 mg). Fertility, and pre- and postnatal development studies with buprenorphine in rats indicated increases in neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 0.5 times the human 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). Risk Summary 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 available data have not shown adverse reactions in breastfed infants. There are no data on the combination product buprenorphine/naloxone in breastfeeding, however oral absorption of naloxone is limited.  The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for buprenorphine and naloxone sublingual tablets and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. Clinical Considerations Advise breastfeeding women taking buprenorphine products to monitor the infant for increased drowsiness and breathing difficulties. Data 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/day 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 (C avg ) 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. Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2), Clinical Pharmacology (12.2) ,  Nonclinical Toxicology (13.1)] . The safety and effectiveness of Buprenorphine and Naloxone Sublingual Tablets 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 Tablets, buprenorphine and naloxone sublingual film, 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 tablets 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/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 IV administration of 0.3 mg buprenorphine. The effects of renal failure on naloxone pharmacokinetics are unknown. Buprenorphine and naloxone sublingual tablets contain 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 to, 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)] . BUPRENORPHINE (bue” pre nor’ feen) AND NALOXONE (nal ox’ one) Sublingual Tablets, USP (CIII) This “Instructions for Use” contains information on how to correctly take buprenorphine and naloxone sublingual tablets. Important Information You Need to Know Before Taking buprenorphine and naloxone sublingual tablets: - Your healthcare provider should show you how to take buprenorphine and naloxone sublingual tablets the right way. Preparing to take buprenorphine and naloxone sublingual tablets : Preparing to take buprenorphine and naloxone sublingual tablets : - Put the tablets under your tongue. Let them dissolve completely. - While buprenorphine and naloxone sublingual tablet is dissolving, do not chew or swallow the tablet because the medicine will not work as well. - Talking while the tablet is dissolving can affect how well the medicine in buprenorphine and naloxone sublingual tablet is absorbed. - After buprenorphine and naloxone sublingual tablet is completely dissolved, rinse your mouth with water and swallow. Wait for at least one hour before brushing teeth. - If you miss a dose of buprenorphine and naloxone sublingual tablet, take your medicine when you remember. If it is almost time for your next dose, skip the missed dose and take the next dose at your regular time. Do not take 2 doses at the same time unless your healthcare provider tells you to. If you are not sure about your dosing, call your healthcare provider. - Do not stop taking buprenorphine and naloxone sublingual tablet suddenly. You could become sick and have withdrawal symptoms because your body has become used to the medicine. Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction. To have fewer withdrawal symptoms, ask your healthcare provider how to stop using buprenorphine and naloxone sublingual tablet the right way. If you take too much buprenorphine and naloxone sublingual tablet or overdose, call Poison Control or get emergency medical help right away. Storing buprenorphine and naloxone sublingual tablets: - Store buprenorphine and naloxone sublingual tablets at room temperature between 68° to 77°F (20° to 25°C). - Keep buprenorphine and naloxone sublingual tablets in a safe place, out of the sight and reach of children . Disposing of buprenorphine and naloxone sublingual tablets: - Dispose of unused buprenorphine and naloxone sublingual tablets as soon as you no longer need them. - Dispose of expired, unwanted or unused buprenorphine and naloxone sublingual tablets by promptly flushing down the toilet (if a drug take‐back option is not readily available). Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. If you need help with disposal of buprenorphine and naloxone sublingual tablet, call 1‐877‐835‐5472. Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 [phone]

Product summary:

Buprenorphine and Naloxone Sublingual Tablets USP, 2 mg/0.5 mg are supplied as orange, round, biconvex tablet, debossed “A” on one side and “14” on the other side. They are available as follows: NDC: 70518-1007-00 PACKAGING: 30 in 1 BLISTER PACK Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

Authorization status:

Abbreviated New Drug Application

Patient Information leaflet

REMEDYREPACK INC.
----------
MEDICATION GUIDE
BUPRENORPHINE (bue” pre nor’ feen) AND NALOXONE (nal ox’ one)
SUBLINGUAL TABLETS,
USP (CIII)
IMPORTANT:Keep buprenorphine and naloxone sublingual tablets 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 tablets, 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
tablets?
•
Buprenorphine and naloxone sublingual tablets contain 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 tablet 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 tablets may cause serious and
life‐threatening breathing
problems. Get emergency help right away if you:
•
feel faint
•
have blurred vision
•
feel dizzy
•
have slurred speech
•
are confused
•
are breathing slower than normal
•
feel sleepy or
uncoordinated
•
cannot think well or clearly
•
Do not take buprenorphine and naloxone sublingual tablets with certain
medicines. Taking
buprenorphine and naloxone sublingual tablets 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 (“shoot‐up”) buprenorphine and naloxone. Injecting
buprenorphine a

Summary of Product characteristics

BUPRENORPHINE HCL AND NALOXONE HCL- BUPRENORPHINE AND
NALOXONE TABLET
REMEDYREPACK INC.
----------
HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
BUPRENORPHINE AND
NALOXONE SUBLINGUAL TABLETS SAFELY AND EFFECTIVELY. SEE FULL
PRESCRIBING INFORMATION FOR
BUPRENORPHINE AND NALOXONE SUBLINGUAL TABLETS.
BUPRENORPHINE AND NALOXONE SUBLINGUAL TABLETS, CIII
INITIAL U.S. APPROVAL: 2002
INDICATIONS AND USAGE
Buprenorphine and Naloxone Sublingual Tablets contain buprenorphine, a
partial opioid agonist, and
naloxone, an opioid antagonist, and is indicated for the maintenance
treatment of opioid dependence. ( 1)
Buprenorphine and Naloxone Sublingual Tablets should be used as part
of a complete treatment plan that
includes counseling and psychosocial support. ( 1)
DOSAGE AND ADMINISTRATION
Administer Buprenorphine and Naloxone Sublingual Tablets sublingually
as a single daily dose. ( 2.2)
Strongly consider prescribing naloxone at the time Buprenorphine and
Naloxone Sublingual Tablets are
initiated or renewed because patients being treated for opioid use
disorder have the potential for
relapse, putting them at risk for opioid overdose. ( 2.3_)_
To avoid precipitating withdrawal, induction with Buprenorphine
Sublingual Tablets should be undertaken
when objective and clear signs of withdrawal are evident. After
induction, doses of Buprenorphine and
Naloxone Sublingual Tablets should be progressively adjusted to a
level that holds the patient in
treatment and suppresses opioid withdrawal signs and symptoms. ( 2.4)
The recommended target dosage of Buprenorphine and Naloxone Sublingual
Tablets for maintenance
is 16 mg/4 mg. ( 2.4)
Administer Buprenorphine and Naloxone Sublingual Tablets as directed
in the Full Prescribing
Information. ( 2.4, 2.5)
When discontinuing treatment, gradually taper to avoid signs and
symptoms of withdrawal. ( 2.8)
DOSAGE FORMS AND STRENGTHS
Sublingual tablet: (3)
2 mg buprenorphine with 0.5 mg naloxone and
CONTRAINDICATIONS
Hypersensitivity to bupren