Buprenorphine Hydrochloride And Naloxone Hydrochloride Dihydrate

FDA Drug Information • Also known as: Buprenorphine Hydrochloride And Naloxone Hydrochloride Dihydrate

Brand Names: Buprenorphine Hydrochloride And Naloxone Hydrochloride Dihydrate
Route: SUBLINGUAL
Dosage Form: TABLET
Product Type: HUMAN PRESCRIPTION DRUG

Description

11 DESCRIPTION Buprenorphine and Naloxone Sublingual Tablets, USP are available in two dosage strengths intended for sublingual administration as follows: 2 mg buprenorphine with 0.5 mg naloxone free bases and 8 mg buprenorphine with 2 mg naloxone free bases. Each tablet also contains citric acid anhydrous, corn starch, FD & C yellow no. 6, lactose monohydrate, lemon-lime flavor, magnesium stearate, mannitol, povidone, sodium citrate dihydrate and sucralose. Chemically, buprenorphine HCl is (6R, 7R, 14S)-17-Cyclopropylmethyl-7,8-dihydro-7-[(1S)-1-hydroxy-1,2,2-trimethylpropyl]-6-O--methyl-6,14-ethano-17-normorphine hydrochloride. It has the following chemical structure: Buprenorphine hydrochloride, USP has the molecular formula C 29 H 41 NO 4

HCl and the molecular weight is 504.1. It is a white to almost white crystalline powder, sparingly soluble in water, freely soluble in methanol, soluble in alcohol, and practically insoluble in cyclohexane. Chemically, naloxone HCl dihydrate, USP is 17-Allyl-4, 5 α-epoxy-3, 14-dihydroxymorphinan-6-one hydrochloride dihydrate. It has the following chemical structure: Naloxone hydrochloride dihydrate has the molecular formula C 19 H 22 ClNO 4, 2H 2 O and the molecular weight is 399.9. It is a white to slightly off-white powder or almost white crystalline powder and is freely soluble in water, soluble in alcohol, and practically insoluble in toluene and ether. buprenorphine-chem-structure.jpg naloxone-chem-structure.jpg

What Is Buprenorphine Hydrochloride And Naloxone Hydrochloride Dihydrate Used For?

1 INDICATIONS AND USAGE 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 to include counseling and psychosocial support. Buprenorphine and Naloxone Sublingual Tablets contain buprenorphine, a partial opioid agonist, and naloxone, an opioid antagonist, and are 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

2 DOSAGE AND ADMINISTRATION

Administer Buprenorphine and Naloxone Sublingual Tablets sublingually as a single daily dose. ( 2.1 )

Strongly consider recommending or prescribing an opioid overdose reversal agent (e.g., naloxone, nalmefene) 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. ( 2.2 )

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. ( 2.3 )

The maintenance dose of Buprenorphine and Naloxone Sublingual Tablets is generally in the range of 4 mg/1 mg to 24 mg/6 mg per day and should be based on clinical response. ( 2.3 )

Administer Buprenorphine and Naloxone Sublingual Tablets as directed in the Full Prescribing Information. ( 2.3 , 2.4 )

When discontinuing treatment, gradually taper to avoid signs and symptoms of withdrawal. ( 2.7 ) 2.1 Important Dosage and Administration Information Buprenorphine and Naloxone Sublingual Tablets are administered sublingually as a single daily dose. Buprenorphine and Naloxone Sublingual Tablets should be used in patients who have been initially inducted using buprenorphine sublingual tablets. Medication should be prescribed in consideration of the frequency of visits. Provision of multiple refills is not advised early in treatment or without appropriate patient follow-up visits. 2.2 Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene) and discuss the importance of having access to an opioid overdose reversal agent. Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider recommending or prescribing an overdose reversal agent for the emergency treatment of opioid overdose, both when initiating and renewing treatment with Buprenorphine and Naloxone Sublingual Tablets. Also consider recommending or prescribing such an agent if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose [see Warnings and Precautions ( 5.2 )] . Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Warnings and Precautions ( 5.2 )] . There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling:

Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )]

Respiratory and CNS Depression [see Warnings and Precautions ( 5.2 , 5.3 )]

Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.5 )]

Adrenal Insufficiency [see Warnings and Precautions ( 5.6 )]

Opioid Withdrawal [see Warnings and Precautions ( 5.7 , 5.10 )]

Hepatitis, Hepatic Events [see Warnings and Precautions ( 5.8 )]

Hypersensitivity Reactions [see Warnings and Precautions ( 5.9 )]

Orthostatic Hypotension [see Warnings and Precautions ( 5.16 )]

Elevation of Cerebrospinal Fluid Pressure [see Warnings and Precautions ( 5.17 )]

Elevation of Intracholedochal Pressure [see Warnings and Precautions ( 5.18 )] Adverse events commonly observed with administration of buprenorphine/naloxone are oral hypoesthesia, glossodynia, oral mucosal erythema, headache, nausea, vomiting, hyperhidrosis, constipation, signs and symptoms of withdrawal, insomnia, pain, and peripheral edema. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of Buprenorphine and Naloxone Sublingual Tablets was evaluated in 497 opioid-dependent subjects. The prospective evaluation of Buprenorphine and Naloxone Sublingual Tablets was supported by clinical trials using buprenorphine sublingual tablets (buprenorphine tablets without naloxone) and other trials using buprenorphine sublingual solutions. In total, safety data were available from 3,214 opioid-dependent subjects exposed to buprenorphine at doses in the range used in treatment of opioid addiction. Few differences in adverse event profile were noted between Buprenorphine and Naloxone Sublingual Tablets and buprenorphine sublingual tablets or buprenorphine administered as a sublingual solution. The following adverse events were reported to occur by at least 5% of patients in a 4-week study (Table 1). Table 1. Adverse Events ≥ 5% by Body System and Treatment Group in a 4-week Study N (%) N (%) Body System/Adverse Event (COSTART Terminology) Buprenorphine and Naloxone Sublingual Tablets 16 mg/day N=107 Placebo N=107 Body as a Whole Asthenia 7 (6.5%) 7 (6.5%) Chills 8 (7.5%) 8 (7.5%) Headache 39 (36.4%) 24 (22.4%) Infection 6 (5.6%) 7 (6.5%) Pain 24 (22.4%) 20 (18.7%) Pain Abdomen 12 (11.2%) 7 (6.5%) Pain Back 4 (3.7%) 12 (11.2%) Withdrawal Syndrome 27 (25.2%) 40 (37.4%) Cardiovascular System Vasodilation 10 (9.3%) 7 (6.5%) Digestive System Constipation 13 (12.1%) 3 (2.8%) Diarrhea 4 (3.7%) 16 (15.0%) Nausea 16 (15.0%) 12 (11.2%) Vomiting 8 (7.5%) 5 (4.7%) Nervous System Insomnia 15 (14.0%) 17 (15.9%) Respiratory System Rhinitis 5 (4.7%) 14 (13.1%) Skin and Appendages Sweating 15 (14.0%) 11 (10.3%) The adverse event profile of buprenorphine was also characterized in the dose-controlled study of buprenorphine solution, over a range of doses in four months of treatment. Table 2 shows adverse events reported by at least 5% of subjects in any dose group in the dose-controlled study. Table 2. Adverse Events (≥ 5%) by Body System and Treatment Group in a 16-Week Study Body System/Adverse Event (COSTART Terminology) Buprenorphine Dose Sublingual solution. Doses in this table cannot necessarily be delivered in tablet form, but for comparison purposes: “Very low” dose (1 mg solution) would be less than a tablet dose of 2 mg “Low” dose (4 mg solution) approximates a 6 mg tablet dose “Moderate” dose (8 mg solution) approximates a 12 mg tablet dose “High” dose (16 mg solution) approximates a 24 mg tablet dose Very Low (N=184)...

Drug Interactions

7 DRUG INTERACTIONS Table 3 includes clinically significant drug interactions with Buprenorphine and Naloxone Sublingual Tablets. Table 3. Clinically Significant Drug Interactions with Buprenorphine and Naloxone Sublingual Tablets Benzodiazepines or Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death. Intervention: 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. Before co-prescribing benzodiazepines for anxiety or insomnia, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments [see Warnings and Precautions ( 5.2 , 5.3 )]. If concomitant use is warranted, strongly consider recommending or prescribing an opioid overdose reversal agent, as is recommended for all patients on buprenorphine treatment for opioid use disorder [see Warnings and Precautions ( 5.2 )]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids, alcohol. Inhibitors of CYP3A4 Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of Buprenorphine and Naloxone Sublingual Tablets is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see Clinical Pharmacology ( 12.3 )] , potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine. Intervention: If concomitant use is necessary, consider dosage reduction of Buprenorphine and Naloxone Sublingual Tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the Buprenorphine and Naloxone Sublingual Tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir). CYP3A4 Inducers Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see Clinical Pharmacology ( 12.3 )] , potentially resulting in decreased efficacy or...

Contraindications

4 CONTRAINDICATIONS 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 )]. Hypersensitivity to buprenorphine or naloxone. ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy 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...

Overdosage

10 OVERDOSAGE Clinical Presentation The manifestations of acute overdose include pinpoint pupils, sedation, hypotension, hypoglycemia, respiratory depression, and death. Toxic leukoencephalopathy has been reported after opioid overdose and can present hours, days, or weeks after apparent recovery from the initial intoxication. Treatment of Overdose In the event of overdose, the respiratory and cardiac status of the patient should be monitored carefully. When respiratory or cardiac functions are depressed, primary attention should be given to the re-establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Oxygen, IV fluids, vasopressors, and other supportive measures should be employed as indicated. In the case of overdose, the primary management should be the re-establishment of adequate ventilation with mechanical assistance of respiration, if required. An opioid overdose reversal agent may be of value for the management of buprenorphine overdose. Higher than normal doses and repeated administration may be necessary. The long duration of action of Buprenorphine and Naloxone Sublingual Tablets should be taken into consideration when determining the length of treatment and medical surveillance needed to reverse the effects of an overdose. Insufficient duration of monitoring may put patients at risk.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Buprenorphine and Naloxone Sublingual Tablets, USP 2 mg/0.5 mg are supplied as speckled-peach to peach, flat faced beveled edge tablets with product identification “54” [above] “122” on one side and plain on the other. NDC 0054-0188-13: Bottle of 30 Tablets 8 mg/2 mg are supplied as speckled-peach to peach, flat faced beveled edge tablets with product identification “54” [above] “375” on one side and plain on the other. NDC 0054-0189-13: Bottle of 30 Tablets Storage Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in USP. Store Buprenorphine and Naloxone Sublingual Tablets securely and dispose of properly [see Patient Counseling Information ( 17 )] .

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.