Subutex

Buprenorphine is used to treat dependence/addiction to narcotics (opioids). Buprenorphine belongs to a class of drugs called mixed narcotic agonist-antagonists. It helps prevent withdrawal symptoms caused by stopping other opiate-type narcotics. It is used as part of a complete treatment program for drug abuse (such as compliance monitoring, counseling, behavioral contract, lifestyle changes).

Drowsiness, dizziness, constipation, or headache may occur. If any of these effects persist or worsen, tell your doctor or pharmacist immediately.To prevent constipation, eat a diet adequate in fiber, drink plenty of water, and exercise. Consult your pharmacist for help in selecting a laxative (such as a stimulant type with stool softener).To reduce the risk of dizziness and lightheadedness, get up slowly when rising from a sitting or lying position.Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.Severe (possibly fatal) breathing problems can occur if this medication is abused, injected, or mixed with other depressants (such as alcohol, benzodiazepines including diazepam, other narcotics).Tell your doctor right away if you have any serious side effects, including: mental/mood changes (such as agitation, confusion, hallucinations), stomach/abdominal pain.Get medical help right away if any of these rare but serious side effects occur: fainting, fast/irregular heartbeat, severe dizziness, slow/shallow breathing, unusual drowsiness/difficulty waking up.Although this medication is used to prevent withdrawal reactions, it may rarely cause narcotic withdrawal symptoms, including diarrhea, severe mental/mood changes (such as anxiety, irritability, trouble sleeping), muscle stiffness or shakiness. This is more likely when you first start treatment or if you have been using long-acting narcotics such as methadone. If such symptoms occur, notify your doctor or pharmacist immediately.This drug may rarely cause serious liver disease. Get medical help right away if you have any symptoms of liver damage, including: dark urine, persistent nausea/vomiting, yellowing eyes/skin, severe stomach/abdominal pain.A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.In the US -Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.Some products that may interact with this drug include: narcotic antagonists (such as naltrexone), certain narcotic pain medications (mixed narcotic agonist-antagonists such as butorphanol, nalbuphine, pentazocine).Many drugs besides buprenorphine may affect the heart rhythm (QT prolongation), including amiodarone, bretylium, disopyramide, dofetilide, ibutilide, procainamide, quinidine, sotalol, among others.Other medications can affect the removal of buprenorphine from your body, which may affect how buprenorphine works. Examples include azole antifungals (such as ketoconazole), HIV medications (such as ritonavir, saquinavir), macrolide antibiotics (such as erythromycin), rifamycins (such as rifabutin), St. John's wort, drugs used to treat seizures (such as carbamazepine, phenytoin), among others.The risk of serious side effects (such as slow/shallow breathing, severe drowsiness, dizziness) may be increased if this medication is taken with other products that may also affect breathing or cause drowsiness. Therefore, tell your doctor or pharmacist if you are taking other products such as alcohol, allergy or cough-and-cold products, anti-seizure drugs (such as phenobarbital), medicine for sleep or anxiety (such as alprazolam, diazepam, zolpidem), muscle relaxants, other narcotics (such as hydrocodone, oxycodone), and psychiatric medicines (such as risperidone, amitriptyline, trazodone). Your medications or doses of your medications may need to be changed.Deaths have occurred when buprenorphine has been misused by injecting it ("shooting up"), especially when used in combination with benzodiazepines (such as diazepam) or other depressants such as alcohol or additional narcotics.

Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets.Properly discard this product when it is expired or no longer needed. Read the Medication Guide for details. To discard this medication, the FDA recommends flushing down the toilet or pouring into a drain. However, consult your pharmacist or local waste disposal company.

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Reviewed on 4/16/2014 References

Included as part of the PRECAUTIONS section.

Mechanism Of Action

SUBUTEX sublingual tablet contains buprenorphine, a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor.

Pharmacodynamics

Subjective Effects

Comparisons of buprenorphine to full opioid agonists such as methadone and hydromorphone suggest that sublingual buprenorphine produces typical opioid agonist effects which are limited by a ceiling effect.

Opioid agonist ceiling-effects were also observed in a double-blind, parallel group, dose-ranging comparison of single doses of buprenorphine sublingual solution (1, 2, 4, 8, 16, or 32 mg), placebo and a full agonist control at various doses. The treatments were given in ascending dose order at intervals of at least one week to 16 opioid-experienced subjects who were not physically dependent. Both active drugs produced typical opioid agonist effects. For all measures for which the drugs produced an effect, buprenorphine produced a dose-related response. However, in each case, there was a dose that produced no further effect. In contrast, the highest dose of the full agonist control always produced the greatest effects. Agonist objective rating scores remained elevated for the higher doses of buprenorphine (8-32 mg) longer than for the lower doses and did not return to baseline until 48 hours after drug administration. The onset of effects appeared more rapidly with buprenorphine than with the full agonist control, with most doses nearing peak effect after 100 minutes for buprenorphine compared to 150 minutes for the full agonist control.

Physiologic Effects

Buprenorphine in IV (2, 4, 8, 12 and 16 mg) and sublingual (12 mg) doses has been administered to opioid-experienced subjects who were not physically dependent to examine cardiovascular, respiratory and subjective effects at doses comparable to those used for treatment of opioid dependence. Compared to placebo, there were no statistically significant differences among any of the treatment conditions for blood pressure, heart rate, respiratory rate, O2 saturation, or skin temperature across time. Systolic BP was higher in the 8 mg group than placebo (3-hour AUC values). Minimum and maximum effects were similar across all treatments. Subjects remained responsive to low voice and responded to computer prompts. Some subjects showed irritability, but no other changes were observed.

The respiratory effects of sublingual buprenorphine were compared with the effects of methadone in a double-blind, parallel group, dose ranging comparison of single doses of buprenorphine sublingual solution (1, 2, 4, 8, 16, or 32 mg) and oral methadone (15, 30, 45, or 60 mg) in non-dependent, opioid-experienced volunteers. In this study, hypoventilation not requiring medical intervention was reported more frequently after buprenorphine doses of 4 mg and higher than after methadone. Both drugs decreased O2 saturation to the same degree.

Androgen Deficiency

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation.

Pharmacokinetics

Absorption

Plasma levels of buprenorphine increased with the sublingual dose of SUBUTEX sublingual tablet (Table 4). There was wide inter-patient variability in the sublingual absorption of buprenorphine, but within subjects the variability was low. Both Cmax and AUC of buprenorphine increased in a linear fashion with the increase in dose (in the range of 4 to 16 mg), although the increase was not directly dose-proportional.

Table 4 : Pharmacokinetic Parameters of Buprenorphine and Norbuprenorphine after the sublingual administration of SUBUTEX sublingual tablets

Dose	Analyte	Mean SD	Cmax (ng/mL)	Tmax (h)	AUCinf (h•ng/mL)	t½(h)
2 mg	Buprenorphine	Mean	1.25	1.84	10.93	31.66
		SD	0.584	0.62	3.945	12.66
	Norbuprenorphine	Mean	0.301	2.36	12.39	39.28
		SD	0.127	2.75	4.526	20.85
8 mg	Buprenorphine	Mean	2.88	1.28	28.39	35.01
		SD	1.14	0.46	10.22	14.7
	Norbuprenorphine	Mean	1.38	1.75	50.18	44.33
		SD	0.752	2.11	22.61	19.27
16 mg	Buprenorphine	Mean	4.70	1.42	47.09	36.51
		SD	2.16	0.50	20.03	13.99
	Norbuprenorphine	Mean	2.65	1.52	92.31	40.35
		SD	1.62	1.34	34.74	12.07

Distribution

Buprenorphine is approximately 96% protein bound, primarily to alpha and beta globulin.

Excretion

Metabolism

Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation. The N-dealkylation pathway is mediated primarily by CYP3A4. Norbuprenorphine, the major metabolite, can further undergo glucuronidation. Norbuprenorphine has been found to bind opioid receptors in vitro; however, it is not known whether norbuprenorphine contributes to the overall effect of SUBUTEX.

Elimination

A mass balance study of buprenorphine showed complete recovery of radiolabel in urine (30%) and feces (69%) collected up to 11 days after dosing. Almost all of the dose was accounted for in terms of buprenorphine, norbuprenorphine, and two unidentified buprenorphine metabolites. In urine, most of buprenorphine and norbuprenorphine was conjugated (buprenorphine, 1% free and 9.4% conjugated; norbuprenorphine, 2.7% free and 11% conjugated). In feces, almost all of the buprenorphine and norbuprenorphine were free (buprenorphine, 33% free and 5% conjugated; norbuprenorphine, 21% free and 2% conjugated).

When SUBUTEX tablets are administered sublingually, buprenorphine has a mean elimination half-life from plasma ranging from 31 to 35 hours.

Drug Interactions Studies

CYP3A4 Inhibitors And Inducers

Subjects receiving SUBUTEX sublingual tablet should be monitored if inhibitors of CYP3A4 such as azole antifungal agents (e.g., ketoconazole), macrolide antibiotics (e.g., erythromycin) or HIV protease inhibitors and may require dose-reduction of one or both agents. The interaction of buprenorphine with all CYP3A4 inducers has not been studied, therefore it is recommended that patients receiving SUBUTEX sublingual tablet be monitored for signs and symptoms of opioid withdrawal if inducers of CYP3A4 (e.g., phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered [see DRUG INTERACTIONS].

Buprenorphine has been found to be a CYP2D6 and CYP3A4 inhibitor and its major metabolite, norbuprenorphine has been found to be a moderate CYP2D6 inhibitor in in vitro studies employing human liver microsomes. However, the relatively low plasma concentrations of buprenorphine and norbuprenorphine resulting from therapeutic doses are not expected to raise significant drug-drug interaction concerns.

Specific Populations

Hepatic Impairment

In a pharmacokinetic study, the disposition of buprenorphine was determined after administering a 2.0/0.5 mg SUBOXONE (buprenorphine with naloxone) sublingual tablet in subjects with varied degrees of hepatic impairment as indicated by Child-Pugh criteria. The disposition of buprenorphine in patients with hepatic impairment was compared to disposition in subjects with normal hepatic function.

In subjects with mild hepatic impairment, the changes in mean Cmax, AUC0-last, and half-life values of buprenorphine were not clinically significant. No dose adjustment is needed in patients with mild hepatic impairment.

For subjects with moderate and severe hepatic impairment, mean Cmax, AUC0-last, and half-life values of buprenorphine were increased (Table 5). [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].

Table 5 : Changes in Buprenorphine Pharmacokinetic Parameters in Subjects with Moderate and Severe Hepatic Impairment

Hepatic Impairment	PK Parameters	Increase in buprenorphine compared to healthy subjects
Moderate	C max	8%
	AUC0-last	64%
	Half-life	35%
Severe	C max	72%
	AUC0-last	181%
	Half-life	57%

HCV Infection

In subjects with HCV infection but no sign of hepatic impairment, the changes in the mean Cmax, AUC0-last, and half-life values of buprenorphine were not clinically significant in comparison to healthy subjects without HCV infection. No dose adjustment is needed in patients with HCV infection.

Clinical Studies

Clinical data on the safety and efficacy of SUBUTEX were derived from studies of buprenorphine sublingual tablet formulations, with and without naloxone, and from studies of sublingual administration of a more bioavailable ethanolic solution of buprenorphine.

SUBUTEX tablets were studied in 1834 patients; SUBOXONE tablets (buprenorphine with naloxone) in 575 patients, and buprenorphine sublingual solutions in 2470 patients. A total of 1270 women received buprenorphine in those clinical trials. Dosing recommendations are based on data from one trial of both tablet formulations and two trials of the ethanolic solution. All trials used buprenorphine in conjunction with psychosocial counseling as part of a comprehensive addiction treatment program. There were no clinical studies conducted to assess the efficacy of buprenorphine as the only component of treatment.

In a double-blind placebo-and active-controlled study, 326 heroin-addicted subjects were randomly assigned to either SUBOXONE sublingual tablets, 16/4 mg per day; SUBUTEX sublingual tablets, 16 mg per day; or placebo sublingual tablets. For subjects randomized to either active treatment, dosing began with one 8 mg SUBUTEX on Day 1, followed by 16 mg (two 8 mg tablets) of SUBUTEX on Day 2. On Day 3, those randomized to receive SUBOXONE sublingual tablets were switched to the combination tablet. Subjects randomized to placebo received one placebo tablet on Day 1 and two placebo tablets per day thereafter for four weeks. Subjects were seen daily in the clinic (Monday through Friday) for dosing and efficacy assessments. Take-home doses were provided for weekends. Subjects were instructed to hold the medication under the tongue for approximately 5 to 10 minutes until completely dissolved. Subjects received counseling regarding HIV infection and up to one hour of individualized counseling per week. The primary study comparison was to assess the efficacy of SUBOXONE sublingual tablets and SUBUTEX sublingual tablets individually against placebo sublingual tablet. The percentage of thrice-weekly urine samples that were negative for non-study opioids was statistically higher for both SUBOXONE sublingual tablets and SUBUTEX sublingual tablets than for placebo sublingual tablets.

In a double-blind, double-dummy, parallel-group study comparing buprenorphine ethanolic solution to a full agonist active control, 162 subjects were randomized to receive the ethanolic sublingual solution of buprenorphine at 8 mg/day (a dose which is roughly comparable to a dose of 12 mg per day of SUBUTEX sublingual tablets), or two relatively low doses of active control, one of which was low enough to serve as an alternative to placebo, during a 3-10 day induction phase, a 16-week maintenance phase and a 7-week detoxification phase. Buprenorphine was titrated to maintenance dose by Day 3; active control doses were titrated more gradually.

Maintenance dosing continued through Week 17, and then medications were tapered by approximately 20%-30% per week over Weeks 18-24, with placebo dosing for the last two weeks. Subjects received individual and/or group counseling weekly.

Based on retention in treatment and the percentage of thrice-weekly urine samples negative for non-study opioids, buprenorphine was more effective than the low dose of the control, in keeping heroin addicts in treatment and in reducing their use of opioids while in treatment. The effectiveness of buprenorphine, 8mg per day was similar to that of the moderate active control dose, but equivalence was not demonstrated.

In a dose-controlled, double-blind, parallel-group, 16-week study, 731 subjects were randomized to receive one of four doses of buprenorphine ethanolic solution: 1 mg, 4 mg, 8 mg, and 16 mg. Buprenorphine was titrated to maintenance doses over 1-4 days and continued for 16 weeks. Subjects received at least one session of AIDS education and additional counseling ranging from one hour per month to one hour per week, depending on site.

Based on retention in treatment and the percentage of thrice-weekly urine samples negative for non-study opioids, the three highest tested doses were superior to the 1 mg dose. Therefore, this study showed that a range of buprenorphine doses may be effective. The 1 mg dose of buprenorphine sublingual solution can be considered to be somewhat lower than a 2 mg tablet dose. The other doses used in the study encompass a range of tablet doses from approximately 6 mg to approximately 24 mg.

Subutex is a prescription medication used to treat patients who are dependent on opioids (addiction to opioid drugs, including heroin and narcotic painkillers). Subutex belongs to a group of drugs called opioid partial agonist-antagonists, which work because it produces similar effects to opioids.

This medication comes in tablet form to be dissolved under the tongue (sublingual) once daily.

Some of the common side effects of Subutex include constipation, nausea, and headache. Subutex can cause dizziness and drowsiness. Do not drive or operate machinery until you know how Subutex will affect you. Do not drink alcohol while taking this medication.

Brand name Subutex sublingual tablets are no longer available. Generic versions are made available by several manufacturers.

 

Subutex is part of the drug class:

• Drugs used in opioid dependence

Before taking Subutex, tell your doctor about all of your medical conditions including if you have:

• breathing or lung problems
• history of a heart problem called Long QT syndrome (or if a family member has this condition)
• head injury or brain problems
• low blood pressure
• liver problems
• kidney problems
• hepatitis B or hepatitis C
• had convulsions or seizures
• severe scoliosis
• thyroid problems
• prostate problems or trouble urinating
• Addison’s disease
• alcoholism, or a family history of this problem
• depression or hallucinations (seeing or hearing things that are not there)
• drug abuse or addiction problem, or a past problem, or a family history of this problem
• have any other medical conditions

Tell your doctor if you are pregnant or breastfeeding.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

It is very important that your doctor check your progress while you are using this medicine. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it. Blood and urine tests may be needed to check for unwanted effects.

It is against the law and dangerous for anyone else to use your medicine. Keep your unused tablets and buccal films in a safe and secure place. People who are addicted to drugs might want to steal this medicine.

Before having any kind of surgery (including dental surgery) or emergency treatment, tell the medical doctor or dentist in charge that you are using this medicine. Serious unwanted effects can occur if certain medicines are given together with buprenorphine.

This medicine will add to the effects of alcohol and other central nervous system (CNS) depressants. CNS) depressants are medicines that slow down the nervous system, which may cause drowsiness or make you less alert. Some examples of CNS depressants are antihistamines or medicine for hay fever, allergies, or colds, sedatives, benzodiazepines, tranquilizers, or sleeping medicine, other prescription pain medicine or narcotics, barbiturates or seizures medicines, muscle relaxants, or anesthetics (numbing medicines), including some dental anesthetics. Check with your doctor before taking any of the medicines listed above while you are using this medicine.

Dizziness, lightheadedness, or fainting may occur when you get up suddenly from a lying or sitting position. Getting up slowly may help lessen this problem. Also, lying down for a while may relieve the dizziness or lightheadedness.

This medicine may make you dizzy, drowsy, or lightheaded. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or not alert.

This medicine may cause serious allergic reactions, including anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Call your doctor right away if you have a rash, itching, hoarseness, trouble breathing, trouble swallowing, or any swelling of your hands, face, or mouth while you are using this medicine.

Contact your doctor right away if you have any changes to your heart rhythm. You might feel dizzy or faint, or you might have a fast, pounding, or uneven heartbeat. Make sure your doctor knows if you or anyone in your family has ever had a heart rhythm problem such as QT prolongation.

This medicine may be habit-forming. If you feel that the medicine is not working as well, do not use more than your prescribed dose. Call your doctor for instructions.

Using narcotics for a long time can cause severe constipation. To prevent this, your doctor may direct you to take laxatives, drink a lot of fluids, or increase the amount of fiber in your diet. Be sure to follow the directions carefully, because continuing constipation can lead to more serious problems.

If you have been using this medicine regularly for several weeks or longer, do not suddenly stop using it without checking with your doctor. Your doctor may want you to gradually reduce the amount you are using before stopping it completely. This may help reduce the possibility of withdrawal symptoms, such as abdominal or stomach cramps, anxiety, fever, nausea, runny nose, sweating, tremors, or trouble with sleeping.

Using this medicine while you are pregnant may cause serious unwanted effects in your newborn baby. Tell your doctor right away if you think you are pregnant or if you plan to become pregnant while using this medicine.

Using too much of this medicine may cause reduced infertility (unable to have children). Talk with your doctor before using this medicine if you plan to have children.

Check with your doctor right away if you have anxiety, restlessness, a fast heartbeat, fever, sweating, muscle spasms, twitching, nausea, vomiting, diarrhea, or see or hear things that are not there. These may be symptoms of a serious condition called serotonin syndrome. Your risk may be higher if you also take certain other medicines that affect serotonin levels in your body.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.