Suboxone

Buprenorphine HCl, naloxone HCl dihydrate.

Each Suboxone 2 mg/0.5 mg tablet contains buprenorphine 2 mg as buprenorphine HCl and naloxone 0.5 mg as naloxone HCl dihydrate.
Each Suboxone 8 mg/2 mg tablet contains buprenorphine 8 mg as buprenorphine HCl and naloxone 2 mg as naloxone HCl dihydrate.

Pharmacology: Buprenorphine is an opioid partial agonist/antagonist which binds to the mc (mu) and κ (kappa) receptors of the brain. Its activity in opioid maintenance treatment is attributed to its slowly reversible properties with the mu receptors, which over a prolonged period, might minimize the need of addicted patients for drugs.
Opioid agonist ceiling effects were observed during clinical pharmacology studies in opioid-dependent persons.
Naloxone is an antagonist at mu-opioid receptors. Because of its almost complete first pass metabolism, naloxone administered orally or sublingually has no detectable pharmacological activity. However, when administered IV to opioid-dependent persons, the presence of naloxone in Suboxone produces marked opioid antagonist effects and opioid withdrawal, thereby, deterring IV abuse.
Pharmacokinetics: Buprenorphine: Absorption: Buprenorphine, when taken orally, undergoes first pass metabolism with N-dealkylation and glucuroconjugation in the small intestine and the liver. The use of Suboxone by the oral route is therefore inappropriate.
Peak plasma concentrations are achieved 90 min after sublingual administration. Plasma levels of buprenorphine increased with the sublingual dose of Suboxone. Both C_max and AUC of buprenorphine increased with an increase in dose (in the range of 4-16 mg), although the increase was less than dose proportional.


Click on icon to see table/diagram/image


Values in the table represent the mean and [coefficient of variation in percentage (%)].
Distribution: The absorption of buprenorphine is followed by a rapid distribution phase (distribution half-life of 2-5 hrs).
Metabolism and Elimination: Buprenorphine is metabolized by 14-N-dealkylation and glucuroconjugation of the parent molecule and the dealkylated metabolite. Clinical data confirm that CYP3A4 is responsible for the N-dealkylation of buprenorphine. N-dealkylbuprenorphine is a mu-opioid agonist with weak intrinsic activity.
Elimination of buprenorphine is bi- or tri-exponential and has a mean half-life from plasma of 32 hrs. Buprenorphine is eliminated in the feces by biliary excretion of the glucuroconjugated metabolites (70%), the rest being eliminated in the urine. Naloxone: Absorption and Distribution: Following IV administration, naloxone is rapidly distributed (distribution half-life ~4 min). Following oral administration, naloxone is barely detectable in plasma, following sublingual administration of Suboxone, plasma naloxone concentrations are low and decline rapidly.
Metabolism and Elimination: Naloxone is metabolized in the liver, primarily by glucuronide conjugation and excreted in the urine. Naloxone has a mean half-life from plasma of 1.2 hrs.
Special Populations: Elderly: No pharmacokinetic data in elderly patients are available.
Renal Impairment: Renal elimination plays a relatively small role (~30%) in the overall clearance of Suboxone. No dose modification based on renal function is required but caution is recommended when dosing subjects with severe renal impairment.
Hepatic Impairment: Hepatic elimination plays a relatively large role (~70%) in the overall clearance of Suboxone and the action of buprenorphine may be prolonged in subjects with impaired hepatic clearance. Lower initial Suboxone doses and cautious titration of dosage may be required in patients with mild to moderate hepatic dysfunction. Suboxone is contraindicated in patients with severe hepatic dysfunction (see Contraindications).
Clinical Efficacy: Efficacy and safety data for Suboxone are primarily derived from a 1-year clinical trial, comprising a 4-week randomized double-blind comparison of Suboxone, buprenorphine and placebo tablets followed by a 48-week safety study of Suboxone. In this trial, 326 heroin-addicted subjects were randomly assigned to either Suboxone 16 mg/day, buprenorphine 16 mg/day or placebo tablets. For subjects randomized to either active treatment, dosing began with one 8-mg tablet of buprenorphine on day 1, followed by buprenorphine 16 mg (two 8-mg tablets) on day 2. On day 3, those randomized to receive Suboxone were switched to the combination tablet. Subjects were seen daily in the clinic (Monday through Friday) for dosing and efficacy assessments. Take-home doses were provided for weekends. The primary study comparison was to assess the efficacy of buprenorphine and Suboxone individually against placebo. The percentage of thrice-weekly urine samples that were negative for non-study opioids was statistically higher for both Suboxone versus placebo (p<0.0001) and buprenorphine versus placebo (p<0.0001).
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 Suboxone 12 mg/day), or 2 relatively low doses of active control, 1 of which was low enough to serve as an alternative to placebo, during a 3- to 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. 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 8 mg/day was similar to that of the moderate active control dose, but equivalence was not demonstrated.

Substitution treatment for opioid drug dependence, within a framework of medical, social and psychological treatment. The intention of the naloxone component is to deter IV misuse. Treatment is intended for use in adults who have agreed to be treated for addiction.

Administration is sublingual.
Treatment must be under the supervision of a physician experienced in the management of opiate dependence/addiction.
Physicians must warn patients that the sublingual route is the only effective and safe route of administration for Suboxone (see Precautions). Suboxone sublingual tablets are to be placed under the tongue until dissolved, which usually requires 5-10 min. The dose is made up from Suboxone 2 mg/0.5 mg and Suboxone 8 mg/2 mg sublingual tab, which may be taken all at the same time or in 2 divided portions; the 2nd portion to be taken directly after the 1st portion has dissolved.
Adults: Baseline liver function tests and documentation of viral hepatitis status is recommended prior to commencing therapy. Patients who are positive for viral hepatitis, on concomitant medicines (see Interactions) and/or have existing liver dysfunction are at risk of accelerated liver injury. Regular monitoring of liver function is recommended (see Precautions). Induction: Prior to treatment induction, consideration should be given to the type of opioid dependence (ie, long- or short-acting opioid), the time since last opioid use and the degree of opioid dependence. To avoid precipitating withdrawal, induction with Suboxone or buprenorphine only tablets should be undertaken when objective and clear signs of withdrawal are evident.
Initiation Therapy: Recommended Starting Dose: 1-2 tabs of Suboxone 2 mg/0.5 mg sublingual tablet. An additional 1-2 tablets of the Suboxone 2 mg/0.5 mg sublingual tablet may be administered on day 1 depending on the individual patient's requirement.
Opioid-Dependent Drug Addicts Who Have Not Undergone Withdrawal: When treatment starts, the 1st dose of Suboxone should be taken when signs of withdrawal appear, but not less than 6 hrs after the patient last used opioids (eg, heroin, short-acting opioids). Patients Receiving Methadone: Before beginning Suboxone therapy, the dose of methadone must be reduced to a maximum of 30 mg/day. The 1st dose of Suboxone should be taken when signs of withdrawal appear, but not less than 24 hrs after the patient last used methadone. Buprenorphine may precipitate symptoms of withdrawal in patients dependent upon methadone.
Dosage Adjustment and Maintenance: The dose of Suboxone should be increased progressively according to the clinical effect of the individual patient and should not exceed a maximum single daily dose of 24 mg. The dosage is titrated according to reassessment of the clinical and psychological status of the patient and should be made in steps of 2-8 mg.
During the initiation of treatment, daily dispensing of buprenorphine is recommended. After stabilization, a reliable patient may be given a supply of Suboxone sufficient for several days of treatment. It is recommended that the amount of Suboxone be limited to 7 days or according to local requirements.
Less Than Daily Dosing: After a satisfactory stabilization has been achieved, the frequency of Suboxone dosing may be decreased to dosing every other day at twice the individually titrated daily dose. For example, a patient stabilized to receive a daily dose of 8 mg may be given 16 mg on alternate days, with no medication on the intervening days. However, the dose given on any day should not exceed 24 mg. In some patients, after a satisfactory stabilization has been achieved, the frequency of Suboxone dosing may be decreased to 3 times a week (eg, on Monday, Wednesday and Friday). The dose on Monday and Wednesday should be twice the individually titrated daily dose, and the dose on Friday should be 3 times the individually titrated daily dose, with no dose on the intervening days. However, the dose given on any day should not exceed 24 mg. Patients requiring a titrated daily dose >8 mg/day may not find this regimen adequate.
Dosage Reduction and Termination of Treatment: After a satisfactory stabilization has been achieved, if the patient agrees, the dosage may be reduced gradually to a lower maintenance dose; in some favorable cases, treatment may be discontinued. The availability of the sublingual tablet in doses of 2 mg and 8 mg allows for a downward titration of dosage. For patients who may require a lower buprenorphine dose, buprenorphine 0.4 mg sublingual tablets may be used. Patients should be monitored following termination of treatment because of the potential for relapse.
Elderly: No data is available on elderly patients.
Pediatrics: Suboxone is not recommended for use in children.
Patients with Impaired Hepatic Function: The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone is unknown. Since both active medicines are extensively metabolized, the plasma levels will be expected to be higher in patients with moderate and severe hepatic impairment. It is not known whether both active substances are affected to the same extent.
As Suboxone pharmacokinetics may be altered in patients with hepatic insufficiency, lower initial doses and careful dose titration in patients with mild to moderate hepatic impairment are recommended (see Pharmacology under Actions).
Patients with Impaired Renal Function: Modification of the Suboxone dose is not required in patients with renal insufficiency. Caution is recommended when dosing patients with severe renal impairment (Cl_Cr <30 ml/min) (see Pharmacology under Actions).

In the event of overdose, general supportive measures should be instituted, including close monitoring of respiratory and cardiac status of the patient. The major symptom requiring intervention is respiratory depression, which could lead to respiratory arrest and death. If the patient vomits, care must be taken to prevent aspiration of the vomitus.
Treatment: Symptomatic treatment of respiratory depression and standard intensive care measures should be implemented. A patent airway and assisted or controlled ventilation must be assured. The patient should be transferred to an environment within which full resuscitation facilities are available.
Use of an opioid antagonist (eg, naloxone) is recommended, despite the modest effect it may have in reversing the respiratory symptoms of buprenorphine compared with its effects on full agonist opioid agents.
The long duration of action of Suboxone should be taken into consideration when determining the length of treatment and medical surveillance needed to reverse the effects of an overdose.

Hypersensitivity to buprenorphine, naloxone or to any of the excipients, severe respiratory and hepatic insufficiencies, and acute alcoholism or delirium tremens.

Patients should be closely monitored during the switching period from buprenorphine or methadone to Suboxone since withdrawal symptoms have been reported.
Diversion: Diversion refers to the introduction of buprenorphine into the illicit market either by patients or by individuals who obtain the medicinal product through theft from patients or pharmacies. This diversion may lead to new addicts using buprenorphine as the primary drug of abuse, with the risks of overdose, spread of blood-borne viral infections, respiratory depression and hepatic injury. Because the naloxone in the combination tablet precipitated withdrawal in individuals dependent on heroin, methadone or other full agonists, Suboxone is expected to be less likely to be diverted for IV use.
Precipitated Withdrawal: When initiating treatment with buprenorphine, the physician must be aware of the partial agonist profile of buprenorphine and that it can precipitate withdrawal in opioid-dependent patients particularly if administered <6 hrs after the last use of heroin or other short-acting opioid, or if administered <24 hrs after the last dose of methadone (see Dosage & Administration). Conversely, withdrawal symptoms may also be associated with suboptimal dosing.
The risk of serious undesirable effects eg, overdose or treatment dropout is greater if a patient is underdosed with Suboxone and continues to self-medicate withdrawal symptoms with opioids, alcohol or other sedative-hypnotics in particular benzodiazepines.
Dependence: Buprenorphine is a partial agonist at the mu-opiate receptor and chronic administration produces dependence of the opioid type.
Discontinuation of treatment may result in a withdrawal syndrome that may be delayed.
Suboxone may cause drowsiness, particularly when taken together with alcohol or central nervous system depressants (eg, tranquilizers, sedatives or hypnotics) (see Interactions).
Studies in animals, as well as clinical experience, have demonstrated that buprenorphine may produce dependence but at a lower level than morphine.
Respiratory Depression: A number of cases of death due to respiratory depression have been reported, particularly when buprenorphine was used in combination with benzodiazepines (see Interactions), or when buprenorphine was not used according to prescribing information.
Deaths have been reported in association with concomitant administration of buprenorphine and other depressants eg, alcohol or other opioids.
Hepatitis, Hepatic Events: Cases of acute hepatic injury have been reported in opioid-dependent addicts both in clinical trials and in post-marketing adverse event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of hepatic failure, hepatic necrosis, hepatorenal syndrome and hepatic encephalopathy. In many cases, the presence of preexisting liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant use of other potentially hepatotoxic medicines and ongoing injecting drug use may have a causative or contributory role. These underlying factors must be taken into consideration before prescribing Suboxone and during treatment. When a hepatic event is suspected, further biological and etiological evaluation is required. Depending upon the findings, the medicinal product may be discontinued cautiously so as to prevent withdrawal symptoms and to prevent a return to illicit drug use. If the treatment is continued, hepatic function should be monitored closely.
As buprenorphine is an opioid, pain as a symptom of a disease may be attenuated.
Athletes must be aware that Suboxone may cause a positive reaction to 'anti-doping' tests.
As with other opioids, caution is requested in patients using buprenorphine and having head injury, increased intracranial pressure, hypotension, prostatic hypertrophy or urethral stenosis.
Suboxone should be used with care in patients with: Asthma or respiratory insufficiency (cases of respiratory depression have been reported with buprenorphine); renal insufficiency (30% of the administered dose is eliminated by the renal route; thus, renal elimination may be prolonged); hepatic insufficiency (hepatic metabolism of buprenorphine may be altered) (see Contraindications ).
Medicines that inhibit the enzyme CYP3A4 may give rise to increased concentrations of buprenorphine. A reduction of the Suboxone dose may be needed. Patients already treated with CYP3A4 inhibitors should have their dose of Suboxone titrated carefully since a reduced dose may be sufficient in these patients (see Interactions).
The concomitant use of monoamine oxidase inhibitors (MAOI) might produce exaggeration of the effects of opioids, based on experience with morphine.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take Suboxone.
Effects on the Ability to Drive or Operate Machinery: In general, Suboxone has minor to moderate influence on the ability to move safely in traffic, use machines, or perform other hazardous activities. Suboxone may cause drowsiness, dizziness, or impaired thinking, particularly when taken together with alcohol or central nervous system depressants. Therefore,caution is advised when performing the above mentioned activities (see Interactions and Precautions).
Use in pregnancy & lactation: There is very limited experience with buprenorphine/naloxone in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Towards the end of pregnancy, high doses of buprenorphine may induce respiratory depression in the neonate even after a short period of administration. Long-term administration of buprenorphine during the last 3 months of pregnancy may cause a withdrawal syndrome in the neonate.
Suboxone should not be used during pregnancy. If it is the prescriber's opinion that therapy in pregnancy is required, the use of buprenorphine may be considered according to the local buprenorphine labeling.
In case pregnancy occurs while on Suboxone treatment, the mother and the unborn child should be closely monitored and switched to buprenorphine if further treatment is required. It is unknown whether naloxone is excreted in human breast milk. Buprenorphine and its metabolites are excreted in human breast milk. In rats, buprenorphine has been found to inhibit lactation. Therefore, breastfeeding should be discontinued during treatment with Suboxone.

There is very limited experience with buprenorphine/naloxone in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Towards the end of pregnancy, high doses of buprenorphine may induce respiratory depression in the neonate even after a short period of administration. Long-term administration of buprenorphine during the last 3 months of pregnancy may cause a withdrawal syndrome in the neonate.
Suboxone should not be used during pregnancy. If it is the prescriber's opinion that therapy in pregnancy is required, the use of buprenorphine may be considered according to the local buprenorphine labeling.
In case pregnancy occurs while on Suboxone treatment, the mother and the unborn child should be closely monitored and switched to buprenorphine if further treatment is required. It is unknown whether naloxone is excreted in human breast milk. Buprenorphine and its metabolites are excreted in human breast milk. In rats, buprenorphine has been found to inhibit lactation. Therefore, breastfeeding should be discontinued during treatment with Suboxone.

The most common treatment-related undesirable effects reported during clinical trials with Suboxone were those related to withdrawal symptoms (eg, abdominal pain, diarrhea, muscle aches, anxiety, sweating).
In the pivotal clinical study of Suboxone, 342 of 472 patients (72.5%) reported treatment-related adverse reactions. These reactions are listed as follows by system, organ class and frequency [very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000 to <1/100)].
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Treatment-Related Undesirable Effects Reported in the Pivotal Clinical Study of Suboxone (≥0.1% of Suboxone-Treated Patients):
Infections and Infestations: Common: Infection. Uncommon: Vaginitis.
Blood and Lymphatic System Disorders: Uncommon: Anemia, thrombocytopenia, leucopenia, lymphadenopathy, leukocytosis.
Immune System Disorders: Uncommon: Allergic reaction.
Metabolism and Nutrition Disorders: Common: Peripheral edema, decreased weight. Uncommon: Hyperglycemia, hyperlipemia, hypoglycemia.
Psychiatric Disorders: Common: Anxiety, nervousness, depression, decreased libido, abnormal thinking. Uncommon: Drug dependence, amnesia, hostility, speech disorder, depersonalization, abnormal dream, apathy, euphoria.
Nervous System Disorders: Very Common: Insomnia. Common: Somnolence, dizziness, paresthesia, hypertonia. Uncommon: Convulsion, agitation, tremor, hyperkinesia.
Eye Disorders: Common: Lacrimation disorder, amblyopia. Uncommon: Miosis, conjunctivitis.
Cardiac Disorders: Uncommon: Myocardial infarction, angina pectoris, palpitation, tachycardia, bradycardia.
Vascular Disorders: Common: Vasodilation, hypertension, migraine. Uncommon: Hypotension, heat stroke.
Respiratory, Thoracic and Mediastinal Disorders: Common: Rhinitis, pharyngitis, increased cough. Uncommon: Dyspnea, asthma, yawning.
Gastrointestinal Disorders: Very Common: Constipation, nausea. Common: Vomiting, dyspepsia, diarrhea, anorexia, flatulence. Uncommon: Ulcerative stomatitis, tongue discoloration.
Hepatobiliary Disorders: Common: Abnormal liver function.
Skin and Subcutaneous Tissue Disorders: Very Common: Sweating. Common: Rash, pruritus, urticaria. Uncommon: Exfoliative dermatitis, acne, skin nodule, alopecia, dry skin.
Musculoskeletal, Connective Tissue and Bone Disorders: Common: Arthralgia, myalgia, leg cramps. Uncommon: Arthritis.
Renal and Urinary Disorders: Common: Albuminuria, urine abnormality. Uncommon: Hematuria, kidney calculus, increased creatinine, urinary tract infection, dysuria, urinary retention.
Reproductive System and Breast Disorders: Uncommon: Impotence, amenorrhea, abnormal ejaculation, menorrhagia, metrorrhagia.
General Disorders: Very Common: Withdrawal syndrome, headache. Common: Asthenia, fever, flu syndrome, malaise, accidental injury, chills; chest, abdominal and back pain, pain.
Injury, Poisoning and Procedural Complications: Uncommon: Hypothermia.
Buprenorphine used alone for treatment of opioid dependency has been associated with the following symptoms (>1%): Constipation, headache, insomnia, asthenia, drowsiness, nausea and vomiting, fainting and dizziness, orthostatic hypotension and sweating. Other undesirable effects (<0.1%) have been reported in association with buprenorphine alone. These are respiratory depression (see Interactions and Precautions), hepatic necrosis and hepatitis (see Precautions), hallucinations, cases of bronchospasm, angioneurotic edema and anaphylactic shock.
In cases of IV misuse, local reactions, sometimes septic and potentially serious acute hepatitis, have been reported (see Precautions).
In patients presenting with marked drug dependence, initial administration of buprenorphine can produce a withdrawal effect similar to that associated with naloxone.
Spontaneous abortion has been reported with both buprenorphine and buprenorphine-naloxone. It is not possible to establish a causal relationship since cases typically involve other drug use or risk factors for spontaneous abortion (see Use in pregnancy & lactation under Precautions).
A neonatal abstinence syndrome has been reported among newborns of women who have received buprenorphine during pregnancy. The syndrome may be milder and more protracted than that from short-acting full mu-opioid agonists. The nature of the syndrome may vary depending upon the mother's drug use history (see Use in pregnancy & lactation under Precautions).

Suboxone should not be taken together with alcoholic drinks or medications containing alcohol, as alcohol increases the sedative effect of buprenorphine (see Effects on the Ability to Drive or Operate Machinery under Precautions).
Suboxone should be used cautiously when co-administered with: Benzodiazepines: This combination may result in death due to respiratory depression of central origin. Therefore, dosages must be limited and this combination must be avoided in cases where there is a risk of misuse (see Precautions).
Other central nervous system depressants, other opioid derivatives (eg, methadone, analgesics and antitussives), certain antidepressants, sedative H₁-receptor antagonists, barbiturates, anxiolytics other than benzodiazepines, neuroleptics, clonidine and related substances: These combinations increase central nervous system depression. The reduced level of alertness can make driving and using machines hazardous.
CYP3A4 Inhibitors: An interaction study of buprenorphine with ketoconazole (a potent inhibitor of CYP3A4) resulted in increased C_max and area under the curve (AUC) of buprenorphine (approximately 70% and 50%, respectively) and to a lesser extent, of norbuprenorphine. Patients receiving Suboxone should be closely monitored and may require dose reduction if combined with potent CYP3A4 inhibitors (eg, protease inhibitors eg, ritonavir, nelfinavir or indinavir or azole antifungals eg, ketoconazole or itraconazole).
CYP3A4 Inducers: The interaction of buprenorphine with CYP3A4 inducers has not been investigated. Therefore, it is recommended that patients receiving Suboxone should be closely monitored if inducers (eg, phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered.
To date, no notable interaction has been observed with cocaine, the agent most frequently used by multi-drug abusers in association with opioids.

Instructions for Use/Handling and Disposal: Medicines which are no longer required should not be disposed of via wastewater or the municipal sewage system. Patients should be instructed to return them to the pharmacy or to ask their pharmacist how to dispose of them in accordance with the national regulations. These measures will help to protect the environment.

Store below 30°C.

Drugs Used in Substance Dependence

N07BC51 - buprenorphine, combinations ; Belongs to the class of drugs used in the management of opioid dependence.

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