Suboxone 8mg/2mg Sublingual Tablets

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Indivior UK Limited

Indivior UK Limited

Company Products

Medicine NameActive Ingredients
Medicine Name Suboxone 2mg/0.5mg Sublingual Tablets Active Ingredients Buprenorphine hydrochloride, Naloxone Hydrochloride dihydrate
Medicine Name Suboxone 8mg/2mg Sublingual Tablets Active Ingredients Buprenorphine hydrochloride, Naloxone Hydrochloride dihydrate
Medicine Name Subutex 0.4mg, 2mg and 8mg Sublingual Tablets Active Ingredients Buprenorphine hydrochloride
Medicine Name Subutex Sublingual Tablets Active Ingredients Buprenorphine hydrochloride
1 - 0 of 4 items.Total: Infinity pages

When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 17 October 2017 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 6.6 - Special precautions for disposal and other handling

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

·         Change to section 2 - Qualitative and quantitative composition

·         Change to section 4.2 - Posology and method of administration

·         Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

·         Change to section 6.6 - Special precautions for disposal and other handling

Updated on 17 October 2017 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 5 July 2013 PIL

Reasons for updating

  • Change to storage instructions
  • Change to side-effects
  • Change to drug interactions
  • Change to information about pregnancy or lactation
  • Change to date of revision
  • Change to warnings or special precautions for use

Updated on 5 July 2013 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Section 4.2-  Addition of Clinical Opioid Withdrawal Scale (COWS) as a useful reference assessment.

Section 4.4 (Respiratory depression) - Addition of a warning about potentially fatal respiratory depression when buprenorphine is administered to non-opioid dependent individuals.

Section 4.4 (Respiratory depression) – Inclusion of examples of conditions that may lead to respiratory depression.

Section 4.4 (Respiratory depression) - Addition of a warning about severe, possibly fatal, respiratory depression in children and non-dependent persons in case of accidental or deliberate ingestion.

Section 4.4 (Hepatitis and hepatic events) – Inclusion death in the spectrum of abnormalities. Addition of pre-existing mitochondrial impairment, genetic disease, alcohol abuse and anorexia.

Section 4.4 (Renal impairment) – Addition of a caution when dosing patients with severe renal impairment.

Section 4.4 – Inclusion of additional general warnings relevant to the administration of opioids.

Section 4.5 – Addition of information regarding analgesia. Inclusion of Naltrexone. Addition of macrolide antibiotics in the CYP3A4 inhibitors. Potential sub-optimal dosing with concomitant use of CYP3A4 inducers included.

Section 4.6 – Further information on withdrawal syndrome in the neonate added. Treatment switch to monobuprenorphine removed and replaced by use of Suboxone during pregnancy based on a risk/benefit approach.

Section 4.8 – Spontaneous abortion removed.  Addition of hepatic transaminase increase, hepatitis, acute hepatitis, cytolytic hepatitis, jaundice, hepatorenal syndrome, hepatic encephalopathy, and hepatic necrosis.

Section 4.9 – Addition of miosis, hypotension, nausea, vomiting in the overdose symptoms. Inclusion of additional information for the use of naloxone in the treatment of overdose.

 

Updated on 5 July 2013 PIL

Reasons for updating

  • New PIL for new product

Updated on 11 April 2013 PIL

Reasons for updating

  • Change due to user-testing of patient information

Updated on 22 March 2012 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.6 - Special precautions for disposal and other handling

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Due to the amount of changes in the SPC during the renewal, I am therefore copying the whole of the SPC with track changes shown.

1.       NAME OF THE MEDICINAL PRODUCT

 

Suboxone 8 mg/2 mg sublingual tablets

 

 

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Each tablet contains 8 mg buprenorphine (as buprenorphine hydrochloride) and 2 mg naloxone (as naloxone hydrochloride dihydrate).

 

Excipients:

Each sublingual tablet contains 168 mg lactose 168 mg

 

For a full list of excipients, see section 6.1.

 

 

3.       PHARMACEUTICAL form

 

Sublingual tablet

 

White hexagonal biconvex tablets of 11 mm, embossed with a sword logo on one side and “N8” on the reverse side.

 

 

4.       Clinical particulars

 

4.1     Therapeutic indications

 

Substitution treatment for opioid drug dependence, within a framework of medical, social and psychological treatment. The intention of the naloxone component is to deter intravenous misuse. Treatment is intended for use in adults and adolescents over 15 years of age who have agreed to be treated for addiction.

 

4.2     Posology and method of administration

 

Treatment must be under the supervision of a physician experienced in the management of opiate dependence/addiction.

 

Each Suboxone sublingual tablet contains buprenorphine and naloxone. Suboxone containing 8 mg buprenorphine and 2 mg naloxone is referred to as the "8 mg" tablets.

Posology

 

Physicians must warn patients that the sublingual route is the only effective and safe route of administration for this medicinal product (see section 4.4). Suboxone sublingual tablets are Precautions to be placed under the tongue until dissolved, which usually requires 5 to 10 minutes. The dose is made up from Suboxone 2 mg/0.5 mg and Suboxone 8 mg/2 mg sublingual tablets, which may be taken all at the same time or in two divided portions; the second portion to be taken directly after the first portion has dissolved.before induction

 

Adults:

Baseline liver function tests and documentation of viral hepatitis status is are recommended prior to commencing therapy. Patients who are positive for viral hepatitis, on concomitant medicinal products (see section 4.5) and/or have existing liver dysfunction are at risk of accelerated liver injury. Regular monitoring of liver function is recommended (see section 4.4).

 

Induction:

Prior to treatment inductioninitiation, consideration should be given to the type of opioid dependence (i.e. long- or short-acting opioid), the time since last opioid use and the degree of opioid dependence. To avoid precipitating withdrawal, induction with Suboxonebuprenorphine/naloxone or buprenorphine only tablets should be undertaken when objective and clear signs of withdrawal are evident.

 

Initiation therapy:

The recommended starting dose is one to two tablets of Suboxone 2 mg/0.5 mg sublingual tablets. An additional one to two tablets of the Suboxone 2 mg/0.5 mg may be administered on day one depending on the individual patient’s requirement.

 

  • Opioid-For patients dependent drug addicts who have not undergone withdrawal: When treatment startsupon heroin or short-acting opioids, the first dose of Suboxonebuprenorphine/naloxone should be taken when signs of withdrawal appear, but not less than 6 hours after the patient last used opioids (eg. heroin; short acting opioids).

 

  • Patients For patients receiving methadone: Before beginning Suboxone therapy, the dose of methadone mustshould be reduced to a maximum of 30 mg/day before beginning buprenorphine/naloxone therapy. The long half life of methadone should be considered when starting buprenorphine/naloxone. The first dose of Suboxonebuprenorphine/naloxone should be taken only when signs of withdrawal appear, but not less than 24 hours 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.

 

 

Initiation therapy (induction)

The recommended starting dose in adults and adolescents over 15 years of age is one to two Suboxone 2 mg/0.5 mg.  An additional one to two Suboxone 2 mg/0.5 mg may be administered on day one depending on the individual patient’s requirement.

During the initiation of treatment, daily dispensing of buprenorphinesupervision of dosing is recommended. After stabilisation, a reliable patient may be given a supply of Suboxone sufficient for several days of to ensure proper sublingual placement of the dose and to observe patient response to treatment as a guide to effective dose titration according to clinical effect.  

 

Dosage adjustment and maintenance therapy

Following treatment. It is recommended that the amount of Suboxone be limited to 7 days or according to local requirements.

 induction on day one, the patient should be stabilised to a maintenance dose during the next few days by progressively adjusting the dose according to the clinical effect of the individual patient.  Dose titration in steps of 2-8 mg is guided by reassessment of the clinical and psychological status of the patient, and should not exceed a maximum single daily dose of 24 mg.

 

Less than daily dosing:  

After a satisfactory stabilisation 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 stabilised to receive a daily dose of 8 mg may be given 16 mg on alternate days, with no dose on the intervening days. However, the dose given on any one day should not exceed 24 mg. In some patients, after a satisfactory stabilisation has been achieved, the frequency of Suboxone dosing may be decreased to 3 times a week (for example 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 three times the individually titrated daily dose, with no dose on the intervening days. However, the dose given on any one day should not exceed 24 24 mg. Patients requiring a titrated daily dose > 8 > 8 mg/day may not find this regimen adequate. 

 

Dosage reduction and termination of treatment:

Medical withdrawal

After a satisfactory stabilisation has been achieved, if the patient agrees, the dosage may be reduced gradually to a lower maintenance dose; in some favourable cases, treatment may be discontinued. The availability of the sublingual tablet in doses of 2 mg/0.5 mg and 88 mg/2 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 treatmentmedical withdrawal because of the potential for relapse.

 

Special populations

 

Elderly:

No data is available on elderly patients.

 

Paediatrics:

Suboxone is not recommended for use in children below age 15 years due to lack of data on The safety and efficacy of buprenorphine/naloxone in elderly patients over 65 years of age have not been established. No recommendation on posology can be made.

 

Patients with impaired hepatic function:

           

Hepatic impairment

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 medicinal products (see section 4.5) and/or have existing liver dysfunction are at risk of accelerated liver injury. Regular monitoring of liver function is recommended (see section 4.4).

The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone is unknown. Since both active substances 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 Suboxonebuprenorphine/naloxone pharmacokinetics may be altered in patients with hepatic insufficiencyimpairment, lower initial doses and careful dose titration in patients with mild to moderate hepatic impairment are recommended (see section 5.2). Buprenorphine/naloxone is contraindicated in patients with severe hepatic dysfunction (see section 4.3).

 

Patients with impaired renal function:

 

Renal impairment

Modification of the Suboxonebuprenorphine/naloxone dose is not required in patients with renal insufficiencyimpairment. Caution is recommended when dosing patients with severe renal impairment (CLcr CLcr < 30 ml/min) (see section section 5.2).

 

Paediatric population

The safety and efficacy of buprenorphine/naloxone in children below the age of 15 years have not been established. No data are available.

 

Method of administration

Physicians must warn patients that the sublingual route is the only effective and safe route of administration for this medicinal product (see section 4.4). The tablet is to be placed under the tongue until completely dissolved. Patients should not swallow or consume food or drink until the tablet is completely dissolved.

 

The dose is made up from Suboxone 2 mg/0.5 mg and Suboxone 8 mg/2 mg, which may be taken all at the same time or in two divided portions; the second portion to be taken directly after the first portion has dissolved.

 

 

4.3       Contraindications

           

Suboxone is contraindicated in Hypersensitivity to the following instances:

hypersensitivity to buprenorphine, to naloxone,active substances or to any of the excipients,

severeSevere respiratory insufficiency,

severeSevere hepatic insufficiency,impairment

acuteAcute alcoholism or delirium tremens.

 

4.4     Special warnings and precautions for use

 

Due to the lack of data in adolescents (age 15-<18), Suboxone should be used only with caution in this age group.

 

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 intravenous 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 less than 6 hours after the last use of heroin or other short acting opioid, or if administered less than 24 hours after the last dose of methadone (see section 4.2). Conversely, withdrawal symptoms may also be associated with suboptimal dosing.

 

The risk of serious undesirable effects such as overdose or treatment dropout is greater if a patient is under dosed 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 (such as tranquilisers, sedatives or hypnotics) (see section 4.5).

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 section 4.5), or when buprenorphine was not used according to prescribing information.

 

Deaths have been reported in association with concomitant administration of buprenorphine and other depressants such as alcohol or other opioids.

 

Hepatitis and 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 pre-existing 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.

General warnings relevant to the administration of opioids

Buprenorphine/naloxone may produce orthostatic hypotension in ambulatory patients.

 

Caution is requested in patients using buprenorphine and having head injury, increased intracranial pressure, hypotension, prostatic hypertrophy or urethral stenosis.

 

As buprenorphine is an opioid, pain as a symptom of a disease may be attenuated.

 

Athletes must be aware that this medicine 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.

 

This product 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 section 4.3).

 

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 section 4.5).

 

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 lactase deficiency or glucose-galactose malabsorption should not take this medicine.

The concomitant use of monoamine oxidase inhibitors (MAOI) might produce exaggeration of the effects of opioids, based on experience with morphine (see section 4.5).

 

Misuse, abuse and diversion

Buprenorphine can be misused or abused in a manner similar to other opioids, legal or illicit. Some risks of misuse and abuse include overdose, spread of blood borne viral infections, respiratory depression and hepatic injury. Buprenorphine misuse by someone other than the intended patient poses the additional risk of new drug dependent individuals using buprenorphine as the primary drug of abuse, and may occur if the medicine is distributed for illicit use directly by the intended patient or if the medicine is not safeguarded against theft.

 

Sub-optimal treatment with buprenorphine/naloxone may prompt medication misuse by the patient, leading to overdose or treatment dropout. A patient who is under-dosed with buprenorphine/naloxone may continue responding to uncontrolled withdrawal symptoms by self-medicating with opioids, alcohol or other sedative-hypnotics such as benzodiazepines.

 

To minimize the risk of misuse, abuse and diversion, physicians should take appropriate precautions when prescribing and dispensing buprenorphine, such as to avoid prescribing multiple refills early in treatment, and to conduct patient follow-up visits with clinical monitoring that is appropriate to the patient's needs.

 

Combining buprenorphine with naloxone in Suboxone is intended to deter misuse and abuse of the buprenorphine. Intravenous or intranasal misuse of Suboxone is expected to be less likely than buprenorphine alone since the naloxone in Suboxone can precipitate withdrawal in individuals dependent on heroin, methadone, or other opioid agonists.

 

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 section 4.5), or when buprenorphine was not used according to prescribing information.  Deaths have also been reported in association with concomitant administration of buprenorphine and other depressants such as alcohol or other opioids.

 

This product should be used with care in patients with asthma or respiratory insufficiency.

 

CNS depression

Buprenorphine/naloxone may cause drowsiness, particularly when taken together with alcohol or central nervous system depressants (such as tranquilisers, sedatives or hypnotics) (see section 4.5).

 

Dependence

Buprenorphine is a partial agonist at the µ (mu)-opiate receptor and chronic administration produces dependence of the opioid type.  Studies in animals, as well as clinical experience, have demonstrated that buprenorphine may produce dependence, but at a lower level than a full agonist e.g. morphine.

 

Abrupt discontinuation of treatment is not recommended as it may result in a withdrawal syndrome that may be delayed in onset.

 

Hepatitis and hepatic events

Cases of acute hepatic injury have been reported in opioid-dependent addicts both in clinical trials and in post marketing adverse reaction 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 pre-existing 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 buprenorphine/naloxone 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.

 

Precipitation of opioid withdrawal syndrome

When initiating treatment with buprenorphine/naloxone, 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 less than 6 hours after the last use of heroin or other short-acting opioid, or if administered less than 24 hours after the last dose of methadone. Patients should be clearly monitored during the switching period from buprenorphine or methadone to buprenorphine/naloxone since withdrawal symptoms have been reported. To avoid precipitating withdrawal, induction with buprenorphine/naloxone should be undertaken when objective signs of withdrawal are evident (see section 4.2).

 

Withdrawal symptoms may also be associated with sub-optimal dosing.

 

Hepatic impairment

Hepatic metabolism of buprenorphine may be altered in patients with hepatic impairment, which may give rise to increased plasma concentrations of buprenorphine. A reduction of the buprenorphine/naloxone dose may be needed. (see section 4.2).

 

Renal impairment

Renal elimination may be prolonged since 30 % of the administered dose is eliminated by the renal route (see section 5.2).

 

Use in adolescents (Age 15-<18)

Due to the lack of data in adolescents (age 15-<18), patients in this age group should be more closely monitored during treatment.

 

CYP 3A inhibitors

Medicines that inhibit the enzyme CYP3A4 may give rise to increased concentrations of buprenorphine. A reduction of the buprenorphine/naloxone dose may be needed. Patients already treated with CYP3A4 inhibitors should have their dose of buprenorphine/naloxone titrated carefully since a reduced dose may be sufficient in these patients (see section 4.5).

 

Suboxone contains lactose.  Patients with rare hereditary problems of galactose intolerance, should not take this medicine.

 

 

4.5       Interaction with other medicinal products and other forms of interaction

 

Suboxone should not be taken together with:

 

·                alcoholic drinks or medicationsmedicines containing alcohol, as alcohol increases the sedative effect of buprenorphine (see section 4.7).

 

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. Patients should be warned that it is extremely dangerous to self-administer non-prescribed benzodiazepines while taking this product, and should also be cautioned to use benzodiazepines concurrently with this product only as directed by their physician (see section 4.4).

 

·                other central nervous system depressants, other opioid derivatives (e.g. 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 Cmax and AUC (area under the curve) 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 (e.g. protease inhibitors like ritonavir, nelfinavir or indinavir or azole antifungals such as 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 (e.g. phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered.

 

·                the concomitant use of monoamine oxidase inhibitors (MAOI) might produce exaggeration of the effects of opioids, based on experience with morphine.

 

To date, no notable interaction has been observed with cocaine, the agent most frequently used by multi-drug abusers in association with opioids.

 

4.6     Pregnancy Fertility, pregnancy and lactation

 

Pregnancy:

There is very limited experience with buprenorphine/naloxone are no adequate data from the use of Suboxone in pregnant women.  Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

 

Towards the end of pregnancy high doses of buprenorphine may induce respiratory depression in the neonatenewborn infant even after a short period of administration. Long-term administration of buprenorphine during the last three 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 buprenorphine/naloxone treatment, the mother and the unborn child should be closely monitored and switcheda switch to treatment with buprenorphine alone should be considered if further treatment is required.

 

Breast-feeding:

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, breast-feeding should be discontinued during treatment with Suboxone.

 

Fertility

Animal studies have shown a reduction in female fertility at high doses (systemic exposure > 2.4 times the human exposure at the maximum recommended dose of 24 mg buprenorphine, based on AUC). Also see section 5.3.

 

 

4.7     Effects on ability to drive and use machines

 

In general SuboxoneBuprenorphine/naloxone has minor to moderate influence on the ability to move safely in traffic, drive and use machines, or perform other hazardous activities. Suboxone when administered to opioid dependent patients.  This product may cause drowsiness, dizziness, or impaired thinking, particularly when especially during treatment induction and dose adjustment. If taken together with alcohol or central nervous system depressants. Therefore caution is advised when performing, the above mentioned activitieseffect is likely to be more pronounced (see sections 4.4 and 4.5).

 

Patients should be cautioned about driving or operating hazardous machinery in case buprenorphine/naloxone may affect their ability to engage in such activities.

 

 

4.8     Undesirable effects

 

The most common-treatment related undesirable effects reported during clinical trials with Suboxone were those related to withdrawal symptoms (e.g. abdominal pain, diarrhoea, 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 in Table 1 by system organ class and frequency (very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1,000 to ≤ 1/100).

 

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

 

Table 1: Treatment-related undesirable effects reported in the pivotal clinical study of Suboxone (³ 0.1 % of Suboxone-treated patients)

 

Infections and infestations

 

Common:

Uncommon:

 

 

Infection

Vaginitis

Summary of the safety profile

The most commonly reported treatment related adverse reactions reported during the pivotal clinical studies were constipation and symptoms commonly associated with drug withdrawal (i.e. insomnia, headache, nausea, and hyperhidrosis). Some reports of seizure, vomiting, diarrhoea, and elevated liver function tests were considered serious.

 

Tabulated list of adverse reactions

Table 1 summarizes adverse reactions reported from pivotal clinical studies in which, 342 of 472 patients (72.5 %) reported adverse reactions. 

 

The frequency of possible side effects listed below is defined using the following convention:

Very common (³1/10), Common (³1/100 to <1/10), Uncommon (³1/1,000 to <1/100), Rare (³1/10,000 to <1/1,000), Very rare (<1/10,000), Not known (events not reported in registration trials cannot be estimated from the available postmarketing spontaneous reports).

 

Table 1: Treatment-related adverse reactions reported in clinical studies of buprenorphine/naloxone

 

 

Very common

(≥1/10)

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1000 to <1/100)

Not Known

Infections and infestations

 

 

 

Anaemia, thrombocytopenia, leucopenia, lymphadenopathy, leukocytosis

Immune system disorders

 

Uncommon:

 

 

Allergic reaction

Metabolism

Influenza

Infection

Pharyngitis

Rhinitis

Urinary tract infection

Vaginal infection

 

Blood and nutritionlymphatic system disorders

 

Common:

Uncommon:

 

 

Peripheral oedema, weight decreased

Hyperglycaemia, hyperlipemia, hypoglycemia

Psychiatric disorders

 

Common:

 

Uncommon:

 

 

 

Anxiety, nervousness, depression, libido decreased, thinking abnormal

Drug dependence, amnesia, hostility, speech disorder, depersonalization, abnormal dream, apathy, euphoria

Nervous

 

Anaemia

Leukocytosis

Leukopenia

Lymphadenopathy

Thrombocytopenia

 

Immune system disorders

 

Very Common:

Common:

Uncommon:

 

 

Insomnia

Somnolence, dizziness, paresthesia, hypertonia

Convulsion, agitation, tremor, hyperkinesia

Eye disorders

 

Common:

Uncommon:

 

 

Lacrimation disorder, amblyopia

Miosis, conjunctivitis

Cardiac

 

Hypersensitivity

 

Metabolism and nutrition disorders

 

Uncommon:

 

 

Myocardial infarction, angina pectoris, palpitation, tachycardia, bradycardia

Vascular disorders

 

Common:

Uncommon:

 

 

Vasodilation, hypertension, migraine

Hypotension, heat stroke

Respiratory, thoracic and mediastinal

Decreased appetite

Hyperglycaemia

Hyperlipidaemia

Hypoglycaemia

 

Psychiatric disorders

 

Common:

Uncommon:

 

 

 

Rhinitis, pharyngitis, cough increased

Dyspnoea, asthma, yawn

Gastrointestinal disorders

 

Very Common:

Common:

Uncommon:

 

 

Constipation, nausea

Vomiting, dyspepsia, diarrhoea, anorexia, flatulence

Ulcerative stomatitis, tongue discolouration

HepatobiliaryInsomnia

Anxiety

Depression

Libido decreased

Nervousness

Thinking abnormal

Abnormal dreams

Agitation

Apathy

Depersonalisation

Drug dependence

Euphoric mood

Hostility

 

Nervous system disorders

 

Common:

 

 

Liver function abnormal

Skin and subcutaneous tissue disorders

 

Very Common:

Common:

Uncommon:

 

 

 

Sweating

Rash, pruritus, urticaria

Exfoliative dermatitis, acne, skin nodule, alopecia, dry skin

Musculoskeletal, connective tissue and boneHeadache

Migraine

Dizziness

Hypertonia

Paraesthesia

Somnolence

Amnesia

Convulsion

Hyperkinesia

Speech disorder

Tremor

 

Eye disorders

 

Common:

Uncommon:

 

 

 

Arthralgia, myalgia, leg cramps

Arthritis

Renal and urinary disorders

 

Common:

Uncommon:

 

 

 

Albuminuria, urine abnormality

Haematuria, kidney calculus, increased creatinine, urinary tract infection, dysuria, urinary retention

Reproductive system and breast

 

Amblyopia

Lacrimal disorder

Conjunctivitis

Miosis

 

Cardiac disorders

 

Uncommon:

 

 

 

 

Impotence, amenorrhoea, abnormal ejaculation, menorrhagia, metrorrhagia

General disorders

 

Very Common:

Common:

 

 

 

Withdrawal syndrome, headache

Asthenia, fever, flu syndrome, malaise, accidental injury, chills, chest pain, abdominal pain, back pain, pain

Injury, poisoning and procedural

complications

 

Uncommon:

 

Angina Pectoris

Bradycardia

Myocardial infarction

Palpitations

Tachycardia

 

Vascular disorders

 

 

 

Hypothermia

 

Buprenorphine used alone for

Hypertension

Vasodilatation

Hypotension

 

Respiratory, thoracic and mediastinal disorders

 

 

Cough

Asthma

Dyspnoea

Yawning

 

Gastrointestinal disorders

 

Constipation

Nausea

Abdominal Pain

Diarrhoea

Dyspepsia

Flatulence

Vomiting

Mouth ulceration

Tongue discolouration

 

Hepatobiliary disorders

 

 

Hepatic function abnormal

 

 

Skin and subcutaneous tissue disorders

 

Hyperhidrosis

Pruritus

Rash

Urticaria

Acne

Alopecia

Dermatitis exfoliative

Dry skin

Skin mass

 

Musculoskeletal and connective tissue disorders

 

 

Back Pain

Arthralgia

Muscle spasms

Myalgia

Arthritis

 

Renal and urinary disorders

 

 

Urine Abnormality

Albuminuria

Dysuria

Haematuria

Nephrolithiasis

Urinary retention

 

Pregnancy, puerperium and perinatal conditions

 

 

 

Abortion, spontaneous

Reproductive system and breast disorders

 

 

Erectile dysfunction

Amenorrhoea

Ejaculation disorder

Menorrhagia

Metrorrhagia

 

General disorders and administration site conditions

 

Drug withdrawal syndrome

Asthenia

Chest Pain

Chills

Pyrexia

Malaise

Pain

Oedema peripheral

Hypothermia

Drug withdrawal syndrome, neonatal

Investigations

 

 

Weight decreased

Blood creatinine increased

 

Injury, poisoning and procedural complications

 

 

Injury

Heat stroke

 

 

Table 2: Adverse reactions reported for buprenorphine alone for the treatment of opioid dependency has been associateddependence.

Very common

(≥1/10)

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1000 to <1/100)

Rare

(³1/10,000 to <1/1,000)

Not Known

Immune system disorders

 

 

 

Anaphylactic, shock

Sepsis

Psychiatric disorders

Insomnia

 

 

Hallucination

 

Intentional drug misuse

Nervous system disorders

Headache

Dizziness,

Somnolence,

Syncope

 

 

 

Vascular disorders

 

Orthostatic, hypotension

 

 

 

Respiratory, thoracic and mediastinal disorders

 

 

 

Respiratory, depression,

Bronchospasm

 

Gastrointestinal disorders

Nausea,

Vomiting

Constipation

 

 

 

Hepatobiliary disorders

 

 

 

Hepatic necrosis ,Hepatitis

 

Skin and subcutaneous tissue disorders

 

Hyperhydrosis

 

Angioedema

 

Pregnancy, puerperium and perinatal conditions

 

 

 

 

Abortion, spontaneous

General disorders and administration site conditions

 

Asthenia

 

 

 

Drug withdrawal syndrome, Neonatal drug withdrawal syndrome,

Local reaction

 

Description of other selected adverse reactions

 

Adverse reactions listed in Tables 1 and 2 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 %)unknown frequency have been reported in association with buprenorphine alone. These are:under the following circumstances:

·               respiratory depression (see sections 4.4 and 4.5),

·               hepatic necrosis and hepatitis (see section 4.4),

·               hallucinations,

·               cases of bronchospasm, angioneurotic oedema and anaphylactic shock.

·                

·               In cases of intravenous drug misuse, local reactions, sometimes septic, and potentially serious acute hepatitis have been reported (see section 4.4).

·                

·               In patients presenting with marked drug dependence, initial administration of buprenorphine can produce a drug withdrawal effectsyndrome similar to that associated with naloxone (see sections 4.2 and 4.4).

·                

·               Spontaneous abortion has been reported with both buprenorphine and buprenorphine-/naloxone. It is not possible to establish a causal relationship, or frequency since cases typically involve other drug use or risk factors for spontaneous abortion (see section 4.6).

·                

·               A neonatal abstinencedrug withdrawal 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 µ-opioid agonists. The nature of the syndrome may vary depending upon the mother’s drug use history (see section 4.6).

 

 

4.9       Overdose

 

InRespiratory depression as a result of central nervous system depression is the eventprimary symptom requiring intervention in the case of overdose, general because it may lead to respiratory arrest and death. Signs of overdose may also include somnolence, amblyopia and/or speech disorders.  .

 

Treatment: 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.

 

If the patient vomits, care must be taken to prevent aspiration of the vomitus.

 

Use of an opioid antagonist (i.e., 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 Suboxonebuprenorphine should be taken into consideration when determining the length of treatment and medical surveillance needed to reverse the effects of an overdose.

 

 

5.       PHARMACOLOGICAL PROPERTIES

 

5.1     Pharmacodynamic properties

 

Pharmacotherapeutic group: DrugsOther nervous system drugs, drugs used in opioid dependenceaddictive disorders, ATC code: N07B C51.

N07BC51.

 

Mechanism of action:

Buprenorphine is an opioid partial agonist/antagonist which binds to the m (mu) and k (kappa) opioid receptors of the brain. Its activity in opioid maintenance treatment is attributed to its slowly reversible properties with the mm-opioid receptors, which, over a prolonged period, might minimise 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 m (mu)-m-opioid receptors. When administered orally or sublingually in usual doses to patients experiencing opioid withdrawal, naloxone exhibits little or no pharmacological effect because of its almost complete first pass metabolism. However, when administered intravenously to opioid -dependent persons, the presence of naloxone in Suboxone produces marked opioid antagonist effects and opioid withdrawal, thereby deterring intravenous abuse.

 

Clinical efficacy:

Efficacy and safety data for Suboxonebuprenorphine/naloxone are primarily derived from a one-year clinical trial, comprising a 4-week randomised double blind comparison of Suboxonebuprenorphine/naloxone, buprenorphine and placebo tablets followed by a 48 week safety study of Suboxonebuprenorphine/naloxone. In this trial, 326 heroin-addicted subjects were randomly assigned to either Suboxonebuprenorphine/naloxone 16 mg per day, 16 mg buprenorphine per day or placebo tablets. For subjects randomized to either active treatment, dosing began with one 8 mg tablet of buprenorphine on Day Day 1, followed by 16 mg (two 8 mg tablets) of buprenorphine on Day Day 2. On Day Day 3, those randomized to receive Suboxonebuprenorphine/naloxone 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 Suboxonebuprenorphine/naloxone individually against placebo. The percentage of thrice-weekly urine samples that were negative for non-study opioids was statistically higher for both Suboxonebuprenorphine/naloxone versus placebo (p < 0.0001) and buprenorphine versus placebo (p < 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 12 mg/day of Suboxonebuprenorphine/naloxone), or two relatively low doses of active control, one of which was low enough to serve as an alternative to placebo, during a 3 to10 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 per day was similar to that of the moderate active control dose, but equivalence was not demonstrated.

 

 

5.2     Pharmacokinetic properties

 

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 this medicinal product by the oral route is therefore inappropriate.

 

Peak plasma concentrations are achieved 90 minutes after sublingual administration. Plasma levels of buprenorphine increased with the sublingual dose of Suboxonebuprenorphine/naloxone. Both Cmax and AUC of buprenorphine increased with the increase in dose (in the range of 4-16 mg), although the increase was less than dose -proportional.

 

Pharmacokinetic Parameter

 

Suboxone 4 mg

Suboxone 8 mg

Suboxone 16 16 mg

Cmax · Cmax ng/ml

 

1.84 (39)

3.0 (51)

5.95 (38)

AUC0-48  

hour · hour ng/ml

12.52 (35)

20.22 (43)

34.89 (33)

 

Distribution:

The absorption of buprenorphine is followed by a rapid distribution phase (distribution half-life of 2 to 5 hours).

 

MetabolismBiotransformation and elimination:

Buprenorphine is metabolised 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 m (mu)-m-opioid agonist with weak intrinsic activity.

 

Elimination of buprenorphine is bi‑ or tri‑exponential, and has a mean half-life from plasma of 32 hours.

Buprenorphine is eliminated in the faeces by biliary excretion of the glucuroconjugated metabolites (70 %), the rest being eliminated in the urine.

 

Naloxone

 

Absorption and distribution:

Following intravenous administration, naloxone is rapidly distributed (distribution half-life life ~ 4 minutes). Following oral administration, naloxone is barely detectable in plasma; following sublingual administration of Suboxonebuprenorphine/naloxone, plasma naloxone concentrations are low and decline rapidly.

 

Metabolism and eliminationBiotransformation:

The medicinal product 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 hours.

 

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 Suboxonebuprenorphine/naloxone. No dose modification based on renal function is required but caution is recommended when dosing subjects with severe renal impairment (see Section 4.3).

 

Hepatic impairment: Hepatic elimination plays a relatively large role (~70 %) in the overall clearance of Suboxonebuprenorphine/naloxone and the action of buprenorphine may be prolonged in subjects with impaired hepatic clearance. Lower initial Suboxonebuprenorphine/naloxone doses and cautious titration of dosage may be required in patients with mild to moderate hepatic dysfunction. SuboxoneBuprenorphine/naloxone is contraindicated in patients with severe hepatic dysfunction (see section 4.3).

 

5.3     Preclinical safety data

 

The combination of buprenorphine and naloxone has been investigated in acute and repeated dose (up to 90 days in rats) toxicity studies in animals. No synergistic enhancement of toxicity has been observed. Undesirable effects were based on the known pharmacological activity of opioid agonistic and/or antagonistic substances.

 

The combination (4:1) of buprenorphine hydrochloride and naloxone hydrochloride was not mutagenic in a bacterial mutation assay (Ames test), and was not clastogenic in an in vitro cytogenetic assay in human lymphocytes or in an intravenous micronucleus test in the rat.

 

Reproduction studies by oral administration of buprenorphine: naloxone (ratio ratio 1:1) indicated that embryolethality occurred in rats in the presence of maternal toxicity at all doses. The lowest dose studied represented exposure multiples of 1x for buprenorphine and 5x for naloxone at the maximum human therapeutic dose calculated on a mg/m² basis. No developmental toxicity was observed in rabbits at maternally toxic doses. Further, no teratogenicity has been observed in either rats or rabbits. A peri-postnatal study has not been conducted with Suboxonebuprenorphine/naloxone; however, maternal oral administration of buprenorphine at high doses during gestation and lactation resulted in difficult parturition (possible as a result of the sedative effect of buprenorphine), high neonatal mortality and a slight delay in the development of some neurological functions (surface righting reflex and startle response) in neonatal rats.

 

Dietary administration of Suboxonebuprenorphine in the rat at dose levels of 500 ppm or greater produced a reduction in fertility demonstrated by reduced female conception rates. A dietary dose of 100 ppm (estimated exposure approximately 2.4x for buprenorphine at a human dose of 24 mg Suboxonebuprenorphine/naloxone based on AUC, plasma levels of naloxone were below the limit of detection in rats) had no adverse effect on fertility in females.

 

A carcinogenicity study with Suboxonebuprenorphine/naloxone was conducted in rats at doses of 7, 30 and 120 mg/kg/day, with estimated exposure multiples of 3 to 75 times, based on a human daily sublingual dose of 16 mg calculated on a mg/m² basis. Statistically significant increases in the incidence of benign testicular interstitial (Leydig's) cell adenomas were observed in all dosage groups.

 

An Environmental Risk Assessment of buprenorphine/naloxone concluded that the use of Suboxone is not expected to have an adverse impact on the environment.

 

 

6.         PHARMACEUTICAL PARTICULARS

 

6.1     List of excipients

 

Lactose monohydrate,

Mannitol,

Maize starch,

Povidone K 30,

Citric acid anhydrous,

Sodium citrate,

Magnesium stearate,

Acesulfame potassium,

Natural lemon and lime flavour.

 

6.2     Incompatibilities

 

Not applicable.

 

6.3     Shelf life

 

3 years

 

6.4       Special precautions for storage

 

This medicinal product does not require any special storage conditions.

 

6.5     Nature and contents of container

 

7 tablets in blister packs Nylon/AluminumAluminium/PVC.

 

28 28 tablets in blister packs Nylon/AluminumAluminium/PVC.

 

Not all pack sizes may be marketed.

 

6.6       Special precautions for disposal

 

Medicines no longer required should not be disposed of via wastewater or the municipal sewage system. Patients should be instructed to return them to a 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.  No special requirements

 

 

7.         MARKETING AUTHORISATION HOLDER

 

RB Pharmaceuticals Limited

103-105 Bath Road

Slough

Berkshire

SL1 3UH

United Kingdom

 

 

8.       MARKETING AUTHORISATION NUMBER(S)

 


EU/1/06/359/003

EU/1/06/359/004

 

 

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

26 September 2006

Date of first authorisation: 26 September 2006

Date of latest renewal:

 

 

10.     DATE OF REVISION OF THE TEXT

 

Detailed information on this product is available on the web-site of the European Medicines Agency

http://www.ema.europa.eu/

 

Last revised 06 August 2010

http://www.ema.europa.eu/

 

 


Updated on 14 March 2012 PIL

Reasons for updating

  • Change to, or new use for medicine
  • Change to warnings or special precautions for use
  • Change to instructions about missed dose
  • Change to instructions about overdose
  • Change to drug interactions
  • Change to information about drinking alcohol
  • Change to information about pregnancy or lactation
  • Change to information about driving or using machinery
  • Change to further information section
  • Change to appearance of the medicine

Updated on 20 July 2011 SmPC

Reasons for updating

  • New individual SPC (was previously included in combined SPC)

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

None provided

Updated on 18 July 2011 PIL

Reasons for updating

  • New individual PIL (was previously included in a combined PIL)