Suboxone 8mg/2mg

300,001.150,00

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.

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Description

What is Suboxone 8mg 2mg?

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.

Precautions to be taken before induction

Prior to treatment initiation, 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 buprenorphine/naloxone or buprenorphine only should be undertaken when objective and clear signs of withdrawal are evident (demonstrated e.g. by a score indicating mild to moderate withdrawal on the validated Clinical Opioid Withdrawal Scale, COWS).

o For patients dependent upon heroin or short-acting opioids, the first dose of buprenorphine/naloxone should be taken when signs of withdrawal appear, but not less than 6 hours after the patient last used opioids.

o For patients receiving methadone, the dose of methadone should 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 Suboxone 8mg 2mg 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.

Posology Suboxone 8mg 2mg

Initiation therapy (induction)

The recommended starting dose in adults and adolescents over 15 years of age is one to two Suboxone 8mg 2mg. An additional one to two Suboxone 8mg 2mg may be administered on day one depending on the individual patient’s requirement.

During the initiation of treatment, daily supervision of dosing is recommended 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 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 buprenorphine 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 buprenorphine.

Less than daily dosing

After a satisfactory stabilisation has been achieved the frequency of 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 buprenorphine may be given 16 mg buprenorphine on alternate days, with no dose on the intervening days. In some patients, after a satisfactory stabilisation has been achieved, the frequency of 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 mg buprenorphine. Patients requiring a titrated daily dose> 8 mg buprenorphine /day may not find this regimen adequate.

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 doses of 2 mg/0.5 mg and 8 mg/2 mg allows for a downward titration of dosage. For patients who may require a lower Suboxone 8mg 2mg dose, buprenorphine 0.4 mg may be used. Patients should be monitored following medical withdrawal because of the potential for relapse.

Special populations

Elderly

The safety and efficacy of Suboxone 8mg 2mg in elderly patients over 65 years of age have not been established. No recommendation on posology can be made.

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).

Both active substances of Suboxone, buprenorphine and naloxone, are extensively metabolized in the liver, and the plasma levels were found to be higher for both buprenorphine and naloxone in patients with moderate and severe hepatic impairment. Patients should be monitored for signs and symptoms of precipitated opioid withdrawal, toxicity or overdose caused by increased levels of naloxone and/or buprenorphine.

As buprenorphine/naloxone pharmacokinetics may be altered in patients with hepatic impairment, lower initial doses and careful dose titration in patients with mild to moderate hepatic impairment are recommended. Buprenorphine/naloxone is contraindicated in patients with severe hepatic impairment. (see section 4.3 and 5.2).

Renal impairment

Modification of the buprenorphine/naloxone dose is not required in patients with renal impairment. Caution is recommended when dosing patients with severe renal impairment (creatinine clearance < 30 ml/min) (see section 4.4 and 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 multiple Suboxone tablets of different strengths, 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

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Severe respiratory insufficiency

Severe hepatic impairment

Acute alcoholism or delirium tremens.

Concomitant administration of opioid antagonists (naltrexone, nalmefene) for the treatment of alcohol or opioid dependence.

4.4 Special warnings and precautions for use

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 or localised and systemic 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 medicinal product is not safeguarded against theft.

Sub-optimal treatment with buprenorphine/naloxone may prompt medicine 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. If buprenorphine is administered to some non-opioid dependent individuals, who are not tolerant to the effects of opioids, potentially fatal respiratory depression may occur.

This product should be used with care in patients with asthma or respiratory insufficiency (e.g. chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, pre-existing respiratory depression or kyphoscoliosis (curvature of spine leading to potential shortness of breath)).

Buprenorphine/naloxone may cause severe, possibly fatal, respiratory depression in children and non-dependent persons in case of accidental or deliberate ingestion. Patients must be warned to store the blister safely, to never open the blister in advance, to keep them out of the reach of children and other household members, and not to take this medicine in front of children. An emergency unit should be contacted immediately in case of accidental ingestion or suspicion of ingestion.

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, hepatic encephalopathy and death. In many cases the presence of pre-existing mitochondrial impairment (genetic disease, liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, alcohol abuse, anorexia 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

The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone were evaluated in a post-marketing study. Since both buprenorphine and naloxone are extensively metabolized, plasma levels were found to be higher for both buprenorphine and naloxone in patients with moderate and severe hepatic impairment after single-dose administration. Patients should be monitored for signs and symptoms of precipitated opioid withdrawal, toxicity or overdose caused by increased levels of naloxone and/or buprenorphine. Suboxone sublingual tablets should be used with caution in patients with moderate hepatic impairment (See section 4.3 and 5.2). In patients with severe hepatic insufficiency the use of buprenorphine/naloxone is contraindicated.

Renal impairment

Renal elimination may be prolonged since 30 % of the administered dose is eliminated by the renal route. Metabolites of buprenorphine accumulate in patients with renal failure. Caution is recommended when dosing patients with severe renal impairment (creatinine clearance <30 ml/min) (see sections 4.2 and 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 Suboxone 8mg 2mg. A reduction of the buprenorphine/naloxone dose may be needed. Patients already treated with CYP3A4 inhibitors should have their dose of Suboxone 8mg 2mg titrated carefully since a reduced dose may be sufficient in these patients (see section 4.5).

General warnings relevant to the administration of opioids

Opioids may produce orthostatic hypotension in ambulatory patients.

Opioids may elevate cerebrospinal fluid pressure, which may cause seizures, so opioids should be used with caution in patients with head injury, intracranial lesions, other circumstances where cerebrospinal pressure may be increased, or history of seizure.

Opioids should be used with caution in patients with hypotension, prostatic hypertrophy or urethral stenosis.

Opioid-induced miosis, changes in the level of consciousness, or changes in the perception of pain as a symptom of disease may interfere with patient evaluation or obscure the diagnosis or clinical course of concomitant disease.

Opioids should be used with caution in patients with myxoedema, hypothyroidism, or adrenal cortical insufficiency (e.g., Addison’s disease).

Opioids have been shown to increase intracholedochal pressure, and should be used with caution in patients with dysfunction of the biliary tract.

Opioids should be administered with caution to elderly or debilitated patients.

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

Suboxone 8mg 2mg 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 medicines containing alcohol, as alcohol increases the sedative effect of buprenorphine (see section 4.7).

Suboxone should be used cautiously when co-administered with:

o 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).

o 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.

o Furthermore, adequate analgesia may be difficult to achieve when administering a full opioid agonist in patients receiving buprenorphine/naloxone. Therefore the potential to overdose with a full agonist exists, especially when attempting to overcome buprenorphine partial agonist effects, or when buprenorphine plasma levels are declining.

o naltrexone and nalmefene are opioid antagonists that can block the pharmacological effects of Suboxone 8mg 2mg. Co-administration during buprenorphine/naloxone treatment is contraindicated due to the potentially dangerous interaction that may precipitate a sudden onset of prolonged and intense opioid withdrawal symptoms (see section 4.3).

o 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 50 % and 70 % 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, macrolide antibiotics).

o CYP3A4 inducers: Concomitant use of CYP3A4 inducers with Suboxone 8mg 2mg may decrease buprenorphine plasma concentrations, potentially resulting in sub-optimal treatment of opioid dependence with buprenorphine. It is recommended that patients receiving buprenorphine/naloxone should be closely monitored if inducers (e.g. phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered. The dose of Suboxone 8mg 2mg or the CYP3A4 inducer may need to be adjusted accordingly.

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

4.6 Fertility, pregnancy and lactation

Pregnancy

There 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 buprenorphine may induce respiratory depression in the newborn infant even after a short period of administration. Long-term administration of Suboxone 8mg 2mg during the last three months of pregnancy may cause a withdrawal syndrome in the neonate (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus or convulsions). The syndrome is generally delayed from several hours to several days after birth.

Due to the long half-life of buprenorphine, neonatal monitoring for several days should be considered at the end of pregnancy, to prevent the risk of respiratory depression or withdrawal syndrome in neonates.

Furthermore, the use of buprenorphine/naloxone during pregnancy should be assessed by the physician. Buprenorphine/naloxone should be used during pregnancy only if the potential benefit outweighs the potential risk to the foetus.

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, breastfeeding should be discontinued during treatment with Suboxone 8mg 2mg.

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). See section 5.3.

4.7 Effects on ability to drive and use machines

Suboxone 8mg 2mg has minor to moderate influence on the ability to drive and use machines when administered to opioid dependent patients. This product may cause drowsiness, dizziness, or impaired thinking, especially during treatment induction and dose adjustment. If taken together with alcohol or central nervous system depressants, the effect 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

Summary of the safety profile

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