Posology : מינונים

4.2    Posology and method of administration

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

Posology
Precautions to be taken before induction
Baseline liver function tests and documentation of viral hepatitis status 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).

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 buprenorphine/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.

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 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 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 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.

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. Patients requiring a titrated daily dose> 8 mg/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 buprenorphine dose, buprenorphine 0.4 mg may be used. Patients should be monitored following medical withdrawal because of the potential for relapse.

Special populations

Older People
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.

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. It is not known whether both active substances are affected to the same extent.

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 generally 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 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.