Posology : מינונים

4.2 Posology and method of administration

Posology

Sifrol IR                                                                       Updated Prescribing Information 0.25 mg, 1 mg                                                                                        April 2020 Parkinson’s disease:
The daily dose is administered in equally divided doses 3 times a day.

Initial treatment
Doses should be increased gradually from a starting-dose of 0.375 mg salt (0.264 mg of base) per day and then increased every 5-7 days. Providing patients do not experience intolerable undesirable effects, the dose should be titrated to achieve a maximal therapeutic effect.

Ascending – Dose Schedule of SIFROL
Week              Dose                   Total Daily Dose (mg     Dose                   Total Daily Dose (mg (mg of salt)           of salt)                 (mg of base)           of base) 1                 3 x 0.125              0.375                    3 x 0.088              0.264  2                 3 x 0.25               0.75                     3 x 0.18               0.54
3                 3 x 0.5                1.5                      3 x 0.35               1.1 
If a further dose increase is necessary the daily dose should be increased by 0.75 mg of salt (0.54 mg base) at weekly intervals up to a maximum dose of 4.5 mg of salt (3.3 mg of base) per day.
However, it should be noted that the incidence of somnolence is increased at doses higher than 1.5 mg (of salt) per day (see section 4.8).

Maintenance treatment
The individual dose of pramipexole should be in the range of 0.375 mg salt (0.264 mg base) to a maximum of 4.5 mg salt (3.3 mg base) per day. During dose escalation in pivotal studies, efficacy was observed starting at a daily dose of 1.5 mg salt (1.1 mg base). Further dose adjustments should be done based on the clinical response and the occurrence of adverse reactions. In clinical trials approximately 5% of patients were treated at doses below 1.5 mg salt (1.1 mg base). In advanced Parkinson's disease, pramipexole doses higher than 1.5 mg salt (1.1 mg base) per day can be useful in patients where a reduction of the levodopa therapy is intended. It is recommended that the dose of levodopa is reduced during both the dose escalation and the maintenance treatment with SIFROL, depending on reactions in individual patients (see section 4.5).

Treatment discontinuation
Abrupt discontinuation of dopaminergic therapy can lead to the development of a neuroleptic malignant syndrome or a dopamine agonist withdrawal syndrome. Pramipexole should be tapered off at a rate of 0.75 mg salt (0.54 mg base) per day until the daily dose has been reduced to 0.75 mg salt (0.54 mg base). Thereafter the dose should be reduced by 0.375 mg salt (0.264 mg base) per day (see section 4.4). Dopamine agonist withdrawal syndrome could still appear while tapering and a temporary increase of the dose could be necessary before resuming tapering (see section 4.4)


Renal impairment
The elimination of pramipexole is dependent on renal function. The following dose schedule is suggested for initiation of therapy:

Patients with a creatinine clearance above 50 ml/min require no reduction in daily dose or dosing frequency.

In patients with a creatinine clearance between 20 and 50 ml/min, the initial daily dose of SIFROL should be administered in two divided doses, starting at 0.125 mg salt (0.088 mg base) twice a day (0.25 mg salt/0.176 mg base daily). A maximum daily dose of 2.25 mg salt (1.57 mg base) should not be exceeded.



Sifrol IR                                                                         Updated Prescribing Information 0.25 mg, 1 mg                                                                                          April 2020 In patients with a creatinine clearance less than 20 ml/min, the daily dose of SIFROL should be administered in a single dose, starting at 0.125 mg salt (0.088 mg base) daily. A maximum daily dose of 1.5 mg salt (1.1 mg base) should not be exceeded.

If renal function declines during maintenance therapy the SIFROL daily dose should be reduced by the same percentage as the decline in creatinine clearance, i.e. if creatinine clearance declines by 30%, then the SIFROL daily dose should be reduced by 30%. The daily dose can be administered in two divided doses if creatinine clearance is between 20 and 50 ml/min and as a single daily dose if creatinine clearance is less than 20 ml/min.

Hepatic impairment
Dose adjustment in patients with hepatic failure is probably not necessary, as approx. 90% of absorbed active substance is excreted through the kidneys. However, the potential influence of hepatic insufficiency on SIFROL pharmacokinetics has not been investigated.

Paediatric population
The safety and efficacy of SIFROL in children below 18 years has not been established. There is no relevant use of SIFROL in the paediatric population in Parkinson’s Disease.

Restless Legs Syndrome:
The recommended starting dose of SIFROL is 0.125 mg salt (0.088 mg base) taken once daily 2-3 hours before bedtime. For patients requiring additional symptomatic relief, the dose may be increased every 4-7 days to a maximum of 0.75 mg salt (0.54 mg base) per day (as shown in the table below).

Dose Schedule of SIFROL
Titration Step                   Once Daily Evening Dose (mg of           Once Daily Evening Dose salt)                                    (mg of base)
1                                0.125                                    0.088        2*                               0.25                                     0.18
3*                               0.50                                     0.35        4*                               0.75                                     0.54
* if needed

Patient´s response should be evaluated after 3 months treatment and the need for treatment continuation should be reconsidered. If treatment is interrupted for more than a few days it should be re-initiated by dose titration carried out as above.

Treatment discontinuation
Since the daily dose for the treatment of Restless Legs Syndrome will not exceed 0.75 mg salt (0.54 mg base) SIFROL can be discontinued without tapering off. In a 26 week placebo controlled trial, rebound of RLS symptoms (worsening of symptom severity as compared to baseline) was observed in 10% of patients (14 out of 135) after abrupt discontinuation of treatment. This effect was found to be similar across all doses.

Renal impairment
The elimination of pramipexole is dependent on renal function. Patients with a creatinine clearance above 20 ml/min require no reduction in daily dose.
The use of SIFROL has not been studied in haemodialysis patients, or in patients with severe renal impairment.

Hepatic impairment
Dose adjustment in patients with hepatic failure is not required, as approx. 90% of absorbed active substance is excreted through the kidneys.

Sifrol IR                                                                         Updated Prescribing Information 0.25 mg, 1 mg                                                                                          April 2020 Paediatric population
SIFROL is not recommended for use in children and adolescents below 18 years due to a lack of data on safety and efficacy.

Tourette Disorder:

Paediatric population
SIFROL is not recommended for use in children and adolescents below 18 years since the efficacy and safety has not been established in this population. SIFROL should not be used in children or adolescents with Tourette Disorder because of a negative benefit-risk balance for this disorder (see section 5.1).


Method of administration
The tablets should be taken orally, swallowed with water, and can be taken either with or without food.